Conditions: Influenza Influenza Immunisation
Keywords: Immunogenicity Influenza Influenza Vaccine Phase 1 Quadrivalent Safety
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 241
Healthy volunteers: yes

Brief summary:
This is a Phase I, randomized, double blinded, clinical trial in up to 240 males and non-pregnant females, 18-45 years of age, inclusive, who are in good health and meet all eligibility criteria. This clinical trial is designed to assess the safety, reactogenicity and immunogenicity of either the 2018/2019 seasonal Fluzone or Flublok Quadrivalent Influenza Vaccine (QIV) manufactured by Sanofi Pasteur (SP) given without adjuvant or with one of two adjuvant formulations, AF03 or Advax-CpG55.2. Eight Vaccine and Treatment Evaluation Unit (VTEU) sites will be included in the study. Study duration is approximately 18 months, and subject participation duration is 12 months. The primary objectives of this study are: 1) to assess the safety and reactogenicity of 2018/2019 Fluzone and Flublok with and without AF03 or Advax-CpG55.2 adjuvant; 2) to assess the serum hemagglutination inhibition (HAI) antibody responses against 2018/2019 QIV strains from baseline (Day 1) to approximately Day 29 after receipt of 2018/2019 Fluzone and Flublok with and without AF03 or Advax-CpG55.2 adjuvant; 3) to assess the serum neuraminidase inhibition antibody (NAI) responses by enzyme-linked lectin assay (ELLA) against NA antigens in the 2018/2019 QIV from baseline (Day 1) to approximately Day 29 after receipt of 2018/2019 Fluzone and Flublok with and without AF03 or Advax-CpG55.2 adjuvant; 4) to assess the influenza neutralizing (Neut) antibody titer responses against 2018/2019 QIV strains from baseline (Day 1) to approximately Day 29 after receipt of 2018/2019 Fluzone and Flublok with and without AF03 or Advax- CpG55.2 adjuvant.

Detailed description:
This is a Phase I, randomized, double blinded, clinical trial in up to 240 males and non-pregnant females, 18-45 years of age, inclusive, who are in good health and meet all eligibility criteria. This clinical trial is designed to assess the safety, reactogenicity and immunogenicity of either the 2018/2019 seasonal Fluzone or Flublok Quadrivalent Influenza Vaccine (QIV) manufactured by Sanofi Pasteur (SP) given without adjuvant or with one of two adjuvant formulations, AF03 or Advax-CpG55.2. Subjects will be stratified by prior receipt of licensed, seasonal influenza vaccine (defined as receipt of at least one of the 2017/2018 and/or 2018/2019 influenza vaccines) and will be randomly assigned to 1 of 6 treatment arms to receive a single dose of one of the two seasonal 2018/2019 QIV vaccine formulations with or without one of the two adjuvants (Day 1). On approximately Day 90, each subject will receive a single dose of the seasonal 2019/2020 QIV. Groups 1, 2 and 3 will receive 2019/2020 Fluzone QIV and Groups 4, 5 and 6 will receive 2019/2020 Flublok QIV. Eight Vaccine and Treatment Evaluation Unit (VTEU) sites will be included in the study. Study duration is approximately 18 months, and subject participation duration is 12 months. The primary objectives of this study are: 1) to assess the safety and reactogenicity of 2018/2019 Fluzone and Flublok with and without AF03 or Advax-CpG55.2 adjuvant; 2) to assess the serum hemagglutination inhibition (HAI) antibody responses against 2018/2019 QIV strains from baseline (Day 1) to approximately Day 29 after receipt of 2018/2019 Fluzone and Flublok with and without AF03 or Advax-CpG55.2 adjuvant; 3) to assess the serum neuraminidase inhibition antibody (NAI) responses by enzyme-linked lectin assay (ELLA) against NA antigens in the 2018/2019 QIV from baseline (Day 1) to approximately Day 29 after receipt of 2018/2019 Fluzone and Flublok with and without AF03 or Advax-CpG55.2 adjuvant; 4) to assess the influenza neutralizing (Neut) antibody titer responses against 2018/2019 QIV strains from baseline (Day 1) to approximately Day 29 after receipt of 2018/2019 Fluzone and Flublok with and without AF03 or Advax- CpG55.2 adjuvant. The secondary objectives of this study are: 1) to assess protocol specified adverse events of special interest (AESI), medically-attended adverse events (MAAEs), including new-onset chronic medical conditions (NOCMCs) and potentially immune-mediated medical conditions (PIMMCs) that occur after receipt of study product; 2) to assess the HAI, Neut and NAI ELLA responses to the 2019/2020 QIV strains prior to (Day 1) and approximately 28 days after vaccination with the 2019/2020 QIV in all study groups; 3) to assess the HAI antibody responses against heterologous influenza A/H1 and H3 strains from baseline (Day 1) to approximately Days 8, 29, 57, 90 and 118 after receipt of 2018/2019 Fluzone or Flublok with and without AF03 or Advax-CpG55.2 adjuvant; 4) to assess NAI ELLA responses against heterologous N1 and N2 NA antigens from baseline (Day 1) to approximately Days 8, 29, 57, 90 and 118 after administration of 2018/2019 Fluzone with and without AF03 or Advax-CpG55.2 adjuvant; 5) to assess the influenza neutralizing (Neut) antibody titer responses against heterologous influenza A/H1 and H3 strains from baseline (Day 1) to approximately Days 8, 29, 57, 90 and 118 after administration of 2018/2019 Fluzone and Flublok with and without AF03 or Advax-CpG55.2 adjuvant; 6) to assess the longitudinal kinetics and durability of the HAI, NAI, and Neut responses against the 2018/2019 QIV strains on approximately Days 8, 57, 90 and 118 following receipt of the 2018/2019 Fluzone and Flublok with and without AF03 or Advax-CpG55.2 adjuvant.

Arms:
arm 1: 0.5 mL of 2018/2019 Fluzone QIV intramuscular injection on Day 1 and 0.5 ml of 2019/2020 Fluzone QIV intramuscular injection on Day 90, n=40 arm 2: 0.5 mL of 2018/2019 Fluzone QIV + 0.25 mL of AF03 (admixed with vaccine) intramuscular injection on Day 1 and 0.5 ml of 2019/2020 Fluzone QIV intramuscular injection on Day 90, n=40 arm 3: 0.5 mL of 2018/2019 Fluzone QIV + 0.5 mL of Delta Inulin-CpG55.2 (admixed with vaccine) intramuscular injection on Day 1 and 0.5 2019/2020 of Fluzone QIV intramuscular injection on Day 90, n=40 arm 4: 0.5 mL of 2018/2019 Flublok QIV intramuscular injection on Day 1 and 0.5 ml of 2019/2020 Flublok QIV intramuscular injection on Day 90, n=40 arm 5: 0.5 mL of 2018/2019 Flublok QIV + 0.25 mL AF03 (admixed with vaccine) intramuscular injection on Day 1 and 0.5 ml of 2019/2020 Flublok QIV intramuscular injection on Day 90, n=40 arm 6: 0.5 mL of 2018/2019 Flublok QIV + 0.5 mL of Delta Inulin-CpG55.2 (admixed with vaccine) intramuscular injection on Day 1 and 0.5 ml of 2019/2020 Flublok QIV intramuscular injection on Day 90, n=40

Interventions: intervention 1: AF03 intervention 2: Delta Inulin-CpG55.2 intervention 3: Influenza Virus Quadrivalent Inactivated Vaccine intervention 4: Quadrivalent Recombinant Seasonal Influenza Vaccine
Intervention descriptions: intervention 1: A squalene-in-PBS emulsion stabilized by nonionic surfactants, sorbitan oleate and macrogol cetostearyl ether intervention 2: A combination adjuvant supplied as two separate components, Delta Inulin (Sypharma Pty Ltd.) and CpG55.2 (Nikko Denka Avecia and Sypharma Pty Ltd) intervention 3: 2018/2019 Fluzone QIV and 2019/2020 Fluzone QIV vaccines will be given with 90 days interval intervention 4: 2018/2019 Flublok QIV and 2019/2020 Flublok QIV vaccines will be given with 90 days interval

Protocol document:
ICF_000.pdf: 
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INFORMED CONSENT DOCUMENT 
Project Title: 
A Phase I Study to Assess the Safety, Reactogenicity and Immunogenicity of Two 
Quadrivalent Seasonal Influenza Vaccines (Fluzone® or Flublok®) With or Without One of Two 
Adjuvants (AF03 or Advax-CpG55.2) in Healthy Adults 18-45 Years of Age 
Principal Investigator: 
Patricia Winokur  
Research Team Contact: 
Deb Pfab 
This consent form describes the research study to help you decide if you want to participate.  This form 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights as a research subject.   
•
If you have any questions about or do not understand something in this form, you should ask
the research team for more information.
•
You should discuss your participation with anyone you choose such as family or friends.
•
Do not agree to participate in this study unless the research team has answered your
questions and you decide that you want to be part of this study.
WHAT IS THE PURPOSE OF THIS STUDY? 
This is a research study. We are inviting you to participate in this research study because you are in good 
health and between the ages of 18 to 45 years. 
The purpose of this research study is to assess the safety, reactogenicity (reactions at the injection site 
and overall side –effects) and effectiveness of either the 2018-2019 seasonal Fluzone or Flublok given 
without or with one of two adjuvant formulations. An adjuvant is a substance that may cause the body to 
produce more antibodies when it is given with a vaccine.  The two adjuvants being evaluated in this 
study are AF03 and Advax-CpG55.2.  The adjuvants are investigational and have not been approved or 
licensed by the US Food and Drug Administration (FDA).  Fluzone and Flublok are quadrivalent 
influenza vaccines (QIV) for the 2018-2019 season and are licensed and approved by the FDA.   
Influenza is a common acute viral respiratory illness. Seasonal flu in the U.S. causes an estimated 
100,000 to 600,000 hospitalizations and up to 50,000 deaths annually.  Use of vaccines is the primary 
means for preventing the flu. Current licensed inactivated (virus is dead) influenza vaccines are good for 
preventing flu but are less effective than desirable.  Several approaches have been used to increase the 
effectiveness of the flu vaccines including the use of adjuvants.  Adjuvants can reduce the dose needed 
to achieve a good immune response and improve the antibody responses to the flu vaccines. 
HOW MANY PEOPLE WILL PARTICIPATE? 
Approximately 125 people will provide consent for this study, with about 30 people randomized 
(enrolled) into the study conducted by investigators at the University of Iowa.  Up to 240 people are 
expected to be enrolled nationwide.   


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HOW LONG WILL I BE IN THIS STUDY? 
If you agree to take part in this study your involvement will last for approximately 12 months.  The 
following visits/procedures will take place:  
•
A screening visit which will take about 1 ½ hours.
•
An enrollment/vaccination visit which will take about 2 ½ hours.
•
A vaccination visit at Day 90 where you will receive next season’s flu vaccine.  This visit will
take about 1 ½ hours.
•
Seven study visits which will take about 30 minutes each.
•
A blood draw at each study visit. The total amount of blood collected in the study will be
approximately 27 tablespoons. The maximum amount drawn at a single study visit will be about
7 tablespoons.
•
Women who are able to become pregnant will be required to have a urine pregnancy test at the
screening visit and/or at least 24 hours prior to the first study vaccination.
WHAT WILL HAPPEN DURING THIS STUDY? 
The follow up study visits will take place at the University of Iowa Hospitals and Clinics VTEU area, 
which is located on the third floor of the General Hospital. The two vaccination visits will take place at 
the Clinical Research Unit which is on the second floor of the General Hospital.   
Screening Visit  
At the screening visit, you will be given information about the study and asked to read this informed 
consent. After you have read the consent and your questions have been answered, and you have had time 
to think about whether to participate in the study and if you wish, discussed it with your family, friends 
or doctor, you will be asked to sign this consent agreeing to take part in the study.   
If you agree to take part in the study, the following will be done: 
•
You will be asked about your complete medical history including any medications you are taking
or have recently taken
•
You will be asked if you have received the 2018-2019 seasonal flu vaccine and non-seasonal flu
vaccines including investigational ones
•
You will have your temperature, pulse and blood pressure taken.  We will measure your height
and weight.
•
You will have a physical examination.
•
We will draw blood from a vein in your arm for laboratory tests. One of the tests will check for
inflammation. If the test results are too high, you will not be able to continue in the study.
•
Women who are able to become pregnant must use an acceptable method of birth control for at
least 30 days before your study vaccination until at least 60 days after your study vaccination.
You will have a urine pregnancy test at the screening visit and/or within 24 hours prior to
receiving the study vaccination. If your pregnancy test is positive, you will not be able to
continue in the study.


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For your own safety, you need to be in good health to participate in this study.  You cannot take part in 
this study if you: 
•
are pregnant, plan to become pregnant and/or breastfeed,
•
have an autoimmune health condition such as thyroiditis, psoriasis and rheumatoid arthritis,
•
have had the flu (diagnosed by a physician) within the past 6 months,
•
have a history of Guillain- Barré syndrome (GBS) (see below),
•
plan to travel outside the U.S. within 3 months after receiving your study vaccination,
•
have received another experimental agent 30 days prior to this study or plan to receive an
experimental agent during the 12 month study period,
•
plan to donate blood within 4 months after receiving your study vaccination,
•
have received or plan to receive an inactivated vaccine within 14 days before or after your study
vaccination,
•
have received or plan to receive a live vaccine within 30 days before or after your study
vaccination,
•
have received a 2018-2019 seasonal flu vaccine within 6 months before your study vaccination,
•
plan to receive a 2019-2020 seasonal flu vaccine within 90 days after receiving your study
vaccination.
There may be other reasons why you cannot participate in this study, which the research nurse or doctor 
will discuss with you. 
After the screening visit, if you are eligible to participate in the study, you will be scheduled for your 
study vaccination visit. 
Study Visit 1 (Day 1) 
Before you are given the study vaccination, the following will take place: 
•
You will be asked if there have been any changes in your health and medications.
•
Your temperature, pulse and blood pressure will be taken.
•
If you are a woman able to become pregnant, a urine sample will be collected to test for
pregnancy.
•
You will have blood taken for study and lab tests.
You will be randomly assigned to receive one of the six study treatments (see table below). This means 
that whichever study treatment you receive will be determined purely by chance, like flipping a coin. 
You will have an equal chance to be randomized to each of the study treatments. Neither you nor the 
research team will know which study treatment you receive, but we will be able to get this information 
quickly if we need it to ensure your safety.   
Study Group Study Vaccine at Visit 1, Day 1 
Adjuvant 
Seasonal Vaccine at Visit 6, Day 90 
1 
Fluzone 2018-2019 QIV 
None 
Fluzone 2019-2020 
2 
Fluzone 2018-2019 QIV 
AF03 
Fluzone 2019-2020 
3 
Fluzone 2018-2019 QIV 
Advax-CpG55.2 Fluzone 2019-2020 
4 
Flublok 2018-2019 QIV 
None 
Flublok 2019-2020 
5 
Flublok 2018-2019 QIV 
AF03 
Flublok 2019-2020 
6 
Flublok 2018-2019 QIV 
Advax-CpG55.2 Flublok 2019-2020 


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•
You will be given the study vaccine as an intra-muscular injection in the upper arm or deltoid
area.
•
After the vaccination, you must remain in the clinic for at least 20 minutes.
•
The study staff will give you the following:
A memory aid with instructions for you to record any symptoms you may have on a daily
basis, starting the day of vaccination and for the next 7 days.
A thermometer to take your daily temperature and a ruler to measure any swelling/redness at
the injection site.
Study Visits 2 (Day 2), Visit 3 (Day 8), Visit 4 (Day 29) 
•
You will be asked if there have been any changes in your health and medications including if
you have received a non-study flu vaccine.
•
Your memory aid will be reviewed and your injection site will be examined (Visits 2 & 3)
•
We will collect blood for study and/or safety tests.
Study Visit 5 (Day 57) 
•
You will be asked if there have been any serious changes in your health.
•
You will be asked if you have received a non-study flu vaccine.
•
We will collect blood for study tests.
Study Visit 6 (Day 90) 
•
You will be asked if there have been any serious changes in your health.
•
You will be asked if you have received a non-study flu vaccine.
•
We will collect blood for study tests.
•
We will give you the 2019-2020 Fluzone or Flublok QIV as an intra-muscular injection in your
upper arm.
You will receive Fluzone QIV if you received the Fluzone study vaccine at Visit 1.
You will receive Flublok QIV if you received the Flublok study vaccine at Visit 1.
•
After the vaccination, you must remain in the clinic for at least 20 minutes.
Study Visits 7 (Day 118), 8 (Day 180) and 9 (Day 365) 
•
You will be asked if there have been any serious changes in your health.
•
You will be asked if you have received a non-study flu vaccine.
•
We will collect blood for study tests.
Early Termination Visit  
If you decide to leave the study early, we will ask you to complete a final study visit.  At this visit, the 
following will be done: 
•
You will be asked about your current health and any changes in your medications or if you have
received a non-study flu vaccine.
•
You may have a brief physical examination based on your current health.
•
We may collect blood for study or safety tests.
Unscheduled Study Visits 


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Unscheduled visits may occur for further evaluations.  At these visits, the following may be done: 
•
You will be asked about your current health and any changes in your medications or if you have
received a non-study flu vaccine.
•
You may have a brief physical examination based on your health.
•
You may have your vital signs taken - temperature, pulse, and blood pressure.
•
We may collect blood for safety or study tests.
Blood Storage for Future Use 
As part of this study, we are obtaining blood samples from you.  We would like to study your blood in 
the future, after this study is over.  We may not need to use all of the blood we collect for the study tests 
so some residual blood may be left over. The residual blood samples will be stored indefinitely at a site 
determined by the study sponsor, National Institute of Health (NIH). In addition to the blood samples for 
the study tests, extra blood will be taken specifically for future research and will be stored indefinitely at 
a site determined by the NIH. Each residual and future research blood sample will be labeled only with a 
barcode and a unique tracking number to protect your confidentiality. Personnel at the storage facility 
and testing lab will not know your identity, or the volunteer ID code assigned to you for the study.  
The tests we might want to use to study your blood may not even exist at this time.  Stored residual and 
future research blood samples will be used only for research purposes. The samples will not be sold or 
used directly for production of any commercial product. No human genetic (DNA) tests will be done on 
these samples. There are no benefits to you in the collection, storage and future use of your blood 
samples. The results of any future testing will be kept confidential in the same way as the results of other 
testing done for this study. Please feel free to ask the study staff any questions you may have about how 
your blood samples may be used.  
Please initial the statement below indicating your understanding what will happen to your 
residual and future research blood samples: 
______ I understand that if I take part in this study, my residual and future research blood samples will 
be stored for an indefinite period and may be used for future research.  
Future Studies 
We may want to contact you in the future to ask if you would like to participate in another research 
study. If you agree, we would like to keep your name, address, phone number and e-mail address in our 
vaccine research registry. This information will be kept confidential and will not be shared with anyone 
outside of the research team. Agreeing to be in this study does not obligate you to participate in any of 
our future studies and a separate consent document would be signed for future studies. Your decision to 
participate in future studies will not affect your participation in this study. 
Please initial your decision about permission for us to contact you in the future for upcoming studies: 
________ YES, you may contact me in the future by telephone, email or mail to inform me of upcoming 
studies. 


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________ NO, you may not contact me in the future regarding upcoming studies. 
Study Results 
When the study results are available, after the study is completed (generally several months after your 
last visit), we will provide you with a summary, and a summary will appear on 
http://www.ClinicalTrials.gov. In addition, you may choose to learn your treatment assignment. 
Learning about study results can cause people to become upset, especially if the results are different 
from what you expected. If you have any questions or concerns about your results, please contact the 
Principal Investigator, Patricia Winokur, MD at XXX-XXXX. 
Please initial your decision about whether you wish to receive your treatment assignment for this study: 
________ YES, I would like to receive my treatment assignment. 
Preferred method of contact:  Email   Letter   Telephone    I will contact you 
________ NO, I would not like to receive my treatment assignment. 
WHAT ARE THE RISKS OF THIS STUDY? 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study.  
The potential risks of participating in this trial are those related with having blood drawn, receiving an 
intramuscular (IM) injection, and possible reactions to Fluzone or Flublok QIV, with or without AF03 or 
Advax-CpG55.2 adjuvant, and breach of confidentiality.  
Risks related to Fluzone and Flublok Vaccines 
The 2018-2019 and 2019-2020 QIV vaccine formulations used in this study are licensed and approved 
by the FDA.   
Sometimes after receiving an inactivated flu vaccine people may have flu like symptoms such as fever, 
tiredness, headache, nausea, muscle pain, joint pain and body aches. Also, there may be reactions at the 
injection site such as redness, tenderness, swelling, itching or bruising. Most of these reactions are in the 
first day of receiving the vaccination and disappear without treatment within 1 or 2 days.  Taking 
ibuprofen or acetaminophen and resting may relieve these side effects.   
During the clinical development of Flublok, a subject fainted within 20 minutes of receiving the vaccine.  
This was thought to be related to the injection process rather than the vaccine.  Another subject had a 
pericardial effusion which is excess fluid between the heart and sac surrounding the heart.   
The following are other reactions that may occur, but these are rare: 
•
inflammation of a nerve or nervous system
•
convulsions (seizure)
•
severe allergic reactions


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•
fainting
•
inflammation of the brain
•
low platelet count
•
inflammation of blood vessels
•
Guillain-Barré syndrome
•
autoimmune disorders
A small number of people (approx. 1 in 4 million) have immediate and serious allergic reactions to 
licensed vaccines called anaphylaxis. These reactions can include: 
•
skin rash (hives)
•
swelling around the mouth, throat, and eyes
•
having a hard time breathing
•
fast heart rate
•
fainting due to decrease in blood pressure
If these reactions occur, they can usually be stopped by the administration of emergency medications by 
the study staff. Most people who experience anaphylaxis recover completely. The research physician 
does not expect death to occur, but it does happen in extremely rare cases.  
During the swine flu (H1N1) vaccine campaign of 1976, about 1 out of 100,000 people who received the 
swine flu shot got a serious illness called Guillain-Barré syndrome (GBS). GBS is a rare nerve disease 
that can range from a very mild case with brief weakness to a severe case which could leave you 
paralyzed. Fortunately, most people recover completely, but some people can be paralyzed for a long 
time. Since then, this illness has not been seen regularly with other influenza vaccines. Overall, 
vaccination rates have increased in the last 10 years, but the numbers of reported cases of vaccine-
associated GBS have declined.  
Adjuvants: 
The study vaccine you receive may contain adjuvants. Rarely, people who have received vaccines with 
adjuvant have developed illnesses, sometimes serious, called autoimmune disease, where their immune 
system harms their own body. These illnesses have also developed in people who have not received 
these vaccines. We do not know if the study vaccines can actually cause autoimmune diseases.  The 
makers of the study vaccines continue to follow this question closely.  
Risks related to AF03 Adjuvant 
The AF03 adjuvant is investigational. There may be risks and side effects we do not know about right 
now. 
Over 1500 people have been in clinical trials in Europe and the U.S. evaluating inactivated, H5N1 or 
H1N1 flu vaccine with AF03. The data shows when people are given flu vaccines with the AF03 
adjuvant, they have redness, swelling and pain at the vaccination site that occurs more often and more 
severely.  Headaches and an overall unwell feeling were also reported.  The reactions may last a little 
longer, but will go away with time.  
Risks related to Advax-CpG55.2 Adjuvant 
The combination adjuvant, Advax-CpG55.2 is investigational.  There may be risks and side effects we 


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do not know about right now. The clinical experience with Advax (alone) is limited. CpG55.2 has never 
been tested in humans.  The combination of the two adjuvants has also not been tested in humans.  Trials 
with an adjuvant similar to CpG55.2 have shown similar reactions to those seen in subjects who 
received flu vaccines without adjuvants. Flu like symptoms such as fever, tiredness, headache, nausea, 
muscle pain, joint pain and body aches have been reported. There may be more reactions at the injection 
site such as redness, tenderness, swelling or bruising with an adjuvanted flu vaccine. Most of these 
reactions take place in the first day of receiving the vaccination and disappear without treatment within 1 
or 2 days.  Taking ibuprofen or acetaminophen and resting may relieve these side effects.   
For women participating in the study 
If you are a woman who is capable of becoming pregnant, we will ask you to take a pregnancy test 
before beginning this study and/or within 24 hours prior to the first study vaccination. You must use 
effective birth control methods and try not to become pregnant while participating in this study. If you 
become pregnant, there may be unknown risks to your fetus, or risks to your fetus that we did not 
anticipate, associated with being in the study. There may be long-term effects of the treatment being 
studied that could increase the risk of harm to an unborn child.   
You should not be in this study if you are capable of becoming pregnant; you have sex with men and 
cannot use an acceptable form of birth control from 30 days before the study vaccination (Visit 1) until 
at least 60 days after you receive the study vaccination. Acceptable birth control methods include non-
male sexual relationships, full abstinence from sexual intercourse with a male partner, monogamous 
relationship with vasectomized partner who has been vasectomized for 180 days or more and shown to 
be azoospermic prior to you receiving the study vaccination, barrier methods such as condoms or 
diaphragms/cervical cap with spermicide, effective intrauterine devices, NuvaRing®, tubal ligation, and 
licensed hormonal methods such as implants, injectables or oral contraceptives (“the pill”). 
If you become pregnant during this study, please contact Deb Pfab at XXX-XXXX as soon as possible. 
Risks related to blood draws 
Having your blood taken from your arm can cause temporary discomfort, bruising and fainting with a 
rare risk of infection.  
Risks with confidentiality 
Subjects will be asked to provide personal health information (PHI). All attempts will be made to keep 
this PHI confidential within the limits of the law. However, there is a chance that unauthorized persons 
will see the subject’s PHI. All study records will be kept in a locked file cabinet or maintained in a 
locked room at the VTEU area. Electronic files will be password-protected. Only people who are 
involved in the conduct, oversight, monitoring, or auditing of this trial will be allowed access to the PHI 
that is collected. Any publications from this trial will not use information that will identify subjects by 
name. Organizations that may inspect and/or copy research records maintained at the VTEU site for 
quality assurance and data analysis include groups such as the IRB, NIH and the FDA. 
WHAT ARE THE BENEFITS OF THIS STUDY? 
We don’t know if you will benefit from being in this study.  You will be receiving a seasonal flu vaccine 


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in this study at Study Visit 1; however the timing of the study is designed to happen at time when 
influenza virus is unlikely to be circulating.  All participants will receive a dose of 2019-2020 QIV at 
Study Visit 6 which may provide protection from the flu in the fall/winter season of 2019-2020.   
There may be benefits to society through the improvement of our understanding of these two adjuvants 
and how they affect the immune response to seasonal influenza vaccine.   
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
You will not have any additional costs for being in this research study. You/your health insurance 
company will remain responsible for your regular medical care expenses that are not part of this study. 
WILL I BE PAID FOR PARTICIPATING? 
You will be paid for being in this research study. You will need to provide your social security number 
(SSN) in order for us to pay you. You may choose to participate without being paid if you do not wish to 
provide your social security number (SSN) for this purpose.  You may also need to provide your address 
if a check will be mailed to you. If your social security number is obtained for payment purposes only, it 
will not be retained for research purposes.    
Total amount of compensation will be $XXX, if all study visits are completed. Compensation is outlined 
below: 
•
1 screening visit - $XX
•
2 vaccination visits - $XX each
•
7 clinic study visits - $XX each
•
Unscheduled study visit - $XX
•
Parking passes will be provided to cover all parking expenses at each study visit 
WHO IS FUNDING THIS STUDY? 
National Institute of Health (NIH) is funding this research study. This means that the University of Iowa 
is receiving payments from NIH to support the activities that are required to conduct the study.  No one 
on the research team will receive a direct payment or increase in salary from NIH for conducting this 
study. 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
•
If you are injured or become ill from taking part in this study, medical treatment is available at
the University of Iowa Hospitals and Clinics.
•
The University of Iowa does not plan to provide free medical care or payment for treatment of
any illness or injury resulting from this study unless it is the direct result of proven negligence by
a University employee.


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201903884 
APPROVAL DATE: 06/04/19 
Version 2.0, 5-22-19 
Page 10 of 13 
•
If you experience a research-related illness or injury, you and/or your medical or hospital
insurance carrier will be responsible for the cost of treatment.
•
NIH or the Federal Government has no plans to provide long-term medical care or financial
compensation for research related injuries.
WHAT ABOUT CONFIDENTIALITY? 
We will keep your participation in this research study confidential to the extent permitted by law.  
However, it is possible that other people such as those indicated below may become aware of your 
participation in this study and may inspect and copy records pertaining to this research.  Some of these 
records could contain information that personally identifies you.  
•
federal government regulatory agencies,
•
the U.S. Food and Drug Administration,
•
NIH,
•
ICON (study monitoring group),
•
auditing departments of the University of Iowa, and
•
The University of Iowa Institutional Review Board (a committee that reviews and approves
research studies).
To help protect your confidentiality, we will use ID numbers on research data. The data will be stored in 
locked offices when not in use. Only research team members who are involved in the conduct, oversight 
or auditing of this study will have access to the research data. Electronic data will be stored in password 
protected computers and websites. For this study, each blood sample will be labeled with a barcode and 
a unique tracking number to protect your confidentiality. Personnel at the central storage and testing lab 
will not know your identity or the volunteer ID assigned to you for the study. If we write a report or 
article about this study or share the study data set with others, we will do so in such a way that you 
cannot be directly identified. 
To help us protect your privacy, we have received a Certificate of Confidentiality from NIH. The 
certificate says that the investigators may not disclose research information that may identify you in any 
Federal, State, or local civil, criminal, administrative, legislative, or other proceedings, unless you have 
consented for this use. Research information protected by this certificate cannot be disclosed to anyone 
else who is not connected with the research unless:  
•
There is a law that requires disclosure (such as to report child abuse or communicable diseases
but not for legal proceedings).
•
You have consented to the disclosure, including for your medical treatment.
•
The research information is used for other scientific research, as allowed by federal regulations
protecting research subjects.
As noted above, disclosure is required, however, for audit or program evaluation requested by the 
agency that is funding this project or for information that is required by the FDA. 
You should understand that a Confidentiality Certificate does not prevent you or a member of your 
family from voluntarily releasing information about yourself or your involvement in this research.  


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201903884 
APPROVAL DATE: 06/04/19 
Version 2.0, 5-22-19 
Page 11 of 13 
Finally, you should understand that the investigator is not prevented from taking steps, including 
reporting to authorities, to prevent serious harm to yourself or others. 
The University of Iowa Hospitals and Clinics generally requires that we document in your medical 
record chart that you are participating in this study. The information included in the chart will provide 
contact information for the research team as well as information about the risks associated with this 
study. We will keep this Informed Consent Document in our research files; it will not be placed in your 
medical record chart. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time. 
WILL MY HEALTH INFORMATION BE USED DURING THIS STUDY? 
The Federal Health Insurance Portability and Accountability Act (HIPAA) requires University of Iowa 
Health Care to obtain your permission for the research team to access or create “protected health 
information” about you for purposes of this research study. Protected health information is information 
that personally identifies you and relates to your past, present, or future physical or mental health 
condition or care. We will access or create health information about you, as described in this document, 
for purposes of this research study. Once University of Iowa Health Care has disclosed your protected 
health information to us, it may no longer be protected by the Federal HIPAA privacy regulations, but 
we will continue to protect your confidentiality as described under “Confidentiality.” 
We may share your health information related to this study with other parties including federal 
government regulatory agencies, the University of Iowa Institutional Review Boards and support staff, 
the National Institute of Health, Technical Resources International (TRI) (pharmacovigilance group), 
ICON, and the Emmes Corporation (data coordinating center).  
You cannot participate in this study unless you permit us to use your protected health information. If you 
choose not to allow us to use your protected health information, we will discuss any non-research 
alternatives available to you. Your decision will not affect your right to medical care that is not research-
related. Your signature on this Consent Document authorizes University of Iowa Health Care to give us 
permission to use or create health information about you. 
Although you may not be allowed to see study information until after this study is over, you may be 
given access to your health care records by contacting your health care provider. Your permission for us 
to access or create protected health information about you for purposes of this study has no expiration 
date. You may withdraw your permission for us to use your health information for this research study by 
sending a written notice to Dr. Patricia Winokur, University of Iowa, Department of Medicine, Iowa 
City, IA 52242. However, we may still use your health information that was collected before 
withdrawing your permission. Also, if we have sent your health information to a third party, such as the 
study sponsor, or we have removed your identifying information, it may not be possible to prevent its 
future use. You will receive a copy of this signed document. 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201903884 
APPROVAL DATE: 06/04/19 
Version 2.0, 5-22-19 
Page 12 of 13 
IS BEING IN THIS STUDY VOLUNTARY? 
Taking part in this research study is completely voluntary. You may choose not to take part at all. If you 
decide to be in this study, you may stop participating at any time. If you decide not to be in this study, or 
if you stop participating at any time, you won’t be penalized or lose any benefits for which you 
otherwise qualify. 
What if I Decide to Drop Out of the Study? 
If you decide to leave the study early, we will ask you to permit the study staff to contact you to follow 
up on any reactions you may have had and to collect blood samples, if possible.  
Will I Receive New Information About the Study while Participating? 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
Can Someone Else End my Participation in this Study? 
Under certain circumstances, the researchers [or the study sponsor] might decide to end your 
participation in this research study earlier than planned.  This might happen because you are not 
following study-related directions or a serious reaction occurs or because the entire study has been 
stopped.   
WHAT IF I HAVE QUESTIONS? 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact: Deb Pfab at XXX-XXXX. If you experience a research-related injury, please contact: Pat 
Winokur, MD at XXX-XXXX. If it is an emergency during the evening, night or weekend or holiday 
you call XXX-XXXX and tell the hospital operator you are a research subject of Dr. Winokur in 
Infectious Diseases. 
If you have questions, concerns, or complaints about  your rights as a research subject or about a 
research related injury, please contact the Human Subjects Office, 105 Hardin Library for the Health 
Sciences, 600 Newton Rd, The University of Iowa, Iowa City, IA  52242-1098, (319) 335-6564, or e-
mail irb@uiowa.edu.  General information about being a research subject can be found by clicking “Info 
for Public” on the Human Subjects Office web site, http://hso.research.uiowa.edu/. To offer input about 
your experiences as a research subject or to speak to someone other than the research staff, call the 
Human Subjects Office at the number above. 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201903884 
APPROVAL DATE: 06/04/19 
Version 2.0, 5-22-19 
Page 13 of 13 
This Informed Consent Document is not a contract. It is a written explanation of what will happen 
during the study if you decide to participate. You are not waiving any legal rights by signing this 
Informed Consent Document. Your signature indicates that this research study has been explained to 
you, that your questions have been answered, and that you agree to take part in this study.  You will 
receive a copy of this form. 
Subject's Name (printed):  __________________________________________________________ 
__________________________________________ 
_______________________________ 
(Signature of Subject)  
(Date) 
Statement of Person Who Obtained Consent 
I have discussed the above points with the subject or, where appropriate, with the subject’s legally 
authorized representative.  It is my opinion that the subject understands the risks, benefits, and 
procedures involved with participation in this research study. 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
(Date) 

SAP_002.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 18-0011 
 
Study Title: 
A Phase I Study to Assess the Safety, Reactogenicity and Immunogenicity of Two 
Quadrivalent Seasonal Influenza Vaccines (Fluzone® or Flublok®) With or Without 
One of Two Adjuvants (AF03 or Advax-CpG55.2) in Healthy Adults  
18-45 Years of Age 
 
NCT03945825 
 
Version 3.0 
 
DATE: 04 May 2021 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL 
 


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STUDY TITLE  
Protocol Number Code: 
DMID Protocol: 18-0011 
Development Phase: 
Phase I 
Products: 
Sanofi 2018/2019 and 2019/2020 Fluzone Quadrivalent Influenza 
Vaccine (QIV) 
Sanofi 2018/2019 and 2019/2020 Flublok QIV 
Sanofi AF03 adjuvant  
Vaxine Advax- CpG55.2 adjuvant 
Form/Route: 
IM 
Indication Studied: 
Influenza 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
18 June 2019 
Clinical Trial Completion Date: 
18 September 2020 
Date of the Analysis Plan: 
04 May 2021 
Version Number: 
3.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is confidential. This 
information may not be disclosed to third parties without written authorization from Division of Microbiology and Infectious Diseases. This 
report may not be reproduced, stored in a retrieval system or transmitted in any form or by any means - electronic, mechanical, recording or 
otherwise - without the prior authorization from Division of Microbiology and Infectious Diseases. This document must be returned to Division 
of Microbiology and Infectious Diseases upon request. 
 


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TABLE OF CONTENTS 
STUDY TITLE ........................................................................................................................... 1 
LIST OF ABBREVIATIONS...................................................................................................... 5 
1. 
PREFACE ................................................................................................................ 8 
2. 
INTRODUCTION .................................................................................................... 9 
2.1. 
Purpose of the Analyses ............................................................................................ 9 
3. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................... 10 
3.1. 
Study Objectives and Outcome Measures ............................................................... 10 
3.2. 
Study Definitions and Derived Variables ................................................................ 20 
4. 
INVESTIGATIONAL PLAN ................................................................................. 21 
4.1. 
Overall Study Design and Plan ............................................................................... 21 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ..................... 22 
4.3. 
Selection of Study Population ................................................................................. 22 
4.4. 
Treatments .............................................................................................................. 22 
4.4.1. 
Treatments Administered ........................................................................................ 22 
4.4.2. 
Identity of Investigational Product(s) ...................................................................... 22 
4.4.3. 
Method of Assigning Subjects to Study Arms (Randomization) .............................. 22 
4.4.4. 
Selection of Doses in the Study ............................................................................... 22 
4.4.5. 
Selection and Timing of Dose for Each Subject ...................................................... 23 
4.4.6. 
Blinding.................................................................................................................. 23 
4.4.7. 
Prior and Concomitant Therapy .............................................................................. 23 
4.4.8. 
Treatment Compliance ............................................................................................ 23 
4.5. 
Efficacy (Immunogenicity) and Safety Variables .................................................... 23 
4.5.1. 
Safety Variables ..................................................................................................... 24 
4.5.2. 
Immunogenicity Variables ...................................................................................... 24 
5. 
SAMPLE SIZE CONSIDERATIONS .................................................................... 26 
6. 
GENERAL STATISTICAL CONSIDERATIONS ................................................. 27 
6.1. 
General Principles .................................................................................................. 27 
6.2. 
Timing of Analyses ................................................................................................ 27 
6.2.1. 
Expedited Report .................................................................................................... 27 
6.2.2. 
Clinical Study Report ............................................................................................. 28 
6.3. 
Analysis Populations .............................................................................................. 28 


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6.3.1. 
Safety Population.................................................................................................... 28 
6.3.2. 
Modified Intention-to-Treat (mITT) Population ...................................................... 28 
6.3.3. 
Per Protocol Population .......................................................................................... 28 
6.4. 
Covariates and Subgroups ....................................................................................... 29 
6.5. 
Missing Data .......................................................................................................... 29 
6.6. 
Interim Analyses and Data Monitoring ................................................................... 29 
6.6.1. 
Interim Safety Review ............................................................................................ 29 
6.6.2. 
Interim Immunogenicity Review ............................................................................. 30 
6.7. 
Multicenter Studies ................................................................................................. 30 
6.8. 
Multiple Comparisons/Multiplicity ......................................................................... 30 
7. 
STUDY SUBJECTS ............................................................................................... 31 
7.1. 
Disposition of Subjects ........................................................................................... 31 
7.2. 
Protocol Deviations ................................................................................................ 31 
8. 
IMMUNOGENICITY EVALUATION .................................................................. 32 
8.1. 
Primary Immunogenicity Analysis .......................................................................... 32 
8.2. 
Secondary Immunogenicity Analyses ..................................................................... 32 
8.3. 
Exploratory Immunogenicity Analyses ................................................................... 33 
9. 
SAFETY EVALUATION....................................................................................... 35 
9.1. 
Demographic and Other Baseline Characteristics .................................................... 35 
9.1.1. 
Prior and Concurrent Medical Conditions ............................................................... 35 
9.1.2. 
Prior and Concomitant Medications ........................................................................ 35 
9.2. 
Measurements of Treatment Compliance ................................................................ 35 
9.3. 
Adverse Events ....................................................................................................... 36 
9.3.1. 
Solicited Events and Symptoms .............................................................................. 36 
9.3.2. 
Unsolicited Adverse Events .................................................................................... 36 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ................... 37 
9.5. 
Pregnancies ............................................................................................................ 38 
9.6. 
Clinical Laboratory Evaluations .............................................................................. 38 
9.7. 
Vital Signs and Physical Evaluations ...................................................................... 38 
9.8. 
Concomitant Medications ....................................................................................... 38 
10. 
REPORTING CONVENTIONS ............................................................................. 40 


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11. 
TECHNICAL DETAILS ........................................................................................ 41 
12. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ........................................................................................ 42 
13. 
REFERENCES ....................................................................................................... 43 
14. 
LISTING OF TABLES, FIGURES, AND LISTINGS ............................................ 44 
APPENDICES .......................................................................................................................... 45 
APPENDIX 1. TABLE MOCK-UPS ...................................................................................... 46 
APPENDIX 2. FIGURE MOCK-UPS .................................................................................. 197 
APPENDIX 3. LISTINGS MOCK-UPS ............................................................................... 229 
 
 


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LIST OF ABBREVIATIONS 
A/H1N1 
Influenza A Virus of the H1N1 Subtype 
A/H1N2v 
Influenza A Virus of the H1N2 Variant Subtype 
A/H2N2 
Influenza A Virus of the H2N2 Subtype 
A/H3N2 
Influenza A Virus of the H3N2 Subtype 
A/H3N2v 
Influenza A Virus of the H3N2 Variant Subtype 
A/H5N1 
Influenza A Virus of the H5N1 Subtype 
A/H5N6 
Influenza A Virus of the H5N6 Subtype 
A/H5N8 
Influenza A Virus of the H5N8 Subtype 
A/H7N1 
Influenza A Virus of the H7N1 Subtype 
A/H7N7 
Influenza A Virus of the H7N7 Subtype 
A/H7N9 
Influenza A Virus of the H7N9 Subtype 
A/H9N2 
Influenza A Virus of the H9N2 Subtype 
Advax  
Trade name for delta inulin adjuvant formulation 
AE 
Adverse Event 
AESIs 
Adverse Events of Special Interest 
AF03 
Adjuvant formulation (03) 
ALP 
Alkaline phosphatase 
ALT 
Alanine Aminotransferase 
ANCA 
Anti-Neutrophil Cytoplasmic Antibody 
AS03 
Adjuvant System (03) 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure  
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CI 
Confidence Interval 
CpG55.2 
Class B CPG oligonucleotide adjuvant  
Cr 
Creatinine 
CRF 
Case Report Form 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 


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List of Abbreviations (continued) 
 
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EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked Immunosorbent Assay 
ELISpot 
Enzyme-Linked Immunosorbent Spot 
ELLA 
Enzyme-Linked Lectin Assay 
ER 
Emergency Room 
ESR 
Erythrocyte Sedimentation Rate 
F 
Fahrenheit 
FDA 
U.S. Food and Drug Administration 
GCI 
Global Clinical Immunology 
GGT 
Gamma-Glutamyl Transferase 
GMT 
Geometric Mean Titer 
GMFR 
Geometric Mean Fold Rise 
HA 
Hemagglutinin 
HAI 
Hemagglutination Inhibition Antibody 
Hgb 
Hemoglobin 
HHS 
U.S. Department of Health and Human Services 
ICH 
International Conference on Harmonisation 
IIV 
Inactivated Influenza Vaccine 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
L 
Liter 
LLN 
Lower Limit of Normal 
MAAEs 
Medically Attended Adverse Events 
mcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligram 
mITT 
Modified Intention to Treat 
mL 
Milliliter 
MAR 
Missing at Random 
MCAR 
Missing Completely at Random 
MNAR 
Missing Not at Random 


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List of Abbreviations (continued) 
 
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N, n 
Number  
NA 
Neuraminidase 
NAI 
Neuraminidase Inhibition 
Neut 
Neutralizing Antibody 
NIH 
National Institutes of Health 
NOCMCs 
New-Onset Chronic Medical Conditions 
PBMCs 
Peripheral Blood Mononuclear Cells 
PI 
Principal Investigator 
PIMMCs 
Potentially Immune-Mediated Medical Conditions 
PLT 
Platelets 
PP 
Per Protocol 
PT 
Preferred Term 
QIV 
Quadrivalent Influenza Vaccine 
RBC 
Red Blood Cell 
RCD 
Reverse Cumulative Distribution  
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOC  
System Organ Class 
SP 
Sanofi Pasteur 
T. Bili 
Total Bilirubin 
TFH 
T Follicular Helper  
ULN 
Upper Limit of Normal 
ULOQ 
Upper Limit of Quantitation 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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1. 
PREFACE 
The Statistical Analysis Plan (SAP) for “A Phase I Study to Assess the Safety, Reactogenicity and 
Immunogenicity of Two Quadrivalent Seasonal Influenza Vaccines (Fluzone® or Flublok®) With or Without 
One of Two Adjuvants (AF03 or Advax-CpG55.2) in Healthy Adults 18-45 Years of Age” (DMID Protocol 
18-0011) describes and expands upon the statistical information presented in the protocol. 
This document describes all planned analyses except transcriptomics analysis and provides reasons and 
justifications for these analyses. It also includes sample tables, figures, listings (TFLs) planned for (1) final 
analyses included in (1) the expedited report, (2) the Clinical Study Report (CSR). Regarding the final 
analyses and CSR, this SAP follows the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines, as indicated in Topic E3 
(Structure and Content of Clinical Study Reports), and more generally is consistent with Topic E8 (General 
Considerations for Clinical Trials) and Topic E9 (Statistical Principles for Clinical Trials). The structure and 
content of the SAP provides sufficient detail to meet the requirements identified by the U.S. Food and Drug 
Administration (FDA) and ICH, while all work planned and reported for this SAP will follow internationally 
accepted guidelines published by the American Statistical Association and the Royal Statistical Society for 
statistical practice.  
This document contains four sections: (1) a review of the study design, (2) general statistical considerations, 
(3) comprehensive statistical analysis methods for immunogenicity and safety outcomes, and (4) a list of 
proposed tables, figures and listings (TFLs). Following any protocol amendment, this SAP will be reviewed 
and revised (if needed) to address any changes in the protocol impacting analysis. Any deviation from the 
final SAP will be described and justified in the CSR. The reader of this SAP is encouraged to also review the 
study protocol for details on conduct of the study and the operational aspects of clinical assessments. 


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2. 
INTRODUCTION 
Influenza poses perpetual threats to human populations. Use of influenza vaccines is the primary means for 
preventing influenza. Current licensed inactivated influenza vaccines (IIVs) containing Hemagglutinin (HA) 
and Neuraminidase (NA) antigens are good for preventing influenza but are less effective than desirable. The 
inclusion of an adjuvant provides another mechanism to improve the immune response to IIV antigens.  
The goal of this clinical trial is to assess in healthy adults, 18-45 years of age, the safety, reactogenicity and 
immunogenicity of one dose of 2018/2019 Quadrivalent Influenza Vaccine (either Fluzone or Flublok) 
administered intramuscularly (IM) with or without one of two adjuvants (AF03 or Advax-CpG55.2). The 
study will evaluate the traditional Hemagglutination Inhibition (HAI) and Neutralizing or Neutralization 
(Neut) responses among groups, but also will explore additional immunological parameters. Since antibodies 
targeting the NA may represent an independent correlate of protection against influenza infection, we plan to 
assess the Neuraminidase Inhibiting or Inhibition (NAI) responses in each group. The longitudinal kinetics 
and durability of HAI, Neut, and NAI responses will be evaluated for one year following vaccination.  
This clinical trial will also assess cellular correlates of immunity to influenza including memory B cell 
populations, plasmablasts, TFH cells, functional non-neutralizing Fc-effector antibodies, as well as determine 
the transcriptional profiling responses following vaccination. 
2.1. 
Purpose of the Analyses 
These analyses will assess the safety and immunogenicity of one dose of 2018/2019 Quadrivalent Influenza 
Vaccine (either Fluzone or Flublok) administered IM with or without one of two adjuvants (AF03 or Advax-
CpG55.2) and will be included in the expedited report and clinical study report.  
 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives and Outcome Measures 
 
Primary Safety Objectives 
Primary Safety Outcome Measures 
• To assess the safety and reactogenicity of 
2018/2019 Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 adjuvant.  
 
• Occurrence of solicited injection site and 
systemic reactogenicity events through 
approximately Day 8 after the first study 
vaccination. 
• Occurrence of unsolicited adverse events from 
the time of the first study vaccination through 
approximately Day 29. 
• Occurrence of all SAEs through 
approximately 12 months following receipt of 
the first study vaccination. 
• Occurrence of abnormal clinical safety 
laboratory AEs from the time of study 
vaccination through approximately Day 8 
after the first study vaccination. 
Primary Immunogenicity Objectives 
Primary Immunogenicity Outcome Measures 
• To assess the serum hemagglutination 
inhibition (HAI) antibody responses against 
2018/2019 QIV strains from baseline (Day 
1) to approximately Day 29 after receipt of 
2018/2019 Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 adjuvant. 
 
• The percentage of subjects achieving HAI 
titer seroconversion against the 2018/2019 
QIV strains (defined as either a pre-
vaccination titer <1:10 and a post-vaccination 
titer ≥1:40 or a pre-vaccination titer ≥1:10 and 
a minimum four-fold rise in post-vaccination 
antibody titer) on approximately Day 29 for 
each study group. 
• The percentage of subjects with an HAI titer 
≥1:40 against the 2018/2019 QIV strains at 
baseline and approximately Day 29 for each 
study group. 
• Geometric mean titers (GMTs) of serum HAI 
against the 2018/2019 QIV strains at baseline 
and approximately Day 29 for each study 
group. 


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• Ratio of GMTs of serum HAI against the 
2018/2019 QIV strains between adjuvanted 
and unadjuvanted study groups at baseline and 
approximately Day 29. 
• Geometric mean fold rise (GMFR) in HAI 
titers from baseline (Day 1) against the 
2018/2019 QIV strains at approximately Day 
29 for each study group 
• To assess the serum neuraminidase 
inhibition antibody (NAI) responses by 
enzyme-linked lectin assay (ELLA) against 
NA antigens in the 2018/2019 QIV from 
baseline (Day 1) to approximately Day 29 
after receipt of 2018/2019 Fluzone and 
Flublok with and without AF03 or Advax-
CpG55.2 adjuvant.   
• The percentage of subjects achieving NAI 
seroconversion (defined as ≥4-fold rise in post 
vaccination antibody titers against the NA 
antigens in the 2018/2019 QIV) on 
approximately Day 29 for each study group. 
• The serum NAI GMT at baseline (Day 1) and 
approximately Day 29 for each study group. 
• Ratio of serum NAI GMT between adjuvanted 
and unadjuvanted study groups at baseline 
(Day 1) and approximately Day 29. 
• Geometric mean fold rise (GMFR) in NAI 
titers from baseline (Day 1) against NA 
antigens in the 2018/2019 QIV strains at 
approximately Day 29 for each study group 
• To assess the influenza neutralizing (Neut) 
antibody titer responses against 2018/2019 
QIV strains from baseline (Day 1) to 
approximately Day 29 after receipt of 
2018/2019 Fluzone and Flublok with and 
without AF03 or Advax- CpG55.2 
adjuvant.  
 
• The percentage of subjects achieving Neut 
titer seroconversion against the 2018/2019 
QIV strains (defined as either a pre-
vaccination titer <1:10 and a post-vaccination 
titer ≥1:40 or a pre-vaccination titer ≥1:10 and 
a minimum four-fold rise in post-vaccination 
antibody titer) on approximately Day 29 for 
each study group. 
• The percentage of subjects with a Neut titer 
≥1:40 against the 2018/2019 QIV strains at 
baseline (Day 1) and approximately Day 29 
for each study group. 
• Serum Neut GMT at baseline (Day 1) and 
approximately Day 29 for each study group 


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• Ratio of serum Neut GMT between 
adjuvanted and unadjuvanted study groups at 
baseline (Day 1) and approximately Day 29. 
• Geometric mean fold rise (GMFR) in Neut 
titers from baseline (Day 1) against the 
2018/2019 QIV strains at approximately Day 
29 for each study group 
Secondary Safety Objectives 
Secondary Safety Outcome Measures 
• To assess protocol specified AESIs, 
medically-attended adverse events 
(MAAEs), including new-onset chronic 
medical conditions (NOCMCs) and 
potentially immune-mediated medical 
conditions (PIMMCs) that occur after 
receipt of study product. 
• Occurrence of all protocol specified AESIs, 
MAAEs, including NOCMCs and PIMMCs, 
from the time of the first study vaccination 
through approximately 12 months following 
the first vaccination. 
 
Secondary Immunogenicity Objectives  
Secondary Immunogenicity Outcome Measures 
• To assess the HAI, Neut and NAI ELLA 
responses to the 2019/2020 QIV strains 
prior to (Day 1) and approximately 28 days 
after vaccination with the 2019/2020 QIV 
in all study groups 
• The percentage of subjects achieving an HAI 
titer ≥1:40 against 2019/2020 QIV strains 
approximately on Days D90 (baseline) and 
D118 (28 days post-2019/2020 vaccine) for 
each study group. 
• The percentages of subjects achieving HAI, 
Neut and NAI titer seroconversion, against 
2019/2020 QIV strains on approximately Day 
118 for each study group (NAI titers will only 
be assessed on study groups 1,2 and 3). 
• Serum Neut, HAI and NAI GMTs against 
2019/2020 QIV strains approximately on 
Days D90 (baseline) and D118 (28 days post-
2019/2020 QIV) for each study group (NAI 
titers will only be assessed on study groups 
1,2 and 3).  
• Ratio of serum Neut, HAI and NAI GMTs 
against 2019/2020 QIV strains between 
adjuvanted and unadjuvanted study groups 
approximately on Days D90 (baseline) and 
D118 (28 days post-2019/2020 QIV). NAI 


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titers will only be assessed on study groups 
1,2 and 3. 
• Serum Neut, HAI and NAI GMFRs against 
2019/2020 QIV strains from baseline (D90) 
on approximately D118 for each study group 
(NAI titers will only be assessed on study 
groups 1,2 and 3). 
• To assess the HAI antibody responses 
against heterologous influenza A/H1 and 
H3 strains from baseline (Day 1) to 
approximately Days 8, 29, 57, 90, and 118 
after receipt of 2018/2019 Fluzone or 
Flublok with and without AF03 or Advax-
CpG55.2 adjuvant.  
 
• The percentages of subjects achieving HAI 
titer seroconversion, against heterologous H1 
and H3 influenza strains on approximately 
Days 8, 29, 57, 90, and 118 for each study 
group.  
• The percentage of subjects achieving an HAI 
titer ≥1:40 against heterologous H1 and H3 
influenza strains at baseline (Day 1) and 
approximately Days 8, 29, 57, 90, and 118 for 
each study group. 
• Serum HAI GMT against heterologous H1 
and H3 influenza strains at baseline (Day 1) 
and approximately Days 8, 29, 57, 90, and 
118 for each study group.  
• Ratio of serum HAI GMT against 
heterologous H1 and H3 influenza strains 
between adjuvanted and unadjuvanted study 
groups at baseline (Day 1) and approximately 
Days 8, 29, 57, 90, and 118.  
• Geometric mean fold rise (GMFR) in HAI 
from baseline (Day 1) against heterologous 
H1 and H3 influenza strains at approximately 
Days 8, 29, 57, 90, and 118 for each study 
group 
• To assess NAI ELLA responses against 
heterologous N1 and N2 NA antigens from 
baseline (Day 1) to approximately Days 8, 
29, 57, 90, and 118 after administration of 
2018/2019 Fluzone with and without AF03 
or Advax-CpG55.2 adjuvant. 
• The percentage of subjects achieving 
seroconversion against heterologous N1 and 
N2 NA antigens on approximately Days 8, 29, 
57, 90, and 118 for study groups 1, 2 and 3. 
• Serum NAI GMTs against heterologous N1 
and N2 NA antigens at baseline and 


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approximately Days 8, 29, 57, 90, and 118 for 
study groups 1, 2 and 3. 
• Ratio of serum NAI GMTs against 
heterologous N1 and N2 NA antigens between 
adjuvanted and unadjuvanted study groups at 
baseline and approximately Days 8, 29, 57, 
90, and 118 (NAI titers will only be assessed 
on study groups 1,2 and 3). 
• Geometric mean fold rise (GMFR) in serum 
NAI from baseline against heterologous N1 
and N2 NA antigens at baseline and 
approximately Days 8, 29, 57, 90, and 118 for 
study groups 1, 2 and 3. 
 
• To assess the influenza neutralizing (Neut) 
antibody titer responses against 
heterologous influenza A/H1 and H3 strains 
from baseline (Day 1) to approximately 
Days 8, 29, 57, 90, and 118 after 
administration of 2018/2019 Fluzone and 
Flublok with and without AF03 or Advax-
CpG55.2 adjuvant.  
 
• The percentage of subjects achieving Neut 
titer seroconversion against heterologous H1 
and H3 influenza strains on approximately 
Days 8, 29, 57, 90, and 118 for each study 
group. 
• Serum Neut GMT against heterologous H1 
and H3 influenza strains at baseline (Day 1) 
and approximately Days 8, 29, 57, 90, and 
118 for each study group. 
• Ratio of serum Neut GMT against 
heterologous H1 and H3 influenza strains 
between adjuvanted and unadjuvanted study 
groups at baseline (Day 1) and approximately 
Days 8, 29, 57, 90, and 118. 
• Geometric mean fold rise (GMFR) of neut 
antibody titers from baseline against 
heterologous H1 and H3 influenza strains at 
baseline (Day 1) and approximately Days 8, 
29, 57, 90, and 118 for each study group. 
• To assess the longitudinal kinetics and 
durability of the HAI, NAI, and Neut 
responses against the 2018/2019 QIV 
strains on approximately Days 8, 57, 90, 
• The percentage of subjects achieving HAI, 
NAI and Neut titer seroconversion against 
2018/2019 QIV antigens and strains on 
approximately Days 8, 57, 90, and 118 for 


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and 118 following receipt of the 2018/2019 
Fluzone and Flublok with and without 
AF03 or Advax-CpG55.2 adjuvant.   
 
each study group (NAI titers will only be 
assessed on study groups 1,2 and 3). 
• The percentage of subjects achieving an HAI 
and Neut titer ≥1:40 against 2018/2019 QIV 
strains on approximately Days 8, 57, 90, and 
118 for each study group (NAI titers will only 
be assessed on study groups 1,2 and 3). 
• Serum Neut, HAI and NAI GMT against 
2018/2019 QIV strains on approximately 
Days 8, 57, 90, and 118 for each study group 
(NAI titers will only be assessed on study 
groups 1,2 and 3). 
• Ratio of serum Neut, HAI and NAI GMT 
against 2018/2019 QIV strains between 
adjuvanted and unadjuvanted study groups on 
approximately Days 8, 57, 90, and 118 (NAI 
titers will only be assessed on study groups 
1,2 and 3). 
• Geometric mean fold rise (GMFR) in HAI, 
Neut and NAI titers from baseline (Day 1) 
against the 2018/2019 QIV strains at 
approximately Day 8, 57, 90, and 118 for each 
study group (NAI titers will only be assessed 
on study groups 1,2 and 3). 
Exploratory Immunogenicity Objectives 
Exploratory Immunogenicity Study Outcomes 
• To assess the HAI antibody responses 
against heterologous influenza A/H1 and 
H3 strains from baseline (Day 1) to 
approximately Days 180 and 365 after 
receipt of 2018/2019 Fluzone or Flublok 
with and without AF03 or Advax-CpG55.2 
adjuvant.  
 
• The percentages of subjects achieving HAI 
titer seroconversion, against heterologous H1 
and H3 influenza strains on approximately 
Days 180 and 365 for each study group.  
• The percentage of subjects achieving a HAI 
titer ≥1:40 against heterologous H1 and H3 
influenza strains at baseline (Day 1) and 
approximately Days 180 and 365 for each 
study group. 
• Serum HAI GMT against heterologous H1 
and H3 influenza strains at baseline (Day 1) 


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and approximately Days 180 and 365 each 
study group.  
• Ratio of serum HAI GMT against 
heterologous H1 and H3 influenza strains 
between adjuvanted and unadjuvanted study 
groups at baseline (Day 1) and approximately 
Days 180 and 365.  
• Geometric mean fold rise (GMFR) in HAI 
from baseline (Day 1) against heterologous 
H1 and H3 influenza strains at approximately 
Days 180 and 365 for each study group 
• To assess NAI ELLA responses against 
heterologous N1 and N2 NA antigens from 
baseline (Day 1) to approximately Days 
180 and 365 administration of 2018/2019 
Fluzone with and without AF03 or Advax-
CpG55.2 adjuvant. 
 
• The percentage of subjects achieving 
seroconversion against heterologous N1 and 
N2 NA antigens on approximately Days 180 
and 365 for study groups 1, 2 and 3. 
• Serum NAI GMTs against heterologous N1 
and N2 NA antigens at baseline and 
approximately Days 180 and 365 for study 
groups 1, 2 and 3. 
• Ratio of serum NAI GMTs against 
heterologous N1 and N2 NA antigens between 
adjuvanted and unadjuvanted study groups at 
baseline and approximately Days 180 and 365 
for study groups 1,2 and 3. 
• Geometric mean fold rise (GMFR) in serum 
NAI from baseline against heterologous N1 
and N2 NA antigens at baseline and 
approximately Days 180 and 365 for study 
groups 1, 2 and 3. 
 
