Human Immune Responses to an Adjuvanted H5 Vaccine: Durability and Impact of the Seasonal Influenza Vaccine on H5 Induced B Cell Response
Phase: PHASE4
Conditions: Influenza A Subtype H5N1 Infection
Sponsor: Emory University

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Human Immune Responses to an Adjuvanted H5 Vaccine:  
Durability and Impact of the Seasonal Influenza Vaccine on H5 Induced B Cell Responses 
 
 
Protocol Number: HIPCVAX-010 supplement 
 
 
Sponsored by: 
 
National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of 
Health (NIH) 
 
Principal Investigator: 
 
Nadine Rouphael, MD 
 
 
Draft or Version Number:  
 
1.0 
 
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Statement of Compliance 
 
The trial will be carried out in accordance with Good Clinical Practices (GCP) as 
required by the following: 
 
 United States Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, and 21 CFR 
Part 312); 
 International Conference on Harmonization (ICH) E6; 62 Federal Register 25691 
(1997); 
 
Compliance with these standards provides public assurance that the rights, safety and 
wellbeing of study subjects are protected, consistent with the principles that have their 
origin in the Declaration of Helsinki. 
 
All key personnel (all individuals responsible for the design and conduct of this trial) 
have completed Human Subjects Protection Training. 
 

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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances 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 guidelines. 
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
 
Nadine Rouphael, MD 
Hope Clinic of the Emory Vaccine Center 
Associate Professor of Medicine 
Division of Infectious Diseases 
Emory University School of Medicine 
 
 

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Table of Contents 
 
 
Statement of Compliance ............................................................................................................... i 
Signature Page ............................................................................................................................. ii 
Table of Contents ...................................................................................................................... iii-iv 
Protocol Summary .................................................................................................................... v-vi 
 
Key Roles ...................................................................................................................................... 1 
1 
Background Information and Scientific Rationale ................................................................ 2 
1.1 
Background Information ........................................................................................... 2 
1.2 
Rationale .................................................................................................................. 2 
1.3 
Potential Risks and Benefits ..................................................................................... 3 
1.3.1 
Potential Risks .............................................................................................. 3 
1.3.2 
Known Potential Benefits .............................................................................. 4 
2 
Objectives ............................................................................................................................ 5 
 
2.1      Study Objectives ....................................................................................................... 5 
         2.2      Study Outcome Measures………………………………………………………………...5 
3 
Study Design ........................................................................................................................ 6 
4 
Study Population .................................................................................................................. 7 
4.1 
Selection of the Study Population ............................................................................ 7  
4.2 
Inclusion/Exclusion Criteria ...................................................................................... 7 
5 
Study Procedures/Evaluations ........................................................................................... 10 
5.1 
Study Procedures ................................................................................................... 10 
5.1.1 
Laboratory Evaluations/Assays .................................................................. 10 
5.1.2 
Special Assays or Procedures .................................................................... 10 
5.1.3 
Specimen Collection, Preparation, Handling and Analyses ....................... 11 
6 
Study Schedule .................................................................................................................. 12 
6.1 
Screening/Enrollment/Baseline, Visit 01 Day 01 .................................................... 12 
6.2 
Follow-up and Final Visits ...................................................................................... 13 
6.2.1 
Visit 02 Day 08, Visit 03 Day 15 and Visit 04 Day 29 ................................. 13 
 
         6.2.2    Visit 05 Day 100, Visit 06 Day 180, Visit 07 Day 365....……………………13 
6.3 
Early Termination Visit (if needed) ......................................................................... 13 
7 
Statistical Considerations ................................................................................................... 14 
8 
Quality Control and Quality Assurance .............................................................................. 15 
9 
Ethics/Protection of Human Subjects ................................................................................. 16 
9.1 
Ethical Standard ..................................................................................................... 16 
9.2 
Institutional Review Board ...................................................................................... 16 
9.3 
Informed Consent Process ..................................................................................... 16 
9.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 17 
9.5 
Subject Confidentiality ............................................................................................ 17 
9.6 
Future Use of Stored Specimens ........................................................................... 17 
10 
Literature References ......................................................................................................... 19 

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SUPPLEMENTS/APPENDICES 
 
A: Study Schedule 
 
B: Adverse Events Grading 
 
 

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Protocol Summary 
 
Title:  
Human Immune Responses to an Adjuvanted H5 Vaccine: 
Durability and Impact of the Seasonal Influenza Vaccine on H5 
Induced B Cell Responses 
 