• To assess the influenza neutralizing (Neut) 
antibody titer responses against 
heterologous influenza A/H1 and H3 strains 
from baseline (Day 1) to approximately 
Days 180 and 365 after administration of 
2018/2019 Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 adjuvant.  
 
• The percentage of subjects achieving Neut 
titer seroconversion against heterologous H1 
and H3 influenza strains on approximately 
Days 180 and 365 for each study group. 
• Serum Neut GMT against heterologous H1 
and H3 influenza strains at baseline (Day 1) 
and approximately Days 180 and 365 for each 
study group. 


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• Ratio of serum Neut GMT against 
heterologous H1 and H3 influenza strains 
between adjuvanted and unadjuvanted study 
groups at baseline (Day 1) and approximately 
Days 180 and 365. 
• Geometric mean fold rise (GMFR) of neut 
antibody titers from baseline against 
heterologous H1 and H3 influenza strains at 
baseline (Day 1) and approximately Days 180 
and 365 for each study group. 
• To assess the longitudinal kinetics and 
durability of the HAI, NAI, and Neut 
responses against the 2018/2019 QIV 
strains on approximately Days 180 and 365 
following receipt of the 2018/2019 Fluzone 
and Flublok with and without AF03 or 
Advax-CpG55.2 adjuvant.   
 
• The percentage of subjects achieving HAI, 
NAI and Neut titer seroconversion against 
2018/2019 QIV antigens and strains on 
approximately Days 180 and 365 for each 
study group (NAI titers will only be assessed 
on study groups 1,2 and 3). 
• The percentage of subjects achieving an HAI 
and Neut titer ≥1:40 against 2018/2019 QIV 
strains on approximately Days 180 and 365 
for each study group (NAI titers will only be 
assessed on study groups 1,2 and 3). 
• Serum Neut, HAI and NAI GMT against 
2018/2019 QIV strains on approximately 
Days 180 and 365 for each study group (NAI 
titers will only be assessed on study groups 
1,2 and 3). 
• Ratio of serum Neut, HAI and NAI GMT 
against 2018/2019 QIV strains between 
adjuvanted and unadjuvanted study groups on 
approximately Days 180 and 365 (NAI titers 
will only be assessed on study groups 1,2 and 
3). 
• Geometric mean fold rise (GMFR) in HAI, 
Neut and NAI titers from baseline (Day 1) 
against the 2018/2019 QIV strains at 
approximately Day 180 and 365 for each 
study group (NAI titers will only be assessed 
on study groups 1,2 and 3). 
• To assess the HAI, Neut and NAI ELLA 
responses to the 2018/2019 at all timepoints 
• The percentage of subjects achieving an HAI 
titer ≥1:40 against 2018/2019 QIV strains at 


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and 2019/2020 QIV strains prior to and 
approximately 28 days after vaccination 
with the 2019/2020 QIV in all study 
groups, according to serostatus at baseline 
and previous influenza vaccination  
all timepoints and against 2019/2020 QIV 
strains at approximately D90 and D118. 
• The percentages of subjects achieving HAI, 
Neut and NAI titer seroconversion, against 
2018/2019 QIV strains at approximately D29 
and against 2019/2020 QIV strains at 
approximately D118.  
• Serum Neut, HAI and NAI GMTs against 
2018/2019 QIV strains at all timepoints (for 
study groups 4, 5 and 6 NAI titers will only be 
assessed at D1 and D29) and against 
2019/2020 QIV strains at approximately D90 
and D118 (NAI titers will only be assessed on 
study groups 1,2 and 3).  
• Serum Neut, HAI and NAI GMFRs against 
2018/2019 QIV strains on approximately 
Days 8, 29, 57, 90, 118, 180 and 365 (for 
study groups 4, 5 and 6 NAI titers will only be 
assessed at D1 and D29) and against 
2019/2020 QIV strains at approximately D118 
(NAI titers will only be assessed on study 
groups 1,2 and 3).  
• To assess B Cell effector and memory 
responses prior to (Day 1) and following 
receipt of 2018/2019 Fluzone and Flublok 
with and without AF03 or Advax-CpG55.2 
adjuvant. 
 
• Change in the frequency of influenza specific-
IgG, IgM and IgA B memory cells using 
multiplexed FluoroSpot from baseline (Day 1) 
to approximately Days 29 and 90 for each 
study group. 
• Change in frequency of influenza-specific 
IgG, IgM and IgA effector B cells 
(plasmablast) using multiplexed FluoroSpot 
from baseline (Day 1) to approximately Day 8 
for each study group. 
• To assess plasmablast and T follicular 
helper (Tfh cell responses prior to (Day 1) 
and following receipt of 2018/2019 Fluzone 
and Flublok with and without AF03 or 
Advax-CpG55.2 adjuvant. 
• Change in the frequency of plasmablast and 
Tfh cells using multiparametric flow 
cytometry from baseline (Day 1) to 
approximately Day 8 for each study group. 
 
• To assess the functional non-neutralizing 
Fc-effector antibody responses prior to 
(Day 1) and following receipt of 2018/2019 
• GMT of functional non-neutralizing Fc-
effector antibodies against vaccine strain 
antigens at baseline (Day 1) and 


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Fluzone and Flublok with and without 
AF03 or Advax-CpG55.2 adjuvant.   
approximately Day 29 after vaccination for 
each study group. 
• Geometric mean fold rise (GMFR) in 
functional non-neutralizing Fc-effector 
antibody titers from baseline (Day 1) against 
the 2018/2019 QIV strains at approximately 
Day 29 for each study group 
• To assess responses from baseline (Day 1) 
in transcriptomic profiling on 
approximately Days 2 and 8 following 
receipt of 2018/2019 Fluzone and Flublok 
with and without AF03 or Advax-CpG55.2 
adjuvant. 
• Differential expression of transcription 
profiles comparing samples taken just prior to 
(Day 1) and on approximately Days 2 and 8 
following receipt of the 2018/2019 QIV 
vaccination in at least a subset of subjects for 
each study group. 
 
• To evaluate the relationship of non-
neutralizing Fc-effector antibodies titers 
with HAI and NA responses following 
receipt of 2018/2019 Fluzone and Flublok 
with and without AF03 or Advax-CpG55.2 
adjuvant. 
 
• The association of non-neutralizing Fc-
effector antibodies GMT with HAI and Neut 
antibody GMT, seroprotection and 
seroconversion rates to variant influenza 
strains and the 2018/2019 QIV vaccine 
strains. 
• To describe the non-neutralizing Ab 
responses to different influenza HA 
antigens by a multiplex ELISA assay at all 
time points in each study group 
• Quantification of HA binding antibodies 
against different influenza HA antigens at 
baseline (Day 1) and Days 8, 29, 57, 90, 118, 
180 and 365 in each study group. 
• To describe the NA binding antibody 
response to NA antigens corresponding to 
the vaccine strain antigens by an ELISA 
assay after administration of Fluzone with 
and without AF03 or Advax-CpG55.2 
adjuvant. 
• Quantification of NA binding antibodies 
against  influenza NA antigens corresponding 
to the vaccine strain antigens at baseline (Day 
1), Day 29, 57, 90 and D118 in Groups 1, 2, 3.  
Additional studies on Days180 and 365 in 
Groups 1,2,3 will be contingent on seeing 
increased seroconversion rates to homologous 
vaccine strain antigens 


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3.2. 
Study Definitions and Derived Variables  
For individual subjects, fold rise will be calculated as the ratio of: 
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝−𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡
𝑝𝑝𝑝𝑝𝑝𝑝−𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡, where pre-vaccination 
value is the result obtained at Day 1 prior to the priming dose. However, for assay results against 2019/2020 
QIV strains, pre-vaccination titer is the result obtained at Day 90.  
HAI Seroconversion is defined as either a pre-vaccination titer <1:10 and a post-vaccination titer ≥1:40 or a 
pre-vaccination titer ≥1:10 and a minimum four-fold rise in post-vaccination antibody titer [1]. 
NAI seroconversion is defined as ≥4-fold rise in post vaccination antibody titers against the NA antigens in 
the 2018/2019 QIV. 
Neut Seroconversion is defined as either a pre-vaccination titer <1:10 and a post-vaccination titer ≥1:40 or a 
pre-vaccination titer ≥1:10 and a minimum four-fold rise in post-vaccination antibody titer. 
Seronegative baseline status is defined as pre-vaccination antibody titer of ≤1:10. 
Seropositive baseline status is defined as pre-vaccination antibody titer of >1:10.  
For HAI and Neut assays, Seroprotection is defined as titer ≥ 40. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
DMID Protocol 18-0011 follows a Phase I randomized, double blind study design enrolling males and non-
pregnant females aged 18-45 years of age, inclusive, who are in good health as determined by medical history 
and physical examination, and meet all eligibility criteria, including erythrocyte sedimentation rate (ESR) and 
negative urine or serum pregnancy test (for females). This clinical trial is designed to assess the safety, 
reactogenicity and immunogenicity of either the 2018/2019 Fluzone or Flublok Quadrivalent Influenza 
Vaccines (QIV), manufactured by Sanofi Pasteur (SP) given without adjuvant or with one of two adjuvant 
formulations, AF03 (SP) or Advax-CpG55.2 (Vaxine Pty Ltd).  
In this trial, subjects will be stratified by prior receipt of licensed, seasonal influenza vaccine (defined as 
receipt of at least one of the 2017/2018 and/or 2018/2019 influenza vaccines) and will be randomly assigned 
to 1 of 6 study arms to receive a single dose of one of the two seasonal 2018/2019 QIV vaccine formulations 
with or without one of the two adjuvants (Day 1). On approximately Day 90, each subject will receive a single 
dose of the seasonal 2019/2020 influenza vaccine. Treatment will be assigned to each study arm as described 
in Table 1.  
To determine early safety signals for this Phase I study, enrollment will proceed in a staged fashion for the 
first 6 sentinel subjects. The first six subjects will be randomized and vaccinated with one each from Groups 
1-6. These six subjects will be followed through Day 8. If any of the pre-specified halting rules for the 
sentinel subjects occur, the study will be halted and reviewed by the DSMB. If no pre-specified safety signals 
are encountered enrollment will proceed. 
The DSMB will review the data when the 8-day reactogenicity and clinical safety laboratory data following 
the first study vaccination are available for 50% of study subjects. Enrollment will not be paused for this 
review. An additional scheduled DSMB review will occur when all HAI, NAI and Neut data for Day 1, and 
Day 29 and safety data through Day 57 following the first study vaccination, are available.  
Reactogenicity will be measured by the occurrence of solicited injection site and systemic reactions from the 
time of the first study vaccination through Day 8. Unsolicited non-serious adverse events (AEs) will be 
collected from Day 1 through approximately Day 29. Serious adverse events (SAEs); Adverse Events of 
Special Interest (AESIs) including reports of tearing, dry mouth, dry eyes; medically-attended adverse events 
(MAAEs), new-onset chronic medical conditions (NOCMCs); and potentially immune-mediated medical 
conditions (PIMMCs), will be collected Day 1 through approximately 12 months after the first study 
vaccination. Clinical safety laboratory evaluations (hematology and chemistry) will be performed at 
screening, immediately prior to the first study vaccination, and at approximately Day 8. 
Immunogenicity testing will include performing serological assays to assess hemagglutination inhibition 
(HAI), neutralizing (Neut), and neuraminidase inhibition (NAI) titers at multiple time points following both 
study vaccinations. Antibody responses will be determined for both influenza vaccine strains and 
heterologous influenza strains. Additional exploratory immunologic responses will include longitudinal 
assessments of the kinetics, magnitude, specificity, and/or quality of influenza-specific memory B cells, 
plasmablasts, circulating T follicular helper (TFH) cells, and non-neutralizing antibody responses to HA and 
NA antigens (Multiplex ELISA, NA ELISA, Systems Serology). 


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4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
This study uses a dose comparison concurrent control design. All subjects receive the same study product 
(2018/2019 Fluzone or Flublok QIV) with or without adjuvants on Day 1. On Day 90, all subjects receive the 
seasonal vaccine of either Fluzone 2019/2020 QIV or Flublok 2019/2020 QIV. 
4.3. 
Selection of Study Population 
The study population for this clinical trial is 240 males and non-pregnant females, 18-45 years old, who are in 
good health and meet all eligibility criteria. The subjects will be recruited from the general population at the 
participating Vaccine Trial and Evaluation Unit (VTEU) sites that have substantial experience conducting 
large influenza vaccine studies. 
4.4. 
Treatments 
4.4.1. 
Treatments Administered  
2018/2019 Flublok QIV, 2018/2019 Fluzone QIV, 2019/2020 Flublok QIV, 2019/2020 Fluzone QIV, AF03 
adjuvant, and Advax-CpG55.2 adjuvant will be administered. 
4.4.2. 
Identity of Investigational Product(s) 
See the study protocol for details of study product formulation. 
4.4.3. 
 Method of Assigning Subjects to Study Arms (Randomization) 
Enrollment/randomization will be performed through the enrollment module in the electronic data capture 
system maintained by the Statistical and Data Coordinating Center (SDCC).  
Eligible subjects will be stratified by clinical site and prior receipt of licensed, seasonal influenza vaccine 
(defined as receipt of at least one of the 2017/2018 and/or 2018/2019 influenza vaccines) and randomly 
assigned with allocation (1:1:1:1:1:1) to one of 6 study arms indicated in Table 1. The treatment sequence was 
generated using permuted block randomization to provide an approximately balanced allocation to the study 
arms during the study. 
4.4.4. 
Selection of Doses in the Study 
Each subject will receive a dose of either 2018/2019 Fluzone QIV or 2018/2019 Flublok QIV on Day 1 and a 
dose of 2019/2020 Fluzone QIV or 2019/2020 Flublok QIV on approximately day 90.  
• 2018/2019 and 2019/2020 Flublok QIVs are formulated to contain 180 µg of HA per 0.5 mL dose, 
with 45 µg of HA derived from each of four influenza virus strains recommended for the 2018/2019. 
• 2018/2019 and 2019/2020 Fluzone QIVs are formulated to contain 60 µg of HA per 0.5 mL dose with 
15 µg of HA from each of the four influenza virus strains.  
• Each 0.25mL dose of AF03 that will be administered admixed with vaccine contains approximately 
12.5 mg of squalene 
• Each Advax-CpG55.2 adjuvant will be made of two components Advax (delta inulin) and CpG55.2. 
Each 2.0 mL vial contains 0.5 mL of a 50 mg/mL suspension of delta inulin in phosphate buffered 
saline and 0.5 mL of a 2 mg/mL solution of CpG55.2. 


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4.4.5. 
Selection and Timing of Dose for Each Subject 
Each subject is to be randomly assigned to a study group which will define the type and dose of 2018/2019 
QIV and adjuvant that they will receive. The first vaccination takes place on the day of randomization. On 
approximately Day 90 after the first vaccination (protocol defined window of Day 90 +/- 14 days post first 
vaccination), each subject will receive a single dose of the seasonal 2019/2020 influenza vaccine. This dosing 
interval was selected so receipt of the 2019/2020 dose would fall within the recommended timeframe for 
season vaccination.  
4.4.6. 
Blinding 
This trial is double-blinded; subjects, investigators, study personnel performing any study-related assessments 
following study vaccine administration, and laboratory personnel performing antibody assays are blinded to 
dosage within study vaccination schedule. 
The randomization scheme was generated by the SDCC and provided to unblinded study personnel (i.e., 
pharmacists performing study vaccination preparations and unblinded study vaccine administrators) at the 
participating VTEU sites who will not be involved in study-related assessments or have subject contact for 
data collection following study vaccine administration. 
The Data and Safety Monitoring Board (DSMB) may receive data in aggregate and presented by group. The 
DSMB may also be provided with expected and observed rates of the expected AEs in an unblinded fashion 
and may request treatment assignment be unblinded for an individual subject if required for safety assessment. 
The DSMB will review grouped and unblinded data in the closed session only. 
4.4.7. 
Prior and Concomitant Therapy  
Administration of any medications, therapies, or vaccines (including prescription and over-the-counter drugs 
as well as herbals, vitamins, and supplements) from 60 days prior to study vaccination through 21 days post 
final vaccination will be solicited from the participant during screening, enrollment, and follow-up. Any 
reported prior therapies from up to 30 days prior to vaccination through 28 days post first study vaccination 
will be recorded in the appropriate data collection form.  
Use of concomitant medications is allowed prior to and during the trial with the exception of medications and 
therapies that might interfere with the evaluation of the investigational product. Medications in this category 
include the prohibited medication per the Subject Exclusion Criteria (protocol Section 5.1.2). In addition, the 
site principal investigator or appropriate sub-investigator may identify other medications that should not be 
used due to a risk to subject safety or assessment of reactogenicity and immunogenicity. 
4.4.8. 
Treatment Compliance 
All subjects were to receive two doses of study product administered in the clinic. 
4.5. 
Efficacy (Immunogenicity) and Safety Variables 
See Table 2 for schedule of study procedures. 
 
 


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4.5.1. 
Safety Variables 
Safety will be assessed by the frequency and severity of: 
1. SAEs occurring from the time of the first study vaccination through approximately 12 months after the 
first study vaccination. 
2. Solicited AEs – reactogenicity events occurring from the time of study vaccination through 
approximately Day 8 after the first study vaccination. 
a. Injection site reactions including pruritus, ecchymosis, erythema, induration/swelling, edema, pain, 
and tenderness. 
b. Systemic reactions including fever, feverishness, fatigue, malaise, myalgia, arthralgia, headache, 
and nausea. 
3. Clinical safety laboratory AEs occurring from the time of the first study vaccination through 
approximately Day 8 after the first study vaccination. Parameters to be evaluated include white blood 
cells (WBC), hemoglobin (Hgb), platelets (PLT), alanine aminotransferase (ALT), total bilirubin (T. 
Bili), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase 
(ALP) serum lipase and serum amylase and creatinine (Cr). 
4. Unsolicited AEs – non-serious AEs occurring from the time of the first study vaccination through 
approximately Day 29 after the first study vaccination. 
5. All protocol specified AESIs, MAAEs, NOCMCs and PIMMCs, from the time of the first study 
vaccination through approximately 12 months following the first. 
Grading scales for injection site and systemic solicited reactions, vital signs, and clinical laboratory 
parameters are provided in Table 7, Table 8, Table 9, and Table 10. 
4.5.2. 
Immunogenicity Variables 
Individual HAI assay results against the 2018/2019 QIV strains, 2019/2020 QIV strains, and heterologous H3 
influenza strains (A/Kenya/105/2017 [H3N2], A/Louisiana/13/2017 [H3N2], A/Aksaray/4048/2016 [H3N2], 
A/Shandonglaicheng/1763/2016 [H3N2], and A/Michigan/84/2016 [H3N2]) will be performed at Q2 Solution 
laboratory under the responsibility of GCI and results will be reported by GCI. 
Individual Neut assay results will be performed and reported by Global Clinical Immunology (GCI) lab at 
Sanofi Pasteur laboratory for the 2018/2019 QIV strains, 2019/2020 QIV strains, and heterologous H3 
influenza strains (A/Kenya/105/2017 [H3N2], A/Louisiana/13/2017 [H3N2], A/Aksaray/4048/2016 [H3N2], 
A/Shandonglaicheng/1763/2016 [H3N2], and A/Michigan/84/2016 [H3N2]).  
Individual NAI results against the 2019/2020 QIV strains, 2018/2019 QIV strains, and heterologous N1 and 
N2 NA antigens (A/OMAN/5532/2017, A/CAMEROON/9766/2017, A/Human/Hubei/3/2005, 
A/LOUISIANA/13/2017, A/TOWNSVILLE/51/2016, A/AKSARAY/4048/2016) will performed by Q2 
Solution laboratory under the responsibility of GCI and the data will be reported by GCI.  
HAI, NAI, and Neut assay results are reported as a reciprocal titer with values of 10*2k, where k=0, 1, 2, etc. 
The lower limit of detection for the HAI, NAI and Neut assays is 1:10; values below the limit of detection are 
reported as ‘<10’, and for analysis are imputed as one-half the limit of detection (10/2 = 5). The upper limit of 
quantitation (ULOQ) varies by assay and strain. Values above the upper limit of quantitation will be reported 
as ‘>=ULOQ’, and for analysis are imputed as the upper limit of quantitation (ULOQ). HAI, NAI, and Neut 


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assays will be done in duplicates. Both titers will be reported for the HAI and NAI assays, but only one 
Geometric Mean Titer (GMT) will be reported for Neut assay. For analysis of HAI and NAI, the geometric 
mean (calculated on natural log scale) of repeated results for each sample will be computed and used as the 
response for all subsequent calculations. The variation arising from multiple measurements for an individual 
at a single time point is not used in subsequent calculations. See Section 3.2 for definitions of derived 
variables for the analysis of HAI, NAI, and Neut data. 
Influenza-specific IgG, IgM, and IgA memory B cells using Multiplex FluoroSpot assay will be performed by 
Caprion Biosciences Inc. These assay results are reported as Spot Forming Cells (SCF) per million PBMC. 
Two or three replicated will be reported. 
Influenza specific plasmablasts using multiparametric flow cytometry will be reported by SP-VaxDesign. The 
results will be measured in "Arbitrary Units/ml" against serum standard curve. One or two replicates will be 
provided.  
Influenza specific Tfh cells using multiparametric flow cytometry will be reported by SP-VaxDesign. Percent 
Tfh and number of Tfh will be reported, and one or two replicates will be provided.  
Functional non-neutralizing Fc-effector results will be reported by SeromYx Inc. 
Assay results for quantification of HA binding antibodies against different influenza H3 strains obtained by 
Antibody Forensic Technology using multiplex ELISA and NA binding antibodies against different influenza 
NA antigens from ELISA will be reported by Sanofi Pasteur FluNXT Immunology laboratory. No repeats will 
be performed; one result will be reported.   
All immunogenicity data will be uploaded into the SDCC’s electronic data capture system. 
 


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5. 
SAMPLE SIZE CONSIDERATIONS 
This study is planned to enroll a total of 40 subjects in each group. This study is not designed to test a formal 
null hypothesis. Rather, it is intended to obtain sufficient data to obtain meaningful estimates of the immune 
response and to uncover any safety issues that occur at a sufficiently high rate that they might be observed in a 
study of this size. As such, the type one error rate, alpha = 0.05, is not adjusted for multiple comparisons. 
While this study is not designed to test any specific null hypothesis, the following tables illustrate the 
precision and power that is available for select estimates and comparisons of interest. 
Table 3 indicates the probability of observing one or more safety events, such as solicited injection site or 
systemic reactogenicity events or an unsolicited non-serious AE of a particular type for sentinel subjects (N=4 
or 6), for a single adjuvanted/ unadjuvanted study arm/stratum (N = 40 or 60), for all subjects receiving the 
same seasonal QIV (N= 120), for all subjects in the trial (N=240). 
Binomial confidence intervals (CI) are widest (have the least precision) when the response rate is 50%. 
Table 4 is presented to indicate the worst-case scenario for precision of observed exact (Clopper-Pearson) 
binomial confidence intervals. 
Table 5 illustrates the minimum detectable differences in the proportion of subjects responding (e.g., attaining 
seroconversion or a titer ≥1:40) between two adjuvanted study arms using a two-sided Likelihood Ratio Test 
and alpha = 0.05. 
 


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
Unless otherwise specified, all continuous variables will be summarized using the following descriptive 
statistics: n (non-missing sample size), mean, standard deviation, median, maximum and minimum. The 
frequency and percentages (based on the non-missing sample size) of observed levels will be reported for all 
categorical measures. In general, all data will be listed, sorted by treatment and subject, and when appropriate 
by visit number within subject. All summary tables will be structured with a column for each study arm in the 
following order: 
• Group 1: Fluzone 
• Group 2: Fluzone + AF03 
• Group 3: Fluzone + Advax-CpG 
• Group 4: Flublok 
• Group 5: Flublok + AF03 
• Group 6: Flublok + Advax-CpG 
All tables will be annotated with the total population size relevant to that table/treatment, including any 
missing observations. 
6.2. 
Timing of Analyses 
6.2.1. 
Expedited Report  
Clinical, safety, and reactogenicity data through approximately 56 days after study vaccination will represent 
the interim clinical database for this trial. Once the last subject completes the visit that occurs approximately 
56 days after first study vaccination, the interim clinical database will be cleaned, monitored, and locked. 
Upon receipt of immunogenicity data for Day 1 and Day 29 (HAI, NAI, and Neut against 2018/2019 QIV 
strains and heterologous strains) and safety data through Day 57, the sponsor will authorize the SDCC to 
transfer to Sanofi Pasteur a copy of this unblinded data set. An Expedited Report containing analyses of safety 
data through Day 57 and HAI, NAI, and Neut data for 2018/2019 QIV strains from baseline (Day 1) and Day 
29 unblinded by study arm only will be prepared by the SDCC. These analyses may be made available to the 
sponsor and pharmaceutical partners for planning subsequent trials as well as to the DSMB for review. 
The analyses performed for the Expedited Report or using the data set provided to Sanofi Pasteur will not be 
used to make any decisions concerning the conduct of this trial. As it is anticipated that subjects will remain in 
long term safety follow-up at the time of these analyses, blinded investigators and DMID medical monitors 
not involved in the analysis, publication, or Expedited Report preparation will be responsible for assessing 
SAEs and AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) until all subjects 
have completed the final follow-up visit. 
Tables to be included in the Expedited Report are indicated with the symbol * in the title in Appendix 1. 
 


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6.2.2. 
Clinical Study Report  
The final CSR will be completed after the last subject’s last visit is completed, and the final clinical database 
including all long-term safety follow-up data is cleaned, monitored and locked, and all primary and secondary 
immunogenicity data are available. After such data are reported in the database and the data are considered 
clean and complete, a “topline” subset of the immunogenicity tables planned for the CSR will be provided 
to DMID and Sanofi Pasteur. These tables are indicated with a ¥ symbol after the  title in the appendix.  
Analysis of exploratory immunogenicity endpoints may be performed and released as the data are available 
from the research laboratory. Any such analyses would be considered the final analysis for the endpoint and 
included in the CSR. Additional exploratory immunogenicity endpoint data not available at the time of CSR 
preparation may be included in an addendum to the CSR, manuscript(s), or other report. 
6.3. 
Analysis Populations 
6.3.1. 
Safety Population 
The Safety Analysis population includes all subjects who received the first study vaccination. For all safety 
analyses subjects will be grouped based on actual vaccination(s) received. 
6.3.2. 
Modified Intention-to-Treat (mITT) Population 
The modified intent-to-treat (mITT) population includes all randomized subjects who received the first study 
vaccination and contributed at least one post-first study vaccination venous blood samples for 
immunogenicity testing (HAI, NAI or Neut antibody assays) for which valid results were reported. For 
analyses using the mITT population, subjects will be grouped based on randomized study arm. 
6.3.3. 
Per Protocol Population 
The per protocol (PP) population includes all subjects in the mITT with the following 
exclusions: 
• 
Data from all available visits for subjects found to be ineligible at baseline. 
• 
Data from all visits for subjects that did not contribute venous blood samples for immunogenicity testing 
(HAI, NAI or Neut antibody assays) at baseline (Day 1). 
• 
Data from all visits subsequent to major protocol deviations or events, in the opinion of the principal 
investigator and DMID scientific lead, expected to impact immune response such as:  
o Receipt of non-study licensed live vaccine within 30 days before or after study vaccination, 
o Receipt of non-study licensed inactivated vaccine within 14 days before or after study 
vaccination, 
o Receipt of immunosuppressive therapy (e.g., corticosteroids) within 30 days before or after 
the first study vaccination. 
• Data from any visit that occurs out of window by more than one day: 
o Visit 2 data collected before Day 2 or after Day 4 post study vaccination. 
o Visit 3 data collected before Day 6 or after Day 10 post study vaccination. 
o Visit 4 data collected before Day 26 or after Day 32 post study vaccination. 


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o Visit 5 data collected before Day 53 or after Day 61 post study vaccination 
o Visit 6 data collected before Day 75 or after Day 105 post study vaccination. 
o Visit 7 data collected before Day 114 or after Day 122 post study vaccination. 
o Visit 8 data collected before Day 165 or after Day 195 post study vaccination. 
o Visit 9 data collected before Day 350 or after Day 401 post study vaccination. 
For analyses using the PP population, subjects will be grouped based on study vaccinations received. 
6.4. 
Covariates and Subgroups 
This protocol defines a subgroup analysis to summarize HAI, NAI, and Neut antibody titers against vaccine 
strains by baseline seropositive status and previous vaccination by seasonal influenza vaccine as defined for 
stratification (Either 2017-2018 or 2018-2019, Neither 2017-2018 or 2018-2019). As this study is not 
adequately powered to perform subgroup analyses, these subgroup analyses will be used for exploratory 
purposes only. 
6.5. 
Missing Data 
All attempts will be made to collect all data per protocol. As missing data are expected to be minimal, no 
imputation will be performed for missing values. Any data point that appears to be erroneous or inexplicable 
based on clinical judgment will be investigated as a possible outlier. If data points are identified as outliers, 
sensitivity analyses will be performed to examine the impact of including or excluding the outliers. Any such 
analysis will be reported and substantive differences will be described. 
6.6. 
Interim Analyses and Data Monitoring 
Interim analyses will only be used to terminate this trial in the event that unanticipated safety events deemed 
to be of sufficient concern require such action by the sponsor. These assessments will not be made on the 
basis of testing a formal statistical hypothesis; therefore, p-value adjustment will not be made to any analyses. 
A DSMB will be convened by DMID to review study progress and participant, clinical, safety, and 
reactogenicity and immunogenicity data. 
An expedited report of safety data through Day 57 and HAI, NAI, and Neut data against 2018/2019 QIV 
strains and heterologous strains from baseline (Day 1) and Day 29 unblinded by study arm will be prepared in 
Section 6.2.1; though this report will be released while subjects remain in the trial for long-term safety and 
immunogenicity follow-up, it will be considered the final analysis of these data.  
Emergent public health needs may dictate additional interim safety, reactogenicity, and/or immunogenicity 
analyses be performed on available information at any time during the trial. If this occurs, immunogenicity 
data will be analyzed as results are available from the central immunogenicity laboratory. 
6.6.1. 
Interim Safety Review 
An interim safety review may include enrollment and demographic information, medical history, concomitant 
medications, physical assessments, clinical laboratory values, dosing compliance, and solicited and 
unsolicited AE/SAEs. Additional data may be requested by the DSMB, and interim statistical reports may be 
generated as deemed necessary and appropriate by DMID. The DSMB may receive data in aggregate and 
presented by study arm, including expected and observed rates of the expected AEs. The DSMB will review 


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grouped data in the closed session only. The DSMB will meet and review this data at scheduled time points or 
ad hoc as needed during this trial as defined in the DSMB charter. As an outcome of each review/meeting,  
the DSMB will make a recommendation as to the advisability of proceeding with study vaccinations (as 
applicable), and to continue, modify, or terminate this trial. 
Additionally, this trial will be monitored to determine if any of the halting rules described in Section 9.5 of 
the protocol are met. 
6.6.2. 
Interim Immunogenicity Review 
There is no plan to halt this trial prior to full enrollment and completion of all follow-up visits based on 
interim immunogenicity results. An Expedited Interim Immunogenicity Report of HAI, NAI, and Neut serum 
antibody responses will be generated as described in Section 6.2. 
Immune responses will be summarized in terms of strain-specific 2018/2019 QIV HAI, NAI, and Neut 
antibody titers and the relationship to study arm. All analyses will be carried out in parallel for all assays and 
provided in the expedited report. Interim analyses will focus on rates of titers ≥1:40, seroconversion (see 
definition in Section 3.2), GMFRs, and GMTs, along with corresponding 95% confidence intervals. No 
formal hypothesis testing will be included in the interim analysis. All interim analyses will use the mITT 
population. 
Tables to be included in in the Expedited Report are indicated with the symbol * in the title. These include 
Table 21, Table 22, Table 23, Table 24, Table 25, Table 26, Table 27, and Table 28 for HAI antibodies 
against 2018/2019 QIV strains; Table 29, Table 30, Table 31, Table 32, Table 33, Table 34, Table 35, and 
Table 36 for Neut antibodies against 2018/2019 QIV strains; Table 55, Table 56, Table 57, Table 58, 
Table 59, Table 60, Table 61, and Table 62 for NAI antibodies against 2018/2019 QIV strains presenting 
summaries and 95% CIs by study arm. Additionally, HAI, NAI, and Neut results against heterologous strains 
will be presented starting with Table 81 and ending with Table 110. 
6.7. 
Multicenter Studies 
Randomization was stratified by site, but data will be pooled across all clinical sites for all analyses. Center 
effects are not anticipated because the sites use standardized procedures for vaccination and assessment of 
solicited and unsolicited AEs, and the study relies on a central laboratory for immunogenicity assessments. 
6.8. 
Multiple Comparisons/Multiplicity 
This study was designed to obtain preliminary estimates of safety and immune response to 2018/2019 Fluzone 
and Flublok vaccines with or without AF03 or Advax-CpG55.2 adjuvants in healthy adults. The study was not 
designed to test any specific null hypothesis, and as such no adjustment for multiple comparisons will be 
performed. 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
Table 11 will present a summary of the reasons that subjects were screened but not enrolled. 
The number and percentage of enrolled subjects excluded from each analysis population by study arm are 
presented in Table 12. A listing of subjects excluded from each analysis population will be presented in 
Listing 5.  
The disposition of subjects in the study will be tabulated by study arm (Table 13). The table will show the 
total number of subjects screened, randomized, receiving the first study vaccination, receiving the second 
study vaccination, completing the blood draw for the primary immunogenicity endpoints, and completing the 
last visit. 
A flowchart showing the disposition of study subjects, adapted from the CONSORT Statement [2] will be 
included and will present the number of subjects screened, randomized, lost to follow up, and analyzed, by 
study arm (Figure 1). 
A listing of subjects who were discontinued from treatment or terminated from study follow-up and the reason 
will be included in Listing 2. 
7.2. 
Protocol Deviations 
A summary of subject-specific protocol deviations will be presented by the deviation category and deviation 
type, and study arm for all enrolled subjects (Table 6). Major deviations that will be reviewed for possible 
exclusion of immunogenicity results from the PP population including deviations related to eligibility/ 
enrollment, treatment administration schedule, follow-up visit schedule, and receipt of exclusionary vaccines 
or medications. All subject-specific protocol deviations and non-subject-specific protocol deviations will be 
included in Listing 3 and Listing 4. 


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8. 
IMMUNOGENICITY EVALUATION 
Immunogenicity data summaries and analysis for primary and secondary endpoints will be presented for the 
mITT and PP populations. Immune responses in terms of strain-specific 2018/2019, 2019/2020 QIV HAI, 
NAI, and Neut antibody titers will be summarized by study arm at each time point. Descriptive summary 
statistics will be provided for all assays and time points including number of subjects with non-missing 
results, percentage of subjects with titers ≥1:40 for HAI and Neut only, percentage of subjects achieving 
seroconversion, GMTs along with corresponding 95% CI, and GMFRs along with corresponding 95% CI. 
Exact confidence intervals using the Clopper Pearson method will be presented for proportional endpoints. 
Ratios of GMTs along with their 95% CIs between adjuvanted and unadjuvanted groups will be presented at 
each timepoint. Confidence intervals using the Delta Method will be provided for the ratio of GMTs. 
Individual HAI, NAI, and Neut assay results will be provided in Listing 9, Listing 10, and Listing 11. 
Individual exploratory assay results will be provided in Listing 12, Listing 13, and Listing 14 for memory B 
cells, Listing 15 for Tfh cells, Listing 16 for plasmablasts, Listing 17 for neutralizing fc-effector, Listing 18 
for antibody forensics, and Listing 19 for NA ELISA. 
8.1. 
Primary Immunogenicity Analysis 
The primary immunogenicity endpoints HAI, Neut and NAI seroconversion, percentage of subjects with titer 
≥1:40 for HAI and Neut only, GMTs, ratios of GMTs between adjuvanted and unadjuvanted groups, and 
GMFRs against the 2018/2019 QIV strains 28 days after study vaccination (Day 29) will be summarized as 
described above. The primary analysis population will be mITT, with results from the PP population 
providing a comparison of the sensitivity of immunogenicity results to subject adherence to protocol-defined 
conditions.  
Summaries of primary immunogenicity endpoints are presented for the 2018/2019 QIV strains in Table 21, 
Table 22, Table 23, Table 24, Table 25, Table 26, Table 27, and Table 28 for HAI, Table 29, Table 30, 
Table 31, Table 32, Table 33, Table 34, Table 35, and Table 36 for Neut, and Table 53, Table 54, Table 55, 
Table 56, Table 57, Table 58, Table 59, and Table 60 for NAI. 
8.2. 
Secondary Immunogenicity Analyses 
The secondary immunogenicity endpoints HAI, Neut and NAI seroconversion, percentage of subjects with 
titer ≥ 1:40 for HAI, GMFRs, GMTs, and ratios of GMTs (between adjuvanted group and unadjuvanted) 
against the 2019/2020 QIV strains 28 days after vaccination with the 2019/2020 QIV (Day 118) will be 
summarized as described above. HAI and Neut seroconversion, percentage of subjects with HAI titers ≥ 1:40, 
GMFRs, GMTs, and ratios of GMTs for HAI and Neut against heterologous influenza A/H3 strains on 
approximately Days 8, 29, 57, 90, and 118 after study vaccination with the 2018/2019 QIV will be also 
presented. HAI, Neut and NAI seroconversion, percentage of subjects with HAI and Neut titers ≥1:40, and 
GMTs against the 2018/2019 QIV strains on approximately Days 8, 29, 57, 90, and 118 after study 
vaccination will be presented. HAI, Neut, and NAI GMFRs against the 2018/2019 QIV strains on 
approximately Day 57 and Day 90 will also be presented. NAI seroconversion, NAI GMTs and ratios of NAI 
GMTs against heterologous N1 and N2 NA antigens will also be assessed on approximately Days 8, 29, 57, 
90, and 118 for study groups 1, 2 and 3. No formal hypothesis testing is planned. 
 
 


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Secondary summaries for the 2019/2020 QIV strains are provided in Table 69, Table 70, Table 71, Table 72, 
Table 73, Table 74, Table 75, Table 76, Table 77, Table 78, Table 79, and Table 80. Summaries of HAI, and 
Neut against heterologous H3 Influenza strains for both mITT and PP populations will also be provided in 
Table 81, Table 82, Table 83, Table 84, Table 85, Table 86, Table 87, Table 88, Table 89, and Table 90 for 
HAI, and Table 91, Table 92, Table 93, Table 94, Table 95, Table 96, Table 97, and Table 98 for Neut. 
Summaries of NAI against heterologous N1 and N2 antigens will be presented in Table 99, Table 100, Table 
101, Table 102, Table 103, Table 104, Table 105, Table 106, Table 107, Table 108, Table 109, and Table 110. 
Reverse cumulative distribution (RCD) curves will be presented for baseline and post-vaccination HAI, Neut 
and NAI antibody titers against 2018/2019 and 2019/2020 QIV strains, HAI and Neut antibody titers against 
heterologous influenza A/H3 strains, and NAI antibody titers against heterologous N1 and N2 NA antigens. 
Plots for titers HAI, Neut, and NAI titers against the 2018/2019 QIV strains will be generated with eight 
panels (Day 1 (Baseline), Day 8, Day 29, Day 57, Day 90, and Day 118), and separate curves within each 
panel for each study arm, as shown beginning with Figure 2, and ending with Figure 25. RCD curves for HAI, 
Neut, and NAI against the 2019/2020 QIV strains will be generated with four panels (Day 90 (Baseline) and 
Day 118) and be presented starting with Figure 26, and ending with Figure 49. In a similar manner, RCD 
curves of HAI titers against heterologous influenza A/H3 strains will be presented in Figure 50, Figure 51, 
Figure 52, Figure 53, Figure 54, Figure 55, Figure 56, Figure 57, Figure 58, and Figure 59, and those for Neut 
titers against heterologous influenza A/H3 strains in Figure 60, Figure 61, Figure 62, Figure 63, Figure 64, 
Figure 65, Figure 66, Figure 67, Figure 68, and Figure 69 for Neut. RCD curves of NAI titers against 
heterologous N1 and N2 NA antigens will be presented in Figure 70, Figure 71, Figure 72, Figure 73, 
Figure 74, Figure 75, Figure 76, Figure 77, Figure 78, Figure 79, Figure 80, and Figure 81. 
Geometric Mean Titers of HAI, Neut, and HAI against 2018/2019 QIV strains by study day and study arm 
will be plotted in Figure 82, Figure 83, Figure 84, Figure 85, Figure 86, and Figure 87. 
8.3. 
Exploratory Immunogenicity Analyses 
The exploratory immunogenicity endpoints HAI, Neut and NAI seroconversion, percentage of subjects with 
titer ≥ 1:40 for HAI, GMFRs, GMTs, and ratios of GMTs (between adjuvanted group and unadjuvanted) 
against the 2019/2020 QIV strains 28 days after vaccination with the 2019/2020 QIV (Day 118) will be 
summarized as described above. HAI and Neut seroconversion, percentage of subjects with HAI titers ≥ 1:40, 
GMFRs, GMTs, and ratios of GMTs for HAI and Neut against heterologous influenza A/H3 strains on 
approximately Days 180 and 365 after study vaccination with the 2018/2019 QIV will be also presented. HAI, 
Neut and NAI seroconversion, percentage of subjects with HAI and Neut titers ≥1:40, and GMTs against the 
2018/2019 QIV strains on approximately Days 180 and 365 after study vaccination will be presented. NAI 
seroconversion, NAI GMTs and ratios of NAI GMTs against heterologous N1 and N2 NA antigens will also 
be assessed on approximately Days 180 and 365 for study groups 1, 2 and 3. No formal hypothesis testing is 
planned. 
Summaries of HAI, and Neut against heterologous H3 Influenza strains for both mITT and PP populations for 
Days 180 and 365 will also be provided in Table 81, Table 82, Table 83, Table 84, Table 85, Table 86, Table 
87, Table 88, Table 89, and Table 90 for HAI, and Table 91, Table 92, Table 93, Table 94, Table 95, Table 
96, Table 97, and Table 98 for Neut. Summaries of NAI against heterologous N1 and N2 antigens for Days 
180 and 365 will be presented in Table 99, Table 100, Table 101, Table 102, Table 103, Table 104, Table 
105, Table 106, Table 107, Table 108, Table 109, and Table 110. 
 


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Reverse cumulative distribution (RCD) curves will be presented for baseline, Day 180, and Day 365 HAI, 
Neut and NAI antibody titers against 2018/2019 and 2019/2020 QIV strains, HAI and Neut antibody titers 
against heterologous influenza A/H3 strains, and NAI antibody titers against heterologous N1 and N2 NA 
antigens. Two panels will be added to figures described in Section 8.2 to add Day 180 and Day 365 
timepoints. 
Immunogenicity data summaries and analysis for the following exploratory endpoints will be presented for 
the PP populations. Immunogenicity results from the subgroup analysis by baseline serostatus for 2018/2019 
QIV strains will be presented in Table 37, Table 38, Table 39, and Table 40 for HAI, Table 41, Table 42, 
Table 43, and Table 44 for Neut, and Table 61, Table 62, Table 63, and Table 64 for NAI. Similarly, 
subgroup results by previous vaccination will be presented in Table 45, Table 46, Table 47, and Table 48 for 
HAI, Table 49, Table 50, Table 51, and Table 52 for Neut, and Table 65, Table 66, Table 67 and Table 68 for 
NAI. Subgroup analysis results for HAI, Neut, and NAI against 2019/2020 QIV strains are presented in Table 
71,Table 72, Table 75, Table 76, Table 79, and Table 80. Summary statistics for influenza specific IgG, IgM, 
and IgA B memory cells will be presented in Table 111, Table 112, and Table 113. Summary statistics 
including the mean, GM, and mean absolute difference for influenza specific plasmablasts and Tfh cells will 
be presented in Table 114, and Table 115, respectively. GMT and GMFRs of functioning non-neutralizing Fc-
effector antibodies Against 2018/2019 QIV Strains will be provided in Table 116. 
Plots for HA and NA binding antibodies against different H3 strains will be presented in Figure 88 and  
Figure 89. 
Association of non-neutralizing Fc-effector antibody titers and HAI antibody titers, HAI seroconversion, and 
HAI seroprotection against 2018/2019 QIV strains are presented in Figure 90, Figure 92, and Figure 94. 
Similar plots are generated for the association of non-neutralizing Fc-effector antibody titers and Neut 
antibody titers, Neut seroconversion, and Neut seroprotection against 2018/2019 QIV strains and presented in 
Figure 91, Figure 93, and Figure 95. 


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9. 
SAFETY EVALUATION 
All summaries and analysis of safety data will be presented for the Safety Analysis Population. Safety 
summaries will be presented overall and grouped by study arm. 
Continuous variables will be summarized using the following descriptive statistics: n (non-missing sample 
size), mean, standard deviation, median, maximum and minimum. All categorical measures will be 
summarized by the frequency and percentages of observed levels will be reported for all categorical measures. 
The denominator for the percentages may be based on the number of non-missing observations for an 
assessment or based on the number of subjects in a population. This will be described for each table. 
9.1. 
Demographic and Other Baseline Characteristics 
Summaries of age, sex, ethnicity, race, BMI, and prior receipt of seasonal influenza vaccine will be presented 
by site (Table 16, Table 17) and by study arm (Table 18, Table 19). Age will be summarized as a continuous 
variable. Ethnicity is categorized as Hispanic or Latino, or not Hispanic and not Latino. In accordance with 
NIH reporting policy, subjects may self-designate as belonging to more than one race or may refuse to 
identify a race, the latter reflected in the electronic case report form (eCRF) as “No” to each racial option. 
BMI will be summarized as a continuous as well as categorical variable, categorized as (<30, ≥30). Self-
reported history of prior receipt of seasonal influenza vaccine will be categorized as follows: Either 2017-
2018 or 2018-2019, Neither 2017-2018 or 2018-2019, or unknown. Demographic information for individual 
subjects will be provided in Listing 6. Subjects’ prior influenza vaccination history (seasonal and non-
seasonal) will be provided in Listing 8. 
9.1.1. 
Prior and Concurrent Medical Conditions 
All current illnesses and past or pre-existing medical conditions will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA®) version 20.0 or higher. 
Summaries of subjects’ prior and concurrent medical conditions will be presented by study arm (Table 20). 
Individual subject listings will be presented for all reported medical history including prior and concurrent 
medical conditions (Listing 7). 
9.1.2. 
 Prior and Concomitant Medications  
Concomitant medications will be coded to the Anatomical Therapeutic Classification using the WHO Drug 
Dictionary. The use of concomitant medications during the study will be summarized by ATC1 and ATC2 
code and study arm for the Safety Population (Table 169). A listing of concomitant medications will be 
presented (Listing 27).  
9.2. 
Measurements of Treatment Compliance 
All subjects are to receive 2 study vaccinations administered in the clinic. The number of subjects receiving 
study vaccination by month will be presented by study arm and by site in Table 14 and Table 15 and as part of 
the subject disposition table (Table 13). Listing 1 presents subjects who received investigational product with 
randomized study arm and study product received for each study vaccination. 


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9.3. 
Adverse Events 
A summary of all adverse events is provided in Table 117. A summary of those events that occurred in ≥5% 
of subjects in any study arm is provided in Table 118.  
9.3.1. 
Solicited Events and Symptoms 
Systemic solicited adverse events were collected pre-vaccination, and systemic and local solicited adverse 
events were collected at-least 20 minutes post-vaccination and then daily for 7 days after the first study 
vaccination and graded on a scale of 0 (none), 1 (mild), 2 (moderate) and 3 (severe). Systemic events include 
fever, feverishness, fatigue, malaise, myalgia, arthralgia, headache, and nausea. Local events include pruritus, 
ecchymosis, erythema, induration/swelling, pain, and tenderness. Ecchymosis, erythema, and induration are 
measured by both functional and measurement grading scales as defined in Table 7. The grading scale for 
systemic events, including quantitative grading for fever, is included in Table 8. 
When calculating the incidence of solicited events, each subject will be counted once at the highest severity 
following the applicable vaccination, and any repetitions will be ignored. For summaries presented for the 
first study vaccination, the denominator for percentages will be the number of subjects who received the first 
study vaccination with non-missing data for the event summarized.  
The number and percentage of subjects reporting at least one solicited adverse event of each severity will be 
summarized for each solicited symptom, any systemic symptom, any local symptom, and any symptoms. For 
each event the denominator is the number of subjects who received the first study vaccination with non-
missing data for the specific event. The 95% CI calculated using Clopper-Pearson methodology from a 
binomial distribution (SAS Proc Freq with a binomial option) will be presented (Table 119). Logistic 
regression models will be fit to estimate the effect of study arm on the probability of reporting any local event 
or reporting any systemic event (Table 120, Table 121). If statistically significant effects are observed in the 
model for local events or systemic events, then additional models may be fit for each individual event of that 
type. 
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙[𝑃𝑃(𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸)] =  𝛽𝛽0 + 𝛽𝛽1 × 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇+ 𝜀𝜀, 
For each systemic and local event, any systemic event, any local event, and any solicited event, the maximum 
severity over 7 days after the first study vaccination will be summarized for the Safety Population. The 
number and percentage of subjects reporting each event will be summarized by the maximum severity and 
study arm. For each event the denominator is the number of subjects who received the first study vaccination 
with non-missing data for the specific event. The 95% CI calculated using Clopper-Pearson methodology 
from a binomial distribution (SAS Proc Freq with a binomial option) will be presented (Table 122). 
The number of subjects reporting a solicited adverse event will be summarized for each day post the first 
study vaccination combined both in a summary table (Table 123) and graphically in a bar chart (Figure 96 and 
Figure 97).  
Systemic and Local solicited events reported by subject will be presented in Listing 20 and Listing 21, sorted 
by subject ID, vaccination number, parameter, and study day. 
9.3.2. 
Unsolicited Adverse Events 
When calculating the incidence of unsolicited AEs (i.e., on a per subject basis), each subject will only be 
counted once at the highest severity and/or relationship, and any repetitions of AEs within a subject will be 


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ignored; the denominator will be the total number of subjects in the safety population. All AEs reported will 
be included in the summaries and analyses. 
A summary of all unsolicited adverse events by MedDRA SOC, PT, and study arm that occurred from Day 1 
to Day 365 is provided in Table 124. Similarly, a summary of all unsolicited adverse events by MedDRA 
SOC, PT, and study arm that occurred from Day 1 to Day 29 is provided in Table 125. 
The number and percentage of subjects reporting at least one unsolicited AE will be summarized by MedDRA 
system organ class and preferred term. A 95% CI will be presented for the percentage of subjects reporting 
any unsolicited AE (serious or non-serious) for each MedDRA system organ class and preferred term over all 
study vaccinations (Table 126). A similar table summarizing all unsolicited events from Day 1 to Day 29 will 
be provided (Table 127).  
The following summaries for unsolicited AEs will be presented by MedDRA system organ class, preferred 
term, and study arm: 
• Incidence of AEs by severity and relationship to study product (Table 128); 
• Incidence of AEs from Day 1 to Day 29 by severity and relationship to study product (Table 129); 
• Incidence of non-serious, related AEs by severity (Table 130); 
• Incidence of AEs over time (Days 1-8, Days 9-29 post first study vaccination) (Table 131); 
• Incidence of non-serious, related AEs over time (Days 1-8, Days 9-29 post first study vaccination) 
(Table 132)  
• Total frequency of AEs over time (Days 1-8, Days 9-29 post first study vaccination) (Table 133); 
• Subject listing of non-serious AEs of moderate or greater severity (Table 138);  
• Bar chart displaying total frequency of AEs by severity and MedDRA system organ class and study arm 
(Figure 98); 
• Bar chart displaying incidence of AEs by severity and MedDRA system organ class, and study arm 
(Figure 99); 
• Bar chart displaying total frequency and incidence of AEs by relationship to study product, MedDRA 
system organ class, and study arm (Figure 100 and Figure 101). 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
 The following listings will be presented including Subject ID, Age (years) AE Description, AE Onset 
Date/End Date, Last Vaccination Received/Days Post Vaccination, Reason Reported as an SAE, Relationship 
to Study Product, Alternate Etiology if not Related, Outcome, and Duration of Event (days): 
• Deaths and Serious Adverse Events (Table 134); 
• Adverse Events of Special Interest (Table 135); 
• Potentially Immune Mediated Medical Conditions (Table 136); 


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• New Onset Chronic Medical Conditions (Table 137). 
A listing of all reported AEs by subject will be presented in Listing 22, sorted by Study Arm, Subject ID, and 
AE Number. 
9.5. 
Pregnancies 
For any subjects in the Safety Population who became pregnant during the study, every attempt will be made 
to follow these subjects to completion of pregnancy to document the outcome, including information 
regarding any complications with pregnancy and/or delivery.  
Listing 28, Listing 29, Listing 30, Listing 31, and Listing 32 will present any study pregnancies and their 
outcomes. 
9.6. 
Clinical Laboratory Evaluations 
Clinical safety laboratory parameters (WBC, Hgb, PLT, ALT, AST, T. Bili, GGT, ALP, Amylase, Lipase, Cr) 
will be collected from each subject prior to the first study vaccination and approximately 7 days the first study 
vaccination. These evaluations will be performed by the central clinical laboratory. The grading scale for 
clinical laboratory evaluations is presented in Table 10. Clinical laboratory evaluations assessed on Day 1 
prior to the first study vaccination will be considered as baseline. 
The distribution of laboratory results by severity, study day and study arm will be presented starting with 
Table 139 and ending with Table 150. Descriptive statistics including mean, standard deviation, median, 
minimum and maximum values and change from baseline by study day will be summarized for each 
parameter starting with Table 151 and ending with Table 161. Box plots illustrating the change from baseline 
for each laboratory parameter will be presented starting with Figure 102 and ending with Figure 112. Subject 
visits with abnormal laboratory results, Grade 1 severity or higher, will be presented in Table 162 and 
Table 163 for Chemistry and Hematology parameters, respectively. 
A complete listing of individual clinical laboratory results will be presented in Listing 23 and Listing 24 for 
chemistry and hematology, respectively, sorted by subject ID, parameter, and visit number. 
9.7. 
Vital Signs and Physical Evaluations 
Vital signs oral temperature, systolic blood pressure, diastolic blood pressure, and pulse will be assessed prior 
to study vaccination on Day 1. The grading scale for vital sign evaluations is presented in Table 9. Summaries 
of vital signs by maximum severity will be tabulated by visit, and study arm (Table 164, Table 165, Table 166 
, Table 167, Table 168). A listing of vital signs will be presented (Listing 25). 
Targeted physical examinations will be performed, if indicated, based a subject’s medical history. A listing of 
physical exam findings will be presented (Listing 26). 
9.8. 
Concomitant Medications 
Concomitant medications will be collected for the 30 days prior to the first study vaccination through 28 days 
after the first study vaccination. Concomitant medications will be coded to the Anatomical Therapeutic 
Classification using the WHO Drug Dictionary. The use of prior and concomitant medications taken during 
the study will be recorded on the CRFs. A by-subject listing of concomitant medication use will be presented 


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(Listing 27). The use of concomitant medications during the study will be summarized by ATC1, ATC2 code, 
and study arm for the Safety Population (Table 169). 


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10. 
REPORTING CONVENTIONS 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”; p-values greater than 0.999 will be reported as “> 0.999“. The mean, standard deviation, and any 
other statistics other than quantiles, will be reported to one decimal place greater than the original data. 
Quantiles, such as median, or minimum and maximum will use the same number of decimal places as the 
original data. Proportions will be presented as two decimal places; values <0.01 will be presented as “<0.01”. 
Percentages will be reported to the nearest whole number; non-zero values < 1% will be presented as “<1”; 
values greater than 99% but less than 100% will be presented as >99. Estimated parameters, not on the same 
scale as raw observations (e.g. regression coefficients) will be reported to 3 significant figures.  
 


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11. 
TECHNICAL DETAILS 
SAS version 9.4 or above will be used to generate all tables, figures and listings. 


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12. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
This SAP includes one change from the analyses described in the protocol. Logistic regression will be used 
instead of the Chi-Square or Fisher’s exact test to model the relationship of treatment with reporting any local 
or systemic events post vaccination. Besides providing the strength of the association between the treatment 
and probability of reporting any local or systemic event in terms of odds ratio, logistic regression also 
provides a prediction model for the probability of a local or solicited event occurring given the subject’s study 
arm. Version 3.0 of the SAP includes moving Day 180 and Day 365 immunogenicity endpoints from 
secondary to exploratory endpoints and the addition of a topline report. 
 


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13. 
REFERENCES 
 
1. FDA Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated 
Influenza Vaccines (US DHHS, FDA, CBER, May 2007). 
2. Drummond R. CONSORT Revised: Improving the Reporting of Randomized Clinical Trials. 
JAMA. 2001; 285(15):2006-2007. 
 


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14. 
LISTING OF TABLES, FIGURES, AND LISTINGS  
Table, figure, and listing shells are presented in Appendices 1, 2, and 3. 
 