 
Population: 
 
Up to 50 subjects who previously participated in HIPCVAX-010 
Systems Biology of Influenza A (H5N1) Virus Monovalent Vaccine 
with and without AS03 Adjuvant, and who are in good health and 
meet the eligibility criteria 
 
Clinical Site: 
 
The Hope Clinic of the Emory Vaccine Center, Emory University 
 
Study Duration: 
 
Approximately 18 months 
 
Subject Duration: 
 
Approximately 12 months 
 
Description of Agent: 
One dose delivered intramuscularly of the FDA-approved 2018-
2019 seasonal influenza vaccine 
 
Objective:  
 
 
 
 
To assess the durability and impact of the seasonal influenza vaccine on H5 induced B 
cell responses 
 
Study Outcome Measures: 
Primary: 
 
Number of participants with a four-fold increase in stem-specific antibody titers against 
H5N1 at day 29 after vaccination with the seasonal influenza vaccine. 
Secondary:  
 
Number of solicited and unsolicited adverse events grade 2 and above at days 8 and 29, 
respectively, after vaccination with the seasonal influenza vaccine. 
 
Number of serious adverse events after vaccination with the seasonal influenza vaccine 
for the duration of the study.  

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Tertiary: 
 
Rate of seroprotection to H5N1 at days 100, 180, and 365 after vaccination with the 
seasonal influenza vaccine. 
 
Change in memory B cell responses at days 100, 180, and 365 after vaccination with the 
seasonal influenza vaccine. 
 
Rate of seroconversion to the 4 seasonal vaccine strains at days 29, 100, 180, and 365 
after vaccination with the seasonal influenza vaccine. 
 
Baseline H5-specific B cell responses induced by the AS03 adjuvanted vs. un-
adjuvanted H5N1 vaccination up to 4-5 years post-vaccination. 
 
 

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KEY ROLES 
Principal Investigator:  Nadine Rouphael, MD 
 
Co-investigators:  
Alexis Ahonen, APRN  
Matthew Collins, MD 
Alexandra Dretler, MD 
Srilatha Edupuganti, MD 
Colleen Kelley, MD 
Varun Phadke, MD 
Vanessa Raabe, MD 
Amy Sherman, MD 
 
Institution: 
 
The Hope Clinic of Emory University 
500 Irvin Court, Suite 200 
 
Decatur, Georgia 30030 
 
Phone Number: 404.712.1370 
Fax Number: 404.499.9727 
Email: nroupha@emory.edu 
 
 
 
 

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1 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
1.1 Background Information 
 
Antibody responses to seasonal influenza vaccines wane over time and are also narrow 
in terms of the number of epitopes targeted. In addition, the responding B cells do not 
significantly gain additional somatic hypermutations over the course of the response. 
The current seasonal influenza vaccines used in the US in healthy young adults are un-
adjuvanted and the B cell response to such vaccines are dominated by those originating 
from the pre-existing memory B cells. In 2015, we completed a study where we analyzed 
human B cell responses to a pandemic H5N1 vaccine either alone or when combined 
with the GlaxoSmithKline (GSK) adjuvant AS03 (HIPCVAX010, NCT 01910519). Fifty 
subjects received, in 2:1 randomization, two 3.75 μg doses (21 days apart) of the H5N1 
vaccine (derived from A/Indonesia/5/05) formulated with or without the AS03 adjuvant 
with sample collection out to 100 days post-vaccination. Analysis of these samples 
showed that the AS03 adjuvant substantially enhanced both the primary and secondary 
plasmablast response, inducing both H5 HA stem, and head-specific antibodies. The H5 
HA stem antibodies showed a high level of somatic hypermutation (SHM) compared to 
the head-specific antibodies which showed very little SHM. These data indicate that the 
AS03 adjuvant enhanced both naïve and memory B cell responses, with the first wave 
inducing H5 HA stem reactive antibodies coming from pre-existing memory B cell pool, 
and the second wave head-specific antibodies from naïve B cell pool. Interestingly, the 
H5 HA stem antibodies induced by the adjuvanted vaccine were broadly cross-reactive 
to not only group 1 but also group 2 influenza strains. In contrast, the head-specific 
antibodies were highly specific to the immunizing H5 strain. This cohort is now 4-5 years 
post-AS03 adjuvanted H5N1 vaccination. For the proposed study we plan to bring these 
volunteers back into the clinic to collect samples from 4-5 years post-H5N1 vaccination 
(depending on when initially vaccinated). Using this valuable cohort, we aim to address 
important questions that are highly relevant to the development of a universal influenza 
vaccine.  
 
1.2 Rationale 
The longevity of the human immune response, particularly the durability of the primary 
(H5 head) versus the secondary (H5 stem) antibody responses to the adjuvanted AS03 
H5N1 vaccine 4 to 5 years post-vaccination, and the characteristics of the H5 vaccine-

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induced HA head and stem specific antibody responses upon receipt of the seasonal 
influenza vaccine are unknown. Here we attempt to assess the durability of antibody 
responses to the H5N1 vaccine and impact of an FDA-approved seasonal influenza 
vaccine, recommended for individuals greater than 6 months of age, on H5-induced B 
cell responses in subjects who were previously administered the pandemic H5N1 
vaccine either alone or combined with the GSK adjuvant AS03. 
1.3 Potential Risks and Benefits 
The study utilizes an FDA-approved 2018-2019 seasonal influenza vaccine, Fluarix 
Quadrivalent. See package insert for full risks and benefits of the vaccine.1   
1.3.1 Potential Risks 
The potential risks to subjects are those associated with intramuscular administration of 
the seasonal influenza vaccine, possible reactions to the vaccine, and having blood 
drawn.   
 
The potential risks of receiving the seasonal influenza vaccine, Fluarix Quadrivalent, 
include but are not limited to local pain (36%), muscle aches (16%), headache (16%), 
fatigue (16%), arthralgia (8%), gastrointestinal symptoms (7%), shivering (4%), local 
swelling (2%), local redness (2%), and fever (2%).1   
 
Serious adverse events occurring within 21 days of vaccination were reported in 0.5% of 
subjects who received Fluarix Quadrivalent.1 Across 4 clinical trials in adults (N=10,923), 
there was one case of anaphylaxis within one day following administration of Fluarix.1 
 
Associated with the 1976 flu vaccine, a few patients experienced temporary paralysis, a 
condition known as Guillain-Barré Syndrome. However, this syndrome has not been 
seen with the more modern influenza vaccine preparations. Most persons who develop 
Guillain-Barré Syndrome recover completely, although the recovery period may be as 
little as a few weeks or as long as a few years. About 30% of those with Guillain-Barré 
Syndrome 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 Guillain-Barré Syndrome after administration of inactivated influenza 
vaccines since 1976 has shown a slight increase in risk over background cases (more 
than one additional case of Guillain-Barré Syndrome per million persons) following 
vaccination, typically with onset within 6 weeks after vaccination.2 Interestingly, although 
vaccination rates have increased in the last 10 years, the numbers of reported cases of 
vaccine-associated Guillain-Barré Syndrome have declined.3 Randomized, controlled 
clinical trials of the inactivated seasonal influenza vaccine in patients with asthma 

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indicate that there is no significant increase in asthma exacerbations immediately after 
vaccination.  
Blood sample collection involves transient discomfort and may cause fainting, which is 
managed by having the subject lie down prior, if needed. The blood draw site may 
bruise, and this can be ameliorated by holding pressure to this site following the blood 
draw. The sites of blood draw are potential sites of infection, but this risk is made very 
unlikely by the use of sterile technique.  
 
There may be other unknown side effects. 
1.3.2 Known Potential Benefits 
Administration of the seasonal influenza vaccine can offer protection to subjects against 
influenza A subtype viruses and type B viruses contained in the vaccine.1 CDC 
recommends annual influenza vaccination for all individuals greater than 6 months of 
age. The benefit for the study is predominately scientific, allowing for a better 
understanding of the longevity of the immune response to the AS03 adjuvanted H5N1 
vaccine, as well as the immune response to the seasonal influenza vaccine following 
receipt of the AS03 adjuvanted H5N1 vaccine. Findings from this study may assist 
researchers in developing a universal influenza vaccine. 
 

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2 
OBJECTIVES   
2.1 Study Objectives 
 
 
To assess the durability and impact of the seasonal influenza vaccine on H5 induced B 
cell responses 
 
2.2 Study Outcome Measures 
Primary: 
 
Number of participants with a four-fold increase in stem-specific antibody titers against 
H5N1 at day 29 after vaccination with the seasonal influenza vaccine. 
Secondary: 
 
Number of solicited and unsolicited adverse events grade 2 and above at days 8 and 29, 
respectively, after vaccination with the seasonal influenza vaccine. 
 