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APPENDICES 


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APPENDIX 1. TABLE MOCK-UPS 
 
 


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LIST OF TABLES 
Table 1: 
Study Design .......................................................................................................... 59 
Table 2: 
Schedule of Study Procedures and Evaluations ....................................................... 60 
Table 3: 
Probability (%) to Detect Safety Events .................................................................. 62 
Table 4: 
Precision of Binomial Confidence Intervals ............................................................ 62 
Table 5: 
Minimum Detectable Difference in Proportion Responders with 80% Power .......... 63 
Table 6: 
Distribution of Protocol Deviations by Category, Type, and Study Arm ................. 64 
Table 7: 
Solicited Adverse Event Grading Scale - Local ....................................................... 67 
Table 8: 
Solicited Adverse Event Grading Scale – Systemic ................................................. 68 
Table 9: 
Vital Signs Adverse Event Grading Scale ............................................................... 70 
Table 10: Laboratory Adverse Event Grading Scale ............................................................... 71 
Table 11: Ineligibility Summary of Screen Failures ................................................................ 72 
Table 12: Exclusions from Analysis Populations by Study Arm – All Enrolled 
Subjects* ................................................................................................................ 73 
Table 13: Subject Disposition by Study Arm, All Enrolled Subjects* ..................................... 77 
Table 14: Dates of First Study Vaccination by Site and Study Arm for the Safety 
Analysis Population ................................................................................................ 78 
Table 15: Dates of Second Study Vaccination by Site and Study Arm for the Safety 
Analysis Population ................................................................................................ 78 
Table 16: Summary of Categorical Demographic and Baseline Characteristics by Site, 
All Enrolled Subjects .............................................................................................. 79 
Table 17: Summary of Continuous Demographic and Baseline Characteristics by Site, 
All Enrolled Subjects .............................................................................................. 80 
Table 18: Summary of Categorical Demographic and Baseline Characteristics by 
Study Arm, All Enrolled Subjects* .......................................................................... 81 
Table 19: Summary of Continuous Demographic and Baseline Characteristics by 
Study Arm, All Enrolled Subjects* .......................................................................... 82 
Table 20: Summary of Subjects with Prior or Concurrent Medical Conditions by 
MedDRA System Organ Class and Study Arm, Safety Analysis Population ........... 83 
Table 21: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study 
Arm, Modified Intent-to-Treat Population*¥ ............................................................ 84 
Table 22: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study 
Day and Study Arm, Modified Intent-to-Treat Population*¥ .................................... 87 


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Table 23: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and 
Study Arm, Modified Intent-to-Treat Population*¥ .................................................. 87 
Table 24: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day 
and Study Arm, Modified Intent-to-Treat Population*¥............................................ 87 
Table 25: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study 
Arm, Per Protocol Population*¥ ............................................................................... 87 
Table 26: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study 
Day and Study Arm, Per Protocol Population*¥ ....................................................... 87 
Table 27: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and 
Study Arm, Per Protocol Population*¥ ..................................................................... 87 
Table 28: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day 
and Study Arm, Per Protocol Population*¥ .............................................................. 87 
Table 29: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study Arm, Modified 
Intent-to-Treat Population*¥ .................................................................................... 87 
Table 30: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study Day and 
Study Arm, Modified Intent-to-Treat Population*¥ .................................................. 87 
Table 31: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and Study Arm, 
Modified Intent-to-Treat Population*¥ ..................................................................... 87 
Table 32: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day and Study 
Arm, Modified Intent-to-Treat Population*¥ ............................................................ 87 
Table 33: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study Arm, Per 
Protocol Population*¥ .............................................................................................. 87 
Table 34: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study Day and 
Study Arm, Per Protocol Population*¥ ..................................................................... 87 
Table 35: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and Study Arm, 
Per Protocol Population*¥ ........................................................................................ 88 


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Table 36: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day and Study 
Arm, Per Protocol Population*¥ ............................................................................... 88 
Table 37: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day, Study Arm, 
and Baseline Serostatus, Per Protocol Population .................................................... 89 
Table 38: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study 
Day, Study Arm, and Baseline Serostatus, Per Protocol Population ......................... 93 
Table 39: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day, Study 
Arm, and Baseline Serostatus, Per Protocol Population ........................................... 93 
Table 40: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study 
Day, Study Arm, and Baseline Serostatus, Per Protocol Population ......................... 93 
Table 41: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
A/Michigan/45/2015 X-275 (H1N1) by Study, Study Arm, and Baseline 
Serostatus, Per Protocol Population......................................................................... 93 
Table 42: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study Day, Study 
Arm, and Baseline Serostatus, Per Protocol Population ........................................... 93 
Table 43: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
B/Phuket/3073/2013 (B Yamagata lineage) by Study Day, Study Arm, and 
Baseline Serostatus, Per Protocol Population .......................................................... 93 
Table 44: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day, Study 
Arm, and Baseline Serostatus, Per Protocol Population ........................................... 93 
Table 45: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day, Study Arm, 
and Previous Vaccination, Per Protocol Population ................................................. 94 
Table 46: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study 
Day, Study Arm, and Previous Vaccination, Per Protocol Population ...................... 98 
Table 47: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day, Study 
Arm, and Previous Vaccination, Per Protocol Population ........................................ 98 
Table 48: Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 
QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study 
Day, Study Arm, and Previous Vaccination, Per Protocol Population ...................... 98 


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Table 49: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
A/Michigan/45/2015 X-275 (H1N1) by Study, Study Arm, and Previous 
Vaccination, Per Protocol Population ...................................................................... 98 
Table 50: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study Day, Study 
Arm, and Previous Vaccination, Per Protocol Population ........................................ 98 
Table 51: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
B/Phuket/3073/2013 (B Yamagata lineage) by Study Day, Study Arm, and 
Previous Vaccination, Per Protocol Population ....................................................... 98 
Table 52: Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain 
B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day, Study 
Arm, and Previous Vaccination, Per Protocol Population ........................................ 98 
Table 53: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study Arm, 
Modified Intent-to-Treat Population*¥ ..................................................................... 99 
Table 54: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study Day 
and Study Arm, Modified Intent-to-Treat Population*¥.......................................... 101 
Table 55: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and Study 
Arm, Modified Intent-to-Treat Population*¥ .......................................................... 101 
Table 56: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain B/Colorado/06/2017 (B Victoria lineage) by Study Day and Study 
Arm, Modified Intent-to-Treat Population*¥ .......................................................... 101 
Table 57: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study Arm, 
Per Protocol Population*¥ ...................................................................................... 101 
Table 58: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study Day 
and Study Arm, Per Protocol Population*¥ ............................................................ 101 
Table 59: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and Study 
Arm, Per Protocol Population*¥ ............................................................................. 101 
Table 60: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain B/Colorado/06/2017 (B Victoria lineage) (B Victoria lineage) by 
Study Day and Study Arm, Per Protocol Population*¥ ........................................... 101 
Table 61: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day, Study Arm, and 
Baseline Serostatus, Per Protocol Population ........................................................ 102 


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Table 62: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study Day, 
Study Arm, and Baseline Serostatus, Per Protocol Population ............................... 105 
Table 63: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day, Study Arm, 
and Baseline Serostatus, Per Protocol Population .................................................. 105 
Table 64: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day, 
Study Arm, and Baseline Serostatus, Per Protocol Population ............................... 105 
Table 65: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day, Study Arm, and 
Previous Vaccination, Per Protocol Population ..................................................... 106 
Table 66: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study Day, 
Study Arm, and Previous Vaccination, Per Protocol Population ............................ 109 
Table 67: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day, Study Arm, 
and Previous Vaccination, Per Protocol Population ............................................... 109 
Table 68: Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV 
Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day, 
Study Arm, and Previous Vaccination, Per Protocol Population ............................ 109 
Table 69: Summaries of Hemagglutination Inhibition Antibody Against 2019/2020 
QIV Strains by Study Day and Study Arm, Modified Intent-to-Treat 
Population ............................................................................................................ 110 
Table 70: Summaries of Hemagglutination Inhibition Antibody Against 2019/2020 
QIV Strains by Study Day and Study Arm, Per Protocol Population ..................... 112 
Table 71: Summaries of Hemagglutination Inhibition Antibody Against 2019/2020 
QIV Strains by Study Day, Study Arm, and Baseline Serostatus, Per 
Protocol Population .............................................................................................. 113 
Table 72: Summaries of Hemagglutination Inhibition Antibody Against 2019/2020 
QIV Strains by Study Day, Study Arm, and Previous Vaccination, Per 
Protocol Population .............................................................................................. 117 
Table 73: Summaries of Neutralizing Antibody Against 2019/2020 QIV Strains by 
Study Day and Study Arm, Modified Intent-to-Treat Population ........................... 121 
Table 74: Summaries of Neutralizing Antibody Against 2019/2020 QIV Strains by 
Study Day and Study Arm, Per Protocol Population.............................................. 123 
Table 75: Summaries of Neutralizing Antibody Against 2019/2020 QIV Strains by 
Study Day, Study Arm, and Baseline Serostatus, Per Protocol Population ............. 124 


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Table 76: Summaries of Neutralizing Antibody Against 2019/2020 QIV Strains by 
Study Day, Study Arm, and Previous Vaccination, Per Protocol Population .......... 128 
Table 77: Summaries of Neuraminidase Inhibition Antibody Against 2019/2020 QIV 
Strains by Study Day and Study Arm, Modified Intent-to-Treat Population .......... 132 
Table 78: Summaries of Neuraminidase Inhibition Antibody Against 2019/2020 QIV 
Strains by Study Day and Study Arm, Per Protocol Population ............................. 134 
Table 79: Summaries of Neuraminidase Inhibition Antibody Against 2019/2020 QIV 
Strains by Study Day, Study Arm, and Baseline Serostatus, Per Protocol 
Population ............................................................................................................ 135 
Table 80: Summaries of Neuraminidase Inhibition Antibody Against 2019/2020 QIV 
Strains by Study Day, Study Arm, and Previous Vaccination, Per Protocol 
Population ............................................................................................................ 137 
Table 81: Summaries of Hemagglutination Inhibition Antibody Against Heterologous 
H3 Influenza Strain A/Michigan/84/2016 [H3N2] by Study Day and Study 
Arm, Modified Intent-to-Treat Population*¥ .......................................................... 140 
Table 82: Summaries of Hemagglutination Inhibition Antibody Against Heterologous 
H3 Influenza Strain A/Kenya/105/2017 [H3N2] by Study Day and Study 
Arm, Modified Intent-to-Treat Population*¥ ......................................................... 143 
Table 83: Summaries of Hemagglutination Inhibition Antibody Against Heterologous 
H3 Influenza Strain A/Louisiana/13/2017 [H3N2] by Study Day and Study 
Arm, Modified Intent-to-Treat Population*¥ .......................................................... 143 
Table 84: Summaries of Hemagglutination Inhibition Antibody Against Heterologous 
H3 Influenza Strain A/Aksaray/4048/2016 [H3N2] by Study Day and Study 
Arm, Modified Intent-to-Treat Population*¥ ......................................................... 143 
Table 85: Summaries of Hemagglutination Inhibition Antibody Against Heterologous 
H3 Influenza Strain A/Shandonglaicheng/1763/2016 [H3N2] by Study Day 
and Study Arm, Modified Intent-to-Treat Population*¥ ......................................... 143 
Table 86: Summaries of Hemagglutination Inhibition Antibody Against Heterologous 
H3 Influenza Strain A/Michigan/84/2016 [H3N2] by Study Day and Study 
Arm, Per Protocol Population*¥ ............................................................................ 143 
Table 87: Summaries of Hemagglutination Inhibition Antibody Against Heterologous 
H3 Influenza Strain A/Kenya/105/2017 [H3N2] by Study Day and Study 
Arm, Per Protocol Population*¥ ............................................................................ 143 
Table 88: Summaries of Hemagglutination Inhibition Antibody Against Heterologous 
H3 Influenza Strain A/Louisiana/13/2017 [H3N2] by Study Day and Study 
Arm, Per Protocol Population*¥ ............................................................................ 143 
Table 89: Summaries of Hemagglutination Inhibition Antibody Against Heterologous 
H3 Influenza Strain A/Aksaray/4048/2016 [H3N2] by Study Day and Study 
Arm, Per Protocol Population*¥ ............................................................................ 143 


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Table 90: Summaries of Hemagglutination Inhibition Antibody Against Heterologous 
H3 Influenza Strain A/Shandonglaicheng/1763/2016 [H3N2] by Study Day 
and Study Arm, Per Protocol Population*¥ ............................................................ 143 
Table 91: Summaries of Neutralizing Antibody Against Heterologous H3 Influenza 
Strain A/Michigan/84/2016 [H3N2] by Study Day and Study Arm, Modified 
Intent-to-Treat Population*¥.................................................................................. 144 
Table 92: Summaries of Neutralizing Antibody Against Heterologous H3 Influenza 
Strain A/Kenya/105/2017 [H3N2] by Study Day and Study Arm, Modified 
Intent-to-Treat Population*¥.................................................................................. 147 
Table 93: Summaries of Neutralizing Antibody Against Heterologous H3 Influenza 
Strain A/Aksaray/4048/2016 [H3N2] by Study Day and Study Arm, 
Modified Intent-to-Treat Population*¥ .................................................................. 147 
Table 94: Summaries of Neutralizing Antibody Against Heterologous H3 Influenza 
Strain A/Shandonglaicheng/1763/2016 [H3N2] by Study Day and Study 
Arm, Modified Intent-to-Treat Population*¥ ......................................................... 147 
Table 95: Summaries of Neutralizing Antibody Against Heterologous H3 Influenza 
Strain A/Michigan/84/2016 [H3N2] by Study Day and Study Arm, Per 
Protocol Population*¥ ........................................................................................... 147 
Table 96: Summaries of Neutralizing Antibody Against Heterologous H3 Influenza 
Strain A/Kenya/105/2017 [H3N2] by Study Day and Study Arm, Per 
Protocol Population*¥ ........................................................................................... 147 
Table 97: Summaries of Neutralizing Antibody Against Heterologous H3 Influenza 
Strain A/Aksaray/4048/2016 [H3N2] by Study Day and Study Arm, Per 
Protocol Population*¥ ........................................................................................... 147 
Table 98: Summaries of Neutralizing Antibody Against Heterologous H3 Influenza 
Strain A/Shandonglaicheng/1763/2016 [H3N2] by Study Day and Study 
Arm, Per Protocol Population*¥ ............................................................................ 147 
Table 99: Summaries of Neuraminidase Inhibition Antibody Against Heterologous N1 
NA Antigen from A/Oman/5532/2017 H6N1 Strain by Study Day and Study 
Arm, Modified Intent-to-Treat Population*¥ ......................................................... 148 
Table 100: Summaries of Neuraminidase Inhibition Antibody Against Heterologous N1 
NA Antigen from A/Cameroon/9766/2017 H6N1 Strain by Study Day and 
Study Arm, Modified Intent-to-Treat Population*¥ ............................................... 151 
Table 101: Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 
NA Antigen from A/Human/Hubei/3/2005 H3N2 Strain by Study Day and 
Study Arm, Modified Intent-to-Treat Population*¥ ............................................... 151 
Table 102: Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 
NA Antigen from A/Louisiana/13/2017 H6N2 Strain by Study Day and 
Study Arm, Modified Intent-to-Treat Population*¥ ............................................... 151 


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Table 103: Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 
NA Antigen from A/Townsville/51/2016 H6N2 Strain by Study Day and 
Study Arm, Modified Intent-to-Treat Population*¥ ............................................... 151 
Table 104: Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 
NA Antigen from A/Aksaray/4048/2016 H6N2 Strain by Study Day and 
Study Arm, Modified Intent-to-Treat Population*¥ ............................................... 151 
Table 105: Summaries of Neuraminidase Inhibition Antibody Against Heterologous N1 
NA Antigen from A/Oman/5532/2017 H6N1 Strain by Study Day and Study 
Arm, Per Protocol Population*¥ ............................................................................ 151 
Table 106: Summaries of Neuraminidase Inhibition Antibody Against Heterologous N1 
NA Antigen from A/Cameroon/9766/2017 H6N1 Strain by Study Day and 
Study Arm, Per Protocol Population*¥ .................................................................. 151 
Table 107: Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 
NA Antigen from A/Human/Hubei/3/2005 H3N2 Strain by Study Day and 
Study Arm, Per Protocol Population*¥ .................................................................. 151 
Table 108: Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 
NA Antigen from A/Louisiana/13/2017 H6N2 Strain by Study Day and 
Study Arm, Per Protocol Population*¥ .................................................................. 151 
Table 109: Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 
NA Antigen from A/Townsville/51/2016 H6N2 Strain by Study Day and 
Study Arm, Per Protocol Population*¥ .................................................................. 151 
Table 110: Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 
NA Antigen from A/Aksaray/4048/2016 H6N2 Strain by Study Day and 
Study Arm, Per Protocol Population*¥ .................................................................. 151 
Table 111: Summary Statistics of Influenza Specific-IgG B Memory Cells (Spot 
Forming Cells per Million PBMC) by Study Day and Study Arm, Per 
Protocol Population .............................................................................................. 152 
Table 112: Summary Statistics of Influenza Specific-IgM B Memory Cells by Study 
Day and Study Arm, Per Protocol Population ....................................................... 153 
Table 113: Summary Statistics of Influenza Specific-IgA B Memory Cells by Study 
Day and Study Arm, Per Protocol Population ....................................................... 153 
Table 114: Summary Statistics of Influenza Specific Plasmablasts by Study Day and 
Study Arm, Per Protocol Population ..................................................................... 154 
Table 115: Summary Statistics of the Number of Influenza Specific Tfh Cells by Study 
Day and Study Arm, Per Protocol Population ....................................................... 154 
Table 116: Summaries of Functioning Non-Neutralizing Fc-effector Antibodies Against 
2018/2019 QIV Strains by Study Day and Study Arm, Per Protocol 
Population ............................................................................................................ 155 
Table 117: Overall Summary of Adverse Events- Safety Population*¥ ................................... 156 


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Table 118: Adverse Events Occurring in 5% of Subjects in Any Study Arm by 
MedDRA System Organ Class and Preferred Term, and Study Arm - Safety 
Population ............................................................................................................ 158 
Table 119: Number and Percentage of Subjects Experiencing Solicited Events with 95% 
Confidence Intervals by Symptom and Study Arm – Safety Population ................ 159 
Table 120: Logistic Regression Model to Evaluate the Relationship of Treatment with 
Reporting Any Local Event Post First Study Vaccination - Safety Population ....... 161 
Table 121: Logistic Regression Model to Evaluate the Relationship of Treatment with 
Reporting Any Systemic Event Post First Study Vaccination - Safety 
Population ............................................................................................................ 161 
Table 122: Number and Percentage of Subjects Experiencing Solicited Events by 
Symptom, Maximum Severity and Study Arm Post First Study Vaccination 
– Safety Population* ............................................................................................. 162 
Table 123: Number and Percentage of Subjects Experiencing Solicited Events by 
Symptom, Severity, Day Post Dose, and Study Arm Post First Study 
Vaccination - Safety Population ............................................................................ 166 
Table 124: Serious Adverse Events and All Unsolicited Adverse Events Occurring from 
Day 1 through Day 365 following the First Vaccination, in Subjects in Any 
Study Arm by MedDRA System Organ Class and Preferred Term, and by 
Study Arm – Safety Population ............................................................................. 170 
Table 125: Serious Adverse Events and All Unsolicited Adverse Events Occurring from 
Day 1 through Day 29 following the First Vaccination, in Subjects in Any 
Study Arm by MedDRA System Organ Class and Preferred Term, and by 
Study Arm – Safety Population ............................................................................. 170 
Table 126: Number and Percentage of Subjects Experiencing Unsolicited Adverse 
Events with 95% Confidence Intervals by MedDRA System Organ Class 
and Preferred Term, and Study Arm – Safety Population ...................................... 171 
Table 127: Number and Percentage of Subjects Experiencing Any Unsolicited Adverse 
Events from Day 1 through Day 29 with 95% Confidence Intervals by 
MedDRA System Organ Class and Preferred Term, and Study Arm – Safety 
Population ............................................................................................................ 171 
Table 128: Number and Percentage of Subjects Experiencing Unsolicited Adverse 
Events by MedDRA System Organ Class and Preferred Term, Maximum 
Severity, Relationship, and Study Arm – Safety Population .................................. 172 
Table 129: Number and Percentage of Subjects Experiencing Any Unsolicited Adverse 
Events from Day 1 through Day 29 by MedDRA System Organ Class and 
Preferred Term, Maximum Severity, Relationship, and Study Arm – Safety 
Population ............................................................................................................ 174 


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Table 130: Number and Percentage of Subjects Experiencing Non-Serious Related 
Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Maximum Severity, and Study Arm – Safety Population* ........................... 175 
Table 131: Number and Percentage of Subjects Experiencing Unsolicited Adverse 
Events Within 28 Days Post First Study Vaccination by MedDRA System 
Organ Class and Preferred Term, Day Post Vaccination, and Study Arm – 
Safety Population.................................................................................................. 177 
Table 132: Number and Percentage of Subjects Experiencing Non-Serious, Related 
Unsolicited Adverse Events Within 28 Days Post First Study Vaccination by 
MedDRA System Organ Class and Preferred Term, Day Post Vaccination 
and Study Arm – Safety Population ...................................................................... 179 
Table 133: Number of Unsolicited Adverse Events by MedDRA System Organ Class 
and Preferred Term, Day Post Vaccination, and Study Arm – Safety 
Population ............................................................................................................ 181 
Table 134: Listing of Serious Adverse Events* ....................................................................... 183 
Table 135: Listing of Adverse Events of Special Interest*....................................................... 184 
Table 136: Listing of Potentially Immune Mediated Medical Conditions* .............................. 184 
Table 137: Listing of New Onset Chronic Medical Conditions* .............................................. 184 
Table 138: Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events* ........... 184 
Table 139: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study 
Arm – All Laboratory Parameters* ........................................................................ 186 
Table 140: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study 
Arm – White Blood Cells ..................................................................................... 187 
Table 141: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study 
Arm – Hemoglobin ............................................................................................... 187 
Table 142: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study 
Arm – Platelets ..................................................................................................... 187 
Table 143: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study 
Arm – Alanine Aminotransferase (ALT) ............................................................... 187 
Table 144: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study 
Arm – Aspartate Amino Transferase (AST) .......................................................... 187 
Table 145: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study 
Arm – Total Bilirubin ........................................................................................... 187 
Table 146: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study 
Arm – Gamma-Glutamyl Transferase (GGT) ........................................................ 187 
Table 147: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study 
Arm – Alkaline Phosphatase (ALP) ...................................................................... 188 


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Table 148: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study 
Arm – Serum Amylase ......................................................................................... 188 
Table 149: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study 
Arm – Serum Lipase ............................................................................................. 188 
Table 150: Laboratory Results by Parameter, Maximum Severity, Study Day, and Study 
Arm – Creatinine .................................................................................................. 188 
Table 151: Laboratory Summary Statistics of Value and Change from Baseline by Study 
Day, and Study Arm – White Blood Cells ............................................................. 189 
Table 152: Laboratory Summary Statistics of Value and Change from Baseline by Study 
Day, and Study Arm – Hemoglobin ...................................................................... 189 
Table 153: Laboratory Summary Statistics of Value and Change from Baseline by Study 
Day, and Study Arm – Platelets ............................................................................ 189 
Table 154: Laboratory Summary Statistics of Value and Change from Baseline by Study 
Day, and Study Arm – Alanine Aminotransferase (ALT) ...................................... 189 
Table 155: Laboratory Summary Statistics of Value and Change from Baseline by Study 
Day, and Study Arm – Aspartate Amino Transferase (AST) ................................. 189 
Table 156: Laboratory Summary Statistics of Value and Change from Baseline by Study 
Day, and Study Arm – Total Bilirubin .................................................................. 189 
Table 157: Laboratory Summary Statistics of Value and Change from Baseline by Study 
Day, and Study Arm – Gamma-Glutamyl Transferase (GGT) ............................... 190 
Table 158: Laboratory Summary Statistics of Value and Change from Baseline by Study 
Day, and Study Arm – Alkaline Phosphatase (ALP) ............................................. 190 
Table 159: Laboratory Summary Statistics of Value and Change from Baseline by Study 
Day, and Study Arm – Amylase ............................................................................ 190 
Table 160: Laboratory Summary Statistics of Value and Change from Baseline by Study 
Day, and Study Arm – Lipase ............................................................................... 190 
Table 161: Laboratory Summary Statistics of Value and Change from Baseline by Study 
Day, and Study Arm – Creatinine ......................................................................... 190 
Table 162: Listing of Abnormal Laboratory Results - Chemistry ............................................ 192 
Table 163: Listing of Abnormal Laboratory Results - Hematology ......................................... 193 
Table 164: Vital Signs by Assessment, Maximum Severity, Time Point, and Study Arm 
– Any Assessment ................................................................................................ 194 
Table 165: Vital Signs by Assessment, Maximum Severity, Time Point, and Study Arm 
– Oral Temperature ............................................................................................... 194 
Table 166: Vital Signs by Assessment, Maximum Severity, Study Day, and Study Arm 
– Systolic Blood Pressure ..................................................................................... 195 


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Table 167: Vital Signs by Assessment, Maximum Severity, Study Day, and Study Arm– 
Diastolic Blood Pressure ....................................................................................... 195 
Table 168: Vital Signs by Assessment, Maximum Severity, Study Day, and Study Arm 
– Pulse .................................................................................................................. 195 
Table 169: Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification and Study Arm........................................................ 196 
 
 


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9.1 
Overall Study Design and Plan Description 
Table 1: 
Study Design 
 
 
Day 1 
 
Day 90 
Study Group 
N 
Study Vaccine 
Adjuvant 
Seasonal Vaccine 
1 
40 
Fluzone 2018/2019 QIV 
None 
Fluzone 2019/2020 QIV  
2 
40 
Fluzone 2018/2019 QIV 
AF03 
Fluzone 2019/2020 QIV  
3A 
40 
Fluzone 2018/2019 QIV 
Advax-CpG55.2 
Fluzone 2019/2020 QIV  
4 
40 
Flublok 2018/2019 QIV 
None 
Flublok 2019/2020 QIV  
5 
40 
Flublok 2018/2019 QIV 
AF03 
Flublok 2019/2020 QIV  
6A 
40 
Flublok 2018/2019 QIV 
Advax-CpG55.2 
Flublok 2019/2020 QIV  
 
Total N= 240 
 
 
 
Note: Cohorts will be enrolled simultaneously. Randomization at each site will be stratified by prior receipt of licensed, seasonal influenza vaccine (defined as receipt of at least one 
of the 2017/2018 and/or 2018/2019 licensed, seasonal influenza vaccines).  
 
 


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9.5.1 Efficacy/Immunogenicity and Safety Measurements Assessed and Flow Chart 
Table 2: 
Schedule of Study Procedures and Evaluations  
Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
Early Termination  
Unscheduled 
Screening, 
Enrollment/Study Day 
and post first study 
vaccination 
Screening 
D-28 to -1 
Enrollment 
D1 
D2+1d 
D8+/-1d 
D29+/-2d 
D57+/-3d 
D90+/-14d 
Day118+/-3d 
D180 +/-14d 
D365 +/-14d 
Informed Consent∞ 
X∞ 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X†¬1 
 
 
 
 
 
 
 
 
 
 
Medical History@ 
X 
X†¬ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X†¬ 
X 
X 
X 
 
 
 
 
 
X6  
X6 
Vital Signs (Oral 
Temperature%, Pulse and 
BP) 
X 
X$ 
 
 
 
 
 
 
 
 
X  
X 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X2 
{X} 
{X} 
{X} 
{X} 
{X} 
{X}†  
{X} 
{X} 
{X} 
{X} 
{X} 
Urine or Serum Pregnancy 
Test 
X^ 
X†^ 
 
 
 
 
 
 
 
 
 
 
Venous Blood Collection 
for Screening Laboratories 
X≠ 
 
 
 
 
 
 
 
 
 
 
 
Enrollment in Advantage 
eClinicalSM and 
Randomization 
 
X† 
 
 
 
 
 
 
 
 
 
 
Venous Blood Collection 
for Clinical Safety 
Laboratory Evaluations~ 
 
X†,~ 
 
X~ 
 
 
 
 
 
 
X7 
X  
Venous Blood Collection 
for Serological Assays 
 
X† 
 
X 
X 
X 
X† 
X 
X 
X 
X 
X 
Venous Blood Collection 
for Cellular Immunology 
Assays 
 
X† 
 
X 
X 
 
X† 
 
 
 
X8 
 
Venous Blood Collection 
for Transcriptomics 
 
X† 
X 
X 
 
 
 
 
 
 
X9 
 
Pre-Administration 
Reactogenicity 
Assessments 
 
X† 
 
 
 
 
 
 
 
 
 
 
Study Vaccination 
 
X 
 
 
 
 
X* 
 
 
 
 
 
20-minute Evaluation 
After Study Vaccination 
 
X 
 
 
 
 
 
 
 
 
 
 
Examine Study 
Vaccination Site 
 
X 
X 
X 
 
 
  
 
 
 
X7 
X7 
Post-Administration 
Reactogenicity 
Assessments 
 
X 
 
 
 
 
 
 
 
 
X7 
X7 
Distribute Memory Aid 
and Study-Related 
Materials 
 
X 
 
 
 
 
 
 
 
 
 
 


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Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
Early Termination  
Unscheduled 
Screening, 
Enrollment/Study Day 
and post first study 
vaccination 
Screening 
D-28 to -1 
Enrollment 
D1 
D2+1d 
D8+/-1d 
D29+/-2d 
D57+/-3d 
D90+/-14d 
Day118+/-3d 
D180 +/-14d 
D365 +/-14d 
Review Memory Aid 
 
 
X 
X 
 
 
 
 
 
 
X7  
X7 
AE/SAE Assessment 
 
X&,3 
X&,3 
X&,3 
X3 
X 
X4 
X4 
X4 
X4 
X3,6  
X3,6 
∞ Prior to study procedures. 
¬ Review/confirm information or activity in subjects previously consented and screened. 
† Prior to study vaccination. 
1 Review results of ESR and clinical safety laboratory evaluations. 
@ Complete medical history (including solicitation for receipt of any non-study influenza vaccine) will be obtained by interview 
of subjects at the screening visit and interim medical history will be obtained by interview of subjects on Day 1 prior to study 
vaccination and at follow-up visits after study vaccination. 
$ Vital signs assessed on Day 1 prior to the study vaccination will be considered as baseline. 
% Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
2 At the screening visit a physical examination will be performed on all subjects to include the following organs and organ 
systems: skin, head and neck, lungs, heart, liver, spleen, extremities, lymph nodes, and nervous system.  
{} Targeted physical examination if indicated based on review of interim medical history. 
^ Performed locally by the site at the screening visit (optional); Must be performed within 24 hours prior to study vaccination for 
all women of childbearing potential. Results must be negative and known prior to randomization on Day 1 and administration 
of study vaccination. 
≠ ESR Performed by local laboratory, WBC, Hgb, PLT, ALT, T. Bili, AST, GGT, ALP, serum lipase, serum amylase and Cr 
will be sent to the central clinical laboratory.  
~ Includes, WBC, Hgb, PLT, ALT, T. Bili, AST, GGT, ALP, serum lipase, serum amylase and Cr. 
& Inclusive of reactogenicity assessments performed on the day of study vaccination through 7 days after study vaccination. 
3  AEs (if visit occurs on or before Day 29), SAEs, AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and 
PIMMCs), for subjects who are being followed for safety. 
4 SAEs and AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs), for subjects who are being followed 
for safety. 
5 Investigators have the discretion of administering 2019/2020 Fluzone or Flublok earlier than the Day 90 window (i.e. earlier 
than Day 76) if 10% of more of surveillance samples in the CDC geographic region surrounding the local site test positive for 
influenza. 
6If within 365 after first study vaccination 
7 If within the first 7 days after the first study vaccination 
8 If prior to or at the D90 visit 
9 If prior to or at the D8 visit 
* Seasonal QIV 2019/2020 


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9.7.1 Sample Size 
Table 3: 
Probability (%) to Detect Safety Events  
Event 
Frequency 
N = 4 
N = 6 
N = 40 
N = 60 
N = 120 
N = 240 
≥10% 
Very Common 
34 
46 
98 
>99 
>99 
>99 
≥1% 
Common 
3 
5 
33 
45 
70 
91 
≥0.1% 
Uncommon 
<1 
<1 
3 
5 
11 
21 
≥0.01% 
Rare 
<1 
<1 
<1 
<1 
1 
2 
 
Table 4: 
Precision of Binomial Confidence Intervals 
N 
95% CI 
4 
6-94 
6 
11-89 
40 
33 -67 
60 
36-64 
120 
40-60 
240 
43-57 
 
 


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Table 5: 
Minimum Detectable Difference in Proportion Responders with 80% Power 
Assumed Proportion of subjects with 
titer ≥ 40 in comparator arm (pc) 
Minimum detectable difference in response rate (pc-pe), 
N=38 per group 
Minimum detectable difference in response rate (pc-pe), 
N=58 per group 
0.40 
 0.32  
0.26 
0.50 
 0.30 
0.25 
0.60 
 0.28 
0.23 
0.70 
 0.24 
0.20 
0.80 
 0.18 
0.16 
0.90 
 0.10 
0.10 
 
 
 


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10.2 
Protocol Deviations 
Table 6: 
Distribution of Protocol Deviations by Category, Type, and Study Arm 
Category 
Deviation Type 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
All Subjects 
(N=X) 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
Eligibility/enrollment 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Did not meet inclusion 
criterion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Met exclusion criterion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF not signed prior to 
study procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
administration schedule 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Out of window visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missed visit/visit not 
conducted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missed treatment 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Delayed treatment 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up visit schedule Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Out of window visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missed visit/visit not 
conducted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Category 
Deviation Type 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
All Subjects 
(N=X) 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
Protocol 
procedure/assessment 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Incorrect version of ICF 
signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood not collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine not collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool not collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other specimen not 
collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Too few aliquots obtained 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specimen result not 
obtained 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Required procedure not 
conducted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Required procedure done 
incorrectly 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study product temperature 
excursion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specimen temperature 
excursion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
administration 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Required procedure done 
incorrectly 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study product temperature 
excursion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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Category 
Deviation Type 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
All Subjects 
(N=X) 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinding 
policy/procedure 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment unblinded 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of subjects enrolled. 
 


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12.2.2 Displays of Adverse Events 
Table 7: 
Solicited Adverse Event Grading Scale - Local 
Local (Injection Site) Reactogenicity Grading 
Injection Site Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain – experienced 
without touching the 
injection site 
(spontaneous 
discomfort) 
Subject is aware of pain, but it 
does not interfere with daily 
activity, and if pain medication is 
used, it is Over the Counter 
(OTC) and used for less than 24 
hours 
Subject is aware of pain; there is 
interference with daily activity 
or OTC pain medication is used 
for more than 24 hours 
Subject is aware of pain, and 
it prevents daily activity or 
pain requires prescription 
medication 
Tenderness-experienced 
with touching the 
injection site 
Subject is aware of pain, but it 
does not interfere with daily 
activity, and if pain medication is 
used, it is Over the Counter 
(OTC) and used for less than 24 
hours 
Subject is aware of pain; there is 
interference with daily activity 
or OTC pain medication is used 
for more than 24 hours 
Subject is aware of pain, and 
it prevents daily activity or 
pain requires prescription 
medication 
Pruritus 
Does not interfere with daily 
activity 
Interferes with daily activity 
Prevents daily activity or 
requires prescription 
medication 
Ecchymosis (Bruising)* 
Does not interfere with daily 
activity 
Interferes with daily activity 
Prevents daily activity 
Erythema (Redness)* 
Does not interfere with daily 
activity 
Interferes with daily activity 
Prevents daily activity 
Induration 
(Hardness)/Edema 
(Swelling)* 
Does not interfere with daily 
activity 
Interferes with daily activity 
Prevents daily activity 
Local (Injection Site) Reactogenicity Measurements 
Injection Site Reaction 
Small 
Medium 
Large 
Ecchymosis (Bruising)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Erythema (Redness)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Induration 
(Hardness)/Edema 
(Swelling)* 
<20 mm 
20 mm – 50 mm 
>50 mm 


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Local (Injection Site) Reactogenicity Grading 
Injection Site Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
*Will also be measured in mm but size will not be used as halting criteria.  
 
Table 8: 
Solicited Adverse Event Grading Scale – Systemic 
Subjective Systemic Reactogenicity Grading 
Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Feverishness  
No interference with 
daily activity 
Some interference with daily 
activity 
Significant interference, 
prevents daily activity 
Fatigue 
No interference with 
daily activity 
Some interference with daily 
activity 
Significant interference, 
prevents daily activity 
Malaise 
No interference with 
daily activity 
Some interference with daily 
activity 
Significant interference, 
prevents daily activity 
Myalgia* 
No interference with 
daily activity 
Some interference with daily 
activity 
Significant interference, 
prevents daily activity 
Arthralgia* 
No interference with 
daily activity 
Some interference with daily 
activity 
Significant interference, 
prevents daily activity 
Headache 
No interference with 
daily activity 
Some interference with daily 
activity 
Significant interference, 
prevents daily activity or 
headache requires prescription 
medication 
Nausea 
No interference with 
daily activity 
Some interference with daily 
activity 
Significant interference, 
prevents daily activity or 
nausea requires prescription 
medication 
Quantitative Systemic (Oral Temperature) Reactogenicity Grading 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever# – oral† 
38.0°C – 38.4°C 
100.4°F – 101.1°F 
38.5°C – 38.9°C 
101.2°F – 102.0°F 
>38.9°C 
>102.0°F 
* Not at injection site. 
# Oral temperature assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
* * A fever can be considered not related to the study product if an alternative etiology can be documented. 


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Subjective Systemic Reactogenicity Grading 
Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
†Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
 
 


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Table 9: 
Vital Signs Adverse Event Grading Scale 
Physiologic Parameter 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Bradycardia – beats per minute 
45 – 46 
40 – 44 
<40 
Tachycardia – beats per minute 
101 – 130 
131 – 155 
>155 
Hypotension (systolic) mmHg 
80 – 84 
75 – 79 
<75 
Hypotension (diastolic) mmHg 
50 – 54 
45 – 49 
<45 
Hypertension (systolic) mmHg 
141 – 155 
156 – 160 
>160 
Hypertension (diastolic) mmHg 
91 – 100 
101 – 110 
>110 
 # Pulse and blood pressure assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
 
 


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12.4.1 Individual Laboratory Measurements and Abnormal Laboratory Values 
Table 10: 
Laboratory Adverse Event Grading Scale 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
WBC 103/µL (Decrease) 
2.50 – 3.90 
1.50 – 2.49 
<1.50 
WBC 103/µL (Increase) 
10.60 – 15.00 
15.01 – 20.00 
>20.00 
Hgb g/dL (Decrease) (Female) 
10.1 – 11.4 
8.5 – 10 
<8.5 
Hgb g/dL (Decrease) (Male) 
11.0 – 12.4 
9.5 – 10.9 
<9.5 
Platelets 103/µL (Decrease) EDTA 
125 – 139 
100 – 124 
<100 
Platelets 103/µL (Increase) EDTA 
416 – 550 
551– 750 
>750 
Platelets K/cu mm (Decrease) Citrate 
115-124 
100-114 
<100 
Platelets K/cu mm (Increase) Citrate 
376-550 
551-750 
>750 
Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
ALT IU/L (Increase) (Female) 
44 – 100 
101 – 200 
>200 
ALT IU/L (Increase) (Male) 
61 – 138 
139 – 275 
>275 
Aspartate Amino Transferase IU/L 
(Increase) (Female) 
37-90 
91-180 
> 180 
Aspartate Amino Transferase IU/L 
(Increase) (Male) 
44-108 
109-215 
> 215 
Total Bilirubin mg/dL (Increase) – when 
accompanied by any increase in ALT 
1.30 – 1.59 
1.60 – 1.80 
> 1.80 
Total Bilirubin mg/dL (Increase) – when 
ALT is normal 
1.30 – 1.89 
1.90 – 2.40 
> 2.40 
Gamma-Glutamyl Transferase IU/L 
(Increase) (Female) 
33-80 
81-160 
> 160 
Gamma-Glutamyl Transferase IU/L 
(Increase) (Male) 
50-123 
124-245 
> 245 
Alkaline Phosphatase IU/L (Increase) 
(Female) 
116-230 
231-345 
> 345 
Alkaline Phosphatase IU/L (Increase) 
(Male) 
116-230 
231-345 
> 345 
Serum Amylase 
122-182 
183-242 
>243 
Serum Lipase 
61-90 
91-180 
> 181 
Creatinine mg/dL (Increase) (Female) 
1.1 – 1.7 
1.8 – 2.0 
> 2.0 
Creatinine mg/dL (Increase) (Male) 
1.4 – 1.7 
1.8 – 2.0 
> 2.0 


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14.1 
Description of Study Subjects 
14.1.1 Disposition of Subjects 
Table 11: 
Ineligibility Summary of Screen Failures 
Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
Inclusion and Exclusion 
Number of subjects failing any eligibility criterion 
x 
100 
Inclusion 
Any inclusion criterion 
x 
x 
 
[inclusion criterion 1] 
x 
x 
 
[inclusion criterion 2] 
x 
x 
 
[inclusion criterion 3] 
x 
x 
Exclusion 
Any exclusion criterion 
x 
x 
 
[exclusion criterion 1] 
x 
x 
 
[exclusion criterion 2] 
x 
x 
 
[exclusion criterion 3] 
x 
x 
aMore than one criterion may be marked per subject. 
bDenominator for percentages is the total number of screen failures. 
 
 
 
 


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Table 12: 
Exclusions from Analysis Populations by Study Arm – All Enrolled Subjects* 
[Implementation Note: Generate this table for the expedited report and only include Safety Population, modified Intent to Treat and Per Protocol,  
Day 29).]  
Analysis Populations 
Reason Subjects Excluded 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-
CpG 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Safety Population 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Study Dose 1 Not Received  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Modified Intent to Treat 
Any Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Dose 1 Not Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Baseline Results Available 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Post-Vaccination Results 
Available 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per-Protocol, All Visits 
Found to be Ineligible At 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per Protocol, Day 8 
Any Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Vaccination 1 Not 
Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Baseline Results Available 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Day 8 Result Reported by 
Lab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lost to Follow-up Before Day 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Non-Study 
Vaccination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Immunosuppressive 
medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 Visit Out of Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per Protocol, Day 29 
Any Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Analysis Populations 
Reason Subjects Excluded 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-
CpG 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Study Vaccination 1 Not 
Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Baseline Results Available 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Day 29 Result Reported by 
Lab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lost to Follow-up Before Day 29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Non-Study 
Vaccination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Immunosuppressive 
medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 29 Visit Out of Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per Protocol, Day 57 
Any Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Vaccination 1 Not 
Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Baseline Results Available 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Day 57 Result Reported by 
Lab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lost to Follow-up Before Day 57 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Non-Study 
Vaccination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Immunosuppressive 
medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 57 Visit Out of Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per Protocol, Day 90 
Any Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Vaccination 1 Not 
Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Analysis Populations 
Reason Subjects Excluded 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-
CpG 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
No Baseline Results Available 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Day 90 Result Reported by 
Lab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lost to Follow-up Before Day 90 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Non-Study 
Vaccination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Immunosuppressive 
medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 90 Visit Out of Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per Protocol, Day 118 
Any Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Vaccination 1 Not 
Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Baseline Results Available 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Day 118 Result Reported by 
Lab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lost to Follow-up Before Day 
118 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Non-Study 
Vaccination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Immunosuppressive 
medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 118 Visit Out of Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per Protocol, Day 180 
Any Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Vaccination 1 Not 
Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Baseline Results Available 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Analysis Populations 
Reason Subjects Excluded 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-
CpG 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
No Day 180 Result Reported by 
Lab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lost to Follow-up Before Day 
180 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Non-Study 
Vaccination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Immunosuppressive 
medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 180 Visit Out of Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per Protocol, Day 365 
Any Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Vaccination 1 Not 
Received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Baseline Results Available 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Day 365 Result Reported by 
Lab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lost to Follow-up Before Day 
365 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Non-Study 
Vaccination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receipt of Immunosuppressive 
medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 Visit Out of Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of subjects enrolled. 
  


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Table 13: 
Subject Disposition by Study Arm, All Enrolled Subjects* 
Subject 
Disposition 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-
CpG 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Screened 
x 
-- 
x 
-- 
x 
-- 
x 
-- 
x 
-- 
x 
-- 
x 
-- 
Enrolled/Randomized 
x 
100 
x 
100 
x 
100 
x 
100 
x 
100 
x 
100 
x 
100 
Received Vaccination 1 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Received Vaccination 2 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Primary Follow-up (Day 
29)a 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Blood Draw for Primary 
Immunogenicity Analysis (Day 29) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Included in Per Protocol Primary 
Immunogenicity Analysis (Day 29)b 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Day 57 Visit 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Final Study Visit (Day 365)  
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects enrolled. 
aRefer to Listing 2 for reasons subjects discontinued from study vaccinations or terminated early.  
bRefer to Listing 5 for reasons subjects are excluded from the per protocol population. 


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Table 14: 
Dates of First Study Vaccination by Site and Study Arm for the Safety Analysis Population  
[Implementation Note: The dates of dosing will be categorized by month.]  
Dates of Dosing 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + 
AF03 
(N=X) 
Group 3 
Fluzone + 
Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + 
Advax-CpG 
(N=X) 
All Subjects 
(N=X) 
[Site 1] 
Total (Entire period of enrollment) 
x 
x 
x 
x 
x 
x 
x 
17JUN2019-30JUN2019  
x 
x 
x 
x 
x 
x 
x 
01JUL2019-31JUL2019 
x 
x 
x 
x 
x 
x 
x 
01AUG2019-27AUG2019 
x 
x 
x 
x 
x 
x 
x 
[Site 2] 
Total (Entire period of enrollment) 
x 
x 
x 
x 
x 
x 
x 
17JUN2019-30JUN2019  
x 
x 
x 
x 
x 
x 
x 
01JUL2019-31JUL2019 
x 
x 
x 
x 
x 
x 
x 
01AUG2019-27AUG2019 
x 
x 
x 
x 
x 
x 
x 
[Repeat for all sites] 
N = Number of subjects in the Safety Population. 
 
Table with similar format 
Table 15: 
Dates of Second Study Vaccination by Site and Study Arm for the Safety Analysis Population  
[Implementation Note: Update the table to use actual dates of administration of the second vaccination grouped by month.]  
 


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14.1.2 Demographic Data 
Table 16: 
Summary of Categorical Demographic and Baseline Characteristics by Site, All Enrolled Subjects 
Variable 
Characteristic 
[Site 1] 
(N=X) 
[Site 2] 
(N=X) 
[Site 3] 
(N=X) 
[Site 4] 
(N=X) 
[Site 5] 
(N=X) 
[Site 6] 
(N=X) 
[Site 7] 
(N=X) 
[Site 8] 
(N=X) 
[Site 9] 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Sex  
Male 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Female 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI 
< 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≥ 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethnicity  
Not Hispanic or Latino 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Hispanic or Latino 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not Reported 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race  
American Indian or 
Alaska Native 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Asian 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Native Hawaiian or 
Other Pacific Islander 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Black or African 
American 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
White 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multi-Racial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Seasonal 
Influenza Vaccination 
Either 2017-2018 or 
2018-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neither 2017-2018 or 
2018-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N= Number of subjects enrolled. 
 


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Table 17: 
Summary of Continuous Demographic and Baseline Characteristics by Site, All Enrolled Subjects  
Variable 
Statistic 
[Site 1] 
(N=X) 
[Site 2] 
(N=X) 
[Site 3] 
(N=X) 
[Site 4] 
(N=X) 
[Site 5] 
(N=X) 
[Site 6] 
(N=X) 
[Site 7] 
(N=X) 
 
[Site 8] 
(N=X) 
[Site 9] 
(N=X) 
All Subjects 
(N=X) 
Age 
Mean 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Standard Deviation 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
BMI 
Mean 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Standard Deviation 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
N= Number of subjects enrolled. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 18: 
Summary of Categorical Demographic and Baseline Characteristics by Study Arm, All Enrolled Subjects* 
Variable 
Characteristic 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + 
Advax-CpG 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Sex  
Male 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Female 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI 
< 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≥ 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethnicity  
Not Hispanic or Latino 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Hispanic or Latino 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not Reported 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race  
American Indian or Alaska Native 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Asian 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Native Hawaiian or Other Pacific 
Islander 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Black or African American 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
White 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multi-Racial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Seasonal Influenza 
Vaccination 
Either 2017-2018 or 2018-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neither 2017-2018 or 2018-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N= Number of subjects enrolled. 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 82 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 19: 
Summary of Continuous Demographic and Baseline Characteristics by Study Arm, All Enrolled Subjects*  
Variable 
Statistic 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + 
Advax-CpG 
(N=X) 
All Subjects 
(N=X) 
Age 
Mean 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Standard Deviation 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
BMI 
Mean 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Standard Deviation 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
N= Number of subjects enrolled. 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 83 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.1.3 Prior and Concurrent Medical Conditions 
Table 20: 
Summary of Subjects with Prior or Concurrent Medical Conditions by MedDRA System Organ Class and Study Arm, Safety 
Analysis Population  
MedDRA System Organ 
Class 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-
CpG 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
 
 
 
 
 
 
 
 
Any SOC 
x 
xx 
x 
xx 
x 
xx 
 
 
 
 
 
 
 
 
[SOC 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N = Number of subjects in the Safety Population. 
n = Number of subjects reporting medical history within the specified SOC. A subject is only counted once per SOC. 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 84 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.2 
Efficacy/Immunogenicity Data 
Table 21: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study 
Day and Study Arm, Modified Intent-to-Treat Population*¥  
[Implementation Note: This table will be generated for the expedited report to include only results for Day 1 and Day 29] 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-
CpG 
(N=X) 
Day 1 (Pre-Vaccination 1) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Titer < 10 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 8 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xxx.x,xxx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 29 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI)a 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 85 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-
CpG 
(N=X) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 57 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 90 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 180 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-
CpG 
(N=X) 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 365 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer; GMFR = Geometric Mean Fold Rise. 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 87 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format 
Table 22: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 
(H3N2) by Study Day and Study Arm, Modified Intent-to-Treat Population*¥ 
Table 23: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by 
Study Day and Study Arm, Modified Intent-to-Treat Population*¥ 
Table 24: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day and Study Arm, Modified Intent-to-Treat Population*¥ 
Table 25: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study 
Day and Study Arm, Per Protocol Population*¥  
Table 26: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 
(H3N2) by Study Day and Study Arm, Per Protocol Population*¥  
Table 27: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by 
Study Day and Study Arm, Per Protocol Population*¥  
Table 28: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day and Study Arm, Per Protocol Population*¥  
Table 29: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study 
Arm, Modified Intent-to-Treat Population*¥  
Table 30: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by 
Study Day and Study Arm, Modified Intent-to-Treat Population*¥  
Table 31: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and 
Study Arm, Modified Intent-to-Treat Population*¥  
Table 32: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study 
Day and Study Arm, Modified Intent-to-Treat Population*¥  
Table 33: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study 
Arm, Per Protocol Population*¥  
Table 34: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by 
Study Day and Study Arm, Per Protocol Population*¥  


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 88 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 35: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and 
Study Arm, Per Protocol Population*¥  
Table 36: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study 
Day and Study Arm, Per Protocol Population*¥  
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 89 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 37: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study 
Day, Study Arm, and Baseline Serostatus, Per Protocol Population   
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
 
Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative 
Day 1 (Pre-
Vaccination 1) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Titer < 10 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 8 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 90 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Day 29 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% 
CI)a 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 57 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 90 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 91 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 180 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 92 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 365 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer; GMFR = Geometric Mean Fold Rise. 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 93 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format 
Table 38: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 
(H3N2) by Study Day, Study Arm, and Baseline Serostatus, Per Protocol Population 
Table 39: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by 
Study Day, Study Arm, and Baseline Serostatus, Per Protocol Population 
Table 40: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day, Study Arm, and Baseline Serostatus, Per Protocol Population 
Table 41: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study, Study Arm, and 
Baseline Serostatus, Per Protocol Population 
Table 42: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by 
Study Day, Study Arm, and Baseline Serostatus, Per Protocol Population 
Table 43: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day, 
Study Arm, and Baseline Serostatus, Per Protocol Population 
Table 44: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study 
Day, Study Arm, and Baseline Serostatus, Per Protocol Population 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 94 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 45: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study 
Day, Study Arm, and Previous Vaccination, Per Protocol Population   
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
 
Previously 
Vaccinatedb 
Not Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Day 1 (Pre-
Vaccination 1) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Titer < 10 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 8 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 95 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Day 29 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% 
CI)a 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 57 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 90 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 96 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 180 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 97 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 365 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer; GMFR = Geometric Mean Fold Rise. 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the Delta 
Method. 
bPreviously Vaccinated means received either the 2017-2018 or 2018-2019 Seasonal Vaccine. 
c Not Previously Vaccinated means received neither the 2017-2018 or 2018-2019 Seasonal Vaccine. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 98 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format 
Table 46: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 
(H3N2) by Study Day, Study Arm, and Previous Vaccination, Per Protocol Population 
Table 47: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by 
Study Day, Study Arm, and Previous Vaccination, Per Protocol Population 
Table 48: 
Summaries of Hemagglutination Inhibition Antibody Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day, Study Arm, and Previous Vaccination, Per Protocol Population 
Table 49: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study, Study Arm, and 
Previous Vaccination, Per Protocol Population 
Table 50: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by 
Study Day, Study Arm, and Previous Vaccination, Per Protocol Population 
Table 51: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day, 
Study Arm, and Previous Vaccination, Per Protocol Population 
Table 52: 
Summaries of Neutralizing Antibody Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study 
Day, Study Arm, and Previous Vaccination, Per Protocol Population 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 99 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 53: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study 
Day and Study Arm, Modified Intent-to-Treat Population*¥  
[Implementation Note: NAI titers are only assessed for all study groups for Day 1 and Day 29 and assessed for study groups 1, 2 and 3 for the rest of the 
timepoints.] 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Day 1 (Pre-Vaccination 1) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 8 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
N/A 
N/A 
N/A 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N/A 
N/A  
N/A  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N/A 
N/A 
N/A 
Day 29 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x(xx.x, xx.x) 
xx.x(xx.x, xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 57 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
N/A 
N/A 
N/A 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x  
xx.x  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N/A 
N/A 
N/A 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 100 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Day 90 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
N/A 
N/A 
N/A 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x  
xx.x  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N/A 
N/A 
N/A 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
N/A 
N/A 
N/A 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N/A 
N/A  
N/A  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N/A 
N/A 
N/A 
Day 180 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
N/A 
N/A 
N/A 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N/A 
N/A  
N/A  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N/A 
N/A 
N/A 
Day 365 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
N/A 
N/A 
N/A 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N/A 
N/A  
N/A  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N/A 
N/A 
N/A 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer; GMFR = Geometric Mean Fold Rise. 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 101 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format: 
Table 54: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 
(H3N2) by Study Day and Study Arm, Modified Intent-to-Treat Population*¥  
Table 55: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by 
Study Day and Study Arm, Modified Intent-to-Treat Population*¥  
Table 56: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain B/Colorado/06/2017 (B Victoria lineage) by 
Study Day and Study Arm, Modified Intent-to-Treat Population*¥  
Table 57: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study 
Day and Study Arm, Per Protocol Population*¥  
Table 58: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 
(H3N2) by Study Day and Study Arm, Per Protocol Population*¥  
Table 59: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by 
Study Day and Study Arm, Per Protocol Population*¥  
Table 60: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain B/Colorado/06/2017 (B Victoria lineage) (B 
Victoria lineage) by Study Day and Study Arm, Per Protocol Population*¥  


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 102 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 61: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study 
Day, Study Arm, and Baseline Serostatus, Per Protocol Population 
[Implementation Note: NAI titers are only assessed for all study groups for Day 1 and Day 29 and assessed for study groups 1, 2 and 3 for the rest of the 
timepoints.] 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
 
Seropositive Seronegative 
Seropositive 
Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative 
Day 1 (Pre-
Vaccination 1) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x,xx.x) xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 8 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Day 29 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 103 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 57 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Day 90 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 104 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Day 180 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Day 365 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 105 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer; GMFR = Geometric Mean Fold Rise. 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
 
Tables with similar format:  
Table 62: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 
(H3N2) by Study Day, Study Arm, and Baseline Serostatus, Per Protocol Population 
Table 63: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by 
Study Day, Study Arm, and Baseline Serostatus, Per Protocol Population 
Table 64: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day, Study Arm, and Baseline Serostatus, Per Protocol Population 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 106 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 65: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study 
Day, Study Arm, and Previous Vaccination, Per Protocol Population 
[Implementation Note: NAI titers are only assessed for all study groups for Day 1 and Day 29 and assessed for study groups 1, 2 and 3 for the rest of the 
timepoints.] 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Day 1 (Pre-
Vaccination 1) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 8 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A  
N/A 
N/A  
N/A 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Day 29 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 107 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
Day 57 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A  
N/A 
N/A  
N/A 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Day 90 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 108 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A  
N/A 
N/A  
N/A 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Day 180 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A  
N/A 
N/A  
N/A 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Day 365 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A  
N/A 
N/A  
N/A 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 109 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer; GMFR = Geometric Mean Fold Rise. 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
bPreviously Vaccinated means received either the 2017-2018 or 2018-2019 Seasonal Vaccine. 
c Not Previously Vaccinated means received neither the 2017-2018 or 2018-2019 Seasonal Vaccine. 
 