Number of serious adverse events after vaccination with the seasonal influenza vaccine 
for the duration of the study.  
Tertiary: 
 
Rate of seroprotection to H5N1 at days 100, 180, and 365 after vaccination with the 
seasonal influenza vaccine. 
 
Change in memory B cell responses at days 100, 180, and 365 after vaccination with the 
seasonal influenza vaccine. 
 
Rate of seroconversion to the 4 seasonal vaccine strains at days 29, 100, 180, and 365 
after vaccination with the seasonal influenza vaccine. 
 
Baseline H5-specific B cell responses induced by the AS03 adjuvanted vs. un-
adjuvanted H5N1 vaccination up to 4-5 years post-vaccination. 
 
 

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3 
STUDY DESIGN 
This will be an exploratory study with up to 50 subjects total, who previously participated in the 
HIPCVAX-010 Systems Biology of Influenza A (H5N1) Virus Monovalent Vaccine with and 
without AS03 Adjuvant study, are in good health, and meet all eligibility criteria. Each subject 
will make a total of seven visits to the Hope Clinic.  

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4 
STUDY POPULATION 
 
4.1 Selection of the Study Population  
The target sample size will be up to 50 subjects who will receive the 2018-2019 Fluarix 
Quadrivalent seasonal influenza vaccine. Subjects will be screened for eligibility 
according to the inclusion/exclusion criteria by history. Informed consent will be obtained 
for study participation. 
4.2 Inclusion/Exclusion Criteria 
 
Subjects eligible to participate shall meet all of the following inclusion criteria: 
 
1. Participated in HIPCVAX-010 Systems Biology of Influenza A (H5N1) Virus 
Monovalent Vaccine with and without AS03 Adjuvant study 
 
2. Capable of informed consent and provision of written informed consent before 
any study procedures. 
 
3. Capable of attending all study visits according to the study schedule. 
 
 
4. Are in good health, as determined by medical history and targeted physical exam 
related to this history. 
 
5. Female subjects of childbearing* age must have a negative urine pregnancy test 
before study vaccination, and must use at least one form of contraception** to 
avoid pregnancy for 28 days before and 28 days after Fluarix Quadrivalent 
administration. 
 
* Not sterilized via tubal ligation, bilateral oophorectomy, 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 of the last menses if menopausal. 
**Includes, but is not limited to, non-male sexual relationships, abstinence from sexual intercourse with a 
male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 
days or more prior to the subject receiving the first study vaccination, barrier methods such as condoms or 
diaphragms, effective intrauterine devices, NuvaRing®, and licensed hormonal 
methods such as implants, injectables, or oral contraceptives (“the pill). 
 
Subjects eligible to participate shall not meet any of the following exclusion criteria: 
 
1. Have an acute illness, including any fever (> 100.4 F [> 38.0C], regardless of the 
route) within 72 hours before vaccination.a 

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2. Have any acute or chronic medical condition that, in the opinion of the principal 
investigator, would make vaccination unsafe or interfere with the evaluation of 
immune response to study vaccination.b 
3. Alcohol or drug abuse and psychiatric conditions that, in the opinion of the 
investigator, would preclude compliance with the trial or interpretation of safety or 
endpoint data. 
4. Have a suppressed immune system as a result of illness, immunosuppressive 
medication, chemotherapy, or radiation therapy within 3 years prior to study 
vaccination.c 
5. Are pregnant or breastfeeding or plan to within one month of vaccination. 
6. Have taken oral or parenteral corticosteroids of any dose within 28 days before 
study vaccination.a 
7. Have a known history of autoimmune disease.  
8. Have a history of Guillain-Barre Syndrome. 
9. Have a history of bleeding disorders. 
10. Have known hypersensitivity or allergy to any component of the vaccine, including 
egg and latex allergies, or history of anaphylaxis with influenza vaccine or vaccine 
component. 
11. Have received blood or blood products 3 months prior to study entry or expected 
to receive through 6 months after study entry. 
12. Have received any live virus vaccines within 4 weeks prior to study entry or 
expected receipt within 4 weeks after study entry.a 
13. Have received any inactivated vaccine within 2 weeks or expected receipt within 2 
weeks after study entry.a 
14. Have received any experimental agents within 6 weeks prior to study or plan to 
through study duration. 
15. Have received the 2018-2019 influenza seasonal vaccine. 
16. Documented influenza infection during the 2018-2019 influenza season. 
17. Social, occupational, or any other condition that in the opinion of the investigator 
might interfere with compliance with the study and vaccine evaluation. 
aAn individual who initially is excluded from study participation based on one or more of the time-limited exclusion criteria (e.g., acute 
illness, receipt or expected  receipt of live or inactivated vaccines ) may be reconsidered for enrollment once the condition has resolved 
as long as the subject continues to meet all other entry criteria. Subjects receiving > 20 mg/day of prednisone or its equivalent daily 
or on alternate days for more than 2 weeks may enter the study after therapy has been discontinued for more than 3 months. 