Tables with similar format:  
Table 66: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 
(H3N2) by Study Day, Study Arm, and Previous Vaccination, Per Protocol Population 
Table 67: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by 
Study Day, Study Arm, and Previous Vaccination, Per Protocol Population 
Table 68: 
Summaries of Neuraminidase Inhibition Antibody Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day, Study Arm, and Previous Vaccination, Per Protocol Population 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 110 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 69: 
Summaries of Hemagglutination Inhibition Antibody Against 2019/2020 QIV Strains by Study Day and Study Arm, Modified 
Intent-to-Treat Population  
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
A/Brisbane/02/2018 IVR-190 (H1N1) 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
A/Kansas/14/2017 (H3N2) 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 111 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
B/Phuket/3073/2013 (B Yamagata lineage) 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x, xxx.x) 
xxx.x (xxx.x, xxx.x) 
xxx.x (xxx.x, xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
B/Maryland/15/2016 BX-69A (B Victoria lineage) 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 112 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
 
Table with similar format: 
Table 70: 
Summaries of Hemagglutination Inhibition Antibody Against 2019/2020 QIV Strains by Study Day and Study Arm, Per Protocol 
Population 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 113 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 71: 
Summaries of Hemagglutination Inhibition Antibody Against 2019/2020 QIV Strains by Study Day, Study Arm, and Baseline 
Serostatus, Per Protocol Population 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
A/Brisbane/02/2018 IVR-190 (H1N1) 
 
Seropositive Seronegative 
Seropositive 
Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 114 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
A/Kansas/14/2017 (H3N2) 
 
Seropositive Seronegative 
Seropositive 
Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 115 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
B/Phuket/3073/2013 (B Yamagata lineage) 
 
Seropositive Seronegative 
Seropositive 
Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 116 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
B/Maryland/15/2016 BX-69A (B Victoria lineage) 
 
Seropositive Seronegative 
Seropositive 
Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 117 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 72: 
Summaries of Hemagglutination Inhibition Antibody Against 2019/2020 QIV Strains by Study Day, Study Arm, and Previous 
Vaccination, Per Protocol Population 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
A/Brisbane/02/2018 IVR-190 (H1N1) 
 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 118 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
A/Kansas/14/2017 (H3N2) 
 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 119 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
B/Phuket/3073/2013 (B Yamagata lineage) 
 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 120 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
B/Maryland/15/2016 BX-69A (B Victoria lineage) 
 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion 
- % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% 
CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
bPreviously Vaccinated means received either the 2017-2018 or 2018-2019 Seasonal Vaccine. 
c Not Previously Vaccinated means received neither the 2017-2018 or 2018-2019 Seasonal Vaccine. 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 121 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 73: 
Summaries of Neutralizing Antibody Against 2019/2020 QIV Strains by Study Day and Study Arm, Modified Intent-to-Treat 
Population 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
A/Brisbane/02/2018 IVR-190 (H1N1) 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
A/Kansas/14/2017 (H3N2) 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 122 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
B/Phuket/3073/2013 (B Yamagata lineage) 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x, xxx.x) 
xxx.x (xxx.x, xxx.x) 
xxx.x (xxx.x, xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
B/Maryland/15/2016 BX-69A (B Victoria lineage) 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
- 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 123 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
 
Table with similar format:  
Table 74: 
Summaries of Neutralizing Antibody Against 2019/2020 QIV Strains by Study Day and Study Arm, Per Protocol Population   
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 124 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 75: 
Summaries of Neutralizing Antibody Against 2019/2020 QIV Strains by Study Day, Study Arm, and Baseline Serostatus, Per 
Protocol Population   
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
A/Brisbane/02/2018 IVR-190 (H1N1) 
 
Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 125 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
A/Kansas/14/2017 (H3N2) 
 
Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
 
xx (xx, xx) 
 
xx (xx, xx) 
 
xx (xx, xx) 
 
xx (xx, xx) 
 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
 
xx (xx, xx) 
 
xx (xx, xx) 
 
xx (xx, xx) 
 
xx (xx, xx) 
 
GMFR (95% CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
 
xx.x 
(xx.x,xx.x) 
 
xx.x 
(xx.x,xx.x) 
 
xx.x 
(xx.x,xx.x) 
 
xx.x 
(xx.x,xx.x) 
 
B/Phuket/3073/2013 (B Yamagata lineage) 
 
Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 126 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
GMT (95% CI) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
B/Maryland/15/2016 BX-69A (B Victoria lineage) 
 
Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 127 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 128 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 76: 
Summaries of Neutralizing Antibody Against 2019/2020 QIV Strains by Study Day, Study Arm, and Previous Vaccination, Per 
Protocol Population 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
A/Brisbane/02/2018 IVR-190 (H1N1) 
 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 129 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
A/Kansas/14/2017 (H3N2) 
 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
xxx.x 
(xxx.x,xxx.x) 
 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
 
xx (xx, xx) 
 
xx (xx, xx) 
 
xx (xx, xx) 
 
xx (xx, xx) 
 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
 
xx (xx, xx) 
 
xx (xx, xx) 
 
xx (xx, xx) 
 
xx (xx, xx) 
 
GMFR (95% CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
 
xx.x 
(xx.x,xx.x) 
 
xx.x 
(xx.x,xx.x) 
 
xx.x 
(xx.x,xx.x) 
 
xx.x 
(xx.x,xx.x) 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 130 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
B/Phuket/3073/2013 (B Yamagata lineage) 
 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 131 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
B/Maryland/15/2016 BX-69A (B Victoria lineage) 
 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Previously 
Vaccinatedb 
Not 
Previously 
Vaccinatedc 
Day 90 Post 
Vaccination 1 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
xxx.x (xxx.x, 
xxx.x) 
Ratio of GMTsa 
- 
- 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Day 118 Post 
Vaccination 1 
 
 
 
 
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
xxx.x 
(xxx.x,xxx.x) 
Ratio of GMTs 
(95% CI)a 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
- 
- 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
xx.x (xx.x, 
xx.x) 
Seroconversion - 
% (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % 
(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
xx.x 
(xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
bPreviously Vaccinated means received either the 2017-2018 or 2018-2019 Seasonal Vaccine. 
c Not Previously Vaccinated means received neither the 2017-2018 or 2018-2019 Seasonal Vaccine. 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 77: 
Summaries of Neuraminidase Inhibition Antibody Against 2019/2020 QIV Strains by Study Day and Study Arm, Modified Intent-
to-Treat Population 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
A/Brisbane/02/2018 IVR-190 (H1N1) 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
A/Kansas/14/2017 (H3N2) 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 133 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
B/Phuket/3073/2013 (B Yamagata lineage) 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
B/Maryland/15/2016 BX-69A (B Victoria lineage) 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 134 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table with similar format: 
Table 78: 
Summaries of Neuraminidase Inhibition Antibody Against 2019/2020 QIV Strains by Study Day and Study Arm, Per Protocol 
Population 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 135 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 79: 
Summaries of Neuraminidase Inhibition Antibody Against 2019/2020 QIV Strains by Study Day, Study Arm, and Baseline 
Serostatus, Per Protocol Population 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
A/Brisbane/02/2018 IVR-190 (H1N1) 
 
Seropositive 
Seronegative 
Seropositive 
Seronegative 
Seropositive 
Seronegative 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
A/Kansas/14/2017 (H3N2) 
 
Seropositive 
Seronegative 
Seropositive 
Seronegative 
Seropositive 
Seronegative 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 136 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
B/Phuket/3073/2013 (B Yamagata lineage) 
 
Seropositive 
Seronegative 
Seropositive 
Seronegative 
Seropositive 
Seronegative 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
B/Maryland/15/2016 BX-69A (B Victoria lineage) 
 
Seropositive 
Seronegative 
Seropositive 
Seronegative 
Seropositive 
Seronegative 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 137 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 80: 
Summaries of Neuraminidase Inhibition Antibody Against 2019/2020 QIV Strains by Study Day, Study Arm, and Previous 
Vaccination, Per Protocol Population 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
A/Brisbane/02/2018 IVR-190 (H1N1) 
 
Previously Vaccinatedb 
Not Previously 
Vaccinatedc 
Previously Vaccinatedb 
Not Previously 
Vaccinatedc 
Previously Vaccinatedb 
Not Previously 
Vaccinatedc 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
A/Kansas/14/2017 (H3N2) 
 
Previously Vaccinatedb 
Not Previously 
Vaccinatedc 
Previously Vaccinatedb 
Not Previously 
Vaccinatedc 
Previously Vaccinatedb 
Not Previously 
Vaccinatedc 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 138 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
B/Phuket/3073/2013 (B Yamagata lineage) 
 
Previously Vaccinatedb 
Not Previously 
Vaccinatedc 
Previously Vaccinatedb 
Not Previously 
Vaccinatedc 
Previously Vaccinatedb 
Not Previously 
Vaccinatedc 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
B/Maryland/15/2016 BX-69A (B Victoria lineage) 
 
Previously Vaccinatedb 
Not Previously 
Vaccinatedc 
Previously Vaccinatedb 
Not Previously 
Vaccinatedc 
Previously Vaccinatedb 
Not Previously 
Vaccinatedc 
Day 90 Post Vaccination 1 (Baseline) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 139 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
bPreviously Vaccinated means received either the 2017-2018 or 2018-2019 Seasonal Vaccine. 
c Not Previously Vaccinated means received neither the 2017-2018 or 2018-2019 Seasonal Vaccine. 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 140 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 81: 
Summaries of Hemagglutination Inhibition Antibody Against Heterologous H3 Influenza Strain A/Michigan/84/2016 [H3N2] by 
Study Day and Study Arm, Modified Intent-to-Treat Population*¥  
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Day 1 (Pre-Vaccination 1) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Titer ≥ 1:40 - %(95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 8 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 29 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 57 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 141 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 90 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 180 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 142 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 365 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Titer ≥ 1:40 - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 143 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format: 
Table 82: 
Summaries of Hemagglutination Inhibition Antibody Against Heterologous H3 Influenza Strain A/Kenya/105/2017 [H3N2] by 
Study Day and Study Arm, Modified Intent-to-Treat Population*¥  
Table 83: 
Summaries of Hemagglutination Inhibition Antibody Against Heterologous H3 Influenza Strain A/Louisiana/13/2017 [H3N2] by 
Study Day and Study Arm, Modified Intent-to-Treat Population*¥   
Table 84: 
Summaries of Hemagglutination Inhibition Antibody Against Heterologous H3 Influenza Strain A/Aksaray/4048/2016 [H3N2] by 
Study Day and Study Arm, Modified Intent-to-Treat Population*¥   
Table 85: 
Summaries of Hemagglutination Inhibition Antibody Against Heterologous H3 Influenza Strain A/Shandonglaicheng/1763/2016 
[H3N2] by Study Day and Study Arm, Modified Intent-to-Treat Population*¥    
Table 86: 
Summaries of Hemagglutination Inhibition Antibody Against Heterologous H3 Influenza Strain A/Michigan/84/2016 [H3N2] by 
Study Day and Study Arm, Per Protocol Population*¥  
Table 87: 
Summaries of Hemagglutination Inhibition Antibody Against Heterologous H3 Influenza Strain A/Kenya/105/2017 [H3N2] by 
Study Day and Study Arm, Per Protocol Population*¥    
Table 88: 
Summaries of Hemagglutination Inhibition Antibody Against Heterologous H3 Influenza Strain A/Louisiana/13/2017 [H3N2] by 
Study Day and Study Arm, Per Protocol Population*¥    
Table 89: 
Summaries of Hemagglutination Inhibition Antibody Against Heterologous H3 Influenza Strain A/Aksaray/4048/2016 [H3N2] by 
Study Day and Study Arm, Per Protocol Population*¥    
Table 90: 
Summaries of Hemagglutination Inhibition Antibody Against Heterologous H3 Influenza Strain A/Shandonglaicheng/1763/2016 
[H3N2] by Study Day and Study Arm, Per Protocol Population*¥  
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 144 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 91: 
Summaries of Neutralizing Antibody Against Heterologous H3 Influenza Strain A/Michigan/84/2016 [H3N2] by Study Day and 
Study Arm, Modified Intent-to-Treat Population*¥  
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Day 1 (Pre-Vaccination 1) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 8 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 29 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 57 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 145 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
Day 90 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 180 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 365 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
- 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 146 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 147 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format: 
Table 92: 
Summaries of Neutralizing Antibody Against Heterologous H3 Influenza Strain A/Kenya/105/2017 [H3N2] by Study Day and 
Study Arm, Modified Intent-to-Treat Population*¥  
Table 93: 
Summaries of Neutralizing Antibody Against Heterologous H3 Influenza Strain A/Aksaray/4048/2016 [H3N2] by Study Day and 
Study Arm, Modified Intent-to-Treat Population*¥   
Table 94: 
Summaries of Neutralizing Antibody Against Heterologous H3 Influenza Strain A/Shandonglaicheng/1763/2016 [H3N2] by Study 
Day and Study Arm, Modified Intent-to-Treat Population*¥   
Table 95: 
Summaries of Neutralizing Antibody Against Heterologous H3 Influenza Strain A/Michigan/84/2016 [H3N2] by Study Day and 
Study Arm, Per Protocol Population*¥  
Table 96: 
Summaries of Neutralizing Antibody Against Heterologous H3 Influenza Strain A/Kenya/105/2017 [H3N2] by Study Day and 
Study Arm, Per Protocol Population*¥   
Table 97: 
Summaries of Neutralizing Antibody Against Heterologous H3 Influenza Strain A/Aksaray/4048/2016 [H3N2] by Study Day and 
Study Arm, Per Protocol Population*¥  
Table 98: 
Summaries of Neutralizing Antibody Against Heterologous H3 Influenza Strain A/Shandonglaicheng/1763/2016 [H3N2] by Study 
Day and Study Arm, Per Protocol Population*¥   
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 148 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 99: 
Summaries of Neuraminidase Inhibition Antibody Against Heterologous N1 NA Antigen from A/Oman/5532/2017 H6N1 Strain 
by Study Day and Study Arm, Modified Intent-to-Treat Population*¥  
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Day 1 (Pre-Vaccination 1) 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x xx.x (xx.x, xx.x)  
Day 8 Post Vaccination 1 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x xx.x (xx.x, xx.x)  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 29 Post Vaccination 1 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x xx.x (xx.x, xx.x)  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 57 Post Vaccination 1 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x xx.x (xx.x, xx.x)  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 149 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Day 90 Post Vaccination 1 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x xx.x (xx.x, xx.x)  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 118 Post Vaccination 1 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x xx.x (xx.x, xx.x)  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 180 Post Vaccination 1 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x xx.x (xx.x, xx.x)  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 365 Post Vaccination 1 
 
 
 
n 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
Ratio of GMTs (95% CI)a 
- 
xx.x (xx.x, xx.x) 
xx.x xx.x (xx.x, xx.x)  
Seroconversion - % (95% CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 150 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer 
aRatio of GMTs is defined as the ratio of the GMT from the adjuvanted group divided by the GMT from the corresponding unadjuvanted group. Confidence intervals for the ratio of GMTs will use the 
Delta Method. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 151 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format: 
Table 100: 
Summaries of Neuraminidase Inhibition Antibody Against Heterologous N1 NA Antigen from A/Cameroon/9766/2017 H6N1 
Strain by Study Day and Study Arm, Modified Intent-to-Treat Population*¥   
Table 101: 
Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 NA Antigen from A/Human/Hubei/3/2005 H3N2 
Strain by Study Day and Study Arm, Modified Intent-to-Treat Population*¥  
Table 102: 
Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 NA Antigen from A/Louisiana/13/2017 H6N2 Strain 
by Study Day and Study Arm, Modified Intent-to-Treat Population*¥   
Table 103: 
Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 NA Antigen from A/Townsville/51/2016 H6N2 Strain 
by Study Day and Study Arm, Modified Intent-to-Treat Population*¥   
Table 104: 
Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 NA Antigen from A/Aksaray/4048/2016 H6N2 Strain 
by Study Day and Study Arm, Modified Intent-to-Treat Population*¥   
Table 105: 
Summaries of Neuraminidase Inhibition Antibody Against Heterologous N1 NA Antigen from A/Oman/5532/2017 H6N1 Strain 
by Study Day and Study Arm, Per Protocol Population*¥   
Table 106: 
Summaries of Neuraminidase Inhibition Antibody Against Heterologous N1 NA Antigen from A/Cameroon/9766/2017 H6N1 
Strain by Study Day and Study Arm, Per Protocol Population*¥  
Table 107: 
Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 NA Antigen from A/Human/Hubei/3/2005 H3N2 
Strain by Study Day and Study Arm, Per Protocol Population*¥   
Table 108: 
Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 NA Antigen from A/Louisiana/13/2017 H6N2 Strain 
by Study Day and Study Arm, Per Protocol Population*¥   
Table 109: 
Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 NA Antigen from A/Townsville/51/2016 H6N2 Strain 
by Study Day and Study Arm, Per Protocol Population*¥   
Table 110: 
Summaries of Neuraminidase Inhibition Antibody Against Heterologous N2 NA Antigen from A/Aksaray/4048/2016 H6N2 Strain 
by Study Day and Study Arm, Per Protocol Population*¥  
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 152 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 111: 
Summary Statistics of Influenza Specific-IgG B Memory Cells (Spot Forming Cells per Million PBMC) by Study Day and Study 
Arm, Per Protocol Population 
Time Point 
Statistic 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-
CpG 
(N=X) 
All Subjects 
(N = X) 
Day 1 (Pre-Vaccination 1) 
n 
x 
x 
x 
x 
x 
x 
x 
  
Mean (95 %) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
 
GM (95 %) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
 
Median (Min, Max) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 29 Post Vaccination 1  
 
 
 
 
 
 
 
 
  
n 
x 
x 
x 
x 
x 
x 
x 
 
Mean (95 %) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
 
GM (95 %) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
 
Median (Min, Max) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
  
Mean absolute 
difference from 
Baseline (95%CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 90 Post Vaccination 1 
 
 
 
 
 
 
 
 
  
n 
x 
x 
x 
x 
x 
x 
x 
  
Mean (95 %) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
 
GM (95 %) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
 
Median (Min, Max) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
 
Mean absolute 
difference from 
Baseline (95%CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N = Number of subjects in the Per Protocol Population; n = Number of subjects with available results 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 153 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with similar format: 
Table 112: 
Summary Statistics of Influenza Specific-IgM B Memory Cells by Study Day and Study Arm, Per Protocol Population  
Table 113: 
Summary Statistics of Influenza Specific-IgA B Memory Cells by Study Day and Study Arm, Per Protocol Population  
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 154 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 114: 
Summary Statistics of Influenza Specific Plasmablasts by Study Day and Study Arm, Per Protocol Population 
Time Point 
Statistic 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-
CpG 
(N=X) 
All Subjects 
(N = X) 
Day 1 (Pre-Vaccination 1) 
n 
x 
x 
x 
x 
x 
x 
x 
Mean (95 %) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
GM (95 %) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Median (Min, Max) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Day 8 Post Vaccination 1  
 
 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
x 
Mean (95 %) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
GM (95 %) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Median (Min, Max) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
Mean absolute 
difference from 
Baseline (95%CI) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
xx (xx, xx) 
N = Number of subjects in the Per Protocol Population; n = Number of subjects with available results  
 
Table with similar format: 
Table 115: 
Summary Statistics of the Number of Influenza Specific Tfh Cells by Study Day and Study Arm, Per Protocol Population 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
- 155 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 116: 
Summaries of Functioning Non-Neutralizing Fc-effector Antibodies Against 2018/2019 QIV Strains by Study Day and Study 
Arm, Per Protocol Population 
Time Point 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
A/Michigan/45/2015 X-275 (H1N1) 
Day 1 (Pre-Vaccination 1) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 29 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) 
Day 1 (Pre-Vaccination 1) 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Day 29 Post Vaccination 1 
 
 
 
 
 
 
n 
x 
x 
x 
x 
x 
x 
GMT (95% CI) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
xxx.x (xxx.x,xxx.x) 
GMFR (95% CI) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
xx.x (xx.x,xx.x) 
Repeat for B/Phuket/3073/2013 (B Yamagata lineage) 
Repeat for B/Maryland/15/2016 BX-69A (B lineage) 
N = Number of subjects in the Modified Intent-to-Treat Population; n = Number of subjects with available results; GMT = Geometric Mean Titer; GMFR = Geometric Mean Fold Rise. 
 


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14.3 
Safety Data 
14.3.1 Displays of Adverse Events 
Table 117: 
Overall Summary of Adverse Events- Safety Population*¥  
 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + 
Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + 
Advax-CpG 
(N=X) 
All Subjects 
(N=X) 
Subjectsa with 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one local solicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one grade 3 local solicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one systemic solicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one grade 3 systemic solicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one unsolicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one related unsolicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
   Mild (Grade 1) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
   Moderate (Grade 2)  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
   Severe (Grade 3)  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
   Not yet assessed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one severe (Grade 3) unsolicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
   Related  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
   Unrelated 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + 
Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + 
Advax-CpG 
(N=X) 
All Subjects 
(N=X) 
Subjectsa with 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
At least one serious adverse eventb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 At least one related, serious adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one adverse event leading to early terminationc  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one medically attended adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one adverse event of special interest 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one new onset chronic medical condition 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one potentially immune mediated medical 
condition 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one abnormal clinical safety laboratory 
adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 Mild (Grade 1) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 Moderate (Grade 2) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 Severe (Grade 3) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
N = Number of subjects in the Safety Population 
a Subjects are counted once for each category regardless of the number of events. 
b A listing of Serious Adverse Events is included in Tab AE SAE Listing. 
c As reported on the Adverse Event eCRF. 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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Table 118: 
Adverse Events Occurring in 5% of Subjects in Any Study Arm by MedDRA System Organ Class and Preferred Term, and 
Study Arm - Safety Population 
Preferred 
Term 
MedDRA 
System 
Organ Class 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
All Subjects 
(N=X) 
 
 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
 
 
 
 
 
 
 
 
 
 
 
 
Serious Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other (Non-serious) Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of subjects in the Safety Population (number of subjects at risk).  
n = Number of subjects reporting event.  
Events= total frequency of events reported. 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.1.1 
Solicited Adverse Events 
Table 119: 
Number and Percentage of Subjects Experiencing Solicited Events with 95% Confidence Intervals by Symptom and Study Arm – 
Safety Population 
Symptom 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% 
CI 
Any Symptom 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
Any Systemic Symptom 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fever 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Feverishness 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Malaise 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Myalgia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arthralgia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Headache 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any Local Symptom 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tenderness 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pruritus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ecchymosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ecchymosis (measurement) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erythema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erythema (measurement) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Induration/Swelling 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% 
CI 
Induration/Swelling 
(measurement) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of subjects in the Safety Population who received any study vaccination. 
95% CI estimated using Clopper-Pearson exact method 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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Table 120: 
Logistic Regression Model to Evaluate the Relationship of Treatment with Reporting Any Local Event Post First Study 
Vaccination - Safety Population 
Model Parameter 
Parameter Category 
Parameter Estimate 
SE 
p-value 
Odds Ratio 
95%CI 
Intercept 
N/A 
xxx.x 
xxx.x 
x.xxx 
- 
- 
Treatment 
Fluzone 
- 
- 
- 
- 
- 
 
Fluzone + AF03 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
 
Fluzone + Advax-CpG 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
 
Flublok 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
 
Flublok + AF03 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
 
Flublok + Advax-CpG 
xxx.x 
xxx.x 
x.xxx 
xx.x 
xx.x-xx.x 
N = Number of subjects in the safety population. 
 
 
Table with similar format: 
Table 121: 
Logistic Regression Model to Evaluate the Relationship of Treatment with Reporting Any Systemic Event Post First Study 
Vaccination - Safety Population 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 122: 
Number and Percentage of Subjects Experiencing Solicited Events by Symptom, Maximum Severity and Study Arm Post First 
Study Vaccination – Safety Population* 
Symptom 
Severity 
Group 1 
Fluzone 
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok 
(N=X) 
Group 5 
Flublok + AF03 
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
Any Symptom 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Any Systemic Symptom 
None 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
x 
xx (xx-xx) 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Fever 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Feverishness 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Malaise 
None 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Severity 
Group 1 
Fluzone 
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok 
(N=X) 
Group 5 
Flublok + AF03 
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Myalgia 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Arthralgia 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Headache 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Any Local Symptom 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Severity 
Group 1 
Fluzone 
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok 
(N=X) 
Group 5 
Flublok + AF03 
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
Pain 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Tenderness 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Pruritus 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Ecchymosis 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Ecchymosis 
(measurement) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Erythema 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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Symptom 
Severity 
Group 1 
Fluzone 
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok 
(N=X) 
Group 5 
Flublok + AF03 
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
n 
% 
(95% CI) 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Erythema 
(measurement) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Induration/Swelling 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Induration/Swelling 
(measurement) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of subjects in the Safety Population. 
95% CI estimated using Clopper-Pearson exact method. 
Severity is the maximum severity reported over all solicited symptoms post dosing for each subject.  
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 123: 
Number and Percentage of Subjects Experiencing Solicited Events by Symptom, Severity, Day Post Dose, and Study Arm Post 
First Study Vaccination - Safety Population 
Symptom 
Severity 
Pre-Vac 
Post-Vac 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8+ 
 
 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1: Fluzone (N=X) 
Any Symptom 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any Systemic Symptom 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fever 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Feverishness 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Malaise 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Symptom 
Severity 
Pre-Vac 
Post-Vac 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8+ 
 
 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Myalgia 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arthralgia 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Headache 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any Local Symptom 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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Symptom 
Severity 
Pre-Vac 
Post-Vac 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8+ 
 
 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tenderness 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pruritus 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ecchymosis 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ecchymosis (measurement) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erythema 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erythema (measurement) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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Symptom 
Severity 
Pre-Vac 
Post-Vac 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8+ 
 
 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Induration/Swelling 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Induration/Swelling (measurement) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[Repeat for all study arms] 
N = Number of subjects in the Safety Analysis Population. Severity is the maximum severity reported post vaccination for each subject for each day. 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.1.2 
Unsolicited Adverse Events 
Table 124: 
Serious Adverse Events and All Unsolicited Adverse Events Occurring from Day 1 through Day 365 following the First 
Vaccination, in Subjects in Any Study Arm by MedDRA System Organ Class and Preferred Term, and by Study Arm – Safety 
Population 
Preferred 
Term 
MedDRA 
System 
Organ Class 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
All Subjects 
(N=X) 
 
 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
 
 
 
 
 
 
 
 
 
 
 
 
Serious Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of subjects in the Safety Population (number of subjects at risk).  
n = Number of subjects reporting event.  
Events = total frequency of events reported. 
SOC = system organ class 
PT = preferred term 
 
Table with similar format: 
Table 125: 
Serious Adverse Events and All Unsolicited Adverse Events Occurring from Day 1 through Day 29 following the First 
Vaccination, in Subjects in Any Study Arm by MedDRA System Organ Class and Preferred Term, and by Study Arm – Safety 
Population 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
Version 3.0 
04 May 2021 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 126: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events with 95% Confidence Intervals by MedDRA 
System Organ Class and Preferred Term, and Study Arm – Safety Population 
 
 
Group 1 
Fluzone 
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-CpG 
(N=X) 
Group 4 
Flublok 
(N=X) 
Group 5 
Flublok + AF03 
(N=X) 
Group 6 
Flublok + Advax-CpG 
(N=X) 
MedDRA System 
Organ Class 
MedDRA 
Preferred Term 
n 
% 
(95% 
CI) 
n 
% 
(95% 
CI) 
n 
% 
(95% CI) 
n 
% 
(95% 
CI) 
n 
% 
(95% 
CI) 
n 
% 
(95% 
CI) 
Any SOC 
Any PT 
x 
xx 
(xx-xx) 
x 
xx 
(xx-xx) 
x 
xx 
(xx-xx) 
x 
xx 
(xx-xx) 
x 
xx 
(xx-xx) 
x 
xx 
(xx-xx) 
[SOC 1] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
N = number of subjects in the Safety Analysis Population. This table presents number and percentage of subjects. A subject is only counted once per PT. 
 
 
Table with similar format: 
Table 127: 
Number and Percentage of Subjects Experiencing Any Unsolicited Adverse Events from Day 1 through Day 29 with 95% 
Confidence Intervals by MedDRA System Organ Class and Preferred Term, and Study Arm – Safety Population 
 


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Table 128: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Maximum Severity, Relationship, and Study Arm – Safety Population 
Study Arm 
MedDRA 
System Organ 
Class 
MedDRA Preferred 
Term 
Any Incidence 
Severity1 
Relationship to Treatment2 
Mild 
Moderate 
Severe 
Not Related 
Related 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1: Fluzone (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[SOC 1] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
Group 2: Fluzone + AF03 (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[SOC 1] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
Group 3: Fluzone + Advax-CpG (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[SOC 1] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Arm 
MedDRA 
System Organ 
Class 
MedDRA Preferred 
Term 
Any Incidence 
Severity1 
Relationship to Treatment2 
Mild 
Moderate 
Severe 
Not Related 
Related 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 4: Flublok (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[SOC 1] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
Group 5: Flublok+ AF03 (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[SOC 1] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
Group 6: Flublok + Advax-CpG (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[SOC 1] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N = Number of subjects in the Safety Analysis Population.  
1 For severity, a subject is counted once per preferred term and is summarized according to their highest severity. 
2 For relationship, a subject is only counted once per preferred term and is summarized according to their closest relationship. 


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Table with similar format: 
Table 129: 
Number and Percentage of Subjects Experiencing Any Unsolicited Adverse Events from Day 1 through Day 29 by MedDRA 
System Organ Class and Preferred Term, Maximum Severity, Relationship, and Study Arm – Safety Population 
 


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Table 130: 
Number and Percentage of Subjects Experiencing Non-Serious Related Unsolicited Adverse Events by MedDRA System Organ 
Class and Preferred Term, Maximum Severity, and Study Arm – Safety Population* 
Study Arm 
MedDRA System Organ Class 
MedDRA Preferred Term 
Any Incidence 
Severity1 
Mild 
Moderate 
Severe 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1: Fluzone (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
Group 2: Fluzone + AF03 (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
Group 3: Fluzone + Advax-CpG 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 


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Study Arm 
MedDRA System Organ Class 
MedDRA Preferred Term 
Any Incidence 
Severity1 
Mild 
Moderate 
Severe 
n 
% 
n 
% 
n 
% 
n 
% 
Group 4: Flublok (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
Group 5: Flublok+ AF03 (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
Group 6: Flublok + Advax-CpG 
(N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
Note: N = Number of subjects in the Safety Analysis Population. This table presents number and percentage of subjects. 
1 For severity, a subject is counted once per preferred term and is summarized according to their highest severity. 


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Table 131: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events Within 28 Days Post First Study Vaccination by 
MedDRA System Organ Class and Preferred Term, Day Post Vaccination, and Study Arm – Safety Population 
MedDRA System Organ Class 
MedDRA Preferred 
Term 
Day 1-8 
Post Vac 1  
Day 9-29 
Post Vac 1 
Day 1-29 
Post Vac 1 
n 
% 
n 
% 
n 
% 
Group 1: Fluzone (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
Group 2: Fluzone + AF03 (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
Group 3: Fluzone + Advax-CpG (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 


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MedDRA System Organ Class 
MedDRA Preferred 
Term 
Day 1-8 
Post Vac 1  
Day 9-29 
Post Vac 1 
Day 1-29 
Post Vac 1 
n 
% 
n 
% 
n 
% 
Group 4: Flublok (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
Group 5: Flublok + AF03 (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
Group 6: Flublok + Advax-CpG (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the Safety Analysis Population. This table presents number and percentage of subjects. For each time period, a subject is only counted once per PT. 
 
 


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Table 132: 
Number and Percentage of Subjects Experiencing Non-Serious, Related Unsolicited Adverse Events Within 28 Days Post First 
Study Vaccination by MedDRA System Organ Class and Preferred Term, Day Post Vaccination and Study Arm – Safety 
Population 
MedDRA System Organ Class 
MedDRA Preferred Term 
Day 1-8 
Post Vac 1  
Day 9-29 
Post Vac 1 
Day 1-29 
Post Vac 1 
n 
% 
n 
% 
n 
% 
Group 1: Fluzone (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
Group 2: Fluzone + AF03 (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
Group 3: Fluzone + Advax-CpG (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 


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MedDRA System Organ Class 
MedDRA Preferred Term 
Day 1-8 
Post Vac 1  
Day 9-29 
Post Vac 1 
Day 1-29 
Post Vac 1 
n 
% 
n 
% 
n 
% 
Group 4: Flublok (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
Group 5: Flublok + AF03 (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
Group 6: Flublok + Advax-CpG (N=X) 
Any SOC 
Any PT 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
Any PT 
x 
xx 
x 
xx 
x 
xx 
 
[PT 1] 
x 
xx 
x 
xx 
x 
xx 
 
[PT 2] 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the Safety Analysis Population. This table presents number and percentage of subjects. For each time period, a subject is only counted once per PT. 
 


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Table 133: 
Number of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, Day Post Vaccination, and Study 
Arm – Safety Population 
 
 
 
Day 1-8 
Post Vac 1 
Day 9-29 
Post Vac 1 
Day 1-29 
Post Vac 1 
Study Arm 
MedDRA System Organ Class 
MedDRA Preferred Term 
# of Events 
# of Events 
# of Events 
Group 1: Fluzone (N=X) 
Any SOC 
Any PT 
x 
x 
x 
 
[SOC 1] 
Any PT 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
[PT 2] 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
[PT 2] 
 
 
 
Group 2: Fluzone + AF03 (N=X) 
Any SOC 
Any PT 
x 
x 
x 
 
[SOC 1] 
Any PT 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
[PT 2] 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
[PT 2] 
 
 
 
Group 3: Fluzone + Advax-CpG (N=X) 
Any SOC 
Any PT 
x 
x 
x 
 
[SOC 1] 
Any PT 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
[PT 2] 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
[PT 2] 
 
 
 


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Day 1-8 
Post Vac 1 
Day 9-29 
Post Vac 1 
Day 1-29 
Post Vac 1 
Group 4: Flublok (N=X) 
Any SOC 
Any PT 
x 
x 
x 
 
[SOC 1] 
Any PT 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
[PT 2] 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
[PT 2] 
 
 
 
Group 5: Flublok+ AF03 (N=X) 
Any SOC 
Any PT 
x 
x 
x 
 
[SOC 1] 
Any PT 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
[PT 2] 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
[PT 2] 
 
 
 
Group 6: Flublok + Advax-CpG (N=X) 
Any SOC 
Any PT 
x 
x 
x 
 
[SOC 1] 
Any PT 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
[PT 2] 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 


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14.3.2 Listing of Serious and Significant Adverse Events 
Table 134: 
Listing of Serious Adverse Events* 
[Implementation Note: If the event is ongoing (no stop date), indicate “ongoing” in the “Duration” column. If more than one reason is selected for the 
reason reported as an SAE, list all reasons in the column, separated by a comma. In the “If Not Related, Alternate Etiology” column, merge the 2 data 
fields for collecting alternate etiology, separate by a colon. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification.] 
Adverse 
Event 
Associated 
with Vac # 
# of Days 
Post 
Associated 
Dose 
(Duration) 
# of 
Days 
Post Vac 
the 
Event 
Became 
Serious 
Reason 
Reported 
as an SAE 
Severity 
Relationship 
to Study 
Vaccination 
In Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Vaccination 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ Class 
MedDRA 
Preferred 
Term 
Subject ID: , Study Arm: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Subject ID: , Study Arm: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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Table 135: 
Listing of Adverse Events of Special Interest* 
[Implementation Note: This listing is included in the tables section, as it is included in the body of the CSR. If the event is ongoing (no stop date), indicate 
“ongoing” in the “Duration” column. In the “If Not Related, Alternate Etiology” column, merge the 2 data fields for collecting alternate etiology, separate 
by a colon.] 
Adverse 
Event 
Associated 
with Vac # 
# of Days 
Post 
Associated 
Vac 
(Duration) 
SAE? 
Severity 
Relationship 
to Study 
Vaccination 
In Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Vaccination 
Subject 
Discontinued 
Due to AE 
Outcome 
MAAE 
MedDRA 
System 
Organ Class 
MedDRA 
Preferred 
Term 
 
Subject ID: , Study Arm: , AE Number:  
 
 
 
SAE: No 
Mild 
 
 
 
 
 
 
 
 
 
Comments: 
 
 
 
Subject ID: , Study Arm: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Tables with similar format: 
Table 136: 
Listing of Potentially Immune Mediated Medical Conditions* 
Table 137: 
Listing of New Onset Chronic Medical Conditions* 
Table 138: 
Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events* 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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14.3.3 Narratives of Deaths, Other Serious and Significant Adverse Events 
(not included in SAP, but this is a placeholder for the CSR) 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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14.3.4 Displays of Laboratory Results 
Table 139: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Arm – All Laboratory Parameters* 
 
 
Study Arm 
Study Day 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1: Fluzone (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 2: Fluzone + AF03 (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 3: Fluzone + Advax-CpG (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 4: Flublok (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 5: Flublok + AF03 (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 6: Flublok + Advax-CpG (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the Safety Population. 


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Table 140: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Arm – White Blood Cells 
 
Tables with similar format: 
Table 141: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Arm – Hemoglobin 
Table 142: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Arm – Platelets 
Table 143: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Arm – Alanine Aminotransferase (ALT) 
Table 144: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Arm – Aspartate Amino Transferase (AST)  
Table 145: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Arm – Total Bilirubin 
Table 146: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Arm – Gamma-Glutamyl Transferase (GGT)  
Study Arm 
Study Day 
N 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1: Fluzone (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 2: Fluzone + 
AF03 (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 3: Fluzone + 
Advax-CpG (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 4: Flublok (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 5: Flublok + 
AF03 (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 6: Flublok + 
Advax-CpG (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Note: N = Number of subjects in the Safety Population. 


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Table 147: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Arm – Alkaline Phosphatase (ALP) 
Table 148: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Arm – Serum Amylase 
Table 149: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Arm – Serum Lipase  
Table 150: 
Laboratory Results by Parameter, Maximum Severity, Study Day, and Study Arm – Creatinine 
 


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Table 151: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Arm – White Blood Cells 
Study Arm 
Study 
Day 
Value 
Change from Baseline 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Group 1: Fluzone (N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
NA 
Day 8 
x 
xx.x 
xx.x 
xx 
xx, xx 
x 
xx.x 
xx.x 
xx 
xx, xx 
Group 2: Fluzone + AF03 (N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
NA 
Day 8 
x 
xx.x 
xx.x 
xx 
xx, xx 
x 
xx.x 
xx.x 
xx 
xx, xx 
Group 3: Fluzone + Advax-CpG (N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
NA 
Day 8 
x 
xx.x 
xx.x 
xx 
xx, xx 
x 
xx.x 
xx.x 
xx 
xx, xx 
Group 4: Flublok (N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
NA 
Day 8 
x 
xx.x 
xx.x 
xx 
xx, xx 
x 
xx.x 
xx.x 
xx 
xx, xx 
Group 5: Flublok + AF03 (N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
NA 
Day 8 
x 
xx.x 
xx.x 
xx 
xx, xx 
x 
xx.x 
xx.x 
xx 
xx, xx 
Group 6: Flublok + Advax-CpG (N=X) 
Baseline 
x 
xx.x 
xx.x 
xx 
xx, xx 
NA 
NA 
NA 
NA 
NA 
Day 8 
x 
xx.x 
xx.x 
xx 
xx, xx 
x 
xx.x 
xx.x 
xx 
xx, xx 
Note: N = Number of subjects in the Safety Population. 
 
Tables with similar format 
Table 152: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Arm – Hemoglobin 
Table 153: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Arm – Platelets 
Table 154: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Arm – Alanine Aminotransferase 
(ALT) 
Table 155: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Arm – Aspartate Amino 
Transferase (AST)  
Table 156: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Arm – Total Bilirubin 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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Table 157: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Arm – Gamma-Glutamyl 
Transferase (GGT)  
Table 158: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Arm – Alkaline Phosphatase (ALP) 
Table 159: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Arm – Amylase 
Table 160: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Arm – Lipase  
Table 161: 
Laboratory Summary Statistics of Value and Change from Baseline by Study Day, and Study Arm – Creatinine 
 
 
 


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14.3.4.5 
Clinical Laboratory Reference Ranges 
(Placeholder for the CSR) 
 
 


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14.3.5 Abnormal Laboratory Value Listings (by Subject) 
Table 162: 
Listing of Abnormal Laboratory Results - Chemistry  
Subject 
ID 
Study Arm 
Sex 
Age 
(years) 
Planned 
Time Point 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship to 
Study 
Vaccination 
If Not Related, 
Alternate 
Etiology 
Action Taken 
with Study 
Vaccination 
Subject 
Discontinued 
Due to Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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Table 163: 
Listing of Abnormal Laboratory Results - Hematology 
Subject 
ID 
Study Arm 
Sex 
Age 
(years) 
Planned 
Time Point 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate 
Etiology 
Action Taken 
with Study 
Vaccination 
Subject 
Discontinued 
Due to Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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14.3.6 Displays of Vital Signs 
Table 164: 
Vital Signs by Assessment, Maximum Severity, Time Point, and Study Arm – Any Assessment 
Study Arm 
Study Day 
N 
None 
Mild 
Moderate 
Severe 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1: Fluzone (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 2: Fluzone + AF03 (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 3: Fluzone + Advax-CpG (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 4: Flublok (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 5: Flublok + AF03 (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 6: Flublok + Advax-CpG (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population 
 
Table with similar format 
Table 165: 
Vital Signs by Assessment, Maximum Severity, Time Point, and Study Arm – Oral Temperature 
 


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Table 166: 
Vital Signs by Assessment, Maximum Severity, Study Day, and Study Arm – Systolic Blood Pressure 
Study Arm 
Study Day 
N 
None 
Mild 
(Low) 
Mild 
(High) 
Moderate 
(Low) 
Moderate 
(High) 
Severe 
(Low) 
Severe 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Group 1: Fluzone (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 2: Fluzone + AF03 (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 3: Fluzone + Advax-CpG (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 4: Flublok (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 5: Flublok + AF03 (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Group 6: Flublok + Advax-CpG (N=X) 
Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Max Severity Post Baseline 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in the Safety Population. 
 
Tables with similar format: 
Table 167: 
Vital Signs by Assessment, Maximum Severity, Study Day, and Study Arm– Diastolic Blood Pressure 
Table 168: 
Vital Signs by Assessment, Maximum Severity, Study Day, and Study Arm – Pulse 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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14.4 
Summary of Concomitant Medications 
Table 169: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO Drug Classification and Study Arm 
WHO Drug Code 
Level 1, Anatomic Group 
WHO Drug Code 
Level 2, Therapeutic 
Subgroup 
Group 1 
Fluzone  
(N=X) 
Group 2 
Fluzone + AF03 
(N=X) 
Group 3 
Fluzone + Advax-
CpG 
(N=X) 
Group 4 
Flublok  
(N=X) 
Group 5 
Flublok + AF03  
(N=X) 
Group 6 
Flublok + Advax-
CpG 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Level 1 Codes 
Any Level 2 Codes 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[ATC Level 1 - 1] 
Any [ATC 1 – 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[ATC 2 - 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[ATC 2 - 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[ATC 2 - 3] 
 
 
 
 
 
 
 
 
 
 
 
 
[ATC Level 1 – 2] 
[ATC 2 - 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[ATC 2 - 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[ATC 2 - 3] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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APPENDIX 2.  FIGURE MOCK-UPS 
 
 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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LIST OF FIGURES 
Figure 1: 
CONSORT Flow Diagram .................................................................................... 207 
Figure 2: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2018/2019 A/Michigan/45/2015 X-275 (H1N1) by Study Day and 
Study Arm, Modified Intent-to-Treat Population................................................... 208 
Figure 3: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-
186 (H3N2) by Study Day and Study Arm, Modified Intent-to-Treat 
Population ............................................................................................................ 208 
Figure 4: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) 
by Study Day and Study Arm, Modified Intent-to-Treat Population ...................... 208 
Figure 5: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day and Study Arm, Modified Intent-to-Treat Population......... 208 
Figure 6: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by 
Study Day and Study Arm, Per Protocol Population.............................................. 208 
Figure 7: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-
186 (H3N2) by Study Day and Study Arm, Per Protocol Population ..................... 209 
Figure 8: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) 
by Study Day and Study Arm, Per Protocol Population ......................................... 209 
Figure 9: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day and Study Arm, Per Protocol Population ........................... 209 
Figure 10: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day 
and Study Arm, Modified Intent-to-Treat Population ............................................ 209 
Figure 11: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2018/2019 QIV Strain /Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) 
by Study Day and Study Arm, Modified Intent-to-Treat Population ...................... 209 
Figure 12: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study 
Day and Study Arm, Modified Intent-to-Treat Population ..................................... 209 
Figure 13: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by 
Study Day and Study Arm, Modified Intent-to-Treat Population ........................... 209 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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Figure 14: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day 
and Study Arm, Per Protocol Population ............................................................... 209 
Figure 15: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 
(H3N2) by Study Day and Study Arm, Per Protocol Population ............................ 209 
Figure 16: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study 
Day and Study Arm, Per Protocol Population ....................................................... 209 
Figure 17: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by 
Study Day and Study Arm, Per Protocol Population.............................................. 209 
Figure 18: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by 
Study Day and Study Arm, Modified Intent-to-Treat Population ........................... 209 
Figure 19: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-
186 (H3N2) by Study Day and Study Arm, Modified Intent-to-Treat 
Population ............................................................................................................ 209 
Figure 20: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) 
by Study Day and Study Arm, Modified Intent-to-Treat Population ...................... 210 
Figure 21: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day and Study Arm, Modified Intent-to-Treat Population......... 210 
Figure 22: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by 
Study Day and Study Arm, Per Protocol Population.............................................. 210 
Figure 23: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-
186 (H3N2) by Study Day and Study Arm, Per Protocol Population ..................... 210 
Figure 24: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) 
by Study Day and Study Arm, Per Protocol Population ......................................... 210 
Figure 25: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day and Study Arm, Per Protocol Population ........................... 210 
Figure 26: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2019/2020 QIV Strain A/Brisbane/02/2018 (H1N1) by Study Day 
and Study Arm, Modified Intent-to-Treat Population ............................................ 210 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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Figure 27: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2019/2020 QIV Strain A/Brisbane/02/2018 (H1N1) by Study Day 
and Study Arm, Per Protocol Population ............................................................... 210 
Figure 28: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2019/2020 QIV Strain A/Brisbane/02/2018 (H1N1) by Study Day and Study 
Arm, Modified Intent-to-Treat Population ............................................................ 210 
Figure 29: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2019/2020 QIV Strain A/Brisbane/02/2018 (H1N1) by Study Day and Study 
Arm, Per Protocol Population ............................................................................... 210 
Figure 30: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2019/2020 QIV Strain A/Brisbane/02/2018 (H1N1) by Study Day 
and Study Arm, Modified Intent-to-Treat Population ............................................ 210 
Figure 31: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2019/2020 QIV Strain A/Brisbane/02/2018 (H1N1) by Study Day 
and Study Arm, Per Protocol Population ............................................................... 211 
Figure 32: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2019/2020 QIV Strain A/Kansas/14/2017 (H3N2) by Study Day and 
Study Arm, Modified Intent-to-Treat Population................................................... 211 
Figure 33: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2019/2020 QIV Strain A/Kansas/14/2017 (H3N2) by Study Day and 
Study Arm, Per Protocol Population ..................................................................... 211 
Figure 34: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2019/2020 QIV Strain A/Kansas/14/2017 (H3N2) by Study Day and Study 
Arm, Modified Intent-to-Treat Population ............................................................ 211 
Figure 35: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2019/2020 A/Kansas/14/2017 (H3N2) Strain by Study Day and Study Arm, 
Per Protocol Population ........................................................................................ 211 
Figure 36: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2019/2020 QIV Strain A/Kansas/14/2017 (H3N2) by Study Day and 
Study Arm, Modified Intent-to-Treat Population................................................... 211 
Figure 37: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2019/2020 QIV Strain A/Kansas/14/2017 (H3N2) by Study Day and 
Study Arm, Per Protocol Population ..................................................................... 211 
Figure 38: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2019/2020 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) 
by Study Day and Study Arm, Modified Intent-to-Treat Population ...................... 211 
Figure 39: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2019/2020 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) 
by Study Day and Study Arm, Per Protocol Population ......................................... 211 


Statistical Analysis Plan - DMID Protocol: 18-0011 
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Figure 40: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2019/2020 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study 
Day and Study Arm, Modified Intent-to-Treat Population ..................................... 211 
Figure 41: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2019/2020 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study 
Day and Study Arm, Per Protocol Population ....................................................... 211 
Figure 42: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2019/2020 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) 
by Study Day and Study Arm, Modified Intent-to-Treat Population ...................... 212 
Figure 43: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2019/2020 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) 
by Study Day and Study Arm, Per Protocol Population ......................................... 212 
Figure 44: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2019/2020 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day and Study Arm, Modified Intent-to-Treat Population......... 212 
Figure 45: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against 2019/2020 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day and Study Arm, Per Protocol Population ........................... 212 
Figure 46: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2019/2020 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by 
Study Day and Study Arm, Modified Intent-to-Treat Population ........................... 212 
Figure 47: Reverse Cumulative Distribution of Neutralizing Antibody Against 
2019/2020 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by 
Study Day and Study Arm, Per Protocol Population.............................................. 212 
Figure 48: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against QIV Strain 2019/2020 B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day and Study Arm, Modified Intent-to-Treat Population......... 212 
Figure 49: Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody 
Against 2019/2020 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria 
lineage) by Study Day and Study Arm, Per Protocol Population ........................... 212 
Figure 50: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against Heterologous Influenza A/H3 Strain A/Colombia/6639/2017 by 
Study Day and Study Arm, Modified Intent-to-Treat Population ........................... 213 
Figure 51: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against Heterologous Influenza A/H3 Strain A/Victoria/756/2017 by Study 
Day and Study Arm, Modified Intent-to-Treat Population ..................................... 213 
Figure 52: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against Heterologous Influenza A/H3 Strain A/Kenya/105/2017 by Study 
Day and Study Arm, Modified Intent-to-Treat Population ..................................... 213 


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Figure 53: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against Heterologous Influenza A/H3 Strain A/Louisiana/13/2017 by Study 
Day and Study Arm, Modified Intent-to-Treat Population ..................................... 213 
Figure 54: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against Heterologous Influenza A/H3 Strain A/Michigan/84/2016 H3N2 by 
Study Day and Study Arm, Modified Intent-to-Treat Population ........................... 213 
Figure 55: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against Heterologous Influenza A/H3 Strain A/Colombia/6639/2017 by 
Study Day and Study Arm, Per Protocol Population.............................................. 213 
Figure 56: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against Heterologous Influenza A/H3 Strain A/Victoria/756/2017 by Study 
Day and Study Arm, Per Protocol Population ....................................................... 213 
Figure 57: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against Heterologous Influenza A/H3 Strain A/Kenya/105/2017 by Study 
Day and Study Arm, Per Protocol Population ....................................................... 213 
Figure 58: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against Heterologous Influenza A/H3 Strain A/Louisiana/13/2017 by Study 
Day and Study Arm, Per Protocol Population ....................................................... 213 
Figure 59: Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody 
Against Heterologous Influenza A/H3 Strain A/Michigan/84/2016 H3N2 by 
Study Day and Study Arm, Per Protocol Population.............................................. 213 
Figure 60: Reverse Cumulative Distribution of Neutralizing Antibody Against 
Heterologous Influenza A/H3 Strain A/Colombia/6639/2017 by Study Day 
and Study Arm, Modified Intent-to-Treat Population ............................................ 213 
Figure 61: Reverse Cumulative Distribution of Neutralizing Antibody Against 
Heterologous Influenza A/H3 Strain A/Victoria/756/2017 by Study Day and 
Study Arm, Modified Intent-to-Treat Population................................................... 213 
Figure 62: Reverse Cumulative Distribution of Neutralizing Antibody Against 
Heterologous Influenza A/H3 Strain A/Kenya/105/2017 by Study Day and 
Study Arm, Modified Intent-to-Treat Population................................................... 213 
Figure 63: Reverse Cumulative Distribution of Neutralizing Antibody Against 
Heterologous Influenza A/H3 Strain A/Louisiana/13/2017 by Study Day and 
Study Arm, Modified Intent-to-Treat Population................................................... 214 
Figure 64: Reverse Cumulative Distribution of Neutralizing Antibody Against 
Heterologous Influenza A/H3 Strain A/Michigan/84/2016 H3N2 by Study 
Day and Study Arm, Modified Intent-to-Treat Population ..................................... 214 
Figure 65: Reverse Cumulative Distribution of Neutralizing Antibody Against 
Heterologous Influenza A/H3 Strain A/Colombia/6639/2017 by Study Day 
and Study Arm, Per Protocol Population ............................................................... 214 


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Figure 66: Reverse Cumulative Distribution of Neutralizing Antibody Against 
Heterologous Influenza A/H3 Strain A/Victoria/756/2017 by Study Day and 
Study Arm, Per Protocol Population ..................................................................... 214 
Figure 67: Reverse Cumulative Distribution of Neutralizing Antibody Against 
Heterologous Influenza A/H3 Strain A/Kenya/105/2017 by Study Day and 
Study Arm, Per Protocol Population ..................................................................... 214 
Figure 68: Reverse Cumulative Distribution of Neutralizing Antibody Against 
Heterologous Influenza A/H3 Strain A/Louisiana/13/2017 by Study Day and 
Study Arm, Per Protocol Population ..................................................................... 214 
Figure 69: Reverse Cumulative Distribution of Neutralizing Antibody Against 
Heterologous Influenza A/H3 Strain A/Michigan/84/2016 H3N2 by Study 
Day and Study Arm, Per Protocol Population ....................................................... 214 
Figure 70: Reverse Cumulative Distribution of Neuraminidase Inhibition N1 NA 
Antigen from A/Oman/5532/2017 H6N1 Strain by Study Day and Study 
Arm, Modified Intent-to-Treat Population ............................................................ 214 
Figure 71: Reverse Cumulative Distribution of Neuraminidase Inhibition N1 NA 
Antigen from A/Cameroon/9766/2017 H6N1 Strain by Study Day and Study 
Arm, Modified Intent-to-Treat Population ............................................................ 214 
Figure 72: Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA 
Antigen from A/Human/Hubei/3/2005 H3N1 Strain by Study Day and Study 
Arm, Modified Intent-to-Treat Population ............................................................ 214 
Figure 73: Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA 
Antigen from A/Louisiana/13/2017 H6N2 Strain by Study Day and Study 
Arm, Modified Intent-to-Treat Population ............................................................ 214 
Figure 74: Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA 
Antigen from A/Townsville/51/2016 H6N2 Strain by Study Day and Study 
Arm, Modified Intent-to-Treat Population ............................................................ 214 
Figure 75: Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA 
Antigen from A/Aksaray/4048/2016 H6N2 Strain by Study Day and Study 
Arm, Modified Intent-to-Treat Population ............................................................ 215 
Figure 76: Reverse Cumulative Distribution of Neuraminidase Inhibition N1 NA 
Antigen from A/Oman/5532/2017 H6N1 Strain by Study Day and Study 
Arm, Per Protocol Population ............................................................................... 215 
Figure 77: Reverse Cumulative Distribution of Neuraminidase Inhibition N1 NA 
Antigen from A/Cameroon/9766/2017 H6N1 Strain by Study Day and Study 
Arm, Per Protocol Population ............................................................................... 215 
Figure 78: Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA 
Antigen from A/Human/Hubei/3/2005 H3N2 Strain by Study Day and Study 
Arm, Per Protocol Population ............................................................................... 215 


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Figure 79: Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA 
Antigen from A/Louisiana/13/2017 H6N2 Strain by Study Day and Study 
Arm, Per Protocol Population ............................................................................... 215 
Figure 80: Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA 
Antigen from A/Townsville/51/2016 H6N2 Strain by Study Day and Study 
Arm, Per Protocol Population ............................................................................... 215 
Figure 81: Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA 
Antigen from A/Aksaray/4048/2016 H6N2 Strain by Study Day and Study 
Arm, Per Protocol Population ............................................................................... 215 
Figure 82: Geometric Mean Titers of Hemagglutination Inhibition Antibody Against 
2018/2019 QIV strains by Study Day and Study Arm, Modified Intent-to-
Treat Population ................................................................................................... 216 
Figure 83: Geometric Mean Titers of Hemagglutination Inhibition Antibody Against 
2018/2019 QIV strains by Study Day and Study Arm, Per Protocol 
Population ............................................................................................................ 216 
Figure 84: Geometric Mean Titers of Neutralizing Antibody Against 2018/2019 QIV 
strains by Study Day and Study Arm, Modified Intent-to-Treat Population ........... 216 
Figure 85: Geometric Mean Titers of Neutralizing Antibody Against 2018/2019 QIV 
strains by Study Day and Study Arm, Per Protocol Population .............................. 216 
Figure 86: Geometric Mean Titers of Neuraminidase Antibody Against 2018/2019 QIV 
strains by Study Day and Study Arm, Modified Intent-to-Treat Population ........... 216 
Figure 87: Geometric Mean Titers of Neuraminidase Antibody Against 2018/2019 QIV 
strains by Study Day and Study Arm, Per Protocol Population .............................. 216 
Figure 88:  Geometric Mean Titers of HA Binding Antibodies Against Different 
Influenza Strains by Study Day and Study Arm, Per Protocol Population.............. 217 
Figure 89:  Geometric Mean Titers of NA Binding Antibodies Against Different 
Influenza NA Antigens by Study Day and Study Arm, Per Protocol 
Population ............................................................................................................ 218 
Figure 90: Association of Non-Neutralizing Fc-effector Antibody Titers and 
Hemagglutination Inhibition Antibody Titers against 2018/2019 QIV Strains 
by Study Day and Study Arm, Per Protocol Population ......................................... 219 
Figure 91: Association of Non-neutralizing Fc-effector Antibody Titers and 
Neutralizing Antibody Titers against 2018/2019 QIV Strains by Study Day 
and Study Arm, Per Protocol Population ............................................................... 219 
Figure 92: Association of Non-neutralizing Fc-effector Antibody Titers and HAI 
Seroconversion Status against 2018/2019 QIV Strains by Study Arm at Day 
29, Per Protocol Population .................................................................................. 220 


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Figure 93: Association of Non-neutralizing Fc-effector Antibody Titers and 
Neutralizing Antibody Seroconversion Status against 2018/2019 QIV Strains 
by Study Arm at Day 29, Per Protocol Population ................................................. 220 
Figure 94: Association of Non-neutralizing Fc-effector Antibody Titers and 
Hemagglutination Inhibition Antibody Seroprotection Status against 
2018/2019 QIV Strains by Study Day and Study Arm, Per Protocol 
Population ............................................................................................................ 221 
Figure 95: Association of Non-neutralizing Fc-effector Antibody Titers and 
Neutralizing Antibody Seroprotection Status against 2018/2019 QIV Strains 
by Study Day and Study Arm, Per Protocol Population ......................................... 221 
Figure 96: Maximum Severity of Solicited Systemic Symptoms per Subject by Day 
Post First Vaccination ........................................................................................... 222 
Figure 97: Maximum Severity of Solicited Local Symptoms per Subject by Day Post 
First Vaccination .................................................................................................. 222 
Figure 98: Frequency of Unsolicited Adverse Events by MedDRA System Organ Class 
and Severity .......................................................................................................... 223 
Figure 99: Incidence of Unsolicited Adverse Events by MedDRA System Organ Class 
and Maximum Severity ......................................................................................... 224 
Figure 100: Frequency of Adverse Events by MedDRA System Organ Class and 
Relationship to Treatment ..................................................................................... 225 
Figure 101: Incidence of Adverse Events by MedDRA System Organ Class and 
Relationship to Treatment ..................................................................................... 226 
Figure 102: Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory 
Parameter and Study Arm – White Blood Cells .................................................... 227 
Figure 103: Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory 
Parameter and Study Arm – Hemoglobin .............................................................. 228 
Figure 104: Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory 
Parameter and Study Arm – Platelets .................................................................... 228 
Figure 105: Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory 
Parameter and Study Arm – Alanine Aminotransferase (ALT) .............................. 228 
Figure 106: Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory 
Parameter and Study Arm – Aspartate Amino Transferase (AST) ......................... 228 
Figure 107: Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory 
Parameter and Study Arm – Total Bilirubin .......................................................... 228 
Figure 108: Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory 
Parameter and Study Arm – Gamma-Glutamyl Transferase (GGT) ....................... 228 
Figure 109: Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory 
Parameter and Study Arm – Alkaline Phosphatase (ALP) ..................................... 228 


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Figure 110: Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory 
Parameter and Study Arm – Serum Amylase ........................................................ 228 
Figure 111: Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory 
Parameter and Study Arm – Serum Lipase ............................................................ 228 
Figure 112: Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory 
Parameter and Study Arm – Creatinine ................................................................. 228 
 
 


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10.1 
Disposition of Subjects  
Figure 1: 
CONSORT Flow Diagram 
 


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14.2.2 
Immunogenicity Figures  
Figure 2: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2018/2019 A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study Arm, Modified 
Intent-to-Treat Population 
[Implementation Note: A generic sample figure is shown below. The RCD curves should be presented in a 
single figure with eight separate panels for each outcome day (1 (Baseline), 8, 29, 57, 90, 118, 180, and 365 
post vaccination 1). Visit labels should be included in the panel headers. Within each panel individual curves 
should be used for each study arm (six curves). Each study arm should have a separate color and marker shape.] 
 
 
Figures with similar format: 
Figure 3: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study 
Day and Study Arm, Modified Intent-to-Treat Population 
Figure 4: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and 
Study Arm, Modified Intent-to-Treat Population 
Figure 5: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day 
and Study Arm, Modified Intent-to-Treat Population 
Figure 6: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study Arm, 
Per Protocol Population 


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Figure 7: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study 
Day and Study Arm, Per Protocol Population 
Figure 8: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and 
Study Arm, Per Protocol Population 
Figure 9: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day 
and Study Arm, Per Protocol Population 
Figure 10: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2018/2019 QIV Strain 
A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study Arm, Modified Intent-to-
Treat Population 
Figure 11: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2018/2019 QIV Strain 
/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study Day and Study Arm, 
Modified Intent-to-Treat Population 
Figure 12: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2018/2019 QIV Strain 
B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and Study Arm, Modified 
Intent-to-Treat Population 
Figure 13: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2018/2019 QIV Strain 
B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day and Study Arm, 
Modified Intent-to-Treat Population 
Figure 14: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2018/2019 QIV Strain 
A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study Arm, Per Protocol 
Population 
Figure 15: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2018/2019 QIV Strain 
A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study Day and Study Arm, Per 
Protocol Population 
Figure 16: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2018/2019 QIV Strain 
B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and Study Arm, Per Protocol 
Population 
Figure 17: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2018/2019 QIV Strain 
B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day and Study Arm, Per 
Protocol Population 
Figure 18: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study Arm, 
Modified Intent-to-Treat Population 
Figure 19: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study 
Day and Study Arm, Modified Intent-to-Treat Population 


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Figure 20: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and 
Study Arm, Modified Intent-to-Treat Population 
Figure 21: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day 
and Study Arm, Modified Intent-to-Treat Population 
Figure 22: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2018/2019 QIV Strain A/Michigan/45/2015 X-275 (H1N1) by Study Day and Study Arm, 
Per Protocol Population 
Figure 23: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2018/2019 QIV Strain A/Singapore/INFIMH-16-0019/2016 IVR-186 (H3N2) by Study 
Day and Study Arm, Per Protocol Population 
Figure 24: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2018/2019 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and 
Study Arm, Per Protocol Population 
Figure 25: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2018/2019 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day 
and Study Arm, Per Protocol Population 
[Implementation Note: The RCD curves for 2019/2020 QIV strains should be presented in a single figure with 
four separate panels for each outcome day (90 (Baseline),118, 180, and 365 post vaccination 1). Visit labels 
should be included in the panel headers. Within each panel individual curves should be used for each study arm 
(six curves). Each study arm should have a separate color and marker shape.] 
Figure 26: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2019/2020 QIV Strain A/Brisbane/02/2018 (H1N1) by Study Day and Study Arm, 
Modified Intent-to-Treat Population 
Figure 27: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2019/2020 QIV Strain A/Brisbane/02/2018 (H1N1) by Study Day and Study Arm, Per 
Protocol Population 
Figure 28: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2019/2020 QIV Strain 
A/Brisbane/02/2018 (H1N1) by Study Day and Study Arm, Modified Intent-to-Treat 
Population 
Figure 29: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2019/2020 QIV Strain 
A/Brisbane/02/2018 (H1N1) by Study Day and Study Arm, Per Protocol Population 
Figure 30: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2019/2020 QIV Strain A/Brisbane/02/2018 (H1N1) by Study Day and Study Arm, 
Modified Intent-to-Treat Population 
[Implementation Note: NAI titers against 2019/2020 QIV strains are only assessed for study arms 1, 2, and 3. 
Within each panel, three individual curves should be used for study arms 1, 2, and 3. Each study arm should 
have a separate color and marker shape.] 


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Figure 31: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2019/2020 QIV Strain A/Brisbane/02/2018 (H1N1) by Study Day and Study Arm, Per 
Protocol Population 
[Implementation Note: NAI titers against 2019/2020 QIV strains are only assessed for study arms 1, 2, and 3. 
Within each panel, three individual curves should be used for study arms 1, 2, and 3. Each study arm should 
have a separate color and marker shape.] 
Figure 32: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2019/2020 QIV Strain A/Kansas/14/2017 (H3N2) by Study Day and Study Arm, Modified 
Intent-to-Treat Population 
Figure 33: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2019/2020 QIV Strain A/Kansas/14/2017 (H3N2) by Study Day and Study Arm, Per 
Protocol Population 
Figure 34: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2019/2020 QIV Strain 
A/Kansas/14/2017 (H3N2) by Study Day and Study Arm, Modified Intent-to-Treat 
Population 
Figure 35: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2019/2020 
A/Kansas/14/2017 (H3N2) Strain by Study Day and Study Arm, Per Protocol Population 
Figure 36: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2019/2020 QIV Strain A/Kansas/14/2017 (H3N2) by Study Day and Study Arm, Modified 
Intent-to-Treat Population 
[Implementation Note: NAI titers against 2019/2020 QIV strains are only assessed for study arms 1, 2, and 3. 
Within each panel, three individual curves should be used for study arms 1, 2, and 3. Each study arm should 
have a separate color and marker shape.] 
Figure 37: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2019/2020 QIV Strain A/Kansas/14/2017 (H3N2) by Study Day and Study Arm, Per 
Protocol Population 
[Implementation Note: NAI titers against 2019/2020 QIV strains are only assessed for study arms 1, 2, and 3. 
Within each panel, three individual curves should be used for study arms 1, 2, and 3. Each study arm should 
have a separate color and marker shape.] 
Figure 38: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2019/2020 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and 
Study Arm, Modified Intent-to-Treat Population 
Figure 39: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2019/2020 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and 
Study Arm, Per Protocol Population 
Figure 40: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2019/2020 QIV Strain 
B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and Study Arm, Modified 
Intent-to-Treat Population 
Figure 41: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2019/2020 QIV Strain 
B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and Study Arm, Per Protocol 
Population 


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Figure 42: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2019/2020 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and 
Study Arm, Modified Intent-to-Treat Population 
[Implementation Note: NAI titers are only assessed for study arms 1, 2, and 3. Within each panel, three 
individual curves should be used for study arms 1, 2, and 3. Each study arm should have a separate color and 
marker shape.] 
Figure 43: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2019/2020 QIV Strain B/Phuket/3073/2013 (B Yamagata lineage) by Study Day and 
Study Arm, Per Protocol Population 
[Implementation Note: NAI titers are only assessed for study arms 1, 2, and 3. Within each panel, three 
individual curves should be used for study arms 1, 2, and 3. Each study arm should have a separate color and 
marker shape.] 
Figure 44: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2019/2020 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day 
and Study Arm, Modified Intent-to-Treat Population 
Figure 45: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
2019/2020 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day 
and Study Arm, Per Protocol Population 
Figure 46: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2019/2020 QIV Strain 
B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day and Study Arm, 
Modified Intent-to-Treat Population 
Figure 47: 
Reverse Cumulative Distribution of Neutralizing Antibody Against 2019/2020 QIV Strain 
B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day and Study Arm, Per 
Protocol Population 
Figure 48: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against QIV 
Strain 2019/2020 B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day and 
Study Arm, Modified Intent-to-Treat Population 
[Implementation Note: NAI titers against 2019/2020 QIV strains are only assessed for study arms 1, 2, and 3. 
Within each panel, three individual curves should be used for study arms 1, 2, and 3. Each study arm should 
have a separate color and marker shape.] 
Figure 49: 
Reverse Cumulative Distribution of Neuraminidase Inhibition Antibody Against 
2019/2020 QIV Strain B/Maryland/15/2016 BX-69A (B Victoria lineage) by Study Day 
and Study Arm, Per Protocol Population 
[Implementation Note: NAI titers against 2019/2020 QIV strains are only assessed for study arms 1, 2, and 3. 
Within each panel, three individual curves should be used for study arms 1, 2, and 3. Each study arm should 
have a separate color and marker shape.] 
 
[Implementation Note: The RCD curves for Heterologous A/H3 strains should be presented in a single figure 
with eight separate panels for each outcome day (1 (Baseline), 8, 29, 29, 90, 118, 180, and 365 post vaccination 
1). Visit labels should be included in the panel headers. Within each panel individual curves should be used for 
each study arm (six curves). Each study arm should have a separate color and marker shape.] 