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bChronic medical problems including (but not limited to) insulin dependent diabetes, severe heart disease, severe lung disease, severe 
liver disease, severe kidney disease, auto immune diseases, severe gastrointestinal diseases and uncontrolled hypertension. 
cImpaired immune function or chronic infections including (but not limited to) HIV, hepatitis B or C; organ transplant; cancer; current 
and/or expected receipt of chemotherapy, radiation therapy or any other immunosuppressive therapy (i.e. more than 20 mg of 
prednisone given daily or on alternative days for 2 weeks or more in the past 3 monthsa), congenital immunodeficiency, anatomical or 
functional asplenia.  

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5 
STUDY PROCEDURES/EVALUATIONS 
 
5.1 Study Procedures 
Medical history will be obtained by interview of study subjects on Day 1 (Visit 1) prior to 
the study vaccination. Subjects will be asked about a known history of significant 
medical disorders, cancer, immunodeficiency, allergies, psychiatric illness, substance 
use, and autoimmune diseases. 
Medications history will include a review of all current medications and any medications 
taken in the last 28 days before study vaccination and those to be taken for 28 days after 
vaccinations. Medications included in this history will only include prescription 
medication and prohibited treatments listed in the above Inclusion/Exclusion Criteria 
section.  
On Day 1 (Visit 1) and before the study vaccination, a targeted physical examination 
may be performed by the investigator, who is licensed to make medical diagnoses. At 
Visits 2-7, a targeted physical examination may be performed based on interim health 
history.   
Vital signs (oral temperature, pulse rate, and blood pressure) will only be measured on 
Day 1 (Visit 1) and if needed at other visits.  
Height and weight will be measured on Day 1 (Visit 1) before study vaccination.  
Blood will be collected for baseline study labs on Day 1 (Visit 1) before study 
vaccination. At Visits 2-7, blood will be collected for immunogenicity analysis.  
Subjects will be observed in the clinic for at least 20 minutes after study vaccination on 
Day 1 (Visit 1).  
5.1.1 Laboratory Evaluations/Assays 
Urine pregnancy tests will be performed on the same day as and prior to study 
vaccination (Day 1). Results must be negative and known prior to study vaccination. 
5.1.2 Special Assays or Procedures 
The immunologic assays will be performed at Dr. Ahmed’s Laboratory on the Emory 
University main campus. 
 
 

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5.1.3 Specimen Collection, Preparation, Handling and Analyses 
Blood will be collected at each of the seven study visits as per the Study Schedule in 
Appendix A. 

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6 
STUDY SCHEDULE 
 
6.1 Screening/Enrollment/Baseline, Visit 01 Day 01 
Study subjects will be given a description of the study and have an opportunity to have 
their questions and concerns addressed by the study principal investigator or designee. 
Subjects will be given the informed consent form to read and discuss with study staff, 
and if they wish to enroll will sign the document before any study vaccination, 
procedures, or lab draws are performed. 
A medical history, targeted physical exam and vital signs, as outlined in the Study 
Procedures section, will be conducted in order to assess compliance with study inclusion 
and exclusion criteria.  
A list of prescribed medications taken by subjects in the past 28 days and those to be 
taken for 28 days after vaccinations will be documented on the appropriate study form. 
A urine pregnancy test will be conducted for female subjects, and a negative result will 
be required and documented on the appropriate study form prior to any study 
interventions. 
Vital signs, including pulse rate, blood pressure, oral temperature, and height and weight 
will be measured and documented on the appropriate study form. 
Blood will be collected for baseline study labs prior to vaccination as outlined in the 
Study Procedures section. 
Subjects will be given a 7-day memory aid, ruler, and thermometer to record local and 
systemic reactogenicity. 
A single dose of the FDA-approved 2018-2019 seasonal influenza vaccine (Fluarix 
Quadrivalent) will be administered. Subjects will be asked to remain at the clinic for 20 
minutes to monitor for any reactions or adverse events. Any reactions or adverse events 
grade 2 and above will be documented on the appropriate study form.  
Subjects will be informed to contact the study team should they experience any 
concerning reactions to the vaccine, and they will be asked to visit the clinic for 
evaluation should the principal investigator or designee deem the reaction in need of 
evaluation. 

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6.2 Follow-up and Final Visits 
6.2.1 Visit 02 Day 08, Visit 03 Day 15 and Visit 04 Day 29 
Interim medical history, and targeted physical exam and vital signs, if necessary, will be 
conducted. 
Medications taken during the interim from the previous visit and any grade 2 and above 
adverse events or serious adverse events will be documented on the appropriate study 
form. 
Blood will be collected for immunogenicity analysis. 
A review of the memory aid will be done at Visit 02. 
6.2.2. Visit 05 Day 100, Visit 06 Day 180 and Visit 07 Day 365 
Interim medical history, and targeted physical exam and vital signs, if necessary, will be 
conducted. 
Any serious adverse events will be documented on the appropriate study form. 
Blood will be collected for immunogenicity analysis. 
6.3 Early Termination Visit (if needed) 
The following will be performed at any early termination visit, if necessary, for subjects 
who withdraw or who are withdrawn from the study: 
Interim medical history, and targeted physical exam and vital signs, if necessary, will be 
conducted. 
A review of the memory aid will be conducted (if visit occurs within 7 days of 
vaccination).  
Medications taken during the interim from the previous visit will be documented on the 
appropriate study form (if prior to D29).  
Any grade 2 and above adverse events (prior to D29) or serious adverse events will be 
documented on the appropriate study form.  
Blood will be collected for immunogenicity analysis.  

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7 
STATISTICAL CONSIDERATIONS 
 
The goal of this study is to assess the longevity of the human immune response to the 
AS03 H5N1 vaccine and evaluate the immune response to the 2018-2019 seasonal 
influenza vaccine, Fluarix Quadrivalent, in individuals with previous receipt of the 
adjuvanted or unadjuvanted AS03 H5N1 vaccine. This is an exploratory study designed 
to assess the durability and impact of the seasonal influenza vaccine on H5 induced B 
cell responses.  
 
Since this is an exploratory study, our aim is to study a convenient sample of up to 50 
subjects, who previously participated in the HIPCVAX-010 Systems Biology of Influenza 
A (H5N1) Virus Monovalent Vaccine with and without AS03 Adjuvant study, receiving the 
seasonal influenza vaccine. 
 
The biostatistician will perform descriptive statistics to assess the longevity of the H5 
induced B cell responses and the impact that receipt of the seasonal influenza vaccine 
has on these immune responses.  
 
 

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8 
QUALITY CONTROL AND QUALITY ASSURANCE 
The study will undergo internal quality control and quality assurance per the Hope Clinic 
standard operating procedures.   

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9 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
9.1 Ethical Standard 
 
The site principal investigator will ensure that this trial is conducted in full conformity with 
the principles of the Belmont Report: Ethical Principles and Guidelines for the Protection 
of Human Subjects of Research of the 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 56, and ICH E6; 62 Federal Regulations 25691 (1997), if applicable.  
9.2 Institutional Review Board 
 
Prior to enrollment of subjects into this trial, the approved protocol and informed consent 
form will be reviewed and approved by the Emory IRB. The responsible official for the 
IRB will sign the IRB letter of approval of the protocol prior to the start of this study.  
9.3 Informed Consent Process 
 
The site principal investigator and designee will choose subjects in accordance with the 
eligibility criteria detailed in Section 4. Before any study procedures are performed, 
subjects must sign an informed consent form that complies with the requirements of 21 
CFR Part 50 and 45 CFR 46 and the local IRB. 
 