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Figure 50: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
Heterologous Influenza A/H3 Strain A/Colombia/6639/2017 by Study Day and Study 
Arm, Modified Intent-to-Treat Population 
Figure 51: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
Heterologous Influenza A/H3 Strain A/Victoria/756/2017 by Study Day and Study Arm, 
Modified Intent-to-Treat Population 
Figure 52: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
Heterologous Influenza A/H3 Strain A/Kenya/105/2017 by Study Day and Study Arm, 
Modified Intent-to-Treat Population 
Figure 53: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
Heterologous Influenza A/H3 Strain A/Louisiana/13/2017 by Study Day and Study Arm, 
Modified Intent-to-Treat Population 
Figure 54: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
Heterologous Influenza A/H3 Strain A/Michigan/84/2016 H3N2 by Study Day and Study 
Arm, Modified Intent-to-Treat Population  
Figure 55: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
Heterologous Influenza A/H3 Strain A/Colombia/6639/2017 by Study Day and Study 
Arm, Per Protocol Population 
Figure 56: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
Heterologous Influenza A/H3 Strain A/Victoria/756/2017 by Study Day and Study Arm, 
Per Protocol Population 
Figure 57: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
Heterologous Influenza A/H3 Strain A/Kenya/105/2017 by Study Day and Study Arm, 
Per Protocol Population 
Figure 58: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
Heterologous Influenza A/H3 Strain A/Louisiana/13/2017 by Study Day and Study Arm, 
Per Protocol Population 
Figure 59: 
Reverse Cumulative Distribution of Hemagglutination Inhibition Antibody Against 
Heterologous Influenza A/H3 Strain A/Michigan/84/2016 H3N2 by Study Day and Study 
Arm, Per Protocol Population 
Figure 60: 
Reverse Cumulative Distribution of Neutralizing Antibody Against Heterologous 
Influenza A/H3 Strain A/Colombia/6639/2017 by Study Day and Study Arm, Modified 
Intent-to-Treat Population 
Figure 61: 
Reverse Cumulative Distribution of Neutralizing Antibody Against Heterologous 
Influenza A/H3 Strain A/Victoria/756/2017 by Study Day and Study Arm, Modified 
Intent-to-Treat Population 
Figure 62: 
Reverse Cumulative Distribution of Neutralizing Antibody Against Heterologous 
Influenza A/H3 Strain A/Kenya/105/2017 by Study Day and Study Arm, Modified Intent-
to-Treat Population 


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Figure 63: 
Reverse Cumulative Distribution of Neutralizing Antibody Against Heterologous 
Influenza A/H3 Strain A/Louisiana/13/2017 by Study Day and Study Arm, Modified 
Intent-to-Treat Population 
Figure 64: 
Reverse Cumulative Distribution of Neutralizing Antibody Against Heterologous 
Influenza A/H3 Strain A/Michigan/84/2016 H3N2 by Study Day and Study Arm, 
Modified Intent-to-Treat Population  
Figure 65: 
Reverse Cumulative Distribution of Neutralizing Antibody Against Heterologous 
Influenza A/H3 Strain A/Colombia/6639/2017 by Study Day and Study Arm, Per 
Protocol Population 
Figure 66: 
Reverse Cumulative Distribution of Neutralizing Antibody Against Heterologous 
Influenza A/H3 Strain A/Victoria/756/2017 by Study Day and Study Arm, Per Protocol 
Population 
Figure 67: 
Reverse Cumulative Distribution of Neutralizing Antibody Against Heterologous 
Influenza A/H3 Strain A/Kenya/105/2017 by Study Day and Study Arm, Per Protocol 
Population 
Figure 68: 
Reverse Cumulative Distribution of Neutralizing Antibody Against Heterologous 
Influenza A/H3 Strain A/Louisiana/13/2017 by Study Day and Study Arm, Per Protocol 
Population 
Figure 69: 
Reverse Cumulative Distribution of Neutralizing Antibody Against Heterologous 
Influenza A/H3 Strain A/Michigan/84/2016 H3N2 by Study Day and Study Arm, Per 
Protocol Population 
[Implementation Note: The RCD curves NAI against N1 and N2 NA antigens should be presented in a single 
figure with eight separate panels for each outcome day (1 (Baseline), 8, 29, 29, 90, 118, 180, and 365 post 
vaccination 1). Visit labels should be included in the panel headers. Within each panel, three individual curves 
should be used for study arms 1, 2, and 3 since NAI titers are only assessed for study arms 1, 2, and 3. Each 
study arm should have a separate color and marker shape.]  
Figure 70: 
Reverse Cumulative Distribution of Neuraminidase Inhibition N1 NA Antigen from 
A/Oman/5532/2017 H6N1 Strain by Study Day and Study Arm, Modified Intent-to-Treat 
Population 
Figure 71: 
Reverse Cumulative Distribution of Neuraminidase Inhibition N1 NA Antigen from 
A/Cameroon/9766/2017 H6N1 Strain by Study Day and Study Arm, Modified Intent-to-
Treat Population 
Figure 72: 
Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA Antigen from 
A/Human/Hubei/3/2005 H3N1 Strain by Study Day and Study Arm, Modified Intent-to-
Treat Population 
Figure 73: 
Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA Antigen from 
A/Louisiana/13/2017 H6N2 Strain by Study Day and Study Arm, Modified Intent-to-
Treat Population 
Figure 74: 
Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA Antigen from 
A/Townsville/51/2016 H6N2 Strain by Study Day and Study Arm, Modified Intent-to-
Treat Population 


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Figure 75: 
Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA Antigen from 
A/Aksaray/4048/2016 H6N2 Strain by Study Day and Study Arm, Modified Intent-to-
Treat Population 
Figure 76: 
Reverse Cumulative Distribution of Neuraminidase Inhibition N1 NA Antigen from 
A/Oman/5532/2017 H6N1 Strain by Study Day and Study Arm, Per Protocol Population 
Figure 77: 
Reverse Cumulative Distribution of Neuraminidase Inhibition N1 NA Antigen from 
A/Cameroon/9766/2017 H6N1 Strain by Study Day and Study Arm, Per Protocol 
Population 
Figure 78: 
Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA Antigen from 
A/Human/Hubei/3/2005 H3N2 Strain by Study Day and Study Arm, Per Protocol 
Population 
Figure 79: 
Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA Antigen from 
A/Louisiana/13/2017 H6N2 Strain by Study Day and Study Arm, Per Protocol Population 
Figure 80: 
Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA Antigen from 
A/Townsville/51/2016 H6N2 Strain by Study Day and Study Arm, Per Protocol 
Population 
Figure 81: 
Reverse Cumulative Distribution of Neuraminidase Inhibition N2 NA Antigen from 
A/Aksaray/4048/2016 H6N2 Strain by Study Day and Study Arm, Per Protocol 
Population 
 
 


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Figure 82: 
Geometric Mean Titers of Hemagglutination Inhibition Antibody Against 2018/2019 QIV 
strains by Study Day and Study Arm, Modified Intent-to-Treat Population 
[Implementation Note: A generic sample figure is shown below. Planned Study Day (1,8,57,90,118, 180,365) 
is plotted along the x-axis, with visit labels as tick labels. Titer is plotted on the y-axis on the log-10 scale. GMT 
should be plotted at each visit with upper and lower error bars for the 95% CI for each study arm with different 
marker shapes/colors for each study arm. Each study arm should have a separate color and marker shape. Four 
panels will be created with each panel representing a 2018/2019 QIV strain]  
 
 
Figures with similar format: 
Figure 83: 
Geometric Mean Titers of Hemagglutination Inhibition Antibody Against 2018/2019 QIV 
strains by Study Day and Study Arm, Per Protocol Population 
Figure 84: 
Geometric Mean Titers of Neutralizing Antibody Against 2018/2019 QIV strains by 
Study Day and Study Arm, Modified Intent-to-Treat Population 
Figure 85: 
Geometric Mean Titers of Neutralizing Antibody Against 2018/2019 QIV strains by 
Study Day and Study Arm, Per Protocol Population 
Figure 86: 
Geometric Mean Titers of Neuraminidase Antibody Against 2018/2019 QIV strains by 
Study Day and Study Arm, Modified Intent-to-Treat Population 
Figure 87: 
Geometric Mean Titers of Neuraminidase Antibody Against 2018/2019 QIV strains by 
Study Day and Study Arm, Per Protocol Population 
 
 


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Figure 88: 
 Geometric Mean Titers of HA Binding Antibodies Against Different Influenza Strains by 
Study Day and Study Arm, Per Protocol Population 
[Implementation Note: A generic sample figure is shown below. Planned Study Day (1,8,29, 57,90,118, 
180,365) is plotted along the x-axis, with visit labels as tick labels. Titer is plotted on the y-axis on the log-10 
scale. GMT should be plotted at each visit for each strain. Different attributes such as line color, marker shape, 
line style, line transparency will be used to distinguish strains within a similar grouping. Groupings provided 
by Sanofi will be used. Six panels will be created to represent the different study arms.] 
 
 
 


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Figure 89: 
 Geometric Mean Titers of NA Binding Antibodies Against Different Influenza NA 
Antigens by Study Day and Study Arm, Per Protocol Population 
[Implementation Note: A generic sample figure is shown below. Planned Study Day (1,8,29,57,90,118, 
180,365) is plotted along the x-axis, with visit labels as tick labels. Geometric Mean titer is plotted on the y-
axis. GMT should be plotted at each visit for each of the 9 strains with different marker shapes/colors for each 
strain. Each strain should have a separate color and marker shape. Three panels will be created with each panel 
representing study arms 1,2, or 3]  
 
 
 


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Figure 90: 
Association of Non-Neutralizing Fc-effector Antibody Titers and Hemagglutination 
Inhibition Antibody Titers against 2018/2019 QIV Strains by Study Day and Study Arm, 
Per Protocol Population 
[Implementation Note: A generic scatter plot is shown below. HAI antibody titers are plotted along the x-axis 
(x-axis label: HAI Titer) and Fc-effector antibody Titers are plotted on the y-axis (y-axis label: Fc-effector 
Titer). Each study arm will be represented as follow: The same color will be used for the same vaccine 
(Flublok vs. Fluzone), the same symbol (circle, triangle, square) will be used to indicate the name adjuvant 
(i.e. no adjuvant, AF03, Advax), and filled vs. unfilled will be used to distinguish adjuvanted vs. 
unadjuvanted groups.. The spearman correlation should be calculated over all subjects and annotated within 
each panel as “Spearman Correlation (r=0.xx, p=0.xx)”. Eight panels will be created with 4 rows to represent 
the four 2018/2019 QIV strains and 2 columns to represent Day 1 and Day 29.] 
 
 
Figure with Similar format: 
Figure 91: 
Association of Non-neutralizing Fc-effector Antibody Titers and Neutralizing Antibody 
Titers against 2018/2019 QIV Strains by Study Day and Study Arm, Per Protocol 
Population 
[Implementation Note: A generic scatter plot is shown below. Neut antibody titers are plotted along the x-axis 
(x-axis label: Neut Titer) and Fc-effector antibody Titers are plotted on the y-axis (y-axis label: Fc-effector 
Titer). Each study arm should have a separate color and marker shape. The spearman correlation should be 
calculated over all subjects and annotated within each panel as “Spearman Correlation (r=0.xx, p=0.xx)”. 
Eight panels will be created with 4 rows to represent the four 2018/2019 QIV strains and 2 columns to 
represent Day 1 and Day 29.] 


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Figure 92: 
Association of Non-neutralizing Fc-effector Antibody Titers and HAI Seroconversion 
Status against 2018/2019 QIV Strains by Study Arm at Day 29, Per Protocol Population 
[Implementation Note: A generic sample figure is shown below. Eight panels will be created with 4 rows to 
represent the four 2018/2019 QIV strains] 
Figure with similar format: 
Figure 93: 
Association of Non-neutralizing Fc-effector Antibody Titers and Neutralizing Antibody 
Seroconversion Status against 2018/2019 QIV Strains by Study Arm at Day 29, Per 
Protocol Population 
 
 


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Figure 94: 
Association of Non-neutralizing Fc-effector Antibody Titers and Hemagglutination 
Inhibition Antibody Seroprotection Status against 2018/2019 QIV Strains by Study Day 
and Study Arm, Per Protocol Population 
[Implementation Note: A generic sample figure is shown below. Eight panels will be created with 4 rows to 
represent the four 2018/2019 QIV strains and 2 columns to represent Day 1 and Day 29.] 
 
Figure with similar format: 
Figure 95: 
Association of Non-neutralizing Fc-effector Antibody Titers and Neutralizing Antibody 
Seroprotection Status against 2018/2019 QIV Strains by Study Day and Study Arm, Per 
Protocol Population 
 


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14.3.1.1 Solicited Adverse Events 
Figure 96: 
Maximum Severity of Solicited Systemic Symptoms per Subject by Day Post First 
Vaccination 
[Implementation Note: A Generic figure is shown below. A vertical bar chart should be presented in 1 image 
file with separate panels for each study arm (6 panels: Top row: Groups 1, 2, 3; Bottom row: Groups 4, 5, 6). 
Axes should be labeled as follows: x-axis label: Study Day, y-axis label: Percentage of Subjects (%). The study 
arms should be indicated in the panel headers including “(N=X)”, where N = the number of subjects in the in 
the Safety Population who received the first study vaccination. Subjects are counted at most once at the 
maximum severity across all systemic events reported for the specified time point] 
 
 
Figure with similar format: 
Figure 97: 
Maximum Severity of Solicited Local Symptoms per Subject by Day Post First 
Vaccination 
 


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14.3.1.2 Unsolicited Adverse Events 
Figure 98: 
Frequency of Unsolicited Adverse Events by MedDRA System Organ Class and Severity 
[Implementation Note: A Generic figure is shown below. This figure includes all unsolicited events across all 
doses. A horizontal bar chart should be presented in 1 image file separate panels for each study arm (6 panels: 
Top row: Groups 1, 2, 3; Bottom row: Groups 4, 5, 6). Axes should be labeled as follows: y-axis label: System 
Organ Class, y-axis label: Number of Events. The study arms should be indicated in the panel headers including 
“(N=X)”, where N = the number of subjects in the in the Safety Population. The y-axis should present all SOCs 
reported by at least 1 subject and an “All Events” category. Y-axis should be sorted with “All Events first, then 
in decreasing order of total incidence] 
 
 
 
 


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Figure 99: 
Incidence of Unsolicited Adverse Events by MedDRA System Organ Class and Maximum 
Severity  
[Implementation Note: A Generic figure is shown below. This figure includes all unsolicited events across all 
doses. A horizontal bar chart should be presented in 1 image file with separate panels for each study arm (6 
panels: Top row: Groups 1, 2, 3; Bottom row: Groups 4, 5, 6). Axes should be labeled as follows: y-axis label: 
System Organ Class, x-axis label: Percentage of Subjects (%). The study arms should be indicated in the panel 
headers including “(N=X)”, where N = the number of subjects in the in the Safety Population. Subjects are 
counted at most once at the maximum severity across for any events in the applicable SOC. The y-axis should 
present all SOCs reported by at least 1 subject and an “All Events” category. Y-axis should be sorted with “All 
Events” first then in decreasing order of total incidence]  
 
 
 


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Figure 100: 
Frequency of Adverse Events by MedDRA System Organ Class and Relationship to 
Treatment 
[Implementation Note: A generic sample figure is shown below. This figure includes all unsolicited events 
across all doses. A horizontal bar chart should be presented in 1 image file with separate panels for each study 
arm (6 panels: Top row: Groups 1, 2, 3; Bottom row: Groups 4, 5, 6). Axes should be labeled as follows: y-axis 
label: System Organ Class, y-axis label: Number of Events. The study arms should be indicated in the panel 
headers including “(N=X)”, where N = the number of subjects in the in the Safety Population. The y-axis should 
present all SOCs reported by at least 1 subject and an “All Events” category. Y-axis should be sorted with “All 
Events first then in decreasing order of total frequency] 
 
 
 
 
 


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Figure 101: 
Incidence of Adverse Events by MedDRA System Organ Class and Relationship to 
Treatment 
[Implementation Note: A Generic figure is shown below. This figure includes all unsolicited events across all 
doses. A horizontal bar chart should be presented in a 1 image file with separate panels for each study arm (6 
panels: Top row: Groups 1, 2, 3; Bottom row: Groups 4, 5, 6). Axes should be labeled as follows: y-axis label: 
System Organ Class, x-axis label: Percentage of Subjects (%). The study arms should be indicated in the panel 
headers including “(N=X)”, where N = the number of subjects in the in the Safety Population. Subjects are 
counted at most once at the maximum relationship (related >not-related) across for any events in the applicable 
SOC. The y-axis should present all SOCs reported by at least 1 subject and an “All Events” category. Y-axis 
should be sorted with “All Events first, then in decreasing order of total incidence across groups]  
 
 
 


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14.3.5 
Displays of Laboratory Results 
Figure 102: 
Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory Parameter 
and Study Arm – White Blood Cells  
[Implementation note: A generic figure is shown below. Plot should be generated with all study arms in a single 
image file single panel with six boxplots to represent six study arms. Y-axis should be labeled “[Parameter] 
Change from baseline ([units]) and x-axis will be labeled ‘Study Arm’. Repeat for all clinical laboratory 
parameters: WBC, Hgb, PLT, ALT, AST, T. Bili, GGT, ALP, AMY, LIP, Cr] 
 
 
 
 


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Figures with similar format: 
Figure 103: 
Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory Parameter 
and Study Arm – Hemoglobin 
Figure 104: 
Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory Parameter 
and Study Arm – Platelets 
Figure 105: 
Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory Parameter 
and Study Arm – Alanine Aminotransferase (ALT) 
Figure 106: 
Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory Parameter 
and Study Arm – Aspartate Amino Transferase (AST) 
Figure 107: 
Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory Parameter 
and Study Arm – Total Bilirubin 
Figure 108: 
Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory Parameter 
and Study Arm – Gamma-Glutamyl Transferase (GGT) 
Figure 109: 
Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory Parameter 
and Study Arm – Alkaline Phosphatase (ALP) 
Figure 110: 
Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory Parameter 
and Study Arm – Serum Amylase 
Figure 111: 
Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory Parameter 
and Study Arm – Serum Lipase 
Figure 112: 
Laboratory Results at Day 8: Mean Changes from Baseline by Laboratory Parameter 
and Study Arm – Creatinine 
 


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APPENDIX 3. LISTINGS MOCK-UPS 
 
 


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LISTINGS 
Listing 1: 16.1.6: Listing of Subjects Receiving Investigational Product ............................... 232 
Listing 2: 16.2.1: Early Terminations or Discontinued Subjects ............................................ 233 
Listing 3: 16.2.2.1: Subject-Specific Protocol Deviations ..................................................... 234 
Listing 4: 16.2.2.2: Non-Subject-Specific Protocol Deviations.............................................. 235 
Listing 5: 16.2.3: Subjects Excluded from Analysis Populations ........................................... 236 
Listing 6: 16.2.4.1: Demographic Data ................................................................................. 237 
Listing 7: 16.2.4.2: Pre-Existing and Concurrent Medical Conditions ................................... 238 
Listing 8: 16.2.4.3: Influenza Vaccination History ................................................................ 239 
Listing 9: 16.2.6.1: Individual Immunogenicity Response Data – Hemagglutinin 
Inhibition Antibody .............................................................................................. 241 
Listing 10: 16.2.6.2: Individual Immunogenicity Response Data – Neuraminidase 
Inhibition Antibody .............................................................................................. 241 
Listing 11: 16.2.6.3: Individual Immunogenicity Response Data – Neutralizing 
Antibody .............................................................................................................. 242 
Listing 12: 16.2.6.4: Individual Immunogenicity Response Data - IgG Memory B Cells ......... 243 
Listing 13: 16.2.6.5: Individual Immunogenicity Response Data - IgM Memory B Cells ........ 243 
Listing 14: 16.2.6.6: Individual Immunogenicity Response Data - IgA Memory B Cells ......... 243 
Listing 15: 16.2.6.7: Individual Immunogenicity Response Data – T Follicular Helper 
Cells ..................................................................................................................... 244 
Listing 16: 16.2.6.8: Individual Immunogenicity Response Data - Plasmablasts ..................... 244 
Listing 17: 16.2.6.9: Individual Immunogenicity Response Data – Non-Neutralizing Fc-
effector ................................................................................................................. 245 
Listing 18: 16.2.6.10: Individual Immunogenicity Response Data - Antibody Forensics ......... 246 
Listing 19: 16.2.6.11: Individual Immunogenicity Response Data – NA ELISA ..................... 247 
Listing 20: 16.2.7.1: Solicited Events – Systemic Symptoms .................................................. 248 
Listing 21: 16.2.7.2: Solicited Events – Local Symptoms ....................................................... 249 
Listing 22: 16.2.7.3: Unsolicited Adverse Events.................................................................... 250 
Listing 23: 16.2.8.1: Clinical Laboratory Results – Chemistry ................................................ 251 
Listing 24: 16.2.8.2: Clinical Laboratory Results – Hematology ............................................. 252 
Listing 25: 16.2.9.1: Vital Signs ............................................................................................. 253 
Listing 26: 16.2.9.2: Physical Exam Findings ......................................................................... 254 
Listing 27: 16.2.10: Concomitant Medications ........................................................................ 255 


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Listing 28: 16.2.11.1: Pregnancy Reports – Maternal Information .......................................... 256 
Listing 29: 16.2.11.2: Pregnancy Reports – Gravida and Para ................................................. 256 
Listing 30: 16.2.11.3: Pregnancy Reports – Live Birth Outcomes ........................................... 257 
Listing 31: 16.2.11.4: Pregnancy Reports – Still Birth Outcomes ............................................ 257 
Listing 32: 16.2.11.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic 
Abortion Outcomes............................................................................................... 257 
 
 


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Listing 1: 
16.1.6: Listing of Subjects Receiving Investigational Product 
Subject ID 
Randomized Study Arm 
Product Received Study Vaccination 1 
Product Received Study Vaccination 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2 
Database Listings by Subject 
16.2.1 Discontinued Subjects 
Listing 2: 
16.2.1: Early Terminations or Discontinued Subjects 
Study Arm 
 Subject ID 
Category 
Reason for Early Termination or Treatment Discontinuation 
Study Day 
 
 
 
 
 
 
 
 


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16.2.2 Protocol Deviations 
Listing 3: 
16.2.2.1: Subject-Specific Protocol Deviations 
Study Arm 
Subject ID 
DV Number 
Deviation 
Deviation 
Category 
Study Day 
Reason for 
Deviation 
Deviation 
Resulted 
in AE? 
Deviation Resulted 
in Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 4: 
16.2.2.2: Non-Subject-Specific Protocol Deviations 
Site 
Start Date  
Deviation 
End Date 
Reason for 
Deviation 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Category 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.3 Subjects Excluded from the Analysis 
Listing 5: 
16.2.3: Subjects Excluded from Analysis Populations 
Study Arm 
Subject ID 
Analyses in which 
Subject is Included 
Analyses from which  
Subject is Excluded 
Results Available? 
Reason Subject Excluded 
 
 
[e.g., Safety, ITT, PP] 
[e.g., Safety, ITT, PP, Day x] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: “Yes” in the “Results available” column indicates that available data were removed from the analysis. “No” indicates that no data were available for inclusion in the analysis. 
 
 


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16.2.4 Demographic Data 
Listing 6: 
16.2.4.1: Demographic Data 
[Implementation Note: If a subject is multi-racial, in “Race” column, note “Multiple: (list races, separated by a comma).”] 
Subject ID 
Study Arm 
Sex 
Age at Enrollment (years) 
Ethnicity 
Race 
BMI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 7: 
16.2.4.2: Pre-Existing and Concurrent Medical Conditions 
[Implementation Note: “Condition Start Day” and “Condition End Day” are relative to enrollment (which is Day 1, day before enrollment is Day -1). If 
ongoing, display “Ongoing” in the “Condition End Day” column] 
Subject ID 
Study Arm 
MH Number 
Medical History 
Term 
Condition Start 
Day  
Condition End 
Day 
MedDRA System Organ 
Class 
MedDRA Preferred Term 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 8: 
16.2.4.3: Influenza Vaccination History 
Subject ID 
Study Arm 
Vaccine Type 
Month/Year Received 
Vaccination Type / Subtype 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.5 Compliance and/or Drug Concentration Data (if available) 
Not applicable for this study. 
 


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16.2.6 Individual Immunogenicity Response Data 
Listing 9: 
16.2.6.1: Individual Immunogenicity Response Data – Hemagglutinin Inhibition Antibody 
Subject ID 
Study Arm 
Planned Time Point 
Actual Study Day 
Strain 
Titer Replicate 1 
Titer Replicate 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing with similar format: 
Listing 10: 
16.2.6.2: Individual Immunogenicity Response Data – Neuraminidase Inhibition Antibody 
 
 


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Listing 11: 
16.2.6.3: Individual Immunogenicity Response Data – Neutralizing Antibody  
Subject ID 
Study Arm 
Planned Time Point 
Actual Study Day 
Strain 
GM Titer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 12: 
16.2.6.4: Individual Immunogenicity Response Data - IgG Memory B Cells 
Subject ID 
Study Arm 
Planned Time Point 
Actual Study Day 
# of Spot Forming Cells 
per million PBMC 
Replicate 1 
# of Spot Forming Cells 
per million PBMC 
Replicate 2 
# of Spot Forming Cells 
per million PBMC 
Replicate 3a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aTwo or three replicates will be reported for these assays. Use dashes if replicate 3 is not provided 
Listings with similar format: 
Listing 13: 
16.2.6.5: Individual Immunogenicity Response Data - IgM Memory B Cells 
Listing 14: 
16.2.6.6: Individual Immunogenicity Response Data - IgA Memory B Cells 
 
 


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Listing 15: 
16.2.6.7: Individual Immunogenicity Response Data – T Follicular Helper Cells  
Subject ID 
Study Arm 
Planned Time Point 
Actual Study Day 
Number and percent of Tfh cells 
Replicate 1 
Number and percent of Tfh cells 
Replicate 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing with similar format:  
Listing 16: 
16.2.6.8: Individual Immunogenicity Response Data - Plasmablasts  
[Implementation note: Update the last two columns names to use ‘Number and Percent of Plasmablasts’] 
 
 


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Listing 17: 
16.2.6.9: Individual Immunogenicity Response Data – Non-Neutralizing Fc-effector  
Subject ID 
Study Arm 
Planned Time Point 
Actual Study Day 
Strain 
Titer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 18: 
16.2.6.10: Individual Immunogenicity Response Data - Antibody Forensics 
Subject ID 
Study Arm 
Planned Time Point 
Actual Study Day 
Assay 
Strain 
Unit 
Result 
 
 
 
 
  
 
EC50 
 
 
 
 
 
 
 
nMFI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 19: 
16.2.6.11: Individual Immunogenicity Response Data – NA ELISA 
Subject ID 
Study Arm 
Planned Time Point 
Actual Study Day 
Assay 
Strain 
EC50  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.7 Adverse Events 
Listing 20: 
16.2.7.1: Solicited Events – Systemic Symptoms 
Subject ID  
Study Arm 
Post Dose Day 
Assessmenta 
Symptom 
Severity 
Attributed to 
Alternate Etiology?b 
Alternate Etiology 
 
 
 
MA 
 
 
 
 
 
 
 
Clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a MA = Data reported by subject on the Memory Aid and reviewed by clinic staff and reported in Solicited Events eCRF. 
b Grade 3 events only.  
Clinic = Data collected by clinic staff during physical exam or symptom assessment (treatment administration record, in-clinic assessment, etc.) 
 
 


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Listing 21: 
16.2.7.2: Solicited Events – Local Symptoms 
Subject ID  
Study Arm 
Post Dose Day 
Assessmenta 
Symptom 
Severity 
 
 
 
MA 
 
 
 
 
 
Clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a MA = Data reported by subject on the Memory Aid and reviewed by clinic staff and reported in Solicited Events eCRF. 
 Clinic = Data collected by clinic staff during physical exam or symptom assessment (treatment administration record, in-clinic assessment, etc.) 
 
 
 


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Listing 22: 
16.2.7.3: Unsolicited Adverse Events 
Adverse 
Event 
Associated 
with Dose 
No. 
No. of Days 
Post 
Associated 
Dose 
(Duration) 
Severity 
MAAE? 
Relationship 
to Study 
Vaccination 
In Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Vaccination 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ Class 
MedDRA 
Preferred 
Term 
Study Arm: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
Study Arm: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Note: For additional details about SAEs, see Table: xx. 
 
 


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16.2.8 Individual Laboratory Measurements 
Listing 23: 
16.2.8.1: Clinical Laboratory Results – Chemistry 
[Implementation Note: These listings (for hematology and chemistry) include all laboratory results, scheduled and unscheduled. These listings are not 
color-coded, but the severity should be included in parentheses after the result for abnormal results, e.g., 16.2 (Mild). The “extra” fields that are completed 
for abnormal results are not included in this listing; they are included in the listing of abnormal laboratory results that is included in the table shells.] 
Subject ID 
Study Arm 
Sex 
Age (years) 
Planned 
Time 
Point 
Actual 
Study 
Day 
ALT 
(IU/L) 
AST 
(IU/L) 
Total 
Bilirubin 
(mg/dL) 
GGT 
(IU/L) 
ALP 
(IU/L) 
Serum 
Amylase 
(IU/L) 
Serum 
Lipase 
(IU/L) 
Creatinine 
(mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 24: 
16.2.8.2: Clinical Laboratory Results – Hematology 
[Implementation Note: These listings (for hematology and chemistry) include all laboratory results, scheduled and unscheduled. These listings are not 
color-coded, but the severity should be included in parentheses after the result for abnormal results, e.g., 16.2 (Mild). The “extra” fields that are completed 
for abnormal results are not included in this listing; they are included in the listing of abnormal laboratory results that is included in the table shells.] 
Subject ID 
Study Arm 
Sex 
Age (years) 
Planned Time 
Point 
Actual 
Study Day 
White Blood Cell 
(103/µL) 
Hemoglobin 
(g/dL) 
Platelets 
(103/µL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.9 Vital Signs and Physical Exam Findings 
Listing 25: 
16.2.9.1: Vital Signs 
[Implementation Note: This listing includes all vital sign assessments, scheduled and unscheduled. These listings are not color-coded, but the severity 
should be included in parentheses after the result for abnormal assessments, e.g., 100.7 (Mild).] 
Subject ID 
Study Arm 
Planned Time 
Point 
Actual Study Day 
Temperature 
(°C) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
Pulse 
(beats/min) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 26: 
16.2.9.2: Physical Exam Findings 
[Implementation Note: This listing includes all physical exam findings, scheduled and unscheduled. If a subject does not have any findings upon 
examination, they will not be included in this listing. If reported as an AE, display “Yes” with the AE Number in parentheses, e.g., “Yes (7)”.] 
Subject ID 
Study Arm 
Planned Time 
Point 
Actual Study 
Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; Number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.10 Concomitant Medications 
Listing 27: 
16.2.10: Concomitant Medications 
[Implementation Note: “Medication Start Day” and “Medication End Day” are relative to enrollment (which is Day 1, day before enrollment is Day -1). 
For medication start dates that are > 30 days prior to enrollment, rather than use exact study days, categorize as follows: 
• > 5 years prior to enrollment 
• 1-5 years prior to enrollment 
• 1-12 months prior to enrollment 
If ongoing, display “Ongoing” in the “Medication End Day” column. If taken for an AE or MH, display “Yes” with the AE or MH Number in parentheses, 
e.g., “Yes (7)”.] 
Subject ID 
Study Arm 
CM Number 
Medication 
Medication Start Day 
Medication End Day 
Indication 
Taken for an AE? 
(AE Number) 
Taken for a condition on 
Medical History? 
(MH Number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.11 Pregnancy Reports 
[Implementation Note: Only include the “Pregnancy Number” column if a subject has more than 1 pregnancy. Date of Conception will be calculated based 
on estimated delivery date. BMI will be calculated based on pre-pregnancy height and weight. Mother’s weight gain will be calculated based on pre-
pregnancy weight and end of pregnancy weight. If a major congenital anomaly with previous pregnancy, display “Yes” and the text from the “specify” 
field, separated by a colon. If any substance use is reported, include a listing of substance use. If autopsy revealed an alternate etiology, display “Yes” and 
the text from the “specify” field, separated by a colon. If abnormality in product of conception, display “Yes” and the text from the “specify” field, separated 
by a colon.] 
Listing 28: 
16.2.11.1: Pregnancy Reports – Maternal Information 
Subject ID 
Study 
Arm 
Pregnancy 
Number 
Study Day 
Corresponding 
to Estimated 
Date of 
Conception 
Source of 
Maternal 
Information 
Pregnancy 
Status 
Mother’s 
Pre-
Pregnancy 
BMI 
Mother’s 
Weight 
Gain 
During 
Pregnancy 
Tobacco, 
Alcohol, or 
Drug Use 
During 
Pregnancy? 
Medications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Pregnancy? 
Maternal 
Complications 
During Labor, 
Delivery, or 
Post-Partum? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Maternal Complications are included in the Adverse Event listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
Listing 29: 
16.2.11.2: Pregnancy Reports – Gravida and Para 
 
Live Births 
 
Subject 
ID 
Study 
Arm 
Gravida 
Extremely 
PBa 
Very 
Early 
PBa 
Early 
PBa 
Late 
PBa 
Early 
TBb 
Full 
TBb 
Late 
TBb 
Post 
TBb 
Still 
Births 
Spontaneous 
Abortion/ 
Miscarriage 
Elective 
Abortions 
Therapeutic 
Abortions 
Major 
Congenital 
Anomaly 
with 
Previous 
Pregnancy? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Gravida includes the current pregnancy, para events do not. 
a Preterm Birth 
b Term Birth 
 
 


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Listing 30: 
16.2.11.3: Pregnancy Reports – Live Birth Outcomes 
Subject 
ID 
Pregnancy 
Number 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Live 
Birth  
Size for 
Gestational 
Age 
Apgar 
Score, 1 
minute 
Apgar 
Score, 5 
minutes 
Cord pH 
Congenital 
Anomalies? 
Illnesses/ 
Hospitalizations 
within 1 Month of 
Birth? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Congenital Anomalies are included in the Adverse Event listing. 
Listing 31: 
16.2.11.4: Pregnancy Reports – Still Birth Outcomes 
Subject 
ID 
Date of 
Initial 
Report 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Still 
Birth 
Size for 
Gestational 
Age 
Cord pH 
Congenital 
Anomalies? 
Autopsy 
Performed? 
If Autopsy, Etiology 
for Still Birth 
Identified? 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 32: 
16.2.11.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes 
Subject 
ID 
Date of Initial 
Report 
Fetus Number 
Pregnancy Outcome 
(for this Fetus) 
Gestational Age at 
Termination 
Abnormality in Product of Conception? 
Reason for Therapeutic 
Abortion 
 
 
 
 
 
 
 
 

Prot_001.pdf: 
 
A Phase I Study to Assess the Safety, Reactogenicity and Immunogenicity of Two 
Quadrivalent Seasonal Influenza Vaccines (Fluzone® or Flublok®) With or Without 
One of Two Adjuvants (AF03 or Advax-CpG55.2) in Healthy Adults 18-45 Years of 
Age 
 
DMID Protocol Number: 18-0011 
 
DMID Funding Mechanism: Vaccine and Treatment Evaluation Units 
 
Pharmaceutical Support: 
Sanofi Pasteur 
Vaxine Pty Ltd 
 
IND Sponsor: Division of Microbiology and Infectious Diseases, National 
Institute of Allergy and Infectious Diseases, National Institutes of Health 
 
Lead Principal Investigator: Patricia Winokur, MD 
DMID Clinical Project Manager: Kathy Ormanoski, M.S., CCRA 
DMID Medical Monitor: Mohamed Elsafy, MD 
DMID Medical Officer: Mamodikoe Makhene, MD, MPH 
DMID Scientific Lead: Chris Roberts, PhD 
 
Version: 8.0 
01 February 2021 
 
 


DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
1 
STATEMENT OF COMPLIANCE 
This trial will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
• 
United States (US) Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of 
Human Subjects 
• 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 
(Protection of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical 
Investigators), 21 CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 
CFR Part 312 (Investigational New Drug Application), 21 CFR 812 (Investigational 
Device Exemptions) 
• 
 International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH): Good Clinical Practice (GCP) E6(R2) Good Clinical Practice:  
Integrated Addendum to ICH E6(R1) Guidance for Industry,” published in the Federal 
Register (83 Federal Register 8882 (2018) 
• 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects 
of Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• 
National Institutes of Health (NIH) Office of Extramural Research, Research Involving 
Human Subjects, as applicable 
• 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, 
as applicable 
• 
Applicable Federal, State and Local Regulations and Guidance 
 


DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
2 
SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 GCP guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and Institutional Review Board 
(IRB)/Institutional Ethics Committee (IEC) approval, except when necessary to protect the 
safety, rights or welfare of subjects. 
Site Principal Investigator: 
 
Signed: 
 
 
Date: 
 
 
Name 
Title 
 
 
 
 
 
 


DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
3 
TABLE OF CONTENTS 
 
STATEMENT OF COMPLIANCE .................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................8 
LIST OF ABBREVIATIONS ..........................................................................................................9 
PROTOCOL SUMMARY .............................................................................................................13 
1 
Key Roles ..............................................................................................................................29 
2 
Background Information and Scientific Rationale ...............................................................31 
 
Background Information ...........................................................................................31 
 
Scientific Rationale ...................................................................................................36 
 
Potential Risks and Benefits .....................................................................................37 
2.3.1 Potential Risks ..............................................................................................37 
2.3.2 Known Potential Benefits .............................................................................40 
3 
Study Objectives and Outcome Measures ............................................................................42 
4 
Study Design .........................................................................................................................43 
5 
Study Enrollment and Withdrawal........................................................................................45 
 
Eligibility Criteria .....................................................................................................45 
5.1.1 Subject Inclusion Criteria .............................................................................45 
5.1.2 Subject Exclusion Criteria ............................................................................47 
5.1.3 Exclusion Criteria for Second Study Vaccination ........................................49 
 
Treatment Assignment Procedures ...........................................................................50 
5.2.1 Enrollment and Randomization Procedures..................................................50 
5.2.2 Masking Procedures ......................................................................................50 
5.2.3 Reasons for Withdrawals and Discontinuation of Study Product 
Administration ..............................................................................................51 
5.2.4 Handling of Withdrawals and Discontinuation of Study Product 
Administration ..............................................................................................52 
5.2.5 Subject Replacement .....................................................................................52 
5.2.6 Termination of Study ....................................................................................52 
6 
Study Intervention/Investigational Product ..........................................................................54 
 
Study Product Description ........................................................................................54 
6.1.1 Formulation, Storage, Packaging, and Labeling ...........................................56 
6.1.2 Study Product Storage and Stability Procedures ..........................................58 


DMID Protocol 18-0011                                                                                           Version 8.0 
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4 
 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ......................................................................................................................59 
 
Accountability Procedures for the Study Intervention/Investigational Product .......61 
 
Assessment of Subject Compliance with Study Intervention/Investigational Product
...................................................................................................................................63 
 
Concomitant Medications/Treatments ......................................................................63 
7 
Study Procedures/Evaluations ..............................................................................................64 
 
Clinical Evaluations ..................................................................................................64 
 
Laboratory Evaluations .............................................................................................65 
7.2.1 Clinical Laboratory Evaluations ...................................................................65 
7.2.2 Special Assays or Procedures .......................................................................66 
7.2.3 Specimen Preparation, Handling and Shipping ............................................68 
7.2.3.1 Instructions for Specimen Preparation, Handling and Storage .........68 
7.2.3.2 Specimen Shipment ..........................................................................68 
8 
Study Schedule......................................................................................................................69 
 
Screening and Enrollment Visits ..............................................................................69 
8.1.1 Visit 00, Screening (Day -28 to -1), Clinic Visit ..........................................69 
8.1.2 Visit 01, Day 1, Enrollment (Vaccination), Clinic Visit ...............................70 
 
Follow-up Visits........................................................................................................72 
8.2.1 Visit 02, Day 2, Clinic Visit..........................................................................72 
8.2.2 Visit 03, Day 8, Clinic Visit..........................................................................73 
8.2.3 Visit 04, Day 29, Clinic Visit........................................................................74 
8.2.4 Visit 05, Day 57, Clinic Visit........................................................................75 
8.2.5 Visit 06, Day 90, Clinic Visit........................................................................75 
8.2.6 Visit 07, Day 118, Clinic Visit......................................................................76 
8.2.7 Visit 08, Day 180, Clinic Visit......................................................................77 
 
Final Visit..................................................................................................................77 
8.3.1 Visit 09, Day 365, Clinic Visit......................................................................77 
 
Early Termination Visit (if needed) ..........................................................................78 
 
Unscheduled Visit (if needed) ..................................................................................79 
9 
Assessment of Safety ............................................................................................................81 
 
Specification of Safety Parameters ...........................................................................81 
 
Methods and Timing for Assessing, Recording and Analyzing Safety Parameters .81 
9.2.1 Adverse Events .............................................................................................81 
9.2.2 Reactogenicity...............................................................................................84 
9.2.3 Additional Adverse Event Severity Grading ................................................86 
9.2.4 Serious Adverse Events ................................................................................88 
9.2.5 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings .........................................................89 


DMID Protocol 18-0011                                                                                           Version 8.0 
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5 
 
Reporting Procedures ................................................................................................89 
9.3.1 Serious Adverse Events ................................................................................89 
9.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND
.......................................................................................................................90 
9.3.3 Reporting of Pregnancy ................................................................................91 
 
Type and Duration of Follow-up of Subjects after Adverse Events .........................91 
 
Halting Rules ............................................................................................................92 
9.5.1 Halting Rules for the Sentinel Subjects ........................................................92 
9.5.2 Halting for Study...........................................................................................93 
 
Safety Oversight........................................................................................................94 
9.6.1 Independent Safety Monitor (ISM) ...............................................................94 
9.6.2 Data and Safety Monitoring Board (DSMB) ................................................94 
10 
Clinical Monitoring ...............................................................................................................97 
 
Site Monitoring Plan .................................................................................................97 
11 
Statistical Considerations ......................................................................................................98 
 
Introduction ...............................................................................................................98 
 
Study Hypotheses......................................................................................................98 
 
Study Outcome Measures .........................................................................................98 
 
Sample Size Considerations ......................................................................................98 
11.4.1 Study Population ...........................................................................................98 
11.4.2 Subject Enrollment and Follow-up ...............................................................99 
11.4.3 Sample Size ...................................................................................................99 
 
Planned Interim Analyses .......................................................................................101 
11.5.1 Interim Safety Review ................................................................................102 
 
Final Analysis Plan .................................................................................................102 
11.6.1 Analysis Populations ...................................................................................103 
11.6.2 Safety Data ..................................................................................................104 
11.6.3 Humoral Immunogenicity Data ..................................................................104 
11.6.4 Exploratory Cellular Immunogenicity Data................................................105 
11.6.5 Exploratory Transcriptomics Data ..............................................................105 
11.6.6 Missing Values and Outliers .......................................................................106 
12 
Data Collection Forms and Access to Source Data/Documents .........................................107 
13 
Quality Control and Quality Assurance ..............................................................................108 
14 
Ethics/Protection of Human Subjects .................................................................................109 
 
Ethical Standard ......................................................................................................109 
 
Institutional Review Board (IRB) ...........................................................................109 
 
Informed Consent Process ......................................................................................110 
 
Exclusion of Women, Minorities and Children (Special Populations) ...................111 
 
Subject Confidentiality ...........................................................................................112 


DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
6 
 
Study Discontinuation .............................................................................................113 
 
Costs, Subject Compensation and Research Related Injuries .................................113 
 
Future Use of Stored Specimens .............................................................................114 
15 
Data Handling and Record Keeping ...................................................................................116 
 
Data Management Responsibilities.........................................................................116 
 
Data Capture Methods ............................................................................................116 
 
Types of Data ..........................................................................................................117 
 
Timing/Reports .......................................................................................................117 
 
Study Records Retention.........................................................................................118 
 
Protocol Deviations .................................................................................................118 
16 
Publication Policy ...............................................................................................................120 
17 
Literature References ..........................................................................................................121 
18 
Appendices ..........................................................................................................................126 
 
SCHEDULE OF STUDY PROCEDURES AND EVALUATIONS .........127 
 
Adverse Events of special interest ..............................................................130 
 
 
 


DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
7 
LIST OF TABLES 
Table 1: Study Objectives and Outcome Measures .......................................................................14 
Table 2: Study Design ....................................................................................................................27 
Table 3: Venipuncture Volumes ....................................................................................................67 
Table 4: Injection Site Reactogenicity Grading .............................................................................84 
Table 5: Injection Site Reactogenicity Measurements ...................................................................85 
Table 6: Subjective Systemic Reactogenicity Grading ..................................................................85 
Table 7: Quantitative Systemic (Oral Temperature) Reactogenicity Grading ...............................86 
Table 8: Pulse and BP Adverse Event Grading .............................................................................86 
Table 9: Clinical Safety Laboratory Adverse Event Grading ........................................................86 
Table 10: Probability (%) to Detect Safety Events ......................................................................100 
Table 11: Precision of Binomial Confidence Intervals ................................................................100 
Table 12: Minimum Detectable Difference in Proportion Responders with 80% Power ............101 
Table 13: Schedule of Study Procedures and Evaluations...........................................................127 


DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
8 
LIST OF FIGURES 
Figure 1: Schematic of Study Design ............................................................................................28 
 
 
 


DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
9 
LIST OF ABBREVIATIONS 
A/H1N1 
Influenza A Virus of the H1N1 Subtype 
A/H1N2v 
Influenza A Virus of the H1N2 Variant Subtype 
A/H2N2 
Influenza A Virus of the H2N2 Subtype 
A/H3N2 
Influenza A Virus of the H3N2 Subtype 
A/H3N2v 
Influenza A Virus of the H3N2 Variant Subtype 
A/H5N1 
Influenza A Virus of the H5N1 Subtype 
A/H5N6 
Influenza A Virus of the H5N6 Subtype 
A/H5N8 
Influenza A Virus of the H5N8 Subtype 
A/H7N1 
Influenza A Virus of the H7N1 Subtype 
A/H7N7 
Influenza A Virus of the H7N7 Subtype 
A/H7N9 
Influenza A Virus of the H7N9 Subtype 
A/H9N2 
Influenza A Virus of the H9N2 Subtype 
Advax  
Trade name for delta inulin adjuvant formulation 
AE 
Adverse Event/Adverse Experience 
AESIs 
Adverse Events of Special Interest 
AF03 
Adjuvant formulation (03) 
ALP 
Alkaline phosphatase 
ALT 
Alanine Aminotransferase 
ANCA 
Anti-Neutrophil Cytoplasmic Antibody 
AS03 
Adjuvant System (03) 
AST 
Aspartate Aminotransferase 
BARDA 
Biomedical Advanced Research and Development Authority 
BLA 
Biologics License Applications 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
CMS 
Clinical Materials Services 
COI 
Conflict of Interest 
CpG55.2 
Class B CpG oligonucleotide adjuvant  
Cr 
Creatinine 
CROMS 
Clinical Research Operations and Management Support 
CSL 
Commonwealth Serum Laboratories 
CSR 
Clinical Study Report 


DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
10 
°C 
Degrees Celsius 
°F 
Degrees Fahrenheit 
D 
Day(s) 
DCF 
Data Collection Form 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EDCSM 
Electronic Data Capture System 
ELISpot 
Enzyme-Linked Immunosorbent Spot 
ESR 
Erythrocyte Sedimentation Rate 
FACS 
Fluorescence-Activated Cell Sorting 
FDA 
Food and Drug Administration 
FWA 
Federal-wide Assurance 
g/dL 
Grams per Deciliter 
GBS 
Guillain-Barré Syndrome 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GMT 
Geometric Mean Titer 
GSK 
GlaxoSmithKline Biologicals 
HA 
Hemagglutinin 
HAI 
Hemagglutination Inhibition 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HLGT 
High Level Group Term 
HPAI 
Highly Pathogenic Avian Influenza 
HRSA 
Health Resources and Services Administration 
IATA 
International Air Transport Association 
ICD-10 
10th revision of the International Statistical Classification of Diseases and 
Related Health Problems 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Institutional Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IIV 
Inactivated Influenza Virus Vaccine 


DMID Protocol 18-0011                                                                                           Version 8.0 
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IIV3 
Trivalent IIV 
IM 
Intramuscular(ly) 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IU/L 
International Unit(s) per Liter 
MAAE 
Medically-Attended Adverse Event 
mcg 
Microgram(s) 
µL 
Microliter(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF59 
MF59C.1 Adjuvant 
mg/dL 
Milligram(s) per Deciliter 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter(s) 
mm 
Millimeter(s) 
mmHg 
Millimeters of Mercury 
MOP 
Manual of Procedures 
N 
Number of Subjects 
NA 
Neuraminidase 
NAI 
Neuraminidase Inhibiting or Inhibition 
Neut 
Neutralizing or Neutralization 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
NK 
Natural Killer 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
NOCMCs 
New-Onset Chronic Medical Conditions 
OER 
Office of Extramural Research 
OHRP 
Office for Human Research Protections 
PBMC 
Peripheral Blood Mononuclear Cell 
PBS 
Phosphate Buffered Saline 
pH1N1 
2009 H1N1 Influenza 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PIMMCs 
Potentially Immune-Mediated Medical Conditions 
PLT 
Platelets 
PP 
Per Protocol 
 
 
PRN 
As Needed 
QIV 
Quadrivalent Influenza Vaccine 


DMID Protocol 18-0011                                                                                           Version 8.0 
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QA 
Quality Assurance 
QC 
Quality Control 
RIV 
Recombinant Influenza Vaccine 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SDCC 
Statistical and Data Coordinating Center 
SMA 
Secondary Medical Assessor 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SP 
Sanofi Pasteur 
SRID 
Single Radial Immunodiffusion 
SWI 
Sterile Water for Injection 
TBD 
To Be Determined 
TIV 
Trivalent Influenza Vaccine 
TLR 
Toll-like Receptor 
T. Bili 
Total Bilirubin 
US 
United States 
V 
Visit(s) 
VTEU 
Vaccine and Treatment Evaluation Unit 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 


DMID Protocol 18-0011                                                                                           Version 8.0 
Flublok or Fluzone with Advax-CpG55.2 or AF03                                             01 February 2021 
 
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PROTOCOL SUMMARY 
Title: 
A Phase I Study to Assess the Safety, Reactogenicity and Immunogenicity of Two 
Quadrivalent Seasonal Influenza Vaccines (Fluzone® or Flublok®) With or Without 
One of Two Adjuvants (AF03 or Advax-CpG55.2) in Healthy Adults 18-45 Years of 
Age 
Phase: 
I 
Population: 
Up to 240 males and non-pregnant females, 18 to 45 years of age, inclusive, who are in 
good health and meet all eligibility criteria 
Number of Sites: 8 Vaccine and Treatment Evaluation Unit (VTEU) sites  
Study Duration: 
Approximately 18 months 
Subject 
Participation 
Duration: 
Approximately 12 months 
Estimated Time 
to Complete 
Enrollment: 
Approximately 9 weeks 
Description of 
Agents: 
• 
Flublok Quadrivalent Influenza Vaccine (QIV) 2018/2019 Formula 
manufactured by Sanofi Pasteur (SP). 
• 
Fluzone Quadrivalent Influenza Vaccine (QIV) 2018/2019 Formula 
manufactured by SP. 
• 
Flublok Quadrivalent Influenza Vaccine (QIV) 2019/2020 Formula 
manufactured by SP. 
• 
Fluzone Quadrivalent Influenza Vaccine (QIV) 2019/2020 Formula 
manufactured by SP. 
• 
AF03 adjuvant manufactured by SP. 
• 
Advax-CpG55.2 adjuvant is a combination adjuvant comprised of Advax and 
CpG55.2 adjuvants: 
o Advax (delta inulin) adjuvant manufactured for Vaxine by Sypharma 
Pty Ltd.  
o CpG55.2 oligonucleotide adjuvant manufactured for Vaxine by Nikko 
Denka Avecia and Sypharma Pty Ltd.   


DMID Protocol 18-0011                                                                                           Version 8.0 
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Table 1: Study Objectives and Outcome Measures 
Primary Safety Objectives 
Primary Safety Outcome Measures 
• To assess the safety and 
reactogenicity of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant.  
 
• Occurrence of solicited injection site and 
systemic reactogenicity events through 
approximately Day 8 after the first study 
vaccination. 
• Occurrence of unsolicited adverse events 
from the time of the first study 
vaccination through approximately Day 
29. 
• Occurrence of all SAEs through 
approximately 12 months following 
receipt of the first study vaccination. 
• Occurrence of abnormal clinical safety 
laboratory AEs from the time of study 
vaccination through approximately Day 8 
after the first study vaccination. 
Primary Immunogenicity Objectives 
Primary Immunogenicity Outcome Measures 
• To assess the serum 
hemagglutination inhibition (HAI) 
antibody responses against 
2018/2019 QIV strains from 
baseline (Day 1) to approximately 
Day 29 after receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant. 
 
• The percentage of subjects achieving 
HAI titer seroconversion against the 
2018/2019 QIV strains (defined as either 
a pre-vaccination titer <1:10 and a post-
vaccination titer ≥1:40 or a pre-
vaccination titer ≥1:10 and a minimum 
four-fold rise in post-vaccination 
antibody titer) on approximately Day 29 
for each study group. 
• The percentage of subjects with an HAI 
titer ≥1:40 against the 2018/2019 QIV 
strains at baseline and approximately 
Day 29 for each study group. 
• Geometric mean titers (GMTs) of serum 
HAI against the 2018/2019 QIV strains at 
baseline and approximately Day 29 for 
each study group. 


DMID Protocol 18-0011                                                                                           Version 8.0 
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• Ratio of GMTs of serum HAI against the 
2018/2019 QIV strains between 
adjuvanted and unadjuvanted study 
groups at baseline and approximately 
Day 29. 
• Geometric mean fold rise (GMFR) in 
HAI titers from baseline (Day 1) against 
the 2018/2019 QIV strains at 
approximately Day 29 for each study 
group 
• To assess the serum neuraminidase 
inhibition antibody (NAI) 
responses by enzyme-linked lectin 
assay (ELLA) against NA antigens 
in the 2018/2019 QIV from 
baseline (Day 1) to approximately 
Day 29 after receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant.   
• The percentage of subjects achieving 
NAI seroconversion (defined as ≥4-fold 
rise in post vaccination antibody titers 
against the NA antigens in the 2018/2019 
QIV) on approximately Day 29 for each 
study group. 
• The serum NAI GMT at baseline (Day 1) 
and approximately Day 29 for each study 
group. 
• Ratio of serum NAI GMT between 
adjuvanted and unadjuvanted study 
groups at baseline (Day 1) and 
approximately Day 29. 
• Geometric mean fold rise (GMFR) in 
NAI titers from baseline (Day 1) against 
NA antigens in the 2018/2019 QIV 
strains at approximately Day 29 for each 
study group 
• To assess the influenza neutralizing 
(Neut) antibody titer responses 
against 2018/2019 QIV strains from 
baseline (Day 1) to approximately 
Day 29 after receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax- CpG55.2 
adjuvant.  
• The percentage of subjects achieving 
Neut titer seroconversion against the 
2018/2019 QIV strains (defined as either 
a pre-vaccination titer <1:10 and a post-
vaccination titer ≥1:40 or a pre-
vaccination titer ≥1:10 and a minimum 
four-fold rise in post-vaccination 
antibody titer) on approximately Day 29 
for each study group. 


DMID Protocol 18-0011                                                                                           Version 8.0 
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• The percentage of subjects with a Neut 
titer ≥1:40 against the 2018/2019 QIV 
strains at baseline (Day 1) and 
approximately Day 29 for each study 
group. 
• Serum Neut GMT at baseline (Day 1) 
and approximately Day 29 for each study 
group 
• Ratio of serum Neut GMT between 
adjuvanted and unadjuvanted study 
groups at baseline (Day 1) and 
approximately Day 29. 
• Geometric mean fold rise (GMFR) in 
Neut titers from baseline (Day 1) against 
the 2018/2019 QIV strains at 
approximately Day 29 for each study 
group 
Secondary Safety Objectives 
Secondary Safety Outcome Measures 
• To assess protocol specified AESIs, 
medically-attended adverse events 
(MAAEs), including new-onset 
chronic medical conditions 
(NOCMCs) and potentially 
immune-mediated medical 
conditions (PIMMCs) that occur 
after receipt of study product. 
• Occurrence of all protocol specified 
AESIs, MAAEs, including NOCMCs and 
PIMMCs, from the time of the first study 
vaccination through approximately 12 
months following the first vaccination. 
 
Secondary Immunogenicity Objectives  
Secondary Immunogenicity Outcome 
Measures 
• To assess the HAI, Neut and NAI 
ELLA responses to the 2019/2020 
QIV strains prior to (Day 1) and 
approximately 28 days after 
vaccination with the 2019/2020 
QIV in all study groups 
• The percentage of subjects achieving an 
HAI titer ≥1:40 against 2019/2020 QIV 
strains approximately on Days D90 
(baseline) and D118 (28 days post-
2019/2020 vaccine) for each study group. 
• The percentages of subjects achieving 
HAI, Neut and NAI titer seroconversion, 
against 2019/2020 QIV strains on 


DMID Protocol 18-0011                                                                                           Version 8.0 
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approximately Day 118 for each study 
group (NAI titers will only be assessed 
on study groups 1,2 and 3). 
• Serum Neut, HAI and NAI GMTs 
against 2019/2020 QIV strains 
approximately on Days D90 (baseline) 
and D118 (28 days post-2019/2020 QIV) 
for each study group (NAI titers will only 
be assessed on study groups 1,2 and 3).  
• Ratio of serum Neut, HAI and NAI 
GMTs against 2019/2020 QIV strains 
between adjuvanted and unadjuvanted 
study groups approximately on Days D90 
(baseline) and D118 (28 days post-
2019/2020 QIV). NAI titers will only be 
assessed on study groups 1,2 and 3. 
• Serum Neut, HAI and NAI GMFRs 
against 2019/2020 QIV strains from 
baseline (D90) on approximately D118 
for each study group (NAI titers will only 
be assessed on study groups 1,2 and 3). 
• To assess the HAI antibody 
responses against heterologous 
influenza A/H1 and H3 strains from 
baseline (Day 1) to approximately 
Days 8, 29, 57, 90, and 118 after 
receipt of 2018/2019 Fluzone or 
Flublok with and without AF03 or 
Advax-CpG55.2 adjuvant.  
 
• The percentages of subjects achieving 
HAI titer seroconversion, against 
heterologous H1 and H3 influenza strains 
on approximately Days 8, 29, 57, 90, and 
118 for each study group.  
• The percentage of subjects achieving an 
HAI titer ≥1:40 against heterologous H1 
and H3 influenza strains at baseline (Day 
1) and approximately Days 8, 29, 57, 90, 
and 118 for each study group. 
• Serum HAI GMT against heterologous 
H1 and H3 influenza strains at baseline 
(Day 1) and approximately Days 8, 29, 
57, 90, and 118 for each study group.  
• Ratio of serum HAI GMT against 
heterologous H1 and H3 influenza strains 


DMID Protocol 18-0011                                                                                           Version 8.0 
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between adjuvanted and unadjuvanted 
study groups at baseline (Day 1) and 
approximately Days 8, 29, 57, 90, and 
118.  
• Geometric mean fold rise (GMFR) in 
HAI from baseline (Day 1) against 
heterologous H1 and H3 influenza strains 
at approximately Days 8, 29, 57, 90, and 
118 for each study group 
• To assess NAI ELLA responses 
against heterologous N1 and N2 
NA antigens from baseline (Day 1) 
to approximately Days 8, 29, 57, 
90, and 118 after administration of 
2018/2019 Fluzone with and 
without AF03 or Advax-CpG55.2 
adjuvant. 
 
• The percentage of subjects achieving 
seroconversion against heterologous N1 
and N2 NA antigens on approximately 
Days 8, 29, 57, 90, and 118 for study 
groups 1, 2 and 3. 
• Serum NAI GMTs against heterologous 
N1 and N2 NA antigens at baseline and 
approximately Days 8, 29, 57, 90, and 
118 for study groups 1, 2 and 3. 
• Ratio of serum NAI GMTs against 
heterologous N1 and N2 NA antigens 
between adjuvanted and unadjuvanted 
study groups at baseline and 
approximately Days 8, 29, 57, 90, and 
118 (NAI titers will only be assessed on 
study groups 1,2 and 3). 
• Geometric mean fold rise (GMFR) in 
serum NAI from baseline against 
heterologous N1 and N2 NA antigens at 
baseline and approximately Days 8, 29, 
57, 90, and 118 for study groups 1, 2 and 
3. 
 
• To assess the influenza neutralizing 
(Neut) antibody titer responses 
against heterologous influenza 
A/H1 and H3 strains from baseline 
(Day 1) to approximately Days 8, 
• The percentage of subjects achieving 
Neut titer seroconversion against 
heterologous H1 and H3 influenza strains 


DMID Protocol 18-0011                                                                                           Version 8.0 
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29, 57, 90, and 118 after 
administration of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant.  
 
on approximately Days 8, 29, 57, 90, and 
118 for each study group. 
• Serum Neut GMT against heterologous 
H1 and H3 influenza strains at baseline 
(Day 1) and approximately Days 8, 29, 
57, 90, and 118 for each study group. 
• Ratio of serum Neut GMT against 
heterologous H1 and H3 influenza strains 
between adjuvanted and unadjuvanted 
study groups at baseline (Day 1) and 
approximately Days 8, 29, 57, 90, and 
118. 
• Geometric mean fold rise (GMFR) of 
neut antibody titers from baseline against 
heterologous H1 and H3 influenza strains 
at baseline (Day 1) and approximately 
Days 8, 29, 57, 90, and 118 for each 
study group. 
• To assess the longitudinal kinetics 
and durability of the HAI, NAI, and 
Neut responses against the 
2018/2019 QIV strains on 
approximately Days 8, 57, 90, and 
118 following receipt of the 
2018/2019 Fluzone and Flublok 
with and without AF03 or Advax-
CpG55.2 adjuvant.   
 
• The percentage of subjects achieving 
HAI, NAI and Neut titer seroconversion 
against 2018/2019 QIV antigens and 
strains on approximately Days 8, 57, 90, 
and 118 for each study group (NAI titers 
will only be assessed on study groups 1,2 
and 3). 
• The percentage of subjects achieving an 
HAI and Neut titer ≥1:40 against 
2018/2019 QIV strains on approximately 
Days 8, 57, 90, and 118 for each study 
group (NAI titers will only be assessed 
on study groups 1,2 and 3). 
• Serum Neut, HAI and NAI GMT against 
2018/2019 QIV strains on approximately 
Days 8, 57, 90, and 118 for each study 
group (NAI titers will only be assessed 
on study groups 1,2 and 3). 


DMID Protocol 18-0011                                                                                           Version 8.0 
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• Ratio of serum Neut, HAI and NAI GMT 
against 2018/2019 QIV strains between 
adjuvanted and unadjuvanted study 
groups on approximately Days 8, 57, 90, 
and 118  (NAI titers will only be assessed 
on study groups 1,2 and 3). 
• Geometric mean fold rise (GMFR) in 
HAI, Neut and NAI titers from baseline 
(Day 1) against the 2018/2019 QIV 
strains at approximately Day 8, 57, 90, 
and 118 for each study group (NAI titers 
will only be assessed on study groups 1,2 
and 3). 
Exploratory Immunogenicity Objectives 
Exploratory Immunogenicity Study 
Outcomes 
• To assess the HAI antibody 
responses against heterologous 
influenza A/H1 and H3 strains from 
baseline (Day 1) to approximately 
Days 180 and 365 after receipt of 
2018/2019 Fluzone or Flublok with 
and without AF03 or Advax-
CpG55.2 adjuvant.  
 
• The percentages of subjects achieving 
HAI titer seroconversion, against 
heterologous H1 and H3 influenza strains 
on approximately Days 180 and 365 for 
each study group.  
• The percentage of subjects achieving an 
HAI titer ≥1:40 against heterologous H1 
and H3 influenza strains at baseline (Day 
1) and approximately Days 180 and 365 
for each study group. 
• Serum HAI GMT against heterologous 
H1 and H3 influenza strains at baseline 
(Day 1) and approximately Days 180 and 
365 each study group.  
• Ratio of serum HAI GMT against 
heterologous H1 and H3 influenza strains 
between adjuvanted and unadjuvanted 
study groups at baseline (Day 1) and 
approximately Days 180 and 365.  
• Geometric mean fold rise (GMFR) in 
HAI from baseline (Day 1) against 
heterologous H1 and H3 influenza strains 


DMID Protocol 18-0011                                                                                           Version 8.0 
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at approximately Days 180 and 365 for 
each study group 
• To assess NAI ELLA responses 
against heterologous N1 and N2 
NA antigens from baseline (Day 1) 
to approximately Days 180 and 365 
administration of 2018/2019 
Fluzone with and without AF03 or 
Advax-CpG55.2 adjuvant. 
 
• The percentage of subjects achieving 
seroconversion against heterologous N1 
and N2 NA antigens on approximately 
Days 180 and 365 for study groups 1, 2 
and 3. 
• Serum NAI GMTs against heterologous 
N1 and N2 NA antigens at baseline and 
approximately Days 180 and 365 for 
study groups 1, 2 and 3. 
• Ratio of serum NAI GMTs against 
heterologous N1 and N2 NA antigens 
between adjuvanted and unadjuvanted 
study groups at baseline and 
approximately Days 180 and 365 for 
study groups 1,2 and 3. 
• Geometric mean fold rise (GMFR) in 
serum NAI from baseline against 
heterologous N1 and N2 NA antigens at 
baseline and approximately Days 180 
and 365 for study groups 1, 2 and 3. 
 
• To assess the influenza neutralizing 
(Neut) antibody titer responses 
against heterologous influenza 
A/H1 and H3 strains from baseline 
(Day 1) to approximately Days 180 
and 365 after administration of 
2018/2019 Fluzone and Flublok 
with and without AF03 or Advax-
CpG55.2 adjuvant.  
 
• The percentage of subjects achieving 
Neut titer seroconversion against 
heterologous H1 and H3 influenza strains 
on approximately Days 180 and 365 for 
each study group. 
• Serum Neut GMT against heterologous 
H1 and H3 influenza strains at baseline 
(Day 1) and approximately Days 180 and 
365 for each study group. 
• Ratio of serum Neut GMT against 
heterologous H1 and H3 influenza strains 
between adjuvanted and unadjuvanted 
study groups at baseline (Day 1) and 
approximately Days 180 and 365. 


DMID Protocol 18-0011                                                                                           Version 8.0 
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• Geometric mean fold rise (GMFR) of 
neut antibody titers from baseline against 
heterologous H1 and H3 influenza strains 
at baseline (Day 1) and approximately 
Days 180 and 365 for each study group. 
• To assess the longitudinal kinetics 
and durability of the HAI, NAI, and 
Neut responses against the 
2018/2019 QIV strains on 
approximately Days 180 and 365 
following receipt of the 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant.   
 
• The percentage of subjects achieving 
HAI, NAI and Neut titer seroconversion 
against 2018/2019 QIV antigens and 
strains on approximately Days 180 and 
365 for each study group (NAI titers will 
only be assessed on study groups 1,2 and 
3). 
• The percentage of subjects achieving an 
HAI and Neut titer ≥1:40 against 
2018/2019 QIV strains on approximately 
Days 180 and 365 for each study group 
(NAI titers will only be assessed on study 
groups 1,2 and 3). 
• Serum Neut, HAI and NAI GMT against 
2018/2019 QIV strains on approximately 
Days 180 and 365 for each study group 
(NAI titers will only be assessed on study 
groups 1,2 and 3). 
• Ratio of serum Neut, HAI and NAI GMT 
against 2018/2019 QIV strains between 
adjuvanted and unadjuvanted study 
groups on approximately Days 180 and 
365 (NAI titers will only be assessed on 
study groups 1,2 and 3). 
• Geometric mean fold rise (GMFR) in 
HAI, Neut and NAI titers from baseline 
(Day 1) against the 2018/2019 QIV 
strains at approximately Day 180 and 365 
for each study group (NAI titers will only 
be assessed on study groups 1,2 and 3). 
• To assess the HAI, Neut and NAI 
ELLA responses to the 2018/2019 
at all timepoints and 2019/2020 
QIV strains prior to and 
• The percentage of subjects achieving an 
HAI titer ≥1:40 against 2018/2019 QIV 
strains at all timepoints and against 
2019/2020 QIV strains at approximately 
D90 and D118. 


DMID Protocol 18-0011                                                                                           Version 8.0 
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approximately 28 days after 
vaccination with the 2019/2020 
QIV in all study groups, according 
to serostatus at baseline and 
previous influenza vaccination  
• The percentages of subjects achieving 
HAI, Neut and NAI titer seroconversion, 
against 2018/2019 QIV strains at 
approximately D29 and against 
2019/2020 QIV strains at approximately 
D118.  
• Serum Neut, HAI and NAI GMTs 
against 2018/2019 QIV strains at all 
timepoints (for study groups 4, 5 and 6 
NAI titers will only be assessed at D1 
and D29) and against 2019/2020 QIV 
strains at approximately D90 and D118 
(NAI titers will only be assessed on study 
groups 1,2 and 3).  
• Serum Neut, HAI and NAI GMFRs 
against 2018/2019 QIV strains on 
approximately Days 8, 29, 57, 90, 118, 
180 and 365 (for study groups 4, 5 and 6 
NAI titers will only be assessed at D1 
and D29) and against 2019/2020 QIV 
strains at approximately D118 (NAI titers 
will only be assessed on study groups 1,2 
and 3).  
• To assess B Cell effector and 
memory responses prior to (Day 1) 
and following receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant. 
 
• Change in the frequency of influenza 
specific-IgG, IgM and IgA B memory 
cells using multiplexed FluroSpot from 
baseline (Day 1) to approximately Days 
29 and 90 for each study group. 
• Change in frequency of influenza-
specific IgG, IgM and IgA effector B 
cells (plasmablast) using multiplexed 
Fluorospot from baseline (Day 1) to 
approximately Day 8 for each study 
group. 
• To assess plasmablast and T 
follicular helper (Tfh cell responses 
prior to (Day 1) and following 
receipt of 2018/2019 Fluzone and 
Flublok with and without AF03 or 
Advax-CpG55.2 adjuvant. 
• Change in the frequency of plasmablast 
and Tfh cells using multiparametric flow 
cytometry from baseline (Day 1) to 
approximately Day 8 for each study 
group. 
 


DMID Protocol 18-0011                                                                                           Version 8.0 
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• To assess the functional non-
neutralizing Fc-effector antibody 
responses prior to (Day 1) and 
following receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant.   
• GMT of functional non-neutralizing Fc-
effector antibodies against vaccine strain 
antigens at baseline (Day 1) and 
approximately Day 29 after vaccination 
for each study group. 
• Geometric mean fold rise (GMFR) in 
functional non-neutralizing Fc-effector 
antibody titers from baseline (Day 1) 
against the 2018/2019 QIV strains at 
approximately Day 29 for each study 
group 
• To assess responses from baseline 
(Day 1) in transcriptomic profiling 
on approximately Days 2 and 8 
following receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant. 
• Differential expression of transcription 
profiles comparing samples taken just 
prior to (Day 1) and on approximately 
Days 2 and 8 following receipt of the 
2018/2019 QIV vaccination in at least a 
subset of subjects for each study group . 
 
• To evaluate the relationship of non-
neutralizing Fc-effector antibodies 
titers with HAI and NA responses 
following receipt of 2018/2019 
Fluzone and Flublok with and 
without AF03 or Advax-CpG55.2 
adjuvant. 
 
• The association of non-neutralizing Fc-
effector antibodies GMT with HAI and 
Neut antibody GMT, seroprotection and 
seroconversion rates to variant influenza 
strains and the 2018/2019 QIV vaccine 
strains. 
• To describe the non-neutralizing 
Ab responses to different influenza 
HA antigens by a multiplex ELISA 
assay at all time points in each 
study group 
• Quantification of HA binding antibodies 
against different influenza HA antigens 
at baseline (Day 1) and Days 8, 29, 57, 
90, 118, 180 and 365 in each study 
group. 
• To describe the NA binding 
antibody response to NA antigens 
corresponding to the vaccine strain 
antigens by an ELISA assay after 
administration of Fluzone with and 
• Quantification of NA binding antibodies 
against  influenza NA antigens 
corresponding to the vaccine strain 
antigens at baseline (Day 1), Day 29, 57, 
90 and D118 in Groups 1, 2, 3.  
Additional studies on Days180 and 365 


DMID Protocol 18-0011                                                                                           Version 8.0 
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without AF03 or Advax-CpG55.2 
adjuvant. 
in Groups 1,2,3 will be contingent on 
seeing increased seroconversion rates to 
homologous vaccine strain antigens 
 
Description of 
Study Design: 
 
This is a Phase I, randomized, double blinded, clinical trial in up to 240 males and non-
pregnant females, 18-45 years of age, inclusive, who are in good health and meet all 
eligibility criteria. This clinical trial is designed to assess the safety, reactogenicity and 
immunogenicity of either the 2018/2019 Fluzone or Flublok Quadrivalent Influenza 
Vaccines (QIV), manufactured by Sanofi Pasteur (SP) given without adjuvant or with 
one of two adjuvant formulations, AF03 (SP) or Advax-CpG55.2 (Vaxine Pty Ltd).  
Fluzone is a quadrivalent split virion inactivated vaccine whereas Flublok is a 
quadrivalent influenza vaccine that contains recombinant hemagglutinin proteins. AF03 
is a squalene-based emulsion adjuvant, whereas Advax-CpG55.2 is a combination 
adjuvant comprised of delta inulin and the oligonucleotide, CpG55.2. Enrollment will 
occur in the second and third quarters of calendar year 2019 to allow antibody titers to 
previous doses of 2018/2019 IIV to wane. 
Subjects will be stratified by prior receipt of licensed, seasonal influenza vaccine 
(defined as receipt of at least one of the 2017/2018 and/or 2018/2019 influenza 
vaccines) and will be randomly assigned to 1 of 6 treatment arms to receive a single 
dose of one of the two seasonal 2018/2019 QIV vaccine formulations with or without 
one of the two adjuvants (Day 1).  On approximately Day 90, each subject will receive a 
single dose of the seasonal 2019/2020 influenza vaccine.  Groups 1, 2 and 3 will receive 
2019/2020 Fluzone QIV and Groups 4, 5 and 6 will receive 2019/2020 Flublok QIV. 
To determine early safety signals for this Phase I study, enrollment will proceed in a 
staged fashion for the first 6 sentinel subjects. The first six subjects will be randomized 
and vaccinated with one each from Groups 1-6. These six subjects will be followed 
through Day 8. If any of the pre-specified halting rules for the sentinel subjects occur, 
the study will be halted and reviewed by the DSMB.  If no pre-specified safety signals 
are encountered enrollment will proceed. 
It is anticipated that both adjuvant formulations (AF03 and Advax-CpG55.2) will be 
available at the start of study enrollment. However, if the Advax–CpG55.2 is not 
available, the study will proceed only with groups 1, 2, 4 and 5 open for enrollment for 
the remaining subjects (up to 240, 60 per group). For the sentinel subjects, one subject 
from groups 1, 2, 4 and 5 will be enrolled and followed through Day 8.  If any of the 
pre-specified halting rules for sentinel subjects occur, the study will be halted 
and reviewed by the DSMB. If no pre-specified events occur, randomization will 
proceed in groups 1, 2, 4 and 5 for the remaining subjects. 
The DSMB will review the data when the 8-day reactogenicity and clinical safety 
laboratory data following the first study vaccination are available for 50% of study 


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subjects. Enrollment will not be paused for this review.  An additional scheduled DSMB 
review will occur when all HAI, NAI and Neut data for Day 1, and Day 29 and safety 
data through Day 57 following the first study vaccination, are available.  
Reactogenicity will be measured by the occurrence of solicited injection site and 
systemic reactions from the time of the first study vaccination through Day 8. 
Unsolicited non-serious adverse events (AEs) will be collected from Day 1 through 
approximately Day 29. Serious adverse events (SAEs), Adverse Events of Special 
Interest (AESIs) including reports of tearing, dry mouth, dry eyes and medically-
attended adverse events (MAAEs), including new-onset chronic medical conditions 
(NOCMCs) and potentially immune-mediated medical conditions (PIMMCs), will be 
collected from the time of study vaccination through approximately 12 months after the 
first study vaccination. Clinical safety laboratory evaluations (hematology and 
chemistry) will be performed at screening, immediately prior to the first study 
vaccination and at approximately Day 8. 
Only pharmacy personnel, the Emmes unblinded team and an unblinded vaccinator will 
have access to the study codes; all other study personnel will be blinded. 
Immunogenicity testing will include performing serological assays to assess 
hemagglutination inhibition (HAI), neutralizing (Neut) and neuraminidase inhibition 
(NAI) titers at multiple time points following both study vaccinations. Antibody 
responses will be determined for both influenza vaccine strains and heterologous 
influenza strains.  In addition, whole blood transcriptomics and peripheral blood 
mononuclear cells (PBMCs) will be used to determine transcriptional profiling and 
broad immunologic responses and to associate these responses with serological 
antibody responses described above in each of the treatment arms.  Immunologic 
responses will include longitudinal assessments of the kinetics, magnitude, specificity, 
and/or quality of influenza-specific memory B cells, plasmablasts, and circulating T 
follicular helper (TFH) cells and non-neutralizing antibody responses to HA and NA 
antigens 


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Table 2: Study Design 
 
 
 
 
Day 1 
 
Day 90 
Study Group 
N 
Study Vaccine 
Adjuvant 
Seasonal Vaccine 
1 
40 
Fluzone 2018/2019 QIV 
None 
Fluzone 2019/2020 QIV   
2 
40 
Fluzone 2018/2019 QIV 
AF03 
Fluzone 2019/2020 QIV   
3A 
40 
Fluzone 2018/2019 QIV 
Advax-CpG55.2 
Fluzone 2019/2020 QIV   
4 
40 
Flublok 2018/2019 QIV 
None 
Flublok 2019/2020 QIV   
5 
40 
Flublok 2018/2019 QIV 
AF03 
Flublok 2019/2020 QIV   
6A 
40 
Flublok 2018/2019 QIV 
Advax-CpG55.2 
Flublok 2019/2020 QIV   
 
Total N= 240 A 
 
 
 
Note: Cohorts will be enrolled simultaneously. Randomization at each site will be stratified by prior receipt of licensed, seasonal influenza 
vaccine (defined as receipt of at least one of the 2017/2018 and/or 2018/2019 licensed, seasonal influenza vaccines). 
A If Advax-CpG55.2 is not available, the study will proceed only with groups 1, 2, 4 and 5 open for enrollment for the remaining subjects (up to 
240, 60 per group) in groups 1, 2, 4 and 5. 


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Figure 1: Schematic of Study Design 
Planned Enrollment
 Up To n=240
Men & Non Pregnant Women, 18-45 year of age
Consent and evaluate medical status, assess eligibility, 
perform screening and laboratory evaluations
Randomize and vaccinate 6 sentinel 
subjects, one from each groups 1-6
Follow Sentinel subjects for pre-defined safety signals 
through Day 8
DSMB Review 
Day 8 Post 1st Vaccination
50% of all subjects
(Enrollment will not be paused)
Complete Enrollment
Assessment of Final Outcome Measures
Randomize and vaccinate 4 sentinel 
subjects, one from each groups 1,2,4 & 5
If both adjuvants are available 
If Advax-CpG55.2 is not available
Continue Enrollment
DSMB Review
HAI, NAI and Neut data for 
Day 1 and Day 29 and safety data through Day 57
Post 1st vaccination
 


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1 
KEY ROLES 
Lead Principal Investigator: 
 
Patricia Winokur, MD 
University of Iowa Carver College of Medicine 
Iowa City, IA 
 
DMID Clinical Project Manager: 
Kathy Ormanoski, M.S., CCRA 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
 
DMID Medical Monitor: 
Mohamed Elsafy, MD 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
 
DMID Medical Officer: 
 
Mamodikoe Makhene, MD, MPH 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
 
DMID Scientific Lead: 
Chris Roberts, PhD 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
Safety and Pharmacovigilance: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support 
(CROMS) 
Site Principal Investigators 
Emmanuel (Chip) Walter, MD 
Duke University 
 
Hana El Sahly, MD 
Baylor College of Medicine 
 
Robert Frenck, MD 
Cincinnati Children’s Medical Center 
 
Sharon Frey, MD 
Saint Louis University 
 
 


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C. Buddy Creech, MD, MPH 
Vanderbilt University Medical Center 
 
Evan J. Anderson, MD 
Emory University 
 
James D. Campbell, MD, MS 
University of Maryland School of Medicine 
Statistical and Data Coordinating 
Center: 
The Emmes Company, LLC 
 
Clinical Materials Services: 
Fisher BioServices 
 
Central (Clinical) Laboratory: 
PPD Global Central Laboratories 
 
HAI, NAI, Neut Antibody, Cellular 
Immunology, Transcriptomics and 
Additional Serological Assays 
Laboratory: 
Sanofi Pasteur 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
Background Information 
Influenza is a common acute viral respiratory illness.  Seasonal influenza occurs annually, and in 
the United States it causes an estimated 100,000 to 600,000 hospitalizations annually and up to 
50,000 deaths a year [1].  Use of influenza vaccines is the primary means for preventing 
influenza.  Current licensed inactivated influenza vaccines (IIVs) are good for preventing 
influenza but are less effective than desirable.  Meta-analyses examining controlled trials 
comparing seasonal IIV to no vaccine for preventing laboratory-confirmed influenza illness have 
shown remarkable variability between different seasons ranging from 16%-76% with improved, 
though still imperfect, efficacy seen when the IIV strains matched the circulating strains [2].  
Others have evaluated the effectiveness of IIV in preventing severe influenza hospitalizations 
and found a pooled efficacy of 51% in adults aged 18-64 and 37% in adults 65 years of age or 
older [3]. 
Various formulations of IIV have been approved for use in the United States.  Most vaccines 
belong to the inactivated, split virus family of vaccines that are produced from influenza viruses 
grown in embryonated chicken eggs or cell lines that then undergo chemical disruption and 
purification to produce the antigens included in the vaccine. These vaccines include not only the 
immunodominant hemagglutinin protein (HA) from influenza, but also smaller quantities of 
neuraminidase proteins (NA).  Fluzone belongs to this family of IIV.  More recently FDA has 
approved Flublok, which is also a non-replicating vaccine, but the manufacturing process and 
subsequent antigen composition of the vaccine is quite different from that seen with the split 
virus family of vaccines.  Flublok contains only recombinant HA proteins (rHA) produced in an 
insect cell line using a baculovirus vector that encodes the influenza HA gene.  The rHAs are 
purified from the cells and used to create the Flublok vaccine. 
Serum IgG antibody to the influenza virus HA, the major component of inactivated subunit and 
split virus vaccines, has a major role in protective immunity to influenza virus infection [4].  
Resistance to infection with seasonal influenza virus strains correlates directly with both serum 
hemagglutination inhibition (HAI) and neutralizing (Neut) antibody levels, and measurements of 
serum HAI and Neut antibodies are used routinely to assess the immunogenicity of both seasonal 
and pandemic IIVs.  Recent data also support an important role for neuraminidase inhibiting 
(NAI) antibodies in protection against disease [4].  In a recent human influenza challenge study, 
serum NAI antibody levels were also identified as an independent correlate of protection against 


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influenza illness [5].  Cellular immunity also can have a role in preventing influenza-associated 
illness [6].
 
Several approaches have been used to increase the immunogenicity of IIVs. Standard-adult dose 
seasonal IIVs contain 15 mcg of HA antigen per seasonal influenza vaccine strain. Clinical 
studies evaluating increased HA-containing influenza vaccines have shown dose-related 
increases in serum and mucosal antibody responses [7].  In 2009, a high-dose seasonal IIV 
containing 4 times the standard HA antigen per seasonal influenza vaccine strain was approved 
in the United States (US) for use in individuals 65 years of age and older. 
The inclusion of an adjuvant provides another mechanism to improve the immune response to 
IIV antigens.  The addition of MF59, a squalene-based, oil-in-water emulsion, to IIV has been 
shown to increase HAI titers to the homologous vaccine strains and also to induce cross-reactive 
HAI antibodies that bind drifted seasonal influenza viruses. MF59-adjuvanted seasonal IIV was 
approved for use in the elderly in Italy in 1997.  Studies have typically shown the MF59 
adjuvanted groups produce more local vaccination site tenderness and inflammation, but most 
events are mild-moderate [8].  Many studies were subsequently performed in other age groups 
and led to the approval of two MF59- adjuvanted pandemic 2009 H1N1 vaccines for use in 
children and all adults in 2009 [9].  Today 38 countries have approved the use of MF59- 
adjuvanted seasonal trivalent IIV, now called Fluad® (Fluad), and many allow use in all age 
groups.  In 2015, the U.S. FDA approved Fluad, though it restricted the use to adults ages 65 and 
older. 
More recently, studies have explored the use of adjuvants to enhance the antibody responses to 
the much less immunogenic novel avian strains of influenza virus such as A/H5N1 and A/H7N9. 
AS03 is a squalene-based, oil-in-water emulsion that includes -tocopherol. Both AS03 and 
MF59 have resulted in increased antibody responses to IIVs containing novel HAs[9].  Studies 
have shown that the inclusion of these two adjuvants can reduce the antigen dose needed to 
achieve higher HAI and neutralizing titers and the titers are substantially greater than those 
generated with unadjuvanted formulations of vaccine [10]. 
Given the fact that the MF59 and AS03 adjuvants were dose-sparing and improved the antibody 
responses generated when added to otherwise poorly immunogenic influenza vaccines, they are 
considered to be of critical importance for pandemic response planning.  As part of its pandemic 
preparedness efforts, the US Government maintains stockpiles of unique HA-containing 
influenza vaccines, including those against influenza A/H7N9 and A/H5N1 viruses as well as 
AS03 and MF59 adjuvants.   
What has become apparent is that even modest changes to adjuvant formulations can modulate 
immune responses and different adjuvants work better for certain antigens.  Immunological 


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protection for some pathogens requires cellular immune responses while others respond 
predominantly to humoral immune responses. Adjuvants in development or in use include a large 
variety of compounds including aluminum salts, oil emulsions (such as MF59 and AS03 
mentioned above), saponins, immune-stimulating complexes, liposomes, microparticles, 
nonionic block copolymers, polysaccharides, cytokines and bacterial derivatives[11-16]. Given 
the relatively modest effectiveness of influenza vaccines, these vaccines serve as an important 
target for testing new adjuvants.  Clearly, both immunogenicity as well as safety will be 
important factors as new adjuvanted influenza vaccines are reviewed for licensure. 
AF03 is a squalene emulsion-based adjuvant that utilizes an alternative manufacturing process 
that involves phase inversion temperature emulsification and incorporates two non-ionic 
surfactants [17, 18].  During the 2009 H1N1 pandemic, Sanofi Pasteur created an AF03 
adjuvanted A/H1N1 pandemic influenza vaccine (Humenza™) and performed multiple clinical 
trials to support the licensure of the vaccine in the European Union. This included trials in 
children 6 months-17 years of age, adults 18-60 years of age and adults above 60 years of age. 
There is one published study that evaluated children ages 6 months to 17 years who were 
enrolled in a trial comparing AF03- adjuvanted and non-adjuvanted pandemic H1N1 influenza 
vaccine. The youngest children, those ages 6-35 months, showed significantly improved 
antibody titers with the adjuvanted vaccine compared to the unadjuvanted vaccine and the 
adjuvanted vaccine led to better antibody persistence [18].  AF03 clinical trials have also been 
performed with A/H5N1 vaccine [19] (SP AF03 IB).  
To further assess the safety of AF03 when mixed with licensed Fluzone and FluBlok QIV, 
Sanofi conducted a recent GLP toxicology study in rabbits. The objective of the GLP toxicology 
study was to determine the systemic toxicity and the local tolerance of Fluzone and Flublok 
Quadrivalent influenza vaccines adjuvanted with AF03 in New Zealand White (NZW) rabbits 
following three 0.75 mL IM administrations at 2-week intervals (on D1, D15, and D29) in the 
dorsal lumbar muscles. 
 
Three groups of 10 males and 10 females were given either Fluzone or Flublok vaccine (at 15µg 
or 45µg of HA per influenza virus strain per dose) adjuvanted with AF03 (12.5 mg squalene per 
dose), or a saline control (NaCl 0.9%). Mortality, clinical signs and local reactions, 
ophthalmology, body weight, food consumption, clinical pathology, and immunogenicity were 
investigated. Animals were euthanized either 2 or 28 days after the third injection (on D31 or 
D57). A microscopic examination was performed on the preserved tissues from all animals as 
per the WHO guidelines document on the nonclinical evaluation of vaccine adjuvants and 
adjuvanted vaccines (2013). 
AF03-adjuvanted Fluzone and Flublok vaccines were clinically well tolerated in the rabbit with 
no unscheduled deaths, no adverse clinical signs, no ophthalmological findings, and no adverse 


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effects on body weight or food intake. Immunogenicity results demonstrated a good humoral 
response after vaccination in all treated groups. Injections of both vaccines showed reversible 
minimal to moderate inflammatory changes at the injection sites associated with related 
lymphoid hyperplasia in lymph nodes and spleen, as well as increase in white blood cell counts 
and treatment-related increase in C reactive protein, fibrinogen and globulin levels. All changes 
showed either complete or partial recovery by the end of the 4-week observation period and were 
considered as related to the pharmacology activity of the adjuvanted vaccines, but non-adverse. 
Advax™ is yet another adjuvant that has been tested as a component to inactivated seasonal and 
pandemic influenza vaccines including 2009 H1N1 and H5N1 vaccine antigens.  Advax is a 
polysaccharide adjuvant that contains particles of semi-crystalline delta inulin, a plant based 
carbohydrate [13].  In the mid-1980s the studies demonstrated that semi-crystalline particles of 
inulin activated complement through the non-classical pathway and could act as a vaccine 
adjuvant [20].  Advax,  a more temperature stable delta inulin isoform created by Vaxine Pty Ltd 
has been found to have improved adjuvant potency in animal models and humans when 
combined with a number of vaccines including Japanese encephalitis, West Nile virus, HIV, 
influenza , RSV, SARS coronavirus, tuberculosis, Listeria, anthrax, chlamydia and hepatitis B 
[13],[21-34]. This adjuvant enhances both humoral and cellular immunity to co-administered 
antigens and induces a potent antigen-specific CD4+ and CD8+ memory T cell response as well 
as enhanced production of antigen specific IgM, IgG and IgA [35].  Advax adjuvant has been 
shown to enhance vaccine immunogenicity and protection through stimulation of both cellular 
and humoral immune pathways when combined with inactivated influenza virus (in mice, rats 
and sheep), inactivated avian H5N1 influenza (in mice and ferrets) and recombinant HA antigen 
from H1, H5 and H7 strains of influenza virus (in mice, rabbits, and humans) [36-42]. 
Over 10 human trials have been conducted with Advax, including several that evaluated Advax 
adjuvanted IIV for seasonal influenza and 2009 pandemic H1N1, in Australia and Europe 
involving over 2000 subjects.  The first in man Advax-adjuvanted seasonal trivalent IIV (IIV3) 
vaccine study showed that the adjuvant given with 1/10th the dose of the standard IIV vaccine 
generated equivalent seroprotection rates and GMTs compared to the full standard dose of 
unadjuvanted IIV3 vaccine [37].  There were no significant differences seen in solicited, 
unsolicited or serious adverse events, though there was a trend toward reduced incidence of fever 
and arthralgias in the reduced IIV3 dose Advax-adjuvanted arm as compared to the full dose 
standard IIV3.  A rHA vaccine from the pandemic 2009 H1N1 influenza strain adjuvanted with 
Advax also showed significantly improved HAI and Neutralising antibody titers, seroconversion 
and seroprotection rates when compared to unadjuvanted vaccine, with no increase in systemic 
adverse events when compared to the unadjuvanted vaccine, and an unexpected but significant 
reduction in post-immunization headaches in the week following immunization in the Advax-
adjuvanted arms [36]. 


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Unmethylated CpG oligonucleotides have been found to serve as Toll-like Receptor (TLR) 9 
agonists that enhance antigen-specific immune responses and induce pro-inflammatory cytokines 
particularly IL-12, which can enhance downstream production of Th1 cytokines that promote 
survival and proliferation of Th1 cells and can activate TFH, which enhance B cell 
immunoglobulin production.  Thus, CpG enhances both cellular and humoral immune responses. 
A range of CpG oligonucleotides have been evaluated as adjuvants either alone or in 
combination with alum adjuvants, in human trials of vaccines against infectious disease 
(hepatitis B, influenza, anthrax, malaria, and HIV), cancer and allergy.  
Studies have been performed to determine whether the addition of CpG to Advax can improve 
immune responses to various vaccine antigens.  In a mouse study evaluating a candidate 
Mycobacterium tuberculosis vaccine, the addition of CpG246.1 to Advax enhanced the 
generation of chemoattractants and resulted in a rapid influx of monocytes and neutrophils to the 
site of vaccination with significant early priming of vaccine antigen specific CD4+ T cells [33].  
A ferret study evaluated Advax-CpG246.1 and Advax-alone adjuvanted H5N1 vaccine.  Advax-
CpG246.1 adjuvant enhanced HAI titers and protection from influenza virus challenge over and 
above Advax adjuvant alone when combined with influenza H5N1 vaccine [42].  Phase I trials 
have been conducted to evaluate Panblok-H5® vaccine alone or in combination with Advax-
CpG246.1 adjuvant.  An interim analysis was performed on subjects who completed both 
immunizations and had blood samples drawn at 4 weeks.  The highest levels of H5 HAI titers 
were in the Advax-CpG246.1 group; these were statistically improved over unadjuvanted 
vaccine (see Advax-CpG IB).  A similar Phase 1 trial was conducted evaluating Panblok-H7® 
alone or with Advax or Advax-CpG246.1 adjuvant.  The preliminary data indicates that the 
immune responses are similar to those seen in the H5 rHA vaccine trial, with the highest HAI 
titers against H7 in the Advax-CpG246.1 adjuvanted arm, versus very low or undetectable HAI 
titers in the Panblok-H7® alone arm and intermediate results in the Advax arm (see Advax-CpG 
IB).  The version of CpG oligonucleotide that Vaxine used in Advax-CpG clinical trials to date is 
a 24-mer class B CpG oligonucleotide with a phosphorothioate backbone called CpG246.1. 
Vaxine has subsequently further optimized the CpG nucleotide sequence to maximize its activity 
for both human and mouse TLR9, resulting in the oligonucleotide CpG55.2. CpG55.2 is also a 
24-mer class B CpG oligonucleotide with a phosphorothioate backbone, however, the sequence 
order of the nucleotides is different between CpG55.2 and CpG246.1. 
To further assess safety of the Advax-CpG55.2 combination adjuvant when mixed with licensed 
Fluzone and FluBlok QIV, Sanofi conducted a recent GLP toxicology study in rabbits. The 
objective of the GLP toxicology study was to determine the systemic toxicity and local tolerance 
of Fluzone and Flublok Quadrivalent influenza vaccines adjuvanted with Advax-CpG55.2 in 
NZW rabbits following three 1 mL IM administrations at 2-week intervals (on D1, D15, and 
D29) in the dorsal lumbar muscles. 


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Four groups of 10 males and 10 females were given either Fluzone or Flublok vaccine (at 15 µg 
or 45 µg of HA per influenza virus strain per dose) adjuvanted with Advax-CpG55.2 (20 and 0.2 
mg per dose, respectively), Advax-CpG55.2 alone at the same dose level or a saline control 
(NaCl 0.9%). Mortality, clinical signs and local reactions, ophthalmology, body weight, food 
consumption, clinical pathology, and immunogenicity were investigated. Animals were 
euthanized either 2 or 28 days after the third injection (on D31 or D57). A microscopic 
examination was performed on the preserved tissues from all animals as per WHO guidelines 
(2013). 
Advax-CpG55.2-adjuvanted Fluzone and Flublok vaccines were clinically well tolerated in the 
rabbit with no unscheduled deaths, no adverse clinical signs, ophthalmological findings, and no 
effects on body weight or food intake. Immunogenicity results demonstrated a good humoral 
response after vaccination in all vaccinated groups. Injections of both vaccines showed reversible 
inflammatory changes at the injection sites associated with related lymphoid hyperplasia in 
lymph nodes and spleen, as well as increase in C-Reactive Protein and fibrinogen levels. All 
changes showed either complete or partial recovery by the end of the 4-week observation period 
and were considered as related to the pharmacology activity of the adjuvanted vaccines, but non-
adverse. 
The proposed trial will be the first time that an Advax-CpG formulation incorporating CpG55.2 
in place of CpG246.1 will be tested in humans. 
 
Scientific Rationale 
Seasonal influenza vaccines have variable efficacy.  Efficacy can be reduced when the vaccine 
strains have mismatched antigenic profiles as compared to the circulating strains of influenza 
virus. Additionally, populations can have variable efficacy based on the immunological sequence 
of prior exposure to influenza infections or vaccines.  Adjuvants provide a promising strategy to 
enhance the humoral immune responses to influenza proteins and may enhance the cellular 
memory responses, as well.  Two new adjuvants are being evaluated that show promise in animal 
studies (Advax-CpG55.2 and AF03) and early human trials (AF03).  These two products have 
been tested predominantly as adjuvants for novel avian influenza strains that show poor 
immunogenicity.  However, there is great need to improve vaccine efficacy that can overcome 
the problems of antigenic drift, immunosenescence and prior immunological priming.   
The goal of this clinical trial is to assess in healthy adults, 18-45 years of age, the safety, 
reactogenicity and immunogenicity of one dose of 2018/2019 Quadrivalent Influenza Vaccine 
(either Fluzone or Flublok) administered intramuscularly (IM) with or without one of two 
adjuvants (AF03 or Advax-CpG55.2).  The study will evaluate the traditional HAI and Neut 


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responses among groups, but also will explore additional immunological parameters.  Since 
antibodies targeting the NA may represent an independent correlate of protection against 
influenza infection [43] [5], we plan to assess the NAI responses in each group.  The longitudinal 
kinetics and durability of HAI, Neut, and NAI responses will be evaluated for one year following 
vaccination.   
This clinical trial will also assess cellular correlates of immunity to influenza including memory 
B cell populations, plasmablasts, TFH cells, functional non-neutralizing Fc-effector antibodies, as 
well as determine the transcriptional profiling responses following vaccination. 
 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
The potential risks of participating in this trial are those associated with having blood drawn, the 
IM injection, possible reactions to the Fluzone or Flublok QIV, with or without AF03 or Advax- 
CpG55.2 adjuvant, and breach of confidentiality. 
Drawing blood may cause transient discomfort and fainting and lead to or exacerbate iron 
deficiency in those who are not anemic. Fainting is usually transient and managed by having the 
subject lie down and elevating his/her legs. Bruising at the blood draw site may occur but can be 
prevented or lessened by applying pressure to the blood draw site for a few minutes after the 
blood is taken. IM injection may also cause transient discomfort and fainting. Drawing blood and 
IM injection may cause infection. The use of aseptic (sterile) technique will make infection at the 
site where blood will be drawn or where the study vaccination will be given extremely unlikely.  
There is a small amount of risk to subjects who report that they are in good health but who have 
an unknown health problem at the time of screening. This trial will screen by physical exam, 
history, vital signs and erythrocyte sedimentation rate (ESR) and clinical safety labs for white 
blood cells (WBC), hemoglobin (Hgb), platelets (PLT), alanine aminotransferase (ALT), total 
bilirubin (T. Bili), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), 
alkaline phosphatase (ALP) serum lipase and serum amylase and creatinine (Cr).  Only subjects 
with a stable health history, physical exam and laboratories that fall within acceptable range (see 
Section 5.1.1) will proceed to vaccination.  
Fluzone and Flublok Vaccines 
The 2018/2019 and 2019/2020 QIV products used in this study are approved by the FDA for 
active immunization against disease caused by influenza viruses contained in the vaccine.  


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Occasionally, adult recipients of unadjuvanted licensed, inactivated influenza vaccines (IIVs) 
may develop influenza-like reactions, such as fever, feverishness, fatigue, malaise, myalgia, 
arthralgia, headache, and/or nausea. Some subjects may develop reactions at the injection site, 
including pruritus, ecchymosis, erythema, induration, edema, pain, and/or tenderness. Most of 
these reactions peak in intensity in the first 24 hours after vaccination and disappear without 
treatment within 1 or 2 days. Analgesics (e.g., acetaminophen, ibuprofen or similar non-steroidal 
anti-inflammatory drugs (NSAIDs) and rest may generally relieve or lessen these reactions. 
Bruising can sometimes occur due to the vaccination procedure.  
 
During the clinical development of Flublok, which is a recombinant influenza vaccine (RIV), 
both local and systemic reactogenicity symptoms were generally similar in frequency and 
severity to those observed with the active control vaccines (trivalent or quadrivalent influenza 
vaccines, TIV or QIV) in adults. The only SAEs that were considered related or possibly related 
to Flublok in any of the trials were one case of vasovagal syncope (quadrivalent RIV, within 20 
minutes post-vaccination, attributed to the injection process rather than the vaccine material) and 
one case of non-infectious pericardial effusion (trivalent RIV, 11 days post-vaccination). 
Serious immediate reactions, such as hypersensitivity, or delayed reactions, such as Guillain-
Barré syndrome, have not been observed in the clinical trials with any formulations of rHA 
vaccines. 
In addition, post-marketing surveillance of the seasonal IIVs indicates autoimmune and other 
disorders as potential risks; these may also include, but are not limited to, neuritis, convulsions, 
severe allergic reactions, syncope, encephalitis, thrombocytopenia, vasculitis, and Guillain-Barré 
syndrome (GBS). Reports of these reactions were rare; however, exact incidence rates cannot be 
precisely calculated. 
Acute and potentially life-threatening allergic reactions (i.e., anaphylaxis) are also possible. 
These reactions occur in about 1 in 4 million people given a vaccination. These reactions can 
manifest as hives, angioedema, bronchospasm, tachycardia, or hypotension. If these reactions 
occur, they can usually be stopped by the administration of emergency medications by the study 
personnel. As with any vaccine or medication, there is a very small chance of a death, although 
researchers do not expect this to occur. 
During the swine influenza (A/H1N1) vaccine campaign of 1976, some recipients developed a 
paralytic illness called GBS. GBS is an acute inflammatory neuropathy characterized by 
weakness, hyporeflexia or areflexia, and elevated protein concentrations in cerebrospinal fluid. 
The rate of GBS was significantly increased in individuals receiving the 1976 swine influenza 
(A/H1N1) vaccine at about 1 per 100,000 vaccine recipients. This syndrome has not been seen 
consistently with other influenza vaccines. Most persons who develop GBS recover completely, 


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although the recovery period may be as little as a few weeks or as long as a few years. About 
30% of those with GBS still have residual weakness after 3 years and about 3% may suffer a 
relapse of muscle weakness and tingling sensations many years after the initial attack. Intensive 
surveillance of GBS after administration of IIVs since 1976 has shown a slight increase in risk 
over background cases (more than one additional case of GBS per million persons) following 
vaccination, typically with onset within 6 weeks after vaccination [44]. Interestingly, although 
vaccination rates have increased in the last 10 years, the numbers of reported cases of vaccine-
associated GBS have declined [45].  A recent study in Canada showed that the 2009 A/H1N1 
vaccine was associated with a small but significant risk of GBS in persons 50 years of age and 
older [46].  An active, population-based surveillance study conducted in the US during the 2009-
2010 influenza season found less than 1 excess GBS case per million doses of 2009 A/H1N1 
vaccine administered – a rate similar to that associated with some previously administered 
annual influenza vaccines [47-49].   Another study using the Medicare system showed an 
elevated risk of GBS with monovalent 2009 A/H1N1 vaccination (incidence rate ratio = 2.41, 
95% confidence interval (CI): 1.14, 5.11; attributable risk = 2.84 per million doses administered, 
95% CI: 0.21, 5.48) [50].  An international collaboration study also supported a conclusion of an 
association between 2009 A/H1N1 vaccination and GBS [51].    
AF03 
Over 1500 people have been evaluated in clinical trials conducted in the European Union and the 
US evaluating inactivated, monovalent H5N1 or H1N1 influenza vaccine adjuvanted with AF03. 
(SP AF03 IB) 
In Phase I and Phase II clinical trials in adults, the most frequently observed local reactions were 
pain, induration and erythema and the most frequently reported solicited systemic reactions in all 
groups and for each injection were headache and myalgia. Most local and systemic reactions 
generally appeared on the day following vaccination and disappeared within 3 days without 
medication use. The addition of AF03 has been associated with a higher incidence of local 
reactions, mainly characterized by injection site pain and induration, compared to non-
adjuvanted vaccine. The addition of AF03 was associated with an increased incidence of 
systemic reactions when compared to unadjuvanted vaccine in adults. 
Some systemic adverse events have been rarely observed concomitantly with the administration 
of vaccines from other manufacturers containing oil-in-water adjuvants similar to AF03. These 
systemic adverse events include autoimmune diseases and demyelinating neurological disorders. 
No causal relationship has been established between these observations and oil-in-water 
adjuvants. To date, these events have not been observed with AF03 adjuvanted vaccines.  
 
Animal toxicology studies following administration of high doses of AF03 and AF04 have 
shown increased single cell apoptosis or necrosis in acinar tissues including the lacrimal gland 


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and the exocrine pancreas in the rabbit model and the parotid glands in rats. These findings were 
observed only at high doses, of low severity and reversible, they were therefore not considered 
clinically significant.  
 
Advax-CpG55.2  
The clinical experience with combination adjuvants combining Advax and TLR9 agonist 
oligonucleotides such as CpG remains limited.  However, approximately 400 exposures in 
approximately 160 adult humans to an earlier generation combined formulation of Advax with 
CpG246.1, a class B CpG oligonucleotide similar to CpG55.2, have been evaluated in Phase I 
trials with various investigational vaccines. When formulated with influenza vaccines Advax-
CpG246.1 induced similar types of local and systemic reactions to those seen in subjects 
receiving unadjuvanted IIV’s which mimicked influenza-like reactions, with symptoms such as 
feverishness, fatigue, malaise, myalgia, arthralgia, headache, and/or nausea. An increase in local 
injection site reactions, including pruritus, ecchymosis, erythema, induration, edema, pain, 
and/or tenderness is typically seen when using vaccine adjuvants, and was similarly observed in 
trials of Advax-CpG246.1 adjuvanted vaccines, but these local reactions were predominantly 
mild in severity and were self-limiting. Most of these reactions peaked in intensity in the first 24 
hours after vaccination and resolved without treatment within 1 or 2 days. The most common 
solicited systemic adverse reaction in the first seven days post-immunization was headache, 
which affected 20-35% of participants. The next most common solicited systemic adverse 
reactions in the first seven days post- immunization were muscle ache (~20%), fatigue (~10%) 
and shivering and chills (~5%). The frequency of unsolicited adverse events was not 
significantly different between the Advax-CpG, Advax and non-adjuvanted groups. Analgesics 
(e.g., acetaminophen, ibuprofen or similar NSAIDs) and rest generally relieved or lessened these 
reactions 
 
Risks of Genetic Testing 
Genetic data and health information will be stored and shared with other researchers through a 
controlled-access repository, such as dbGaP. There may be a risk that information resulting from 
research genetic testing could be misused for discriminatory purposes. However, state and 
federal laws provide protections against genetic discrimination. Researchers will need to 
maintain confidentiality in order to be granted access to genetic information.   
2.3.2 
Known Potential Benefits 
The unadjuvanted seasonal QIVs are known to stimulate HAI antibody titers that can reduce the 
likelihood of influenza virus infection and/or reduce the likelihood of severe influenza illness.  


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The inclusion of an adjuvant, either AF03 or Advax-CpG55.2, could improve the titers of 
protective antibodies.  However, the timing of the start of this study is designed to coincide with 
a time when influenza virus is unlikely to be circulating so it is not clear that an individual would 
receive any benefit to receiving 2018/2019 QIV. All participants will receive a dose of 
2019/2020 QIV which may provide protection from influenza for the 2019/2020 influenza 
season. There may also   be benefits to society through the improvement of our understanding of 
these two new adjuvants and how they affect the immune response to seasonal influenza vaccine. 


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3 
STUDY OBJECTIVES AND OUTCOME MEASURES 
Refer to Table 1: Study Objectives and Outcome Measures 


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4 
STUDY DESIGN 
This is a Phase I, randomized, double blinded, clinical trial in up to 240 males and non-pregnant 
females, 18-45 years of age, inclusive, who are in good health and meet all eligibility criteria. 
This clinical trial is designed to assess the safety, reactogenicity and immunogenicity of either 
the 2018/2019 seasonal Fluzone or Flublok QIV manufactured by Sanofi Pasteur (SP) given 
without adjuvant or with one of two adjuvant formulations, AF03 (SP) or Advax-CpG55.2 
(Vaxine Pty Ltd as manufactured by Sypharma and Nikko Denka Avecia). Fluzone is a 
quadrivalent split virion inactivated vaccine, whereas Flublok is a quadrivalent influenza vaccine 
that contains recombinant hemagglutinin proteins.  AF03 is a squalene-based emulsion adjuvant, 
whereas Advax-CpG55.2 is a combination adjuvant comprised of Advax (delta inulin) and the 
oligonucleotide, CpG55.2.  Enrollment will occur in the second and third quarters of calendar 
year 2019 to allow antibody titers to previous doses of 2018/2019 IIV to wane.   
Subjects will be stratified by prior receipt of licensed, seasonal influenza vaccine (defined as 
receipt of at least one of the 2017/2018 and/or 2018/2019 influenza vaccines) and will be 
randomly assigned to 1 of 6 treatment arms to receive a single dose of one of the two seasonal 
2018/2019 QIV vaccine formulations with or without one of the two adjuvants (Day 1). On 
approximately Day 90, each subject will receive a single dose of the seasonal 2019/2020 QIV.  
Groups 1, 2 and 3 will receive 2019/2020 Fluzone QIV and Groups 4, 5 and 6 will receive 
2019/2020 Flublok QIV.  
To determine early safety signals for this Phase I study, enrollment will proceed in a staged 
fashion for the first 6 sentinel subjects. The first six subjects will be randomized and vaccinated 
with one each from Groups 1-6.  These six subjects will be followed through Day 8. If any of the 
pre-specified halting rules occur, the study will be halted and reviewed by the DSMB.  If no pre-
specified safety signals are encountered enrollment will proceed. 
It is anticipated that both adjuvant formulations (AF03 and Advax-CpG55.2) will be available at 
the start of study enrollment.  However, if the Advax-CpG55.2 is not available, the study will 
proceed only with groups 1, 2, 4 and 5 open for enrollment for the remaining subjects (up to 240, 
60 per group). For the sentinel subjects, one subject from groups 1, 2, 4 and 5 will be enrolled 
and followed through Day 8. If any of the pre-specified halting rules occur, the study will be 
halted and reviewed by the DSMB.  If no pre-specified events occur, randomization will proceed 
in groups 1, 2, 4 and 5 for the remaining subjects. 
The DSMB will review the data when the 8-day reactogenicity and clinical safety laboratory data 
following the first study vaccination is available for 50% of study subjects.  Enrollment will not 
be paused for this review. An additional scheduled DSMB review will occur when all HAI, NAI 
and Neut data for Day 1, and Day 29 and safety data through Day 57 following the first study 
vaccination, are available. 


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Reactogenicity will be measured by the occurrence of solicited injection site and systemic 
reactions from the time of the first study vaccination through Day 8. Unsolicited non-serious 
adverse events (AEs) will be collected from Day 1 through approximately Day 29. Serious 
adverse events (SAEs), AESIs including reports of tearing, dry mouth, dry eyes and MAAEs, 
including NOCMCs and PIMMCs, will be collected through approximately 12 months after the 
first study vaccination. Clinical safety laboratory evaluations (hematology and chemistry) will be 
performed at screening, immediately prior to the first study vaccination and approximately Day 
8. 
Only pharmacy personnel, the Emmes unblinded team and an unblinded vaccinator will have 
access to the study codes all other study personnel will be blinded.  Immunogenicity testing will 
include performing serological assays to assess hemagglutination inhibition (HAI), neutralizing 
(Neut) and neuraminidase inhibition (NAI) titers at multiple time points following study 
vaccination. Antibody responses will be determined for both influenza vaccine strains and 
heterologous influenza strains.  In addition, whole blood transcriptomics and peripheral blood 
mononuclear cells (PBMCs) will be used to determine transcriptional profiling and broad 
immunologic responses and to associate these responses with serological antibody responses 
described above in each of the treatment arms. Immunologic responses will include longitudinal 
assessments of the kinetics, magnitude, specificity, and/or quality of influenza-specific memory 
B cells, plasmablasts, and circulating T follicular helper (TFH) cells. 
For additional details on study procedures and evaluations and study schedule by study 
visits/days, see Sections 7 and 8 as well as Appendix A: Schedule of Study Procedures and 
Evaluations and Appendix B: Adverse Events of Special Interest. 
 
 


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Up to 240 males and non-pregnant females, 18 to 45 years of age, inclusive, who are in good 
health and meet all eligibility criteria will be enrolled at up to 8 VTEU sites (and their 
subcontractors) participating in this trial. The target population should reflect the community at 
large at each of the participating VTEU sites. Estimated time to complete enrollment in this trial 
is approximately 9 weeks. Information regarding this trial may be provided to potential subjects 
who have previously participated in vaccine trials conducted at each of the participating VTEU 
sites. Other forms and/or mechanisms of recruitment may also be used. The IRB will approve the 
recruitment process and all materials prior to use. 
Subject inclusion and exclusion criteria must be assessed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator (PI) or sub-
investigator. 
No exemptions are granted on subject inclusion or exclusion criteria in DMID-sponsored studies. 
Questions about eligibility should be directed toward the DMID Medical Officer. 
 
Eligibility Criteria 
5.1.1 
Subject Inclusion Criteria 
Subjects eligible to participate in this trial must meet all of the following inclusion criteria: 
1. Provide written informed consent prior to initiation of any study procedures. 
2. Are able to understand and comply with planned study procedures and be available for all 
study visits. 
3. Must agree to the collection of venous blood per protocol. 
4. Are males or non-pregnant females, 18 to 45 years of age, inclusive at time of enrollment. 
5. Are in good health1. 
1As determined by medical history and physical examination to evaluate acute or currently ongoing chronic medical or 
psychiatric diagnoses or conditions, defined as those that have been present for at least 90 days, which would affect the 
assessment of the safety of subjects or the immunogenicity of study vaccinations. Chronic medical diagnoses or 
conditions should be stable for the last 60 days (no hospitalizations, emergency room or urgent care for condition, or 
invasive medical procedure and no adverse symptoms that need medical intervention such as medication 
change/supplemental oxygen). This includes no change in chronic prescription medication, dose or in the 60 days prior 
to enrollment. Any prescription change that is due to change of health care provider, insurance company, etc., or that 
is done for financial reasons, as long as in the same class of medication, will not be considered a deviation of this 


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inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the site PI or 
appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and 
immunogenicity and do not indicate a worsening or treatment of continued symptoms of medical diagnosis or 
condition. Note: Low dose topical, corticosteroids as outlined in the Subject Exclusion Criteria (see Section 5.1.2) as 
well as herbals, vitamins and supplements are permitted. 
6. Oral temperature is less than 100.0°F. 
7. Pulse is 47 to 100 beats per minute, inclusive. 
8. Systolic blood pressure is 85 to 140 mmHg, inclusive. 
9. Diastolic blood pressure is 55 to 90 mmHg, inclusive. 
10. Screening laboratories (ESR, WBC, Hgb, PLTs, ALT, T. Bili, AST, GGT, ALP serum lipase, 
serum amylase and Cr) are within acceptable parameters %  
% ESR must be below 30 mm/hr; WBC >3.90 K/MM3 and <10.60 K/MM3; Hgb ≥11.5 g/dl (women) or ≥12.5 g/dl 
(men); PLTs (EDTA) 140-415 K/MM3;PLTs (Citrate) 125-325 K/MM3 ALT ≤43U/L (women) or ≤60 U/L (men); T Bili 
≤1.20 mg/dl; Cr <1.1mg/dl (women) or < 1.4 mg/dl (men); AST 10-36 U/L (women) or 10-43 U/L (men); GGT 5--32 
U/L (women) or 10-49 U/L (men); ALP 30-115 U/L (women) or 43-115 U/L (men); lipase 13-60 U/L; amylase (Total) 
35-121 U/L, for subjects to qualify for randomization and vaccination. 
11. Women of childbearing potential2 must use an acceptable contraception method3 from at 
least 30 days before the first study vaccination until 60 days after the second study 
vaccination. 
2Not sterilized via bilateral oophorectomy, tubal ligation/salpingectomy, hysterectomy, or successful Essure® 
placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at 
least 90 days after the procedure, and still menstruating or <1 year has passed since the last menses if menopausal. 
3Includes non-male sexual relationships, full abstinence from sexual intercourse with a male partner, monogamous 
relationship with vasectomized partner who has been vasectomized for 180 days or more and shown to be azoospermic 
prior to the subject receiving the study vaccination, barrier methods such as condoms or diaphragms/cervical cap with 
spermicide, effective intrauterine devices, NuvaRing®, , and licensed hormonal methods such as implants, injectables 
or oral contraceptives (“the pill”). 
12. Women of childbearing potential must have a negative urine or serum pregnancy test 
within 24 hours prior to the first study vaccination. 
13. For a woman with potential to become pregnant, she understands that in the event of 
pregnancy during the study she will be approached to enroll in the Sanofi Pregnancy 
Registry. 
14. Must agree to have residual specimens (i.e. residual/excess of per protocol specifications) 
(see Section 14.8). 


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5.1.2 
Subject Exclusion Criteria 
Subjects eligible to participate in this trial must not meet any of the following exclusion criteria: 
1. Have an acute illness4, as determined by the site PI or appropriate sub-investigator, 
within 72 hours prior to study vaccination. 
4An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion 
of the site PI or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety 
parameters as required by the protocol. 
2. Have any medical disease or condition that, in the opinion of the site PI or appropriate 
sub-investigator, is a contraindication to study participation5. 
5Including acute, subacute, intermittent or chronic medical disease or condition that would place the subject at an 
unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or may interfere with 
the evaluation of responses or the subject’s successful completion of this trial. 
3. Have immunosuppression as a result of an underlying illness or treatment, a recent 
history or current use of immunosuppressive or immunomodulating disease therapy. 
4. Use of anticancer chemotherapy or radiation therapy (cytotoxic) within 3 years prior to 
study vaccination. 
5. Have known active or recently active (12 months) neoplastic disease or a history of any 
hematologic malignancy. Non-melanoma, treated, skin cancers are permitted. 
6. Have known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection. 
7. Have known hypersensitivity or allergy to eggs, egg or chicken protein, squalene-based 
adjuvants, or other components of the study vaccine. 
8. Have a history of severe reactions following previous immunization with licensed or 
unlicensed influenza vaccines. 
9. Have a history of GBS. 
10. Have a history of convulsions or encephalomyelitis within 90 days prior to study 
vaccination. 
11. Have a history of PIMMCs6. 


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6Refer to Appendix B: Adverse Events of Special Interest  
12. Have a history of alcohol or drug abuse within 5 years prior to study vaccination. 
13. Have any diagnosis, current or past, of schizophrenia, bipolar disease or other psychiatric 
diagnosis that may interfere7 with subject compliance or safety evaluations. 
7As determined by the site PI or appropriate sub-investigator. 
14. Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement 
for danger to self or others within 5 years prior to study vaccination. 
15. Have taken oral or parenteral (including intra-articular) corticosteroids of any dose within 
30 days prior to study vaccination. 
16. Have taken high-dose inhaled corticosteroids8 within 30 days prior to study vaccination. 
8High-dose defined as per age as using inhaled high-dose per reference chart in the National Heart, Lung and Blood 
Institute Guidelines for the Diagnosis and Management of Asthma (EPR-3) or other lists published in UPTODATE. 
17. Received or plan to receive a licensed, live vaccine (excluding all licensed, seasonal LAIVs) 
within 30 days before or after the study vaccination. 
18. Received or plan to receive a licensed, inactivated vaccine (excluding all licensed, 
seasonal IIVs) within 14 days before or after each study vaccination. 
19. Have received any 2018/2019 seasonal influenza vaccine within the 6 months prior to 
enrollment.   
20. Plans to receive any 2019/2020 seasonal influenza vaccine within approximately 90 days 
of receipt of the first study vaccination. 
21. Have a known history of documented influenza infection within the past 6 months. 
22. Received immunoglobulin or other blood products (except Rho D immunoglobulin) 
within 90 days prior to study vaccination. 
23. Received an experimental agent9 within 30 days prior to the study vaccination or expect 
to receive another experimental agent10 during the trial-reporting period11. 
9Including vaccine, drug, biologic, device, blood product, or medication. 
10Other than from participation in this trial. 


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11Approximately 12 months after the first study vaccination. 
24. Are participating or plan to participate in another clinical trial with an interventional 
agent12 that will be received during the trial-reporting period13. 
12Including licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication. 
13Approximately 12 months after the first study vaccination. 
25. Female subjects who are breastfeeding or plan to breastfeed from the time of the first 
study vaccination through 30 days after the last study vaccination. 
26. Plan to travel outside the US (continental US, Hawaii and Alaska) from the time of study 
vaccination through approximately 90 days after the first study vaccination. 
27. Planning to donate blood within 4 months following first vaccination.   
5.1.3 
Exclusion Criteria for Second Study Vaccination 
All study participants will be expected to receive the second study vaccination   except under the 
circumstances listed below. The second study vaccination will not be administered to a subject if 
any of the following criteria are met: 
• Meets the contraindication on the package insert to receipt of licensed influenza vaccine. 
• As deemed necessary by the site principal investigator or appropriate sub-investigator for 
noncompliance or other reasons. 
• Subject refusal of further study vaccination. 
• Withdrawal of consent. 
• Subject is lost to follow-up. 
• Termination of this trial. 
• New information becomes available that makes further participation unsafe. 


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Treatment Assignment Procedures 
5.2.1 
Enrollment and Randomization Procedures 
Per ICH E6 GCP, screening records will be kept at each participating VTEU site to document the 
reason why an individual was screened, but failed trial entry criteria. The reasons why 
individuals failed screening will be recorded in the Statistical and Data Coordinating Center’s 
(SDCC) Advantage eClinicalSM (Electronic Data Capture System). 
Once consented and upon entry of demographic data and confirmation of eligibility for this trial, 
the subject will be enrolled in the electronic data capture system.  If all study adjuvants are 
available at the time of study start, the subject will be enrolled and randomly assigned with equal 
allocation (1:1:1:1:1:1) to 1 of 6 treatment arms, stratified by the participating VTEU site and 
prior receipt of licensed, seasonal influenza vaccine (defined as receipt of at least one of the 
2017/2018 and/or 2018/2019 licensed, seasonal influenza vaccines).  All subjects will receive a 
licensed 2019/2020 QIV on approximately Day 90.  
If the Advax-CpG55.2 components are not available groups 1, 2, 4, and 5 will be enrolled, and 
subjects (up to 240) will be randomized with equal allocation (1:1:1:1) to these 4 arms, stratified 
by the participating VTEU site and prior receipt of licensed, seasonal influenza vaccine (defined 
as receipt of at least one of the 2017/2018 and/or 2018/2019 licensed, seasonal influenza 
vaccines).  Enrollment of subjects will be done online using the enrollment module of Advantage 
eClinicalSM. The randomization code will be prepared by statisticians at the SDCC and included 
in the enrollment module for this trial. Advantage eClinicalSM will assign each subject to a 
treatment arm after the demographic and eligibility data have been entered into the system. A 
designated individual at each participating VTEU site will be provided with a code list for 
emergency unblinding purposes, which will be kept in a secure place. 
Instructions for use of the enrollment module are included in the Advantage eClinicalSM User’s 
Guide. Manual back-up procedures and instructions are provided for use in the event that a 
participating VTEU site temporarily loses access to the Internet or the online enrollment system 
is unavailable. 
5.2.2 
Masking Procedures 
This is a double-blinded clinical trial. 
Subjects, site investigators and study personnel performing any study-related assessments 
following study vaccine administration to the subject are blinded to vaccination and adjuvant 


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received. Laboratory personnel performing immunological assays will receive serum and cell 
specimens blinded to subject ID number and specimen visit number and allocation group. 
Unblinding by allocation group may occur after data lock. 
The randomization scheme will be generated by the SDCC and provided to unblinded study 
personnel (i.e., research pharmacists performing study vaccination preparations and unblinded 
study vaccine administrators) at the participating VTEU sites. 
The unblinded study vaccine administrator is a study personnel member credentialed to 
administer vaccines and may also participate in dose preparation but will not be involved in 
study-related assessments or have subject contact for data collection following study vaccine 
administration to the subject. 
The Data and Safety Monitoring Board (DSMB) may receive data in aggregate and presented by 
treatment arm. The DSMB may also be provided with expected and observed rates of the 
expected AEs in an unblinded fashion and may request the treatment assignment be unblinded 
for an individual subject if required for safety assessment. The DSMB will review grouped and 
unblinded data in the closed session only. 
5.2.3 
Reasons for Withdrawals and Discontinuation of Study Product Administration 
Subjects may voluntarily withdraw their consent for trial participation at any time and for any 
reason, without penalty or loss of benefits to which they are otherwise entitled. 
The site PI or appropriate sub-investigator may also withdraw a subject from receiving the study 
vaccine for any reason. 
A subject may withdraw or be withdrawn from this trial for any of the following reasons: 
• Medical disease or condition, or any new clinical finding for which continued 
participation, in the opinion of the site PI or appropriate sub-investigator, would 
compromise the safety of the subject, or would interfere with the subject’s successful 
completion of this trial, or would interfere with the evaluation of responses (for example, 
has baseline significant laboratory abnormalities). 
• Subject withdrawal of consent. 
• Subject lost to follow-up. 
• Termination of this trial. 


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• As deemed necessary by the site PI or appropriate sub-investigator for noncompliance or 
other reasons. 
• New information becomes available that makes further participation unsafe. 
 
5.2.4 
Handling of Withdrawals and Discontinuation of Study Product Administration 
The primary reason for withdrawal from this trial will be recorded on the Study Status data 
collection form (DCF). Subjects will be encouraged to complete the Early Termination Visit. 
The Early Termination Visit procedures are listed in Section 8.4. 
Every attempt will be made to follow all AEs, including solicited injection site and systemic 
reactions, unsolicited non-serious AEs, SAEs, AESIs (including Protocol Specified AESIs, 
MAAEs, NOCMCs and PIMMCs) ongoing at the time of early withdrawal through resolution as 
per applicable collection times defined for the specific type of AE. 
In the case of subjects who fail to appear for a follow-up safety assessment, extensive effort (i.e., 
three documented contact attempts via phone calls made on separate occasions and followed by a 
certified letter) will be made to locate or recall them, or at least to determine their health status. 
These efforts will be documented in the subject’s study records. 
The site PI or appropriate sub-investigator will inform the subject that already collected data will 
be retained and analyzed even if the subject withdraws or is withdrawn from this study. 
5.2.5 
Subject Replacement 
Subjects who withdraw, or are withdrawn or terminated from this trial, or are lost to follow-up 
after signing the informed consent form (ICF), randomization and receipt of study vaccine will 
not be replaced. However, if a subject withdraws after signing the ICF, but before randomization 
and/or receipt of study vaccine, they may be replaced. 
5.2.6 
Termination of Study 
Although the sponsor has every intention of completing this trial, it reserves the right to 
terminate this trial at any time for clinical or administrative reasons. Reasons for termination 
include, but are not limited to, study closure due to DSMB review and recommendation, and at 
the discretion of DMID. 


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If this trial is prematurely terminated by the sponsor, any regulatory authority, the site PI, or 
appropriate sub-investigator for any reason, the site PI or appropriate sub-investigator will 
promptly inform the subjects and assure appropriate therapy or follow-up for the subjects, as 
necessary. The site PI or appropriate sub-investigator will provide a detailed written explanation 
of the termination to the IRB. 
 


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6 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
 
Study Product Description 
2018/2019 and 2019/2020 Fluzone Quadrivalent Influenza Vaccine (QIV) 
The Sanofi Pasteur manufactured Fluzone Quadrivalent is an FDA approved vaccine 
indicated for active immunization in persons 6 months of age and older for the prevention of 
influenza disease caused by influenza viruses contained in the vaccine. Fluzone QIV is 
propagated in embryonated chicken eggs, chemically inactivated, disrupted and purified to 
yield a split virus vaccine.   
2018/2019 and 2019/2020 Flublok Quadrivalent Influenza Vaccine (QIV) 
The Sanofi Pasteur (Protein Sciences Corporation) manufactured FluBlok Quadrivalent is an 
FDA approved recombinant HA protein vaccine indicated for active immunization in persons 
18 years of age and older for the prevention of influenza disease caused by influenza viruses 
contained in the vaccine. It contains purified HA proteins produced in a Sf9 insect cell line 
derived from the fall armyworm, Spodoptera frugiperda.   
2018/2019 Fluzone and 2018/2019 Flublok Vaccine Expiry 
The 2018/2019 Fluzone and Flublok are labeled to expire on June 30, 2019. The expiration 
date that is present on the label of licensed seasonal influenza vaccine is to ensure the 
product made for previous years’ influenza strains are not still available for general licensed 
use when new seasonal vaccine becomes available against the most recent circulating 
strains. Historical data exists indicating that flu vaccine maintains potency for a period well 
beyond its expiration date. For this clinical trial, the 2018/2019 Fluzone and Flublok will be 
used beyond the labeled expiration date. 
AF03 Adjuvant  
The Sanofi Pasteur adjuvant formulation AF03 is a squalene-in-PBS emulsion stabilized by non-
ionic surfactants, sorbitan oleate and macrogol cetostearyl ether prepared by the "Phase Inversion 
Temperature” (PIT) method. 
Advax-CpG55.2 Adjuvant 


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The Vaxine adjuvant Advax-CpG55.2 is a combination adjuvant supplied as two separate 
components, Advax (delta inulin) and CpG55.2, in individual aseptic glass vials.  
Advax (Delta Inulin) 
Inulin is a natural storage polysaccharide of plants of the Compositae family, such as 
dahlias, artichoke and chicory. Inulin exists in different polymorphic forms. Advax is 
manufactured from highly purified inulin that is subsequently crystallized into microscopic 
particles of known as delta inulin and then formulated in an aqueous phosphate buffer.  
Advax adjuvant appears as a milky white non-viscous suspension and if left undisturbed on 
a stable surface for several days to weeks the delta inulin particles will slowly sediment to 
the bottom of the vial, leaving a clear slightly off white solution above them. The particles 
can be resuspended easily by simple repeated inversion of the vial several times.  
CpG55.2 
CpG55.2 is a completely synthetic Class B CpG oligonucleotide of 24 nucleotides in 
length with a full phosphorothioate backbone for increased stability. It is presented as a 
clear solution in an aqueous buffer. 
Acquisition 
2018/2019 and 2019/2020 Fluzone QIV and Flublok QIV and the AF03 adjuvant will be 
provided by Sanofi Pasteur. 
Advax and CpG55.2 adjuvants, the individual components of Advax-CpG55.2 adjuvant will be 
provided by Vaxine. 
Sterile Water for Injection (SWI) will be provided by DMID Clinical Materials Services 
Contract. 
Upon request by DMID, 2018/2019 and 2019/2020 Fluzone QIV and Flublok QIV, AF03 and 
Advax and CpG55.2 adjuvants will be transferred to the following address: 
DMID Clinical Materials Services Contract 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350 
Fax: 240-477-1360 
Email: DMID.CMS@thermofisher.com 


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2018/2019 and 2019/2020 Fluzone QIV and Flublok QIV, AF03 and Advax and CpG55.2 
adjuvants, and SWI for study vaccine preparation will be provided through the DMID CMS to 
the participating VTEU sites prior to the start of this trial upon request and with prior approval 
from DMID. Should the site PI require additional 2018/2019 and 2019/2020 Fluzone QIV and 
Flublok QIV, AF03 and Advax and CpG55.2 adjuvants, or SWI during this trial, contact the 
DMID CPM. 
6.1.1 
Formulation, Storage, Packaging, and Labeling 
2018/2019 and 2019/2020 Fluzone QIV  
Fluzone QIV is a sterile clear and slightly opalescent in color suspension of inactivated split 
virus for IM use. It is prepared from seasonal influenza virus candidate vaccine strains 
propagated in embryonated chicken eggs. The single-dose, pre-filled syringes (0.5 mL) are 
formulated without thimerosal or any other preservative and do not contain natural latex rubber.  
2018/2019 Fluzone QIV single dose pre-filled syringes are formulated  to contain 60 µg of HA 
per 0.5 mL dose with 15 µg of HA from each of the following four influenza virus strains 
recommended for the 2018/2019 influenza season:  A/Michigan/45/2015 X-275 (H1N1); 
A/Singapore/INFIMH-16-009/2016 IVR-186 (H3N2); B/Maryland/15/2016 BX-
69A(B/Colorado/06/2017-like;Victoria lineage) and B/Phuket/3073/2013 (Yamagata lineage).   
The pre-filled syringes must be stored at 2°C to 8°C (36°F to 46°F). Do not freeze. 
Detailed mixing instructions and necessary supplies to prepare adjuvanted 2018/2019 QIV are 
described in the protocol-specific MOP. 
2018/2019 and 2019/2020 Flublok QIV  
Flublok QIV is a sterile, clear, colorless solution of recombinant HA proteins from four influenza 
viruses for IM use. Vaccine may also contain residual amounts of baculovirus and Spodoptera 
frugiperda cell proteins, baculovirus and cellular DNA and Triton X-100.  This vaccine contains 
no preservative (thimerosal), antibiotics or egg proteins.  
2018/2019 FluBlok QIV single dose pre-filled syringes are formulated to contain 180 µg of HA 
per 0.5 mL dose, with 45 µg of HA derived from each of four influenza virus strains 
recommended for the 2018/2019:  A/Michigan/45/2015 (H1N1); A/Singapore/INFIMH-16-
009/2016 (H3N2); B/Maryland/15/2016 (a B/Colorado/06/2017-like virus; Victoria lineage) and 
B/Phuket/3073/2013 (Yamagata lineage).  The pre-filled syringes must be stored protected from 


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light at 2°C to 8°C (36°F to 46°F). Do not freeze. Detailed mixing instructions to prepare 
adjuvanted 2018/2019 QIV are included in the protocol-specific MOP. 
AF03 
The AF03 adjuvant is a sterile injectable suspension containing 5% squalene (50 mg/mL), free 
from preservatives, and provided in amber glass vials containing 0.7 mL. Each 0.25 mL dose of 
AF03 that will be administered admixed with vaccine contains approximately 12.5 mg of 
squalene. 
The adjuvant should be stored at a temperature ranging from +2°C to +8°C (36°F to 46°F).  
Detailed mixing instructions to prepare AF03-adjuvanted 2018/2019 QIV are included in the 
protocol-specific MOP. 
Advax-CpG55.2 
Advax-CpG55.2 is a combination adjuvant formulation comprised of two components, Advax 
and the CpG55.2 oligonucleotide, that will be extemporaneously mixed with QIV on the day of 
administration in accordance with the mixing instructions detailed in the protocol-specific MOP.  
Each 0.5 mL dose of Advax-CpG55.2 that will be administered admixed with vaccine contains 
approximately 15 mg of Advax and 0.15 mg of CpG55.2. 
Advax  
 
Advax adjuvant is a sterile injectable suspension, free from preservatives, provided in 2.0 mL 
clear glass vials.  Each 2.0 mL vial contains 0.5 mL of a 50 mg/mL suspension of delta inulin 
in phosphate buffered saline.  
 
The Advax adjuvant will be stored refrigerated, protected from light at a temperature ranging 
from +2°C to +8°C (36°F to 46°F). Do not freeze. 
CpG55.2 
CpG55.2 adjuvant is a sterile injectable solution and provided in clear glass vials containing 
0.5 mL of a 2 mg/ml solution of CpG55.2. 
The CpG55.2 adjuvant will be stored refrigerated, protected from light at a temperature 
ranging from +2°C to +8°C (36°F to 46°F). 
The CpG55.2 and Advax adjuvant components should be extemporaneously mixed with the 
appropriate investigational vaccine, and then stored at +2°C to +8°C (36°F to 46°F) until use. 


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Detailed mixing instructions to prepare Advax-CpG55.2-adjuvanted 2018/2019 QIV are included 
in the protocol-specific MOP. 
Sterile Water for Injection (SWI)  
• 
Sterile Water for Injection, USP, is sterile, nonpyrogenic, distilled water in a single dose 
container for intravenous administration after addition of a suitable solute. It may also be 
used as a dispensing container for diluent use. No antimicrobial or other substance has been 
added. The pH is 5.5 (5.0 to 7.0). The osmolarity is 0.  
• Sterile Water for Injection (SWI) must be stored at room temperature 20°C to 25°C (68°F to 
77°F) (USP Controlled Room Temperature). Avoid storing SWI in any excessive heat. For 
SWI, excursions between 15-30°C (59°F to 86°F) the product can continue to be used (no 
quarantine) but the site needs to complete the DMID Study Product Support Team Temperature 
Excursion Reporting Form and submit to PSTBased on UPS guidelines, excursions between 
15°C and 30°C are allowed and will not be considered deviations.. 
• 
SWI will be used to prepare the Advax-CpG55.2 adjuvant prior to admixing with the 2018/2019 
QIVs.   
Each of the adjuvant study products will be labeled according to manufacturer specifications and 
include the statement “Caution: New Drug Limited by Federal Law to Investigational Use.” 
Further details are included in the respective manufacturers’ package inserts for the 2018/2019 
and 2019/2020 (when available) Fluzone and Flublok QIVs and the manufacturers’ 
Investigator’s Brochures for both adjuvants. 
Sterile empty vials (2-mL or 5-mL) will be provided with latex-free stoppers. 
6.1.2 
Study Product Storage and Stability Procedures 
The temperature of the storage unit must be manually recorded daily (excluding non-business 
days and holidays, as applicable) and continuously monitored and recorded during the course of 
this trial per the participating VTEU site standard operating procedures (SOPs), and 
documentation will be maintained. If the temperature fluctuates outside of the required range, the 
affected study product(s) must be quarantined at the correct storage temperature and labeled as 
‘Do Not Use’ (until further notice). The participating VTEU site’s research pharmacist must alert 
the site PI and study coordinator, if the temperature fluctuates outside of the required range. In 
the event the temperature fluctuates outside of the required range, including accidental deep-
freezing or disruption of the cold chain, the affected study product(s) must not be administered. 
The site PI or responsible person should immediately contact the DMID Product Support Team 


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at DMIDProductSupportTeam@niaid.nih.gov for further instructions before any additional study 
vaccinations are administered. Based on the information collected, DMID and/or the 
manufacturer will determine whether the affected study product(s) can be used. If it cannot be 
used, the site will receive specific instructions on how to return the affected study product(s) to 
the DMID CMS or destroy it on site. Additional instructions for quarantine and DMID contact 
information are provided in the protocol-specific MOP. 
 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
See the protocol-specific MOP Appendices for detailed information on the preparation, labeling, 
storage, and administration of study vaccine for each treatment arm. Study vaccine preparation 
will be performed by the participating VTEU sites’ research pharmacist on the same day of study 
vaccine.  
Visually inspect the Fluzone QIV, Flublok QIV, AF03 adjuvant and the Advax-CpG55.2 
adjuvant individual components, Advax and CpG55.2, and SWI upon receipt and prior to use. If 
the study product(s) appear(s) to have been damaged, contaminated, discolored, contain(s) 
visible particulate matter, or if there are any concerns regarding the integrity, do NOT use the 
affected study product(s). The affected study product(s) must be quarantined at 2°C to 8°C (36°F 
to 46°F) for Fluzone QIV, Flublok QIV, AF03 adjuvant and the Advax-CpG55.2 adjuvant 
individual components, Advax and CpG55.2, and at 20-25°C (68°F to 77ºF, USP Controlled 
Room Temperature) for SWI and labeled as ‘Do Not Use’ (until further notice). The site PI or 
responsible person should immediately contact the DMID Product Support Team at and DMID 
Clinical Project Manager for further instructions before any additional study vaccinations are 
administered. Based on the information collected, DMID and/or the manufacturer will determine 
whether the affected study product(s) can be used. If the affected study product(s) cannot be 
used, the site will receive specific instructions on how to return the affected study product(s) to 
the DMID CMS or destroy the affected study product(s) on site. If the Fluzone QIV, Flublok 
QIV, AF03 adjuvant or Advax-CpG55.2 individual components, Advax and CpG55.2, and SWI 
are unusable, study personnel will use another vial from the study supply. Replacement vials 
may be requested by contacting DMID. Additional instructions for quarantine and DMID contact 
information are provided in the protocol-specific MOP. 
For those doses that must be admixed visually inspect the Fluzone QIV or Flublok QIV plus 
adjuvant admixture (final mixed syringe depending on treatment arm) prior to use. The 
admixtures will be white cloudy suspension or milky in appearance. If the admixture(s) appear(s) 
to have been damaged, contaminated or discolored, contain(s) visible particulate matter, or if 
there are any concerns regarding the integrity, do NOT use the affected admixture(s). The 


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affected admixture(s) must be quarantined at 2°C to 8°C (36°F to 46°F) for the Fluzone QIV or 
Flublok QIV plus adjuvant admixture and labeled as ‘Do Not Use’ (until further notice). The site 
PI or responsible person should immediately contact the DMID Product Support Team at 
DMIDProductSupportTeam@niaid.nih.gov and DMID Clinical Project Manager for further 
instructions before any additional study vaccinations are administered. Based on the information 
collected, DMID and/or the manufacturer will determine whether the affected admixture(s) can 
be used. If the affected admixture(s) cannot be used, the site will receive specific instructions on 
how to send the affected admixture(s) to the DMID CMS or destroy the affected admixture(s) on 
site. If the affected admixture is unusable, the participating VTEU site’s research pharmacist will 
prepare another admixture. Additional instructions for quarantine and DMID contact information 
are provided in the protocol-specific MOP. 
Each dose of study vaccine, including those doses that must be admixed, the Fluzone QIV or 
Flublok QIV plus adjuvant admixture, once mixed, must be administered as soon as possible (not 
to exceed 30 minutes total since admixing at room temperature.   
Only one dose of study vaccine should be administered. For those doses of 2018/2019 Fluzone 
QIV or 2018/2019 Flublok QIV that must be admixed with adjuvant gently invert the final mixed 
syringe 4 times immediately before the single dose of adjuvanted study vaccine is administered. 
Do not shake the final mixed syringe.  
Study vaccine administration to the subject will be performed by an unblinded study personnel 
member who is credentialed to administer vaccines and may also participate in dose preparation, 
but will not be involved in study-related assessments or have subject contact for data collection 
following study vaccine administration to the subject. One dose of study vaccine (volumes may 
vary depending on study arm) will be administered to the subject via a single IM injection into 
the deltoid muscle of the subject’s preferred arm on the day of study vaccine administration to 
the subject. See the protocol-specific MOP for information on how to administer IM injections. 
The site of injection (right or left arm) and time of study vaccine administration to the subject 
will be recorded on the appropriate DCF. Study vaccinations subsequent to the first study 
vaccination may be given in the same preferred arm as long as there is no interference with the 
reactogenicity assessment. 
Aseptic technique will be used for the admixture preparation of vaccine with adjuvant using 
disposable, sterile needles appropriate in length for each subject and a 1-mL disposable, sterile 
syringe.   
 


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Accountability Procedures for the Study Intervention/Investigational 
Product 
The site PI is responsible for study product distribution and disposition and has ultimate 
responsibility for study product accountability. The site PI may delegate to the participating 
VTEU site’s research pharmacist responsibility for study product accountability. The 
participating VTEU site’s research pharmacist will be responsible for maintaining complete 
records and documentation of study product receipt, accountability, dispensation, storage 
conditions, and final disposition of the study product(s). Study product accountability records 
and dispensing logs should include, but are not limited to the following: DMID protocol number; 
name, dosage form, strength of the study product; capture vial numbers (optional) and pre-filled 
syringe number (optional) assigned sequentially by the pharmacists as vials/syringes are used 
(number uniquely, do not start over at 1 or repeat numbers),  , manufacturer or other source; 
control, lot number or other identification number; expiration or retest date (memo from DMID 
or noted on the protocol indicating that the expiration is centrally managed is acceptable); date of 
receipt of the study product; quantity received from supplier; subject identification number, 
quantity dispenses as amount or dose per subject, balance of study product currently available, 
disposition of drug if not dispensed to a study subject (e.g. disposed/destroyed or retuned to 
supplier as per protocol or MOP or as directed by DMID), date of study vaccine 
preparation/administration, time of study vaccine preparation, expiration of study vaccine 
preparation, and amount of study vaccine withdrawn for administration. Time of study vaccine 
administration to the subject will be recorded on the appropriate DCF. All study product(s), 
including the amount of 2018/2019 and 2019/2020 Fluzone QIV and Flublok QIV, vials of AF03 
and Advax-CpG55.2 (Advax and CpG55.2 individual components) adjuvants, SWI and syringe 
and vial admixtures, whether administered or not, must be documented on the appropriate study 
product accountability record or dispensing log. The sponsor’s monitoring staff will verify the 
participating VTEU site’s study product accountability records and dispensing logs per the site 
monitoring plan. 
Used syringes of 2018/2019 and 2019/2020 Fluzone QIV and Flublok QIV may be destroyed in 
accordance with site-specific SOPs.   
There are three options for documenting product accountability and dispensation: 
 
 
  
 


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Option 1:  Retained until monitored and released for disposition 
Used vials of AF03 and Advax-CpG55.2 (Advax and CpG55.2 individual components) 
adjuvants, SWI and vial admixtures will be retained until monitored and released for 
disposition, as applicable. This can occur on an ongoing basis for vials of AF03 and 
Advax-CpG55.2 (Advax and CpG55.2 individual components) adjuvants, SWI and vial 
admixtures. Used vials of AF03 and Advax-CpG55.2 (Advax and CpG55.2 individual 
components) adjuvants, SWI and vial admixtures may be destroyed in accordance with 
site-specific SOPs following each monitoring visit where study product accountability is 
monitored, and resolution of any discrepancies.   
 Option 2: Counted and verified by two personnel before disposition 
Used vials of AF03 and Advax-CpG55.2 (Advax and CpG55.2 individual components) 
adjuvants, SWI and vial admixtures will be retained until counted and verified by two 
pharmacy personnel before being released for disposition.  The documentation for the 
verification performed by two pharmacy personnel needto be retained for sponsor’s 
monitoring staff for review.  This can occur on an ongoing basis for vials of AF03 and 
Advax-CpG55.2 (Advax and CpG55.2 individual components) adjuvants, SWI and vial 
admixtures. After the used vials of AF03 and Advax-CpG55.2 (Advax and CpG55.2 
individual components) adjuvants, SWI and vial admixtures are counted and verified the 
vials may be destroyed in accordance with site-specific SOPs.   
Option 3:  Use of an Electronic Data Capture system 
 Used vials of AF03 and Advax-CpG55.2 (Advax and CpG55.2 individual components) 
adjuvants, SWI and vial admixtures can be captured in an Electronic Data Capture system 
which is 21 CFR Part 11 compliant. Used vials of AF03 and Advax-CpG55.2 (Advax and 
CpG55.2 individual components) adjuvants, SWI and vial admixtures may be destroyed 
on an ongoing basis in accordance with site-specific SOPs. Spornsor’s monitoring staff 
will be provided with access to the data for verification.     
Upon study completion, for all options listed above, unused syringes of 2018/2019 and 
2019/2020 Fluzone QIV and Flublok QIV, unused or expired vials of AF03 and Advax-CpG55.2 
(Advax and CpG55.2 individual components) adjuvants, and SWI will be retained until 
monitored and released for destruction. 


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Assessment of Subject Compliance with Study 
Intervention/Investigational Product 
Study vaccine will be administered to the subject by an unblinded study vaccine administrator 
via IM injection at all dosing times per the subject’s randomized treatment assignment and as 
described in Section 6.2. Noncompliance from the dose schedule may occur. Study vaccine 
administration to the subject and noncompliance with the dose schedule will be recorded on the 
appropriate DCF. 
 
Concomitant Medications/Treatments 
Administration of any medications, therapies or vaccines will be recorded on the appropriate 
DCF. Concomitant medications will include all current medications and medications taken in the 
60 days prior to signing the ICF through approximately Day 29 after first study vaccination or 
early termination, whichever occurs first. Receipt of any influenza vaccine during the 2018/2019 
influenza vaccine season prior to receipt of the study vaccine (regardless of the date of receipt) 
will be documented. Medications reported in the electronic case report form (eCRF) are limited 
to those taken within 30 days prior to the first study vaccination through approximately 28 days 
after the first study vaccination. Prescription and over-the-counter drugs will be included as well 
as herbals, vitamins and supplements.  
In addition, receipt of any non-study influenza vaccines will be solicited through approximately 
365 days after the first study vaccination and reported in the eCRF. Use of a new medication 
should prompt evaluation for the occurrence of any MAAE, including a new diagnosis of chronic 
medical disease or condition. 
Medications that might interfere with the evaluation of the investigational product(s) should not 
be used during the trial-reporting period (approximately 12 months after the first study 
vaccination) unless clinically indicated as part of the subject’s health care. Medications in this 
category include the prohibited medications per the Subject Exclusion Criteria (see Section 
5.1.2). In addition, the site PI or appropriate sub-investigator may identify other medications that 
should not be used due to a risk to subject safety or assessment of reactogenicity and 
immunogenicity. 
 


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7 
STUDY PROCEDURES/EVALUATIONS 
 
Clinical Evaluations 
A complete medical history will be obtained by interview of subjects at the screening visit. 
Subjects will be queried regarding a history of significant medical disorders of the head, eyes, 
ears, nose, throat, mouth, cardiovascular system, lungs, gastrointestinal tract, liver, pancreas, 
kidney, urologic system, nervous system, blood, lymph nodes, endocrine system, 
musculoskeletal system, skin, and genital/reproductive tract. A history of any allergies, cancer, 
immunodeficiency, psychiatric illness, substance abuse, and autoimmune disease will be 
solicited. At all subsequent visits an interim medical history will be obtained by interview of 
subjects and any changes since the previous clinic visit or phone call will be noted. The interim 
medical history should include an assessment for new medical conditions and symptoms 
suggestive of AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs). 
 
Concomitant medications and influenza vaccination history will be collected as described in 
Section 6.5. 
 
At the screening visit a physical examination will be performed on all subjects, by a study 
clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator, to include the following organs and organ systems: skin, head and neck, lungs, 
heart, liver, spleen, extremities, lymph nodes, and nervous system.. At the vaccination visit and 
at follow-up visits after each study vaccination, a targeted physical examination may be 
performed, if indicated based on the subject’s interim medical history, by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
investigator. Targeted physical examinations should also include an assessment for signs 
suggestive of PIMMCs. 
 
Height, weight will be collected at the screening visit, and vital signs (oral temperature, pulse 
and blood pressure) will be collected at the screening visit and prior to the first study 
vaccination. Vital signs assessed on Day 1 prior to the first study vaccination will be considered 
as baseline. Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes 
prior to taking oral temperature. 
 
Reactogenicity assessments will include an assessment of solicited AEs occurring from the time 
of first study vaccination through Day 8, which includes an assessment of injection site reactions 
including pruritus, ecchymosis, erythema, induration, edema, pain, and tenderness as well as 
systemic reactions including fever, feverishness, fatigue, malaise, myalgia (exclusive of the 


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injection site), arthralgia, headache, and nausea. Pre-administration reactogenicity assessments 
will be performed immediately prior to first study vaccination to establish baseline, then the 
study vaccination will be given. 
 
Subjects will be observed in the clinic for at least 20 minutes after the first study vaccination 
only (administered during visit 1). Following the first study vaccination, the vaccination site will 
be examined, post-administration reactogenicity assessments will be performed, and any 
AE/SAEs will be recorded on the appropriate DCF prior to discharge from the clinic. The study 
vaccination site will also be examined on approximately Day 2 and Day 8. 
 
All subjects will complete a Memory Aid from the time of first study vaccination through Day 8. 
Memory Aids will be reviewed with the subjects for any AEs (solicited injection site and 
systemic reactions as well as unsolicited AEs), SAEs and concomitant medications (including 
solicitation for receipt of any non-study influenza vaccines) at clinic study visits on 
approximately Day 2 and Day 8. 
 
Laboratory Evaluations 
Clinical laboratory evaluations and special assays are described below. Refer also to Sections 4 
and 8 as well as Appendix A: Schedule of Study Procedures and Evaluations and Appendix B: 
Adverse Events of Special Interest. 
7.2.1 
Clinical Laboratory Evaluations 
Urine or serum pregnancy tests will be performed locally by the site at the screening visit 
(optional) and within 24 hours prior to first study vaccination for all women of childbearing 
potential. Results must be negative and known prior to randomization on Day 1 and 
administration of first study vaccination to be eligible for participation in this trial and receipt of 
study vaccination. 
 
The ESR evaluation will be performed locally by the site at the screening visit and confirmed as 
less than 30 mm per hour to be eligible for participation in this trial and receipt of the first study 
vaccination. 
 
Clinical safety laboratory parameters (WBC, Hgb, PLT, ALT, AST, GGT, ALP, Bilirubin (total), 
serum lipase and serum amylase and Cr) will be collected at the screening study visit and will be 
sent to the Central Clinical Laboratory. The results from the clinical safety laboratory parameters 
collected at the screening visit must be reviewed prior to the first study vaccination and must be 


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within acceptable ranges to be eligible for receipt of the first study vaccination (see Section 
5.1.1).  The safety laboratories will be repeated prior to receipt of the first study vaccination.  
However, the results from the clinical safety laboratory parameters collected prior to the study 
vaccination will not be available or reviewed prior to the study vaccination.  Clinical safety 
laboratory parameters collected immediately prior to the first study vaccination will serve as the 
baseline and will be repeated on approximately Day 8. 
 
The volume of venous blood to be collected for ESR and clinical safety laboratory evaluations is 
presented in Table 3. 
7.2.2 
Special Assays or Procedures 
Serological Assays 
Serum will be collected for HAI, Neut, NAI, multiplex HA ELISA, NA ELISA and non-
neutralizing Fc-effector antibody studies.  Once the last subject completes the visits that occur 
through approximately 28 days after the first study vaccination, serum specimens collected for 
D1 and Day 29 visits will be shipped from the DMID CMS to Sanofi Pasteur specified research 
laboratories for final serological analyses. Subsequent shipments will occur once the last subject 
completes the visits that occur through approximately Day 118 (inclusive of D8, D57, Day 90 
and Day 118), once the last subject completes the Day 180 and again once the last subject 
completes the Day 365 visit. Preparation of blood samples and shipping instructions for cellular 
immunology assays are outlined in the MOP. 
Cellular Immunology Assays 
This clinical trial will also investigate B cell memory responses using a multiplexed B cell 
FluroSpot assay evaluating IgG, IgM and IgA specific B cells.  Multiparametric flow cytometry 
will be used to identify plasmablast/Tfh cells. PBMCs will be collected and shipped from the 
DMID CMS to Sanofi Pasteur specified research labs to conduct the cellular immunological 
assays. Preparation of blood samples and shipping instructions for cellular immunology assays 
are outlined in the MOP. 
Transcriptomic Analyses 
Whole blood transcriptomics will be done using RNA sequencing. Samples collected will be 
shipped from the DMID CMS to Sanofi Pasteur specified research labs to conduct transcriptomic 
analyses. Preparation of the blood samples and shipping instructions for transcriptomic are 
outlined in the MOP.  


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The volume of venous blood to be collected for serological, cellular immunology assays and 
transcriptomics is presented in Table 3. 
 
Table 3: Venipuncture Volumes  
Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
Cumulative Blood Volume 
Total (mL) 
Study Day post first 
study vaccination 
Screening 
D-28 to -1 
Enrollment 
Dose 1 
D1 
D2 +1 
D8+/-1d 
D29+/-2d 
D57+/-3d 
D90 +/-14 d  
D118 +/-3 d 
D180 +/- 14d 
D365-14/+35d 
Study Vaccination 
 
X 
 
 
 
 
X 
 
 
 
 
ESR 
4^ 
 
 
 
 
 
 
 
 
 
4 
Clinical Safety 
Laboratory Evaluations 
6^ 
6#† 
 
6 
 
 
 
 
 
 
18 
Serological Assays 
 
20† 
 
20 
20 
20 
20† 
20 
20 
20 
160 
Cellular Immunology 
Assays 
 
80† 
 
48 
80 
 
48† 
 
 
 
256 
Tempus RNA Tube 
 
3† 
3 
3 
 
 
 
 
 
 
9 
Per Visit Blood 
Volume Total (mL) 
10 
109 
3 
77 
100 
20 
68 
20 
20 
20 
 
Running Blood Volume 
Total (mL) 
10 
119 
122 
199 
299 
319 
387 
407 
427 
447 
447 
^ Drawn up to 28 days prior to the first study vaccination. The ESR value must be confirmed as less than 30 mm per 
hour prior to randomization and prior to first study vaccination. Screening WBC, Hgb, PLT, ALT, T. Bili, AST, 
GGT, ALP and serum lipase and serum amylase and Cr must be within the accepted ranges outlined in the 
inclusion criteria prior to randomization and study vaccination. 
# Clinical safety laboratory evaluations collected on Day 1 prior to first study vaccination will be considered as 
baseline. 
† Blood must be drawn immediately prior to each study vaccination. 
 
 
 


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7.2.3 
Specimen Preparation, Handling and Shipping 
7.2.3.1 
Instructions for Specimen Preparation, Handling and Storage 
Instructions for specimen preparation, handling and storage are included in the Central Clinical 
Laboratory manual and protocol-specific MOP as appropriate. 
7.2.3.2 
Specimen Shipment 
Specimen shipment will occur at intervals during the course of this trial following all applicable 
International Air Transport Association (IATA) requirements and according to the specifics for 
storage temperature and documentation as detailed in the central (clinical) laboratory manual and 
protocol-specific MOP as appropriate. 
 
Specimens for clinical safety laboratory evaluations will be shipped from the participating VTEU 
sites to the central (clinical) laboratory except those done locally. 
 
Specimens for antibody, cellular and transcriptomic assays will be shipped from the participating 
VTEU as outlined in the MOP. 
 
Further instructions for specimen shipment are included in the central (clinical) laboratory 
manual and protocol-specific MOP, as appropriate. 


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8 
STUDY SCHEDULE 
Complete study schedule details listed by type of visit are described below. Refer also to 
Sections 4 and 7 as well as Appendix A: Schedule of Study Procedures and Evaluations and 
Appendix B: Adverse Events of Special Interest. 
 
Screening and Enrollment Visits 
8.1.1 
Visit 00, Screening (Day -28 to -1), Clinic Visit 
• Subjects will be provided with a description of this trial (purpose and study procedures) 
and asked to read and sign the ICF. The ICF will be signed prior to performing any study 
procedures, including administration of study vaccination. 
• Demographic information will be obtained by interview of subjects. 
• Eligibility criteria will be reviewed with subjects to ensure eligibility. 
• Complete medical history will be obtained by interview of subjects to ensure eligibility. 
• All concomitant medications taken within 60 days prior to signing the ICF will be 
reviewed with subjects to determine stability of chronic diseases and eligibility. 
Medications reported in the eCRF are limited to those taken within 30 days prior to the 
first study vaccination. 
• Subject receipt of licensed, seasonal influenza vaccine over the current (2018-2019), 
what type (inactivated or live attenuated) and approximate date of vaccination will be 
recorded on the appropriate DCF, if known. Prior receipt of licensed, seasonal influenza 
vaccine is not exclusionary, as long as it has been administered within the allowable 
window (see Section 5.1.2). 
• Subject receipt of non-seasonal influenza vaccine, including those that are experimental, 
what type (inactivated or live attenuated), what subtype (e.g., A/H3, A/H5, A/H9) and 
approximate date of vaccination will be recorded on the appropriate DCF, if known. Prior 
receipt of non-seasonal influenza vaccine is not exclusionary (see Section 5.1.2). 
• Vital signs, including oral temperature, pulse and BP, will be obtained to ensure 
eligibility. Subjects must not eat or drink anything hot or cold, or smoke within 10 
minutes prior to taking oral temperature. 


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• Height and weight will be collected for the calculation of BMI. 
• A physical examination will be performed on all subjects to include the following organs 
and organ systems: skin, head and neck, lungs, heart, liver, spleen, extremities, lymph 
nodes, and nervous system, and as an assessment for signs suggestive of PIMMCs, by a 
study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site PI or sub-investigator. 
• A urine or serum pregnancy test may be performed locally by the site for all women of 
childbearing potential. Women of childbearing potential must have a negative urine or 
serum pregnancy test within 24 hours prior to the first study vaccination. Counsel on 
need for avoidance of pregnancy during the study.  
• Approximately 4 mL of venous blood will be collected for ESR and performed locally by 
the site. The ESR value must be confirmed as less than 30 mm per hour to ensure 
eligibility. 
• Approximately 6 mL of venous blood will be collected for WBC, Hgb, PLT, ALT, T. 
Bili, AST, GGT, ALP, serum lipase and amylase and Cr for transport to the Central 
Clinical Laboratory.  The results must be within the acceptable range as outlined in the 
eligibility criteria to be eligible for randomization and vaccination. 
8.1.2 
Visit 01, Day 1, Enrollment (Vaccination), Clinic Visit 
• Subject’s willingness to participate will be reconfirmed and documented in the subject’s 
study records prior to performing any further study procedures, including administration 
of study vaccination. 
• Eligibility criteria, including results from Screening of the ESR, WBC, Hgb, PLT, ALT, T. 
Bili, AST, GGT, ALP, serum lipase and amylase and Cr evaluation, will be reviewed with 
subjects prior to the first study vaccination to ensure continued eligibility. (The ESR 
value must be confirmed as less than 30 mm per hour prior to randomization and study 
vaccination.  The remaining laboratories must be within acceptable parameters as 
outlined in the inclusion criteria).   
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of PIMMCs, will be obtained by interview of 
subjects prior to study vaccination. Any changes in medical history since the screening 
visit will be reviewed with subjects prior to study vaccination to ensure continued 
eligibility. 


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• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be reviewed with subjects prior to study vaccination for accuracy and 
completeness. Any new concomitant medications taken since the screening visit will be 
reviewed with subjects prior to study vaccination to ensure continued eligibility. 
Medications reported in the eCRF are limited to those taken within 30 days prior to the 
first study vaccination. 
• Vital signs, including oral temperature, pulse and BP, will be obtained prior to study 
vaccination to ensure continued eligibility. Vital signs assessed on Day 1 prior to study 
vaccination will be considered as baseline. Subjects must not eat or drink anything hot or 
cold, or smoke within 10 minutes prior to taking oral temperature. 
• A targeted physical examination performed prior to study vaccination, including an 
assessment for signs suggestive of PIMMCs, may be performed prior to study 
vaccination, if indicated based on review of complete medical history and any updates 
obtained by interview of subjects since the screening visit, by a study clinician licensed to 
make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
investigator. 
• A urine or serum pregnancy test will be performed locally by the site within 24 hours 
prior to study vaccination for all women of childbearing potential. Results must be 
negative and known prior to randomization and study vaccination.   
• Approximately 6 mL of venous blood will be collected immediately prior to study 
vaccination for baseline clinical safety labs (WBC, Hgb, PLT, ALT, T. Bili, AST, GGT, 
ALP, serum lipase and serum amylase and Cr) to be performed by the Central Clinical 
Laboratory. The results from these evaluations will not be available or reviewed prior to 
the study vaccination and will serve as a baseline safety assessment only. 
• Approximately 20 mL of venous blood will be collected immediately prior to study 
vaccination for baseline serological assays. 
• Approximately 80 mL of venous blood will be collected immediately prior to study 
vaccination for baseline cellular immunology assays. 
• Approximately 3 mL of venous blood will be collected immediately prior to study 
vaccination for transcriptomic evaluations. 
• Subjects will be enrolled in Advantage eClinicalSM and randomly assigned to a treatment 
arm prior to study vaccination. 


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• Pre-administration reactogenicity assessments will be performed immediately prior to 
study vaccination to establish baseline. 
• Subjects will then receive one dose of study vaccine via a single IM injection into the 
deltoid muscle of the subject’s preferred arm. The site of injection (right or left arm) and 
time of study vaccine administration to the subject will be recorded on the appropriate 
DCF. Subjects will be observed in the clinic for at least 20 minutes after study 
vaccination. The study vaccination site will be examined, post-administration 
reactogenicity assessments will be performed, and any AE/SAEs will be recorded on the 
appropriate DCF prior to discharge from the clinic. 
• Subjects will be provided with a Memory Aid and other study-related materials to record 
daily oral temperature, solicited injection site and systemic reactions, unsolicited AEs, 
and concomitant medications. Subjects will be encouraged to take their oral temperature 
around the same time each day. Subjects must not eat or drink anything hot or cold, or 
smoke within 10 minutes prior to taking oral temperature. Subjects will be instructed on 
how to use their Memory Aid and how to measure and record AEs prior to discharge 
from the clinic. Subjects will be instructed to notify the study center if they develop any 
severe reactions after study vaccination. If the site PI or appropriate sub-investigator 
deems the reaction severe enough, further instructions will be given to the subject on the 
proper course of action, including a return to the clinic for immediate evaluation if 
appropriate. 
• Counsel on avoidance of pregnancy.  
 
Follow-up Visits 
Follow-up visits are scheduled in reference to study vaccination date as indicated for each visit 
window. 
8.2.1 
Visit 02, Day 2, Clinic Visit  
(Window: Day 2 +1 day post study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 


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• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. 
• Memory Aid information will be reviewed with subjects. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs), may be 
performed, if indicated based on review of interim medical history, by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 
• The study vaccination site will be examined. 
• Approximately 3 mL of venous blood will be collected for transcriptomic assays. 
• Counsel on avoidance of pregnancy.  
8.2.2 
Visit 03, Day 8, Clinic Visit 
(Window: Day 8 +/- 1 day post study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. 
• Memory Aid information will be reviewed with subjects. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs), may be 
performed, if indicated based on review of interim medical history, by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 


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• The study vaccination site will be examined. 
• Counsel on avoidance of pregnancy.  
• Approximately 6mL of venous blood will be collected for clinical safety labs (WBC, 
Hgb, PLT, ALT, T. Bili, AST, GGT, ALP, serum lipase and amylase and Cr) to be 
performed by the Central Clinical Laboratory. 
• Approximately 20 mL of venous blood will be collected for serological assays. 
• Approximately 48 mL of venous blood will be collected for cellular immunology assays. 
• Approximately 3 mL of venous blood will be collected for transcriptomic analyses. 
Note: Subjects that complete this visit on Day 7 will be reminded to complete their Memory Aid 
through the end of Day 8, and study personnel will contact these subjects by phone to review 
their Memory Aid information and solicit any AE/SAEs and concomitant medications (including 
solicitation for receipt of any non-study influenza vaccines). 
8.2.3 
Visit 04, Day 29, Clinic Visit 
(Window: Day 29, +/-2 days post study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• All concomitant medications (including solicitation for receipt of any non-study influenza 
vaccines) will be recorded on the appropriate DCF. 
• All AE/SAEs will be recorded on the appropriate DCF. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs), may be 
performed, if indicated based on review of interim medical history, by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 
• Counsel on avoidance of pregnancy.  


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• Approximately 20 mL of venous blood will be collected for serological assays. 
• Approximately 80 mL of venous blood will be collected for cellular immunology assays. 
8.2.4 
Visit 05, Day 57, Clinic Visit 
(Window: Day 57 +/- 3 days post study vaccination) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• Receipt of any non-study influenza vaccines will be recorded on the appropriate DCF. 
•  SAEs, AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) 
will be recorded on the appropriate DCF. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs), may be 
performed, if indicated based on review of interim medical history, by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 
• Counsel on avoidance of pregnancy.  
• Approximately 20 mL of venous blood will be for serological assays. 
8.2.5 
Visit 06, Day 90, Clinic Visit 
(Window: Day 90 +/- 14d) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• Receipt of any non-study influenza vaccines will be recorded on the appropriate DCF. 


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• SAEs, AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) 
will be recorded on the appropriate DCF. 
• A targeted physical examination performed prior to study vaccination, including an 
assessment for signs suggestive of AESIs (including Protocol Specified AESIs, MAAEs, 
NOCMCs and PIMMCs), may be performed, if indicated based on review of interim 
medical history, by a study clinician licensed to make medical diagnoses and listed on the 
Form FDA 1572 as the site PI or sub-investigator . 
• Approximately 20 mL of venous blood will be collected immediately prior to study 
vaccination for serological assays. 
• Approximately 48 mL of venous blood will be collected immediately prior to study 
vaccination for immunological assays.  
• Subjects will then receive one 0.5 mL dose of 2019-2020 Fluzone or Flublok QIV study 
vaccine via a single IM injection into the deltoid muscle of the subject’s preferred arm. 
Subjects who received 2018-2019 Fluzone QIV will receive 2019-2020 Fluzone QIV. 
Subjects who received 2018-2019 Flublok QIV will receive 2019-2020 Flublok QIV. The 
site of injection (right or left arm) and time of study vaccine administration to the subject 
will be recorded on the appropriate DCF.  Any SAE’s will be recorded on the appropriate 
DCF prior to discharge.   
8.2.6 
Visit 07, Day 118, Clinic Visit 
(Window: Day 118 +/- 3d) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• Receipt of any non-study influenza vaccines will be recorded on the appropriate DCF. 
• SAEs, AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) 
will be recorded on the appropriate DCF. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs), may be 
performed, if indicated based on review of interim medical history, by a study clinician 


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licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 
• Approximately 20 mL of venous blood will be collected for serological assays. 
8.2.7 
Visit 08, Day 180, Clinic Visit 
(Window: Day 180+/- 14d) 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• Receipt of any non-study influenza vaccines will be recorded on the appropriate DCF. 
• Only SAEs and AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and 
PIMMCs), will be recorded on the appropriate DCF. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) may be 
performed, if indicated based on review of interim medical history, by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 
• Approximately 20 mL of venous blood will be collected for serological assays. 
 
Final Visit 
8.3.1 
Visit 09, Day 365, Clinic Visit 
(Window: Day 365-14/+35)  
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs) will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• Receipt of any non-study influenza vaccines will be recorded on the appropriate DCF. 


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• Only SAEs and AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and 
PIMMCs) will be recorded on the appropriate DCF. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) may be 
performed, if indicated based on review of interim medical history, by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 
• Approximately 20 mL of venous blood will be collected for serological assays. 
 
Early Termination Visit (if needed) 
The following activities will be performed at the Early Termination Visit on subjects who 
withdraw, or are withdrawn or terminated from this trial: 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs), will be obtained by interview of subjects and 
any changes since the previous clinic visit will be noted. 
• All concomitant medications will be recorded on the appropriate DCF (if prior to 28 days 
after the first study vaccination). Receipt of any non-study influenza vaccines will also be 
recorded on the appropriate DCF (if within 365 days after first study vaccination). 
• All AE/SAEs will be recorded on the appropriate DCF. Unsolicited AEs (if occurs within 
28 days of the first study vaccination). SAEs and AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs) that have occurred since the previous clinic 
visit will be solicited (if within 365 days after first study vaccination). 
• Memory Aid information will be reviewed with subjects (if within 7 days after the first 
study vaccination). 
• Vital signs, including oral temperature, pulse and BP, may be obtained if indicated. 
Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to 
taking oral temperature. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) may be 
performed, if indicated based on review of interim medical history, by a study clinician 


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licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 
• The study vaccination site will be examined (if within 7 days after the first study 
vaccination). 
• Post administration reactogenicity assessment will be performed (if within 7 days after 
the first study vaccination).  
• Approximately 6 mL of venous blood will be collected for clinical safety labs (WBC, 
Hgb, PLT, ALT, T. Bili, AST, GGT, ALP, serum lipase and amylase and Cr) to be 
performed by the Central Clinical Laboratory (if within 7 days after the first study 
vaccination). 
• Approximately 20 mL of venous blood will be collected for serological assays. 
• Approximately 80 mL of venous blood will be collected for cellular immunology assays 
(if prior to or at the Day 90 visit). 
• Approximately 3 mL of venous blood will be collected for transcriptomic assays (if prior 
to or at the Day 8 visit). 
 
Unscheduled Visit (if needed) 
An Unscheduled Visit may occur at any time during this trial. Any of the following activities 
may be performed: 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases and symptoms suggestive of AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs) will be obtained by interview of subjects and 
any changes since the previous clinic visit or phone call will be noted (if indicated). 
• All concomitant medications will be recorded on the appropriate DCF (if within 28 days 
after first study vaccination). Receipt of any non-study influenza vaccines will also be 
recorded on the appropriate DCF (if within 365 days after first study vaccination). 
• All AE/SAEs will be recorded on the appropriate DCF. Unsolicited AEs (if occurs within 
28 days of the first study vaccination). SAEs and AESIs (including Protocol Specified 
AESIs, MAAEs, NOCMCs and PIMMCs) that have occurred since the previous clinic 
visit will be solicited (if within 365 days after first study vaccination). 


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• Memory Aid information will be reviewed with subjects (if within 7 days after the first 
study vaccination). 
• Vital signs, including oral temperature, pulse and BP, may be obtained if indicated. 
Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to 
taking oral temperature. 
• A targeted physical examination, including an assessment for signs suggestive of AESIs 
(including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs), may be 
performed, if indicated based on review of interim medical history, by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 
• The study vaccination site will be examined (if within 7 days after study vaccination). 
• Post administration reactogenicity assessment will be performed (if within 7 days after 
the first study vaccination).  
• Site investigators have the discretion of administering 2019/2020 Fluzone or Flublok 
QIV earlier than the Day 90 window (i.e. earlier than Day 76) if 10% of more of 
surveillance samples in the CDC geographic region surrounding the local site test 
positive for influenza.  
• Approximately 6 mL of venous blood will be collected for clinical safety labs (WBC, 
Hgb, PLT, ALT, T. Bili, AST, GGT, ALP serum lipase and amylase and Cr) to be 
performed by the Central Clinical Laboratory (if indicated). 
• Approximately 20 mL of venous blood will be collected for serological assays. 
 


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9 
ASSESSMENT OF SAFETY 
 
Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of: 
1. SAEs occurring from the time of the first study vaccination through approximately 12 
months after the first study vaccination. 
2. Solicited AEs – reactogenicity events occurring from the time of the first study 
vaccination through 7 days after the first study vaccination: 
a) Injection site reactions including pruritus, ecchymosis, erythema, induration, edema, 
pain, and tenderness. 
b) Systemic reactions including fever, feverishness, fatigue, malaise, myalgia, arthralgia, 
headache, and nausea. 
3. Clinical safety laboratory AEs occurring from the time of the first study vaccination 
through approximately 7 days after the first study vaccination. Parameters to be evaluated 
include WBC, Hgb, PLT, ALT, T. Bili, AST, GGT, ALP, serum lipase, serum amylase, 
and Cr. 
4. Unsolicited AEs –non-serious AEs occurring from the time of the first study vaccination 
through approximately Day 29. 
5. AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) occurring 
from the time of the study vaccination through approximately 12 months after the first 
study vaccination. 
 
Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters 
9.2.1 
Adverse Events 
Adverse Event (AE): ICH E6 GCP defines an AE as any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product regardless of its 
causal relationship to the study treatment. The FDA defines an AE as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related. 


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An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medicinal (investigational) 
product. The occurrence of an AE may come to the attention of study personnel during study 
visits and interviews of a study recipient presenting for medical care, or upon review by a study 
monitor. 
AEs, including solicited injection site and systemic (subjective and quantitative) reactions, not 
meeting the protocol-defined criteria for SAEs, will be recorded on the appropriate DCF and 
entered into the eCRF. Information to be collected for unsolicited non-serious AEs includes 
event description, date of onset, licensed study physician’s assessment of severity and 
relationship to study product or alternate etiology (if not related to study product) (assessed only 
by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as 
the site PI or sub-investigator), date of resolution, seriousness, and outcome. AEs occurring 
during the trial-collection and reporting period will be documented appropriately regardless of 
relationship to study product. AEs will be followed through resolution. 
 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the severity of any pre-existing medical 
condition increases, it will be recorded as an AE. 
 
AEs must be assessed for severity and relationship to study product (see definitions below). AEs 
characterized as intermittent require documentation of onset and duration of each episode. The 
start and stop date of each reported AE will be recorded on the appropriate DCF and entered into 
the eCRF. 
 
Adverse Events of Special Interest (AESI): An adverse event of special interest 
(serious or nonserious) is one of scientific and medical concern specific to the sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (e.g., regulators) might 
also be warranted.  
 
Medically-Attended Adverse Events (MAAEs): For each unsolicited AE experienced, 
the subject will be asked if he/she had received medical attention, defined as 
hospitalization, an emergency room visit or an otherwise unscheduled visit to or from 
medical personnel for any reason. AEs characterized by such unscheduled medical care 
will be designated as MAAEs. 
 


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New-Onset Chronic Medical Conditions (NOCMCs): NOCMCs are defined as any 
new ICD-10 diagnosis (10th revision of the International Statistical Classification of 
Diseases and Related Health Problems) that is applied to the subject during the course of 
the study, after receipt of the study agent, that is expected to continue for at least 3 
months and requires continued health care intervention. 
 
Potentially Immune-Mediated Medical Conditions (PIMMCs): PIMMCs constitute a 
group of AEs that includes diseases which are clearly autoimmune in etiology and other 
inflammatory and/or neurologic disorders which may or may not have autoimmune 
etiologies. PIMMCs currently in effect are presented in Appendix B: Adverse Events of 
Special Interest. 
 
Protocol Specified AESIs: Dry Eye, Dry Mouth and Tearing 
 
Severity of Event: AEs will be assessed by a licensed study physician listed on the Form FDA 
1572 as the site PI or sub-investigator using a protocol-defined grading system (see Sections 
9.2.2 and 9.2.3). For events not included in the protocol-defined grading system, the following 
guidelines will be used to quantify severity: 
• 
Mild (Grade 1): Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• 
Moderate (Grade 2): Events result in a low level of inconvenience or concern with 
therapeutic measures. Moderate events may cause some interference with functioning and 
daily activities. 
• 
Severe (Grade 3): Events interrupt the subject’s daily activities and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
Relationship to Study Product: The licensed study physician’s assessment of an AE’s 
relationship to study product is part of the documentation process, but it is not a factor in 
determining what is or is not reported in this trial. If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. The relationship to study product must be 
assessed for AEs using the terms: related or not related. In a clinical trial, the study product must 
always be suspect. To help assess, the following guidelines are used: 
• Related – There is a reasonable possibility that the study product caused the AE. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the AE. 


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• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
9.2.2 
Reactogenicity 
Reactogenicity events are AEs that are common and known to occur following administration of 
this type of study vaccine. The following Toxicity Grading Scales will be used to grade solicited 
injection site and systemic (subjective and quantitative) reactions: 
 
Table 4: Injection Site Reactogenicity Grading 
Injection Site Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain – experienced 
without touching the 
injection site 
(spontaneous 
discomfort) 
Subject is aware of pain, 
but it does not interfere 
with daily activity, and if 
pain medication is used, it 
is Over the Counter 
(OTC) and used for less 
than 24 hours 
Subject is aware of pain; 
there is interference with 
daily activity or OTC 
pain medication is used 
for more than 24 hours 
Subject is aware of pain, 
and it prevents daily 
activity or pain requires 
prescription medication 
Tenderness-experienced 
with touching the 
injection site 
Subject is aware of pain, 
but it does not interfere 
with daily activity, and if 
pain medication is used, it 
is Over the Counter 
(OTC) and used for less 
than 24 hours 
Subject is aware of pain; 
there is interference with 
daily activity or OTC 
pain medication is used 
for more than 24 hours 
Subject is aware of pain, 
and it prevents daily 
activity or pain requires 
prescription medication 
Pruritus 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity or 
requires prescription 
medication 
Ecchymosis (Bruising)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Erythema (Redness)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Induration 
(Hardness)/Edema 
(Swelling)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
* Will also be measured in mm but size will not be used as halting criteria. 


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Ecchymosis, erythema and induration/edema as analyzed by measurement will be graded as 
follows: 
 
Table 5: Injection Site Reactogenicity Measurements 
Injection Site Reaction 
Small 
Medium 
Large 
Ecchymosis (Bruising)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Erythema (Redness)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
Induration (Hardness)/Edema 
(Swelling)* 
<20 mm 
20 mm – 50 mm 
>50 mm 
* Will not be used as halting criteria. 
Table 6: Subjective Systemic Reactogenicity Grading 
Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Feverishness  
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Fatigue 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Malaise 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Myalgia* 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Arthralgia* 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Headache 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity or 
headache requires 
prescription medication 
Nausea 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity or 
nausea requires prescription 
medication 
* Not at injection site. 


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Oral temperature# will be graded as follows: 
Table 7: Quantitative Systemic (Oral Temperature) Reactogenicity Grading 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever* – oral† 
38.0°C – 38.4°C 
100.4°F – 101.1°F 
38.5°C – 38.9°C 
101.2°F – 102.0°F 
>38.9°C 
>102.0°F 
# Oral temperature assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
* A fever can be considered not related to the study product if an alternative etiology can be documented. 
† Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
9.2.3 
Additional Adverse Event Severity Grading 
Pulse and BP# will be graded as follows: 
Table 8: Pulse and BP Adverse Event Grading 
Physiologic Parameter 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Bradycardia – beats per minute 
45 – 46 
40 – 44 
<40 
Tachycardia – beats per minute 
101 – 130 
131 – 155 
>155 
Hypotension (systolic) mmHg 
80 – 84 
75 – 79 
<75 
Hypotension (diastolic) mmHg 
50 – 54 
45 – 49 
<45 
Hypertension (systolic) mmHg 
141 – 155 
156 – 160 
>160 
Hypertension (diastolic) mmHg 
91 – 100 
101 – 110 
>110 
# Pulse and BP assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
Clinical safety laboratory values# will be graded as follows: 
Table 9: Clinical Safety Laboratory Adverse Event Grading 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
WBC 103/µL (Decrease) 
2.50 – 3.90 
1.50 – 2.49 
<1.50 
WBC 103/µL (Increase) 
10.60 – 15.00 
15.01 – 20.00 
>20.00 


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Hgb g/dL (Decrease) (Female) 
10.1 – 11.4 
8.5 – 10 
<8.5 
Hgb g/dL (Decrease) (Male) 
11.0 – 12.4 
9.5 – 10.9 
<9.5 
Platelets 103/µL (Decrease) EDTA 
125 – 139 
100 – 124 
<100 
Platelets 103/µL (Increase) EDTA 
416 – 550 
551– 750 
>750 
Platelets K/cu mm (Decrease) Citrate 
115-124 
100-114 
<100 
Platelets K/cu mm (Increase) Citrate 
376-550 
551-750 
>750 
Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
ALT IU/L (Increase) (Female) 
44 – 100 
101 – 200 
>200 
ALT IU/L (Increase) (Male) 
61 – 138 
139 – 275 
>275 
Aspartate Amino Transferase IU/L 
(Increase) (Female) 
37-90 
91-180 
> 180 
Aspartate Amino Transferase IU/L 
(Increase) (Male) 
44-108 
109-215 
> 215 
Total Bilirubin mg/dL (Increase) – 
when accompanied by any increase in 
ALT 
1.30 – 1.59 
1.60 – 1.80 
> 1.80 
Total Bilirubin mg/dL (Increase) – 
when ALT is normal 
1.30 – 1.89 
1.90 – 2.40 
> 2.40 
Gamma-Glutamyl Transferase IU/L 
(Increase) (Female) 
33-80 
81-160 
> 160 
Gamma-Glutamyl Transferase IU/L 
(Increase) (Male) 
50-123 
124-245 
> 245 
Alkaline Phosphatase IU/L (Increase) 
(Female) 
116-230 
231-345 
> 345 
Alkaline Phosphatase IU/L (Increase) 
(Male) 
116-230 
231-345 
> 345 
Serum Amylase 
122-182 
183-242 
>243 
Serum Lipase 
61-90 
91-180 
> 181 
Creatinine mg/dL (Increase) (Female) 
1.1  – 1.7 
1.8 – 2.0 
> 2.0 
Creatinine mg/dL (Increase) (Male) 
1.4  – 1.7 
1.8 – 2.0 
> 2.0 
# Clinical safety laboratory evaluations assessed on Day 1 prior to the first study vaccination will be considered 
as baseline. 


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9.2.4 
Serious Adverse Events 
Serious Adverse Event (SAE): An AE or suspected adverse reaction is considered “serious” if, 
in the view of either the site PI (or appropriate sub-investigator) or sponsor, it results in any of 
the following outcomes: 
• Death, 
• A life-threatening AE*, 
• Inpatient hospitalization or prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical 
judgment they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
* Life-threatening AE. An AE is considered “life-threatening” if, in the view of either the site PI 
(or appropriate sub-investigator) or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe form, 
might have caused death. 
SAEs will be: 
• 
Assessed for severity and relationship to study product or alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 
PI or sub-investigator. 
• 
Recorded on the appropriate SAE form and entered into the eCRF. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site PI or sub-investigator. 


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• 
Reviewed and evaluated by the DSMB (periodic review unless related), DMID, and IRB. 
9.2.5 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
The site PI or appropriate sub-investigator is responsible for recording all AE/SAEs that are 
observed or reported during this trial, regardless of relationship to study product. AE/SAEs, 
abnormal laboratory test values or abnormal clinical findings will be collected, assessed, 
documented, reported, and followed appropriately, using a local laboratory as necessary. In 
determining eligibility, refer to Section 5.1 and the protocol-specific MOP. 
 
Reporting Procedures 
Solicited injection site and systemic reactogenicity events will be documented and reported from 
the time of the first study vaccination through 7 days after the first study vaccination. 
 
Clinical safety laboratory AEs will be documented and reported from the time of the first study 
vaccination through approximately 7 days after the first study vaccination. 
 
Unsolicited non-serious AEs will be documented and reported from the time of the first study 
vaccination through approximately Day29. 
 
SAEs and AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) will 
be documented and reported from the time of the first study vaccination through approximately 
12 months after the first study vaccination. 
9.3.1 
Serious Adverse Events 
Any AE that meets a protocol-defined serious criterion must be submitted immediately (within 
24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance Group, at the 
following address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 


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In addition to the SAE form, selected SAE data fields must also be entered into Advantage 
eClinicalSM. Please see the protocol-specific MOP for details regarding this procedure. 
 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. 
 
The site will send a copy of the SAE report(s) to the ISM (as deemed necessary) when they are 
provided to the DMID Pharmacovigilance Group. The DMID Medical Monitor and DMID 
Clinical Project Manager will be notified of the SAE by the DMID Pharmacovigilance Group.  
 
The DMID Medical Monitor will review and assess the SAE for regulatory reporting and 
potential impact on subject safety and protocol conduct. 
 
At any time after completion of this trial, if the site PI or appropriate sub-investigator becomes 
aware of an SAE that is suspected to be related to study product, the site PI or appropriate sub-
investigator will report the event to the DMID Pharmacovigilance Group. 
9.3.2 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the site PI or appropriate sub-investigator, DMID, the 
Investigational New Drug (IND) sponsor, will report any suspected adverse reaction that is both 
serious and unexpected. DMID will report an AE as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the AE. DMID will notify the 
FDA and all investigators (i.e., all participating VTEU site PIs to whom the sponsor is providing 
drug under its IND(s) or under any PI’s IND(s)) in an IND safety report of potential serious risks 
from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar 
days after the sponsor determines that the information qualifies for reporting as specified in 21 
CFR Part 312.32. DMID will also notify the FDA of any unexpected fatal or life-threatening 
suspected adverse reaction as soon as possible, but in no case later than 7 calendar days after the 
sponsor’s initial receipt of the information. Relevant follow up information to an IND safety 
report will be submitted as soon as the information is available. Upon request from the FDA, 
DMID will submit to the FDA any additional data or information that the agency deems 
necessary, as soon as possible, but in no case later than 15 calendar days after receiving the 
request. 
 
All serious events designated as “not related” to study product(s) will be reported to the FDA at 
least annually in a summary format. 


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9.3.3 
Reporting of Pregnancy 
Upon awareness, pregnancies occurring in subjects will be recorded on the Pregnancy Report 
DCF. All pregnancies reported during the course of this trial will be followed to pregnancy 
outcome. With the subject’s permission, a venous blood sample(s) for serological assays will be 
collected per protocol though large volume blood samples for cellular immunological assays will 
be discontinued. Subjects who become pregnant will not be excluded from receiving the seasonal 
flu vaccine at Day 90, unless there are contraindications. Subjects will be followed for safety as 
per the protocol.  
Pregnant subjects will be contacted at least once every 12-16 weeks during pregnancy, following 
delivery, and at approximately one month following birth (if live birth) or one to two months 
following still birth.  
Subjects who become pregnant will be approached regarding their interest to enroll in the Sanofi 
Pregnancy Registry. This Registry program is not a part of this research study. Participation is 
completely voluntary. If subjects choose to enroll they can contact Sanofi via email at 
USPVmailbox@sanofi.com or call Customer Service at 1-800-633-1610 option#2 to discuss 
enrollment in the Pregnancy Registry for Influenza.  
 
Type and Duration of Follow-up of Subjects after Adverse Events 
AEs will be collected, assessed and followed through resolution from the time of first study 
vaccination through approximately 28 days after the first study vaccination. 
 
SAEs and AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) will 
be collected, assessed and followed from the time of the first study vaccination through 
resolution even if this extends beyond the trial-reporting period (approximately 12 months after 
the first study vaccination). 
 
Resolution of an AE/SAE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
 
Follow-up procedures, evaluations and outcomes will be recorded on the appropriate DCF and 
entered into the eCRF. 


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Halting Rules 
Enrollment will start with 6 sentinel subjects, one each from each study group (groups 1-6).  
Subjects will be followed through Day 8.  If any of the pre-specified events outlined in Section 
9.5.1 occur, the study will be halted and reviewed by the DSMB.  If no prespecified events 
occur, randomization and vaccination can proceed. All 6 subjects will then be followed 
according to protocol.   
 
It is anticipated that both adjuvant formulations (AF03 and Advax-CpG55.2) will be available at 
the start of study enrollment.  However, if the Advax or CpG55.2 components for Advax-
CpG55.2 are not available, the study will proceed only with groups 1, 2, 4 and 5 open for 
enrollment for the remaining subjects (up to 240) in groups 1, 2, 4 and 5. For the sentinel 
subjects, one subject from groups 1, 2, 4 and 5 will be enrolled and followed through Day 8. If 
any of the pre-specified halting rules occur, the study will be halted and reviewed by the DSMB. 
If no pre-specified events occur, randomization will proceed in groups 1, 2, 4 and 5 and 
enrollment will continue for the remaining subjects in groups 1, 2, 4 and 5. 
 
9.5.1 
Halting Rules for the Sentinel Subjects 
• Any subject experiences ulceration, abscess or necrosis at the injection site. 
• Any subject experiences laryngospasm, bronchospasm or anaphylaxis within 24 hours 
after administration. 
• Any subject experiences generalized urticaria (defined as occurring at more than two 
body parts) within 72 hours after administration of study product. 
• Any subject experiences an SAE (except for accident or trauma) after administration of 
the study product. 
• Any subject experiences acute weakness of limbs and/or cranial nerve innervated muscles 
(description of potential signal of GBS) after administration of study product. 
• Any subject that experiences grade 3 AE including lab, local or systemic solicited 
reactogenicity events (excluding measured grades of erythema and induration alone) 


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• Two or more subjects experience the same grade 2 (same HLGT by MedDRA coding) 
AE including local or systemic solicited reactogenicity events (excluding measured 
grades of erythema and induration alone) 
9.5.2 
Halting for Study 
 
Additional enrollment and study interventions/administration of study products in this trial will 
be halted for DSMB review/recommendation if any of the following are reported after the first 
study vaccination: 
• Any subject experiences ulceration, abscess or necrosis at the injection site that is 
considered related to study product administration. 
• Any subject experience laryngospasm, bronchospasm or anaphylaxis within 24 hours 
after administration of study product that is considered related to study product. 
• Two or more subjects experience generalized urticaria (defined as occurring at more than 
two body parts) within 72 hours after administration of study product that is considered 
related to study product. 
• Any subject experiences an SAE after administration of study product that is considered 
related to study product. 
• Any subject experiences acute weakness of limbs and/or cranial nerve innervated muscles 
(description of potential signal of GBS) after administration of study product. 
• Any subject develops a PIMMC after administration of study product. 
• 10% of subjects (minimum 3 subjects) experience a grade 3 injection site or systemic 
solicited adverse event (excluding measured grades of erythema and induration alone).   
• 10% of subjects (minimum 3 subjects) experience same grade 3 AE (unsolicited and 
laboratory abnormality), in the same HLGT by MedDRA coding, considered related to 
study product. 
Grading scales for solicited injection site and systemic (subjective and quantitative) reactions are 
included in Section 9.2.2. 
Grading scales for clinical safety laboratory AEs are included in Section 9.2.3. 


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If any of the halting rules are met following any subject receipt of study vaccination, then this 
trial will not continue with the remaining enrollments or study vaccinations without a review by 
and recommendation from the DSMB to proceed. 
 
DMID retains the authority to suspend additional enrollment and study 
interventions/administration of study products during this trial, as applicable. 
 
The DMID Medical Monitor is empowered to stop enrollment and study vaccinations if AEs that 
meet the halting criteria are reported. 
 
Safety Oversight 
9.6.1 
Independent Safety Monitor (ISM) 
An ISM is a physician with relevant expertise whose primary responsibility is to provide to 
DMID an independent safety assessment in a timely fashion. This is a voluntary position that 
does not receive payment. The ISM must meet the requirements of the NIAID Conflict of 
Interest (COI) policy. 
 
For this clinical trial an ISM is not required. However, at each participating VTEU site, upon 
DMID Medical Monitor request, the site PI will identify a physician with relevant expertise, to 
act as a Secondary Medical Assessor (SMA). The SMA will examine a subject and/or medical 
records and provide to DMID a medical assessment (or second medical opinion) of the safety 
event in question. The site PI or appropriate sub-investigator will send to the DMID Medical 
Monitor, a summary of the event and include the site PI or appropriate sub-investigator and SMA 
assessments. 
 
Note: In the case that DMID has requested this type of evaluation multiple times, DMID may 
request the participating VTEU site(s) identify an ISM to assist DMID with safety oversight. 
Data and Safety Monitoring Board (DSMB) 
 
9.6.2 
Data and Safety Monitoring Board (DSMB) 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety and advises DMID. The DSMB members will be separate and 
independent of study personnel participating in this trial and should not have scientific, financial 


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or other COI related to this trial. The DSMB will consist of members with appropriate expertise 
to contribute to the interpretation of the data from this trial. 
 
The DSMB will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to 
assess will be clearly defined. Procedures for DSMB reviews/meetings will be defined in the 
charter. The DSMB will review applicable data to include, but not limited to, study progress and 
subject, clinical, safety, reactogenicity, and immunogenicity data. Reports may include 
enrollment and demographic information, medical history, concomitant medications, physical 
assessments, clinical laboratory values, dosing compliance, solicited and unsolicited AE, SAEs, 
AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) and HAI and 
Neut antibody assay results. The DSMB will review SAEs on a regular basis and ad hoc during 
this trial. The DMID Medical Monitor and the ISM (as deemed necessary) will be responsible for 
reviewing SAEs in real time. 
The DSMB will review the data when the 8-day reactogenicity and clinical safety laboratory data 
following the first study vaccination is available for 50% of study subjects.  Enrollment will not 
be paused for this review.     
The DSMB will conduct the following reviews: 
• An Organizational Meeting that occurs prior to subject enrollment 
• Scheduled Data Review Meeting when 50% of the subjects reach Day 8 post first 
injection and all clinical safety laboratory data following the first study vaccination are 
available.  
• Scheduled Data Review Meeting when an expedited report containing safety and 
immunogenicity analyses for HAI, NAI and Neut antibody assays unblinded by group 
has been created by the SDCC after the interim clinical database is cleaned, monitored 
and locked and all HAI, NAI, and Neut data for Day 1 and Day 29 and safety date 
through Day 57 after the first study vaccination have been received.  If other 
immunological analyses are available, these data may be reviewed at this meeting.  
• Ad hoc when a halting rule is met, or DMID/DSMB chair may convene an ad hoc 
meeting if there are immediate concerns regarding observations during the course of this 
trial. The DMID Medical Monitor is empowered to stop enrollment and study 
vaccinations if AEs that meet the halting criteria are reported. 
• Final review meeting may be conducted: 6 to 8 months after clinical database lock to 
review the cumulative unblinded safety and immunogenicity data for this trial. If a final 
meeting is held, the data may be provided in a standard summary format, or provided as 


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the CSR. The DSMB may be asked to provide recommendations in response to questions 
posed by DMID. 
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by DMID. The DSMB may receive data in aggregate and 
presented by treatment arm. The DSMB may also be provided with expected and observed rates 
of the expected AEs in an unblinded fashion and may request the treatment assignment be 
unblinded for an individual subject if required for safety assessment. The DSMB will review 
grouped and unblinded data in the closed session only. As an outcome of each review/meeting, 
the DSMB will make a recommendation as to the advisability of proceeding with study 
vaccinations, as applicable, and to continue, modify or terminate this trial. 


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10 
CLINICAL MONITORING 
 
Site Monitoring Plan 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study interventions/administration of study products, and data collection processes 
are of high quality and meet sponsor and ICH E6 GCP guidelines and applicable federal 
regulations, and that this trial is conducted in accordance with the protocol, protocol-specific 
MOP and applicable sponsor SOPs. DMID, the sponsoring agency, or its designee will conduct 
site-monitoring visits as detailed in the clinical monitoring plan. DMID-designated clinical 
monitors will verify that this trial is conducted, and data are generated, documented (recorded), 
and reported in compliance with the protocol, ICH E6 GCP guidelines and applicable regulatory 
requirements. Clinical monitoring reports will be submitted to DMID. 
 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID. Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, eCRFs, ICFs, medical and laboratory reports, and 
protocol and GCP compliance. Site monitors will have access to each participating VTEU site, 
study personnel and all study documentation according to the DMID-approved site monitoring 
plan. Study monitors will meet with site PIs to discuss any problems and actions to be taken and 
document visit findings and discussions. 
 


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11 
STATISTICAL CONSIDERATIONS 
 
Introduction  
The goal of this clinical study is to assess, in healthy adults ages 18-45, the safety, reactogenicity 
and immunogenicity of either the 2018/2019 seasonal Fluzone or Flublok QIV manufactured by 
Sanofi Pasteur administered intramuscularly given without adjuvant or with one of two 
adjuvants, AF03 or Advax-CpG55.2.  These study arms are included to allow evaluation of the 
potential of each of the two adjuvants to enhance the immune response to either the 2018/2019 
seasonal Fluzone QIV or the 2018/2019 seasonal Flublok QIV. 
 
Study Hypotheses 
This Phase I study is not designed to test a formal null hypothesis. Rather, it is intended to obtain 
sufficient data to obtain meaningful estimates of the immune response induced by either the 
2018/2019 seasonal Fluzone or Flublok QIV administered without adjuvant or with AF03 or 
Advax-CpG55.2 adjuvants, and to uncover any safety issues that occur at a sufficiently high rate 
that they might be observed in a study of this size. The sample size facilitates formal testing of 
selected hypotheses as discussed in Section 11.4.3, along with the probability of observing safety 
outcomes and the precision of immunogenicity outcomes. 
    
 
Study Outcome Measures 
Please refer to Study Outcome Measures outlined in Table 1. 
 
Sample Size Considerations 
Please refer to Study Design outlined in Section 4. 
11.4.1 
Study Population 
The study population for this clinical trial includes males and non-pregnant females, 18-45 years 
of age, who are in good health and meet all eligibility criteria. The subjects will be recruited 
from the general population at each of the participating VTEU sites that have substantial 
experience conducting large influenza vaccine studies. 


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11.4.2 
Subject Enrollment and Follow-up 
Based on the accrual rates observed in similar studies, it seems reasonable to expect that the 
participating VTEUs will be able to enroll this trial in a timely fashion. In a previous DMID trial 
(DMID 15-0064, NCT02624219), 4 VTEUs recruited 275 healthy subjects, 19 to 64 years of 
age, in 20 weeks. In this trial, approximately 3% of subjects, 19 to 64 years of age, were 
excluded from the per protocol (PP) analysis for the Day 22 primary immunogenicity outcome 
either because they were lost-to-follow-up or because they had a protocol deviation requiring 
their exclusion from the PP analysis. The rate of per protocol exclusions for the Day 29 visit in 
this protocol is expected to follow a similar trend. 
A total of 40 subjects will be enrolled and randomized in each group. Assuming up to 3% drop 
out by Day 29, it is expected that at least 38 subjects per group will be available for the primary 
immunogenicity analysis. If Advax-CpG55.2 is not available, the study will proceed only with 
groups 1, 2, 4 and 5 open for enrollment for the remaining subjects (up to 240 or 60 per group) in 
groups 1, 2, 4 and 5. In this case, assuming the same dropout rate of 3%, it expected that at least 
58 subjects per group will be available for the primary immunogenicity analysis. 
Follow-up will consist of 2 segments. The first encompasses the core data for this trial and will 
consist of results for all study visits through approximately 28 days after study vaccination. The 
second segment consists of a 6-month immunogenicity assessment and follow-up safety 
assessments through approximately 12 months after study vaccination. 
11.4.3 
Sample Size 
This study is planned to enroll 40 subjects per group. If Advax-CpG55.2 is not available, the 
study will proceed only with groups 1, 2, 4 and 5 open for enrollment for the remaining subjects 
(up to 240 or 60 per group) in groups 1, 2, 4 and 5. This study is not designed to test a formal 
null hypothesis. Rather, it is intended to obtain sufficient data to obtain meaningful estimates of 
the immune response and to uncover any safety issues that occur at a sufficiently high rate that 
they might be observed in a study of this size. For the purposes of summarizing we will assume a 
type one error rate, alpha = 0.05, and will not adjust for multiple comparisons. The following 
tables illustrate the precision and power for select estimates and comparisons of interest. Table 
10 indicates the probability of observing one or more safety events, such as solicited injection 
site or systemic reactogenicity events or an unsolicited non-serious AE of a particular type for 
sentinel subjects (N=4 or 6), for a single adjuvanted/ unadjuvanted treatment arm/stratum (N = 
40 or 60), for all subjects receiving the same seasonal QIV (N= 120), for all subjects in the trial 
(N=240). 


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Table 10: Probability (%) to Detect Safety Events 
Event 
Frequency 
N = 4 
N = 6 
N = 40 
N = 60 
N = 120 
N = 240 
≥10% 
Very Common 
34 
46 
98 
>99 
>99 
>99 
≥1% 
Common 
3 
5 
33 
45 
70 
91 
≥0.1% 
Uncommon 
<1 
<1 
3 
5 
11 
21 
≥0.01% 
Rare 
<1 
<1 
<1 
<1 
1 
2 
 
Binomial confidence intervals (CI) are widest (have the least precision) when the response rate is 
50%. Table 11 is presented to indicate the worst-case scenario for precision of observed exact 
(Clopper-Pearson) binomial confidence intervals. 
 
Table 11: Precision of Binomial Confidence Intervals 
For each of the primary immunogenicity objectives, a power analysis is provided below for 
testing the following hypotheses with the planned sample size, where pc = proportion of 
responders in comparator arm; where pe = proportion of responders in experimental arm.  
Test for difference in proportion responders: 
H0: pc – pe = 0 – No difference in proportion responders 
H1: pc – pe ≠ 0 – difference in response rates 
Table 12 illustrates the minimum detectable differences in the proportion of subjects responding 
(e.g., attaining seroconversion or a titer ≥1:40) between two adjuvanted treatment arms using a 
two-sided Likelihood Ratio Test and alpha = 0.05. It is assumed that approximately 3% of the 
N 
95% CI 
4 
6-94 
6 
11-89 
40 
33 -67 
60 
36-64 
120 
40-60 
240 
43-57 


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subjects (N=2) in each treatment arm will be excluded from the per protocol analysis of primary 
immunogenicity endpoints leaving N=38 subjects per treatment arm.  If Advax-CpG55.2 is 
unavailable, approximately 3% of the subjects (N=2) in each treatment arm will be excluded 
from the per protocol analysis of primary immunogenicity endpoints leaving N=58 subjects per 
treatment arm. Seroconversion rates of 40% to 90% are considered. 
Table 12: Minimum Detectable Difference in Proportion Responders with 80% Power 
Assumed Proportion of 
subjects with titer ≥ 40 in 
comparator arm (pc) 
Minimum detectable 
difference in response rate 
(pc-pe), 
N=38 per group 
Minimum detectable 
difference in response rate 
(pc-pe), 
N=58 per group 
0.40 
  0.32  
0.26 
0.50 
  0.30 
0.25 
0.60 
  0.28 
0.23 
0.70 
  0.24 
0.20 
0.80 
  0.18 
0.16 
0.90 
  0.10 
0.10 
  
 
Planned Interim Analyses 
Interim analyses will only be used to terminate this trial in the event that unanticipated safety 
events deemed to be of sufficient concern require such action by the sponsor. These assessments 
will not be made on the basis of testing a formal statistical hypothesis; therefore, p-value 
adjustment will not be made to any analyses. A DSMB will be convened by DMID to review 
study progress and participant, clinical, safety, reactogenicity and immunogenicity data as 
described in Section 9.6.2. 
 
Clinical, safety, and reactogenicity data through approximately 56 days after study vaccination 
will represent the interim clinical database for this trial. Once the last subject completes the visit 
that occurs approximately 56 days after first study vaccination, the interim clinical database will 
be cleaned, monitored and locked. Upon receipt of immunogenicity data for Day 1 and Day 29 
(HAI, NAI, and Neut data) and safety data through Day 57, the sponsor will authorize the DCC 
to transfer to Sanofi Pasteur a copy of this unblinded data set. An expedited report containing 
analyses of safety data through Day 57 and HAI, NAI, and Neut data from baseline (Day 1) and 
Day 29 unblinded by treatment group only will be prepared by the SDCC. These analyses may 
be made available to the sponsor and pharmaceutical partners for planning subsequent trials as 


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well as the DSMB for review. Other immunological analyses that are available may also be 
included in the expedited report and may also be reviewed by the DSMB.  
 
The analyses performed for the expedited report or using the data set provided to Sanofi Pasteur 
will not be used to make any decisions concerning the conduct of this trial. As it is anticipated 
that subjects will remain in long term safety follow-up at the time of these analyses, blinded 
investigators and DMID medical monitors not involved in the analysis, publication, or clinical 
study report preparation will be responsible for assessing SAEs and AESIs (including Protocol 
Specified AESIs, MAAEs, NOCMCs and PIMMCs) until all subjects have completed the final 
follow-up visit.  
11.5.1 
Interim Safety Review 
An interim safety review may include enrollment and demographic information, medical history, 
concomitant medications, physical assessments, clinical laboratory values, dosing compliance, 
and solicited and unsolicited AE/SAEs. Additional data may be requested by the DSMB, and 
interim statistical reports may be generated as deemed necessary and appropriate by DMID. The 
DSMB may receive data in aggregate and presented by treatment arm, including expected and 
observed rates of the expected AEs. The DSMB will review grouped data in the closed session 
only. The DSMB will meet and review these data at scheduled time points or ad hoc as needed 
during this trial as defined in the DSMB charter. As an outcome of each review/meeting, the 
DSMB will make a recommendation as to the advisability of proceeding with study vaccinations 
(as applicable), and to continue, modify, or terminate this trial. 
 
Additionally, this trial will be monitored to determine if any of the halting rules described in 
Section 9.5 are met. 
 
 
Final Analysis Plan 
Subject unblinding will occur and the final CSR will be completed after the last subject’s last 
visit is completed, the final clinical database including all long-term safety follow-up data is 
cleaned, monitored and locked, and all primary and secondary immunogenicity data are 
available. After such data are reported in the database and the data are considered clean and 
complete, a “topline” subset of the immunogenicity tables planned for the CSR will be provided 
to DMID and Sanofi Pasteur.  Additional exploratory immunogenicity endpoint data not 
available at the time of CSR preparation may be included in an addendum to the CSR, 
manuscript(s), or other report. 


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A formal statistical analysis plan which defines the analyses to be included in the expedited 
report and the final CSR will be developed, finalized, and submitted to the FDA, prior to 
unblinding for any analysis. 
11.6.1 
Analysis Populations 
The Safety Analysis population includes all subjects who received the first dose of study 
vaccine. 
The modified intent-to-treat (mITT) population includes all randomized subjects who received 
the first dose of study vaccine and contributed at least one post-first study vaccination venous 
blood samples for immunogenicity testing (HAI, NAI or Neut antibody assays) for which valid 
results were reported. For analyses using the mITT population, subjects will be grouped based on 
randomized treatment arm. 
The per protocol (PP) population includes all subjects in the mITT with the following 
exclusions: 
• 
Data from all available visits for subjects found to be ineligible at baseline. 
• 
Data from all visits for subjects that did not contribute venous blood samples for 
immunogenicity testing (HAI, NAI or Neut antibody assays) at baseline (Day 1). 
• 
Data from all visits subsequent to major protocol deviations, such as:  
o Receipt of non-study licensed live vaccine within 30 days before or after the 
first study vaccination, 
o Receipt of non-study licensed inactivated vaccine within 14 days before or after 
the first study vaccination, 
o Receipt of immunosuppressive therapy (e.g., corticosteroids) within 30 days 
before or after the first study vaccination. 
• Data from any visit that occurs substantially out of window. 
 
 
For analyses using the PP population, subjects will be grouped based on study vaccinations 
received. 


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11.6.2 
Safety Data 
Summaries and analysis of safety data will be presented for the Safety Analysis Population. All 
summaries and analyses will be presented for all subjects. 
 
Solicited AEs will be summarized by severity after the first study vaccination (1-7 days post 
study vaccination) and as the maximum severity over all 8 days. Additionally, solicited AEs will 
be analyzed by taking the most severe response over the follow-up period, dichotomizing into a 
binary variable (none versus mild, moderate, or severe) and using standard techniques, such as 
exact confidence intervals, to summarize the proportion of subjects reporting each symptom, any 
injection site symptom, and any systemic symptom. Summaries of solicited AEs will be 
presented for the first study vaccination by treatment arm. The proportion of subjects reporting 
symptoms may be compared between treatment arms using Chi-square or Fisher’s exact test.  
Unsolicited AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA) for 
preferred term and system organ class (SOC). The numbers of SAEs and AESIs (including 
Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs) are likely to be small in this trial 
and will be reported by detailed listings showing the event description, MedDRA preferred 
term and SOC, relevant dates (study vaccinations and AEs), severity, relatedness, and outcome 
for each event. Non-serious unsolicited AEs will be summarized as number and percentage of 
subjects reporting at least one event in each MedDRA preferred term and SOC, cross tabulated 
by severity and relationship to study product. Additionally, the proportion of subjects and exact 
95% confidence intervals of AEs in aggregate and by MedDRA categories will be computed. 
Clinical laboratory data will be summarized by severity for each visit and as the maximum over 
all post-study vaccination visits. Graphical presentations may include box plots. 
11.6.3 
Humoral Immunogenicity Data 
Summaries and analysis of immunogenicity data will be presented for the mITT and PP 
populations. 
 
Immune responses in terms of strain-specific HAI, NAI, and Neut antibody titers will be 
summarized by treatment arm at each time point. Analyses will include GMTs, ratio of GMTs 
between adjuvanted and unadjuvanted study arms, percentage of subjects achieving 
seroconversion (as defined in Table 1) and percentage of subjects with a titer ≥1:40 (HAI and 
Neut only) along with corresponding 95% confidence intervals. Descriptive summary statistics 
will be provided for all assays and time points. These immune responses against vaccine strains 
will also be presented by serostatus and previous influenza vaccination. The correlation between 


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HAI, NAI and Neut antibody titers will be evaluated. Plots such as reverse cumulative 
distributions or longitudinal presentations of GMTs will be presented. 
 
Further immunogenicity testing and/or analyses may be carried out in the future based upon 
subjects’ prior receipt of non-seasonal influenza vaccines, including type (inactivated or live 
attenuated), what subtype (e.g. A/H3, A/H5, A/H9) and approximate date of vaccination. 
11.6.4 
Exploratory Cellular Immunogenicity Data 
Summaries of exploratory cellular immunology assays will be presented for the Per Protocol 
Population and will be presented overall as well as by treatment arm. 
 
Analysis of the exploratory cellular immunogenicity data will be primarily descriptive.  
Association of exploratory endpoints with HAI, NAI, and Neut antibody titers will be assessed. 
11.6.5 
Exploratory Transcriptomics Data 
For the transcriptomics exploratory analysis, RNA-Seq data will be pre-processed by removing 
adapters and low-quality reads and mapping sequences to the latest human reference genome 
using splice-aware alignment software such as HISAT2[52]. Gene expression quantification will 
be carried out by using the Subread software [53] using the latest Ensembl  [54] gene model 
annotations as a reference. Systematic differences in sequence coverage between samples will be 
accounted for using the TMM normalization method [55] as implemented in the edgeR R 
package [56]. Principal component analysis, non-metric multidimensional scaling, and 
hierarchical clustering analysis will be used to identify potential outliers and systematic batch 
effects. Negative binomial models as implemented in edgeR [56] will be used to identify genes 
for each study group and post-vaccination day (Day 2 and 8) that were differentially expressed 
(DE) compared to pre-vaccination. If the analysis reveals a systematic batch effect that is not 
associated with study group or study visit, it will be accounted for by adding a batch blocking 
factor as part of the negative binomial models. To control for testing multiple genes, the false-
discovery rate (FDR) based on the Benjamini-Hochberg procedure [57] as implemented in the 
p.adjust R function will be applied. The pvclust R package [58] will be used to identify co-
expressed DE gene clusters. Mean cluster log2 fold change time trends and associated 95% 
bootstrap CIs will be presented by group across post-vaccination days. To functionally 
characterize DE genes, pathway enrichment analysis based on the latest MSigDB [59] and 
KEGG [60] databases as well as Blood Transcription Modules [61] will be carried out using the 
implementation provided by the goseq R package [62] which accounts for gene length bias. 
Pathway maps color-coded by treatment effect (log2 fold change compared to pre-vaccination) 


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will be visualized for significantly enriched KEGG pathways. Pathway enrichment trends by 
group across post-vaccination days will be visualized using heatmaps and time trend plots of 
median pathway responses (based on median average log2 fold changes of all pathway members) 
and associated 95% bootstrap CIs. Regularized linear regression analysis as implemented in the 
glmnet R package [63] will be utilized to identify gene expression changes that are predictive of 
later adaptive humoral immune response. Cross-validation will be used to select optimal models. 
11.6.6 
Missing Values and Outliers 
All attempts will be made to collect all data per protocol. As missing data are expected to be 
minimal, no imputation will be performed for missing values. Any data point that appears to be 
erroneous or inexplicable based on clinical judgment will be investigated as a possible outlier. If 
data points are identified as outliers, sensitivity analyses will be performed to examine the 
impact of including or excluding the outliers. Any substantive differences in these analyses will 
be reported. 


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12 
DATA COLLECTION FORMS AND ACCESS TO 
SOURCE DATA/DOCUMENTS 
Each participating VTEU site will maintain appropriate medical and research records for this 
clinical trial, in compliance with ICH E6 GCP Section 4.9 and regulatory and institutional 
requirements for the protection of confidentiality of subjects. Each participating VTEU site will 
permit the study monitor or other authorized representatives of DMID as well as governmental 
regulatory agencies, such as the FDA, to examine (and when required by applicable law, to copy) 
clinical trial records for the purposes of quality assurance reviews, audits, monitoring and 
evaluation of the study safety and progress. These representatives will be permitted access to all 
source data, which include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions certified after verification as being accurate 
and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files, and records kept at the pharmacy, at the laboratories and medico-technical 
departments involved in this clinical trial. Source data are all information, original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the clinical trial. 
 
Interview of subjects is sufficient for obtaining medical history. Solicitation of medical records 
from the subject’s primary care provider is not required. 
 


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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, each participating VTEU site 
(and its subcontractors) is responsible for conducting routine quality assurance (QA) and quality 
control (QC) activities to internally monitor study progress and protocol compliance. Each site PI 
will provide direct access to all study-related sites, source data/DCFs and reports for the purpose 
of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 
Each site PI will ensure all study personnel are appropriately trained and applicable 
documentation is current and maintained on site. 
 
The SDCC will implement QC procedures beginning with the data entry system and generate 
data QC checks that will be run on the database. Any missing data or data anomalies will be 
communicated to the participating VTEU site(s) for clarification and resolution. 
 


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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
Ethical Standard 
The site PIs will ensure that this trial is conducted in full conformity with principles of the 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research (National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research [April 18, 1979]) and codified in 45 CFR 46, 21 CFR 50 and 21 CFR 56, as 
applicable. The site PIs will also ensure conformity with ICH E6 GCP and applicable federal 
regulations, guidance and guidelines for GCP and Clinical Trials with humans. 
 
Institutional Review Board (IRB) 
Each institution engaged in this research will hold a current Federal Wide Assurance (FWA) 
issued by the Office for Human Research Protections (OHRP) for federally funded research. The 
IRB must be registered with OHRP [OHRP-only or OHRP/FDA] as applicable to the research. 
The IRB FWA number will be provided to DMID. 
 
Each site PI will obtain IRB approval for this protocol to be conducted at his/her research site(s), 
and send supporting documentation to DMID before initiating recruitment of subjects. The site 
PI will submit applicable information to the IRB on which it relies for the review, to conduct the 
review in accordance with 45 CFR 46, ICH E6 GCP guidelines, and as applicable, 21 CFR 56 
(Institutional Review Boards), 21 CFR 50 (Protection of Human Subjects), and other federal, 
state and local regulations and guidance. IRB approved recruitment process, screening script, and 
materials for subjects may be utilized.  DMID must receive the documentation that verifies IRB 
approval for this protocol, associated informed consent documents, and upon request, any 
recruitment material and handouts or surveys intended for the subjects, prior to the recruitment 
and enrollment of subjects. 
 
Any amendments to the protocol or consent materials will be approved by the IRB before they 
are implemented. IRB review and approval will occur at least annually throughout the enrollment 
and follow-up of subjects and may cease if annual review is no longer required by applicable 
regulations. The site PI will notify the IRB of protocol deviations and reportable SAEs in 
accordance with IRB requirements. 


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Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation. During recruitment, potential 
subjects may be screened for eligibility by phone or email before obtaining written consent, per 
an IRB-approved process that ensures confidentiality.  At the first clinic visit before any study 
procedures are performed, informed consent will be obtained and documented. Subjects will 
receive a concise and focused presentation of key information about the trial, verbally and with a 
written ICF. The explanation will be organized and presented in lay terminology and language 
that facilitates understanding why one might or might not want to participate. The ICF must not 
include any exculpatory statements. 
 
The site PIs or their designees will describe the protocol to potential subjects face-to-face. The 
key information about the purpose of the trial, the procedures and experimental aspects of the 
trial, risks and discomforts, any expected benefits to the subject, and alternative treatment will be 
presented first to the subject.  The subject will be asked to consent specifically to genetic testing 
(transcriptomics) planned for this study. 
 
Subjects will also receive an explanation that the trial involves research and a detailed summary 
of the proposed study procedures and study interventions/study products. This will include 
aspects of the trial that are experimental, the probability for random assignment to treatment 
arms, any expected benefits, all possible risks (including a statement that the particular treatment 
or procedure may involve risks to the subject or to the embryo or fetus, if the subject is or may 
become pregnant, that are currently unforeseeable), the expected duration of the subject’s 
participation in the trial, alternative treatment/procedures that may be available, and the 
important potential benefits and risks of these available alternative treatment/procedures. 
Subjects will be informed that they will be notified in a timely manner if information becomes 
available that may be relevant to their willingness to continue participation in the trial. Subjects 
will receive an explanation as to whether any compensation and any medical treatments are 
available if injury occurs, and, if so, what they consist of or where further information may be 
obtained. Subjects will be informed of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the subject 
for participating in the trial. They will be informed of whom to contact (e.g., the site PI) for 
answers to any questions relating to the research project. 
 
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated. The subjects will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the subject is otherwise entitled. 


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The extent of the confidentiality of the subjects’ records will be defined, and subjects will be 
informed that applicable data protection legislation will be followed. Subjects will be informed 
that the monitors, auditors, IRB, NIAID, and regulatory authorities will be granted direct access 
to the subject’s original medical records for verification of trial procedures and/or data without 
violating the confidentiality of the subject, to the extent permitted by the applicable laws and 
regulations, and that, by signing a written ICF, the subject is authorizing such access. 
Subjects will be informed that records identifying the subject will be kept confidential and, to the 
extent permitted by the applicable laws and/or regulations, will not be made publicly available 
and, if the results of the trial are published, the subject’s identity will remain confidential. 
Subjects will be informed whether private information collected from this research and/or 
samples/specimens will be used for additional research, even if identifiers are removed. 
Subjects will be allowed sufficient time to consider participation in the trial and have the 
opportunity to discuss the trial with their family, friends or legally authorized representative, or 
think about it prior to agreeing to participate. 
 
ICFs will be IRB-approved and subjects will be asked to read and review the ICF. Subjects must 
sign the ICF prior to starting any study procedures being done specifically for the trial. 
Once signed, a copy of the ICF will be given to the subjects for their records. The subject(s) may 
withdraw consent at any time throughout the course of the trial. The rights and welfare of the 
subjects will be protected by emphasizing to them that the quality of their medical care will not 
be adversely affected if they decline to participate in or withdraw from the trial. 
 
New information that significantly impacts the subject’s risk of receiving the study 
interventions/study products will be communicated by the site PIs or their designees to the 
subjects who consent to participate in the trial in accordance with IRB requirements. The ICF 
will be updated and subjects will be re-consented in accordance with IRB requirements, if 
necessary. Subjects will be given a copy of all ICFs that they sign. 
 
 
Exclusion of Women, Minorities and Children (Special Populations) 
This trial will be inclusive of all subjects, 18 to 45 years of age, who meet the Subject Inclusion 
Criteria (see Section 5.1.1) and do not meet the Subject Exclusion Criteria (see Section 5.1.2), 
regardless of religion, sex or ethnic background. Should the outcome of this trial be deemed 
acceptable, additional trials may be initiated including those in other populations. 
 
It is unknown if Fluzone QIV or Flublok QIV with AF03 or Advax-CpG55.2 adjuvant pose any 
risks to an unborn child. However, the unadjuvanted QIVs are recommended for pregnant 


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women and have not shown safety signals.  Women of childbearing potential must utilize a 
highly effective method of contraception that is defined as one that results in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly (effective methods of birth 
control are outlined in the inclusion criteria, section 5.1.1). In addition to contraceptive use, all 
women of childbearing potential will be required to have a negative urine or serum pregnancy 
test within 24 hours prior to the first study vaccination. Female subjects who become pregnant 
while participating in this trial will be provided information to enroll in the Sanofi Pregnancy 
Registry, if they so choose. This registry program is not a part of this research study and 
participation in the registry program is completely voluntary.   
 
Children will not be included in this trial as presently there are no safety or efficacy data in 
adults. 
 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the site PIs, other study personnel, the sponsor, 
and their agents. This confidentiality includes documentation, investigation data, subject’s 
clinical information, and all other information generated during participation in this trial. No 
information concerning this trial, or the data generated from this trial will be released to any 
unauthorized third party without written consent of the subject and approval by DMID. 
 
Subject confidentiality will be maintained when trial results are published or discussed in 
conferences and is extended to cover testing of samples/specimens. The study monitor or other 
authorized representatives of DMID as well as governmental regulatory agencies, such as the 
FDA, may inspect all documents and records required to be maintained by the site PIs. This 
includes, but is not limited to, medical records (office, clinic or hospital) and pharmacy records 
for the subjects in this trial. The participating VTEU sites will permit access to such records. 
All records will be kept locked and all computer entry and networking programs will be carried 
out with coded numbers only and with password-protected systems. All non-clinical 
samples/specimens, evaluation forms, reports, and other records that leave the site will be 
identified only by a coded number and will not be identified by the subject’s name. 
 
To protect privacy, we have received a Certificate of Confidentiality. With this Certificate, the 
researchers cannot be forced to release information that may identify the subject, even by a court 
subpoena, in any federal, state or local civil, criminal, administrative, legislative, or other 
proceedings. The researchers will use the Certificate to resist any demands for information that 
would identify the subject, except as explained below. 
 


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The Certificate cannot be used to resist a demand for information from personnel of the US 
Government that is used for auditing or evaluation of federally funded projects, like this trial, or 
for information that must be released in order to meet the requirements of the FDA. 
 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research. If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information. 
 
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including: child and elder abuse, sexual 
abuse or wanting to harm themselves or others. 
 
Study Discontinuation 
If this trial is prematurely terminated by the sponsor, any regulatory authority, the site PI, or 
appropriate sub-investigator for any reason, the site PI or appropriate sub-investigator will 
promptly inform the subjects and assure appropriate therapy or follow-up for the subjects, as 
necessary. The site PI or appropriate sub-investigator will provide a detailed written explanation 
of the termination to the IRB. If any subject’s private information will continue to be collected 
for this trial, the IRB must approve an ICF with the study procedures, any risks and discomforts 
as well as applicable elements, and the site PI or designee will re-consent the subjects as 
approved by the IRB. 
 
If this trial is discontinued, subjects, who have signed the ICF, and are randomized and 
vaccinated, will continue to be followed for safety for the duration of the prescribed safety 
follow-up period. No further study vaccinations will be administered. 
 
Costs, Subject Compensation and Research Related Injuries 
There is no cost to subjects for the research tests, study procedures/evaluations or study vaccines 
while taking part in this trial. 
 
Subjects may be compensated for their participation in this trial. Compensation will be in 
accordance with local IRB requirements, and subject to local IRB approval. 
 


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If it is determined by the participating VTEU site and the site PI that an injury occurred to a 
subject as a direct result of the tests or treatments that are done for this trial, then referrals to 
appropriate health care facilities will be provided to the subject. Study personnel will try to 
reduce, control and treat any complications from this trial. Immediate medical treatment may be 
provided by the participating VTEU site, such as giving emergency medications to stop 
immediate allergic reactions to the study vaccine. No financial compensation will be provided to 
the subject by NIAID, NIH or the participating VTEU site for any injury suffered due to 
participation in this trial. 
 
Future Use of Stored Specimens 
Subjects who agree to participate in this trial will have venous blood collected for ESR and 
clinical safety laboratory evaluations, serological and cellular immunology assays, as well as for 
transcriptomic profiling assessments, a form of genetic testing. Subjects will be asked to give 
explicit consent to participate in the per protocol defined transcriptomics study.  
 
Subjects will be asked to consent to the future research use of excess/residual specimens and the 
sharing of genetic information and samples. If they choose to not provide permission for excess 
blood and future use, they will not be eligible for randomization and enrollment into the study.  
To maintain statistical power in follow-on analyses it is important that excess/residual blood 
collection be included in as many subjects as possible, due to the limited sample size per 
treatment arm.  
 
The amount of venous blood collected for serological and cellular immunology assays exceeds 
the amount of blood required to perform per protocol (PP) defined immunologic assays by 
approximately 175 mL collected across the study. This excess/residual blood and corresponding 
serum, plasma and PBMCs will be used as back-up specimens for PP defined assays or 
designated for future research use and stored indefinitely at a central storage facility. Collection 
of excess/residual samples during the course of the study will help facilitate rapid follow-on 
analyses, if warranted, to provide more comprehensive scientific insights into the impact (safety 
and immunological) of two novel adjuvants on the host response to vaccination.  
 
To maintain statistical power in follow-on analyses it is important that excess/residual blood 
collection be included in as many subjects as possible, due to the limited sample size per 
treatment arm. Samples designated for future research use may be used for additional 
immunological assessments that may include but are not limited to antibody epitope mapping, B 
and T cell repertoire determination, non-traditional immune assay development, determination of 
innate immune factors and the ability of vaccine-induced antibodies to cross-react to different 


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influenza proteins and virus strains. These blood samples might be used in new or different 
immunological laboratory tests, to provide information for the development of new vaccines, or 
for the studies of influenza or other infections. Future use DNA testing may also be warranted to 
understand genetic factors involved in vaccination failures, despite the presence of a specific 
adjuvant.  
 
Future research use specimens, upon written request and approval from DMID, may be shared    
with investigators at the participating VTEU sites, with other investigators or company 
designated research laboratories for purposes of conducting additional immunological 
assessments other than PP analysis. DMID would authorize shipment from the DMID CAR. 
There are no benefits to subjects in the collection, storage and future research use of their 
samples/specimens. Risks for excess blood drawn may include anemia, however the risk is low 
since the total amount drawn for this study and future use does not exceed a unit of blood.  
 
Future research use samples/specimens will not be sold or used directly for production of any 
commercial product.   Each sample/specimen will be encoded (labeled) only with a barcode and 
a unique tracking number to protect subject confidentiality. Reports from future research studies 
performed using subjects’ samples/specimens will NOT be kept in their health records. 
  
  
Subjects may withdraw permission to use samples for future use at any time.  They will need to 
contact the study site and the samples will be removed from the study repository after this study 
is completed and documentation will be completed that outlines the reason for withdrawal of 
permission for future use of samples. Subjects who withdraw consent before the last visit will not 
have the excess blood drawn for future use. 
 


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15 
DATA HANDLING AND RECORD KEEPING 
The site PIs are responsible to ensure the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
DCFs will be derived from the eCRF and provided by the SDCC to record and maintain data for 
each subject enrolled in this trial. All DCFs should be completed in a neat, legible manner to 
ensure accurate interpretation of data. Black or blue ink is required to ensure clarity of 
reproduced copies. When making a change or correction, cross out the original entry with a 
single line and initial and date the change. Do not erase, overwrite or use correction fluid or tape 
on the original. 
 
Data reported in the eCRF derived from the DCFs should be consistent with the DCFs or the 
discrepancies should be explained. 
 
The sponsor and/or its designee will provide guidance to the site PIs and other study personnel 
on making corrections to the DCFs and eCRF. 
 
Data Management Responsibilities 
All DCFs and laboratory reports must be reviewed by the clinical team and data entry personnel, 
who will ensure that they are accurate and complete. AEs must be recorded on the appropriate 
DCF, assessed for severity and relationship, and reviewed by the site PI or appropriate sub-
investigator. 
 
Data collection is the responsibility of the study personnel at each participating VTEU site under 
the supervision of the respective site PI. During this trial, the site PIs must maintain complete 
and accurate documentation for this trial. 
 
The SDCC for this trial will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
 
Data Capture Methods 
Clinical (including, but not limited to, AE/SAEs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values), reactogenicity and immunogenicity data 
will be entered into a 21 CFR 11-compliant Internet Data Entry System provided by the SDCC. 
The data system includes password protection and internal quality checks, such as automatic 


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range checks, to identify data that appear inconsistent, incomplete or inaccurate. Clinical and 
reactogenicity data will be entered directly from the DCFs completed by the study personnel. 
 
Types of Data 
Data for this trial will include clinical, safety and outcome measures (e.g., clinical laboratory 
values, and reactogenicity and immunogenicity data). 
 
Timing/Reports 
Clinical, safety and reactogenicity data through approximately 56 days after the first study 
vaccination will represent the interim clinical database for this trial. Once the last subject 
completes the visit that occurs approximately 56 days after the first study vaccination, the 
primary clinical database will be cleaned, monitored and locked. Upon receipt of 
immunogenicity data for Day 1 and Day 29 (HAI, NAI, and Neut data) and safety data through 
Day 57, the sponsor will authorize the DCC to transfer to Sanofi Pasteur a copy of this unblinded 
data set.  
 
An expedited report containing immunogenicity analyses for HAI, NAI, and Neut antibody 
assays unblinded by treatment group only will be created by the SDCC after the interim clinical 
database is cleaned, monitored and locked and all HAI, NAI, and Neut data for Day 1 and Day 
29 after the first study vaccination have been received. Other immunological analyses that are 
available may also be included in the expedited report. These analyses may be made available to 
the sponsor and pharmaceutical partners for planning subsequent trials and the DSMB for 
review. 
 
 The analyses performed for the expedited report or the data set provided to Sanofi Pasteur will 
not be used to make any decisions concerning the conduct of this trial. As it is anticipated that 
subjects will remain in long term safety follow-up at the time of these analyses, blinded 
investigators and DMID medical monitors not involved in the analysis, publication, or clinical 
study report preparation will be responsible for assessing SAEs, AESIs (including Protocol 
Specified AESIs, MAAEs, NOCMCs and PIMMCs) until all subjects have completed the final 
follow-up visit. All analyses of data included in the expedited report for early release will be 
included in the final clinical study report (CSR). 
 
The final CSR will be completed after the last subject’s last visit is completed, the final clinical 
database including all long-term safety follow-up data is cleaned, monitored and locked, and all 
primary and secondary immunogenicity data are available. After such data are reported in the 


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database and the data are considered clean and complete, a “topline” subset of the 
immunogenicity tables planned for the CSR will be provided to DMID and Sanofi Pasteur.  
Additional exploratory immunogenicity endpoint data not available at the time of CSR 
preparation may be included in an addendum to the CSR, manuscript(s), or other report. 
 
A formal statistical analysis plan will be developed, finalized, and submitted to the FDA, prior to 
unblinding for any analysis, which defines the analyses to be included in the expedited report and 
the final CSR. 
 
Additional statistical reports may be generated as deemed necessary and appropriate by DMID. 
Safety and immunogenicity summary reports may be generated for the DSMB. 
 
After the final CSR is complete, and upon request and DMID approval, the SDCC will provide 
the participating VTEU sites with a summary of results by treatment arm and/or subject 
treatment assignment. In this regard, the participating VTEU sites requesting such information to 
share with subjects must do so in accordance with IRB requirements. 
 
Study Records Retention 
Study records and reports, including, but not limited to, eCRFs, source documents, ICFs, and 
study drug disposition records shall be maintained for 2 years after a marketing application is 
approved for the drug for the indication for which it is being investigated; or, if no application is 
to be filed or if the application is not approved for the drug, until 2 years after the investigation is 
discontinued and the FDA has been notified. These documents will be retained for a longer 
period, however, if required by local regulations. ICFs for future research use will be maintained 
as long as the sample/specimen exists. 
 
No records will be destroyed without the written consent of the sponsor. It is the responsibility of 
the sponsor to inform the site PI when these documents no longer need to be retained. The 
participating VTEU sites must contact DMID for authorization prior to the destruction of any 
study records. 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the study protocol, GCP or protocol-specific 
MOP requirements. The noncompliance may be either on the part of the subject, the site PI or 
other study personnel. As a result of protocol deviations, corrective actions are to be developed 
by the site and implemented promptly. 


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These practices are consistent with ICH E6 GCP guidelines: 
4.5 
Compliance with Protocol, Sections 4.5.1, 4.5.2 and 4.5.3 
5.1 
Quality Assurance and Quality Control, Section 5.1.1 
5.20 
Noncompliance, Sections 5.20.1 and 5.20.2 
It is the responsibility of the site PI and other study personnel to use continuous vigilance to 
identify and report protocol deviations within five working days of identification of the protocol 
deviation, or within five working days of the scheduled protocol-required activity. Protocol 
deviations must be promptly reported to DMID, via the SDCC’s Advantage eClinicalSM. 
 
Protocol deviations, as defined above, must be addressed on the appropriate DCF. A completed 
copy of the Protocol Deviation DCF must be maintained in the regulatory file as well as in the 
subject’s chart. Protocol deviations must be sent to the IRB in accordance with IRB 
requirements. The site PI and other study personnel are responsible for knowing and adhering to 
IRB requirements. 
 


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16 
PUBLICATION POLICY 
All investigators funded by the NIH must submit or have submitted for them to the National 
Library of Medicine’s PubMed Central (http://www.ncbi.nlm.nih.gov/pmc/) an electronic 
version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made 
publicly available no later than 12 months after the official date of publication. The NIH Public 
Access Policy ensures the public has access to the published results of NIH funded research. It 
requires all investigators to submit final peer-reviewed journal manuscripts that arise from NIH 
funds to the digital archive PubMed Central upon acceptance for publication. Further, the policy 
stipulates that these papers must be accessible to the public on PubMed Central no later than 12 
months after publication. 
Refer to: 
• 
NIH Public Access Policy, http://publicaccess.nih.gov/ 
• 
NIH Office of Extramural Research (OER) Grants and Funding, 
http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on 
ClinicalTrials.gov, no later than 21 days after the enrollment of the first subject. Results of all 
clinical trials supported by the NIH, generally, need to be submitted no later than 12 months 
following the primary completion date. A delay of up to 2 years is available for trials that meet 
certain criteria and have applied for certification of delayed posting. 
As part of the result posting a copy of this protocol (and its amendments) and a copy of the 
Statistical Analysis Plan will be posted on ClincialTrials.gov. 
 
For this clinical trial, the responsible party is DMID which will register this trial and post results. 
The responsible party does not plan to request certification of delayed posting. 
 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
• 
42CFR11 
• 
NIH NOT-OD-16-149 


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17 
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18 
APPENDICES 
Appendix A: Schedule of Study Procedures and Evaluations 
Appendix B: Adverse Events of Special Interest 
 
 
 


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 SCHEDULE OF STUDY PROCEDURES AND 
EVALUATIONS 
Table 13: Schedule of Study Procedures and Evaluations 
Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
Early Termination  
Unscheduled 
Screening, 
Enrollment/Study 
Day and post first 
study vaccination 
Screening 
D-28 to -1 
Enrollment 
D1 
D2+1d 
D8+/-1d 
D29+/-2d 
D57+/-3d 
D90+/-14d 
Day118+/-3d 
D180 +/-14d 
D365 -14/+35 
Informed Consent∞ 
X∞ 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
Information 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X†¬
1 
 
 
 
 
 
 
 
 
 
 
Medical History@ 
X 
X†¬ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X†¬ 
X 
X 
X 
 
 
 
 
 
X6  
X6 
Vital Signs (Oral 
Temperature%, Pulse 
and BP) 
X 
X$ 
 
 
 
 
 
 
 
 
X  
X 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X2 
{X} 
{X} 
{X} 
{X} 
{X} 
{X}
†  
{X} 
{X} 
{X} 
{X} 
{X} 
Urine or Serum 
Pregnancy Test 
X^ 
X†^ 
 
 
 
 
 
 
 
 
 
 
Venous Blood 
Collection for 
Screening Laboratories 
X≠ 
 
 
 
 
 
 
 
 
 
 
 
Enrollment in 
Advantage eClinicalSM 
and Randomization 
 
X† 
 
 
 
 
 
 
 
 
 
 
Venous Blood 
Collection for Clinical 
Safety Laboratory 
Evaluations~ 
 
X†,~ 
 
X~ 
 
 
 
 
 
 
X7 
X  
Venous Blood 
Collection for 
Serological Assays 
 
X† 
 
X 
X 
X 
X† 
X 
X 
X 
X 
X 
Venous Blood 
Collection for Cellular 
Immunology Assays 
 
X† 
 
X 
X 
 
X† 
 
 
 
X8 
 
Venous Blood 
Collection for 
Transcriptomics 
 
X† 
X 
X 
 
 
 
 
 
 
X9 
 
Pre-Administration 
Reactogenicity 
Assessments 
 
X† 
 
 
 
 
 
 
 
 
 
 


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Study Visit Number 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
Early Termination  
Unscheduled 
Screening, 
Enrollment/Study 
Day and post first 
study vaccination 
Screening 
D-28 to -1 
Enrollment 
D1 
D2+1d 
D8+/-1d 
D29+/-2d 
D57+/-3d 
D90+/-14d 
Day118+/-3d 
D180 +/-14d 
D365 -14/+35 
Study Vaccination 
 
X 
 
 
 
 
X* 
 
 
 
 
 
20-minute Evaluation 
After Study 
Vaccination 
 
X 
 
 
 
 
 
 
 
 
 
 
Examine Study 
Vaccination Site 
 
X 
X 
X 
 
 
  
 
 
 
X7 
X7 
Post-Administration 
Reactogenicity 
Assessments 
 
X 
 
 
 
 
 
 
 
 
X7 
X7 
Distribute Memory Aid 
and Study-Related 
Materials 
 
X 
 
 
 
 
 
 
 
 
 
 
Review Memory Aid 
 
 
X 
X 
 
 
 
 
 
 
X7  
X7 
AE/SAE Assessment 
 
X&,3 
X&,3 
X&,3 
X3 
X 
X4 
X4 
X4 
X4 
X3,6  
X3,6 
 
∞ Prior to study procedures. 
¬ Review/confirm information or activity in subjects previously consented and screened. 
† Prior to study vaccination. 
1 Review results of ESR and clinical safety laboratory evaluations. 
@ Complete medical history (including solicitation for receipt of any non-study influenza vaccine) will be obtained 
by interview of subjects at the screening visit  and interim medical history will be obtained by interview of 
subjects on Day 1 prior to study vaccination and at follow-up visits after study vaccination. 
$ Vital signs assessed on Day 1 prior to the study vaccination will be considered as baseline. 
% Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
2 At the screening visit a physical examination will be performed on all subjects to include the following organs and 
organ systems: skin, head and neck, lungs, heart, liver, spleen, extremities, lymph nodes, and nervous system.  
{} Targeted physical examination if indicated based on review of interim medical history. 
^ Performed locally by the site at the screening visit (optional); Must be performed within 24 hours prior to study 
vaccination for all women of childbearing potential. Results must be negative and known prior to randomization 
on Day 1 and administration of study vaccination. 
≠ ESR Performed by local laboratory, WBC, Hgb, PLT, ALT, T. Bili, AST, GGT, ALP, serum lipase, serum 
amylase and Cr will be sent to the central clinical laboratory.  
~ Includes, WBC, Hgb, PLT, ALT, T. Bili, AST, GGT, ALP, serum lipase, serum amylase and Cr. 
& Inclusive of reactogenicity assessments performed on the day of study vaccination through 7 days after study 
vaccination. 
3  AEs (if visit occurs on or before Day 29), SAEs, AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs 
and PIMMCs), for subjects who are being followed for safety. 
4 SAEs and AESIs (including Protocol Specified AESIs, MAAEs, NOCMCs and PIMMCs), for subjects who are 
being followed for safety. 


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5 Investigators have the discretion of administering 2019/2020 Fluzone or Flublok earlier than the Day 90 window 
(i.e earlier than Day 76) if 10% of more of surveillance samples in the CDC geographic region surrounding the 
local site test positive for influenza. 
6If within 365 after first study vaccination 
7 If within the first 7 days after the first study vaccination 
8 If prior to or at the D90 visit 
9 If prior to or at the D8 visit 
* Seasonal QIV 2019/2020 
 


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 ADVERSE EVENTS OF SPECIAL INTEREST 
 
MAAEs 
NOCMCs 
PIMMCs: 
Gastrointestinal disorders 
• 
Celiac disease 
• 
Crohn’s disease 
• 
Ulcerative colitis 
• 
Ulcerative proctitis 
Liver disorders 
• 
Autoimmune cholangitis 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing cholangitis 
Metabolic diseases 
• 
Addison’s disease 
• 
Autoimmune thyroiditis (including Hashimoto thyroiditis) 
• 
Diabetes mellitus type I 
• 
Grave’s or Basedow’s disease 
Musculoskeletal disorders 
• 
Antisynthetase syndrome 
• 
Dermatomyositis 
• 
Juvenile chronic arthritis (including Still’s disease) 
• 
Mixed connective tissue disorder 
• 
Polymyalgia rheumatic 
• 
Polymyositis 
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Rheumatoid arthritis 
• 
Scleroderma, including diffuse systemic form and CREST syndrome 


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• 
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter’s 
Syndrome) and undifferentiated spondyloarthritis 
• 
Systemic lupus erythematosus 
• 
Systemic sclerosis 
Neuroinflammatory disorders 
• 
Acute disseminated encephalomyelitis, including site-specific variants (e.g., non-
infectious encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitis) 
• 
Cranial nerve disorders, including paralyses/paresis (e.g., Bell’s palsy) 
• 
Guillain-Barré syndrome, including Miller Fisher syndrome and other variants 
• 
Immune-mediated peripheral neuropathies and plexopathies, including chronic 
inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and 
polyneuropathies associated with monoclonal gammopathy 
• 
Multiple sclerosis 
• 
Narcolepsy 
• 
Optic neuritis 
• 
Transverse myelitis 
• 
Myasthenia gravis, including Eaton-Lambert syndrome 
Skin disorders 
• 
Alopecia areata 
• 
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and dermatitis 
herpetiformis 
• 
Cutaneous lupus erythematosus 
• 
Erythema nodosum 
• 
Morphoea 
• 
Lichen planus 
• 
Psoriasis 
• 
Sweet’s syndrome 
• 
Vitiligo 
Vasculitides 
• 
Large vessels vasculitis including: giant cell arteritis such as Takayasu’s arteritis and 
temporal arteritis 
• 
Medium sized and/or small vessels vasculitis including: polyarteritis nodosa, 
Kawasaki’s disease, microscopic polyangiitis, Wegener’s granulomatosis, Churg-
Strauss syndrome (allergic granulomatous angiitis), Buerger’s disease 
thromboangiitis obliterans, necrotizing vasculitis and anti-neutrophil cytoplasmic 


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antibody (ANCA) positive vasculitis (type unspecified), Henoch- Schonlein purpura, 
Behcet’s syndrome, leukocytoclastic vasculitis 
Others 
• 
Antiphospholipid syndrome 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis 
rapidly progressive, membranous glomerulonephritis, membranoproliferative 
glomerulonephritis, and mesangioproliferative glomerulonephritis) 
• 
Autoimmune myocarditis/cardiomyopathy 
• 
Autoimmune parotitis 
• 
Autoimmune thrombocytopenia 
• 
Good pasture syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Pernicious anemia 
• 
Raynaud’s phenomenon 
• 
Sarcoidosis 
• 
Sjögren’s syndrome 
• 
Stevens-Johnson syndrome 
• 
Uveitis 
 
Protocol Specified AESIs 
• Dry Eyes 
• Tearing  
• Dry Mouth