Informed consent is a process that is initiated prior to an individual agreeing to participate 
in a study and continuing throughout the individual’s study participation. Before any study 
procedures are performed, subjects will receive a comprehensive explanation of the 
proposed study procedures and study interventions/products, including the nature and 
risks of the trial, alternate therapies, any known adverse effects, and the other elements 
that are part of obtaining proper informed consent. Subjects will also receive a detailed 
explanation of the proposed use and disclosure of their protected health information, 
including specifically their serum samples. Subjects will be allowed sufficient time to 
consider participation in the study, after having the nature and risks of the trial explained 
to them, 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.  
 
Informed consent forms describing in detail the study interventions/products, study 
procedures, risks and possible benefits are given to subjects. The informed consent form 
must not include any exculpatory statements. Informed consent forms will be IRB-
approved and subjects will be asked to read and review the appropriate document. Upon 
reviewing the appropriate document, the site principal investigator (or designee) will 
explain the research study to subjects and answer any questions that may arise. Subjects 
must sign the informed consent form, and written documentation of the informed consent 
process is required prior to starting any study procedures/interventions being done 
specifically for the trial, including administering study product.  
 

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Study personnel may employ IRB-approved recruitment efforts prior to obtaining the 
subject’s consent; however, before any study procedures are performed to determine 
protocol eligibility an informed consent form must be signed. Subjects will be given a copy 
of all informed consent forms that they sign. 
 
By signing the informed consent form, subjects agree to complete all evaluations required 
by the trial, unless the subject withdraws voluntarily, or is withdrawn or terminated from 
the trial for any reason.  
 
The rights and welfare of subjects will be protected by emphasizing to subjects that the 
quality of their medical care will not be adversely affected if they decline to participate in 
or withdraw from this trial. 
9.4 Exclusion of Women, Minorities, and Children (Special 
Populations) 
 
This trial will be inclusive of all adults who participated in the HIPCVAX-010 Systems 
Biology of Influenza A (H5N1) Virus Monovalent Vaccine with and without AS03 Adjuvant 
study and who meet the Subject Inclusion/Exclusion Criteria, regardless of religion, sex, 
or ethnic background.  
9.5 Subject Confidentiality 
 
Subjects will have the same patient identification number that was assigned to them in 
the HIPCVAX-010 study, followed by the letter, “S,” and will not be identified by name. 
Subject confidentiality is strictly held in trust by principal investigator and the Hope Clinic 
personnel directly involved in the study. This confidentiality is extended to cover testing of 
biological samples, in addition to the clinical information relating to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held 
in strict confidence. 
9.6 Future Use of Stored Specimens 
 
Subjects will be asked for permission to keep any remaining samples for possible use in 
future research studies, such as examining additional immunological assessments or 
testing for antibodies against other viruses or bacteria. The samples will not be sold or 
used directly for production of any commercial product. Human genetic tests may be 
performed on samples for future research only. Each sample will be labeled with a unique 
tracking number to protect subject’s confidentiality. There are no benefits to subjects in 
the collection, storage and subsequent research use of specimens. Reports about future 
research done with subject’s samples will NOT be kept in their health records. 
 
Subjects may be given the option to decide if they want their samples to be used for 
future research or have their samples destroyed at the end of the study. The subject’s 
decision can be changed at any time prior to the end of the study by notifying the study 
doctors or nurses in writing. However, if the subject originally consents to future use and 

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subsequently changes his/her decision, any data from a previously collected sample may 
still be used for this research. 

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10 
LITERATURE REFERENCES 
1. FLUARIX QUADRIVALENT [package insert]. GlaxoSmithKline, Inc., Research Triangle 
Park, NC; 2018. 
 
2. Lasky T, Tarracciano GJ, Magder L, Koski CL, Ballesteros M, Nash D, Clark S, Haber P, 
Stolley PD, Schonberger LB and Chen RT. The Guillain-Barre syndrome and the 1992-
1993 and 1993-1994 influenza vaccines. N. Engl. J. Med.;339:1797-1802 (1998). 
 
3. Haber P, DeStefano F, Angulo FJ, Iskander J, Shadomy SV, Weintraub E and Chen RT. 
Guillain-Barre syndrome following influenza vaccination. JAMA; 292:2478-2481 (2004). 
 
4. National Cancer Institute. National Cancer Institute’s Common Terminology Criteria for 
Adverse Events Version 5.0. (2017). 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
 
  

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SUPPLEMENTS/APPENDICES

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Appendix A: Study Schedule 
 
 
#Prior to study procedures 
*Prior to study vaccination. 
%All current medications and medications taken within 28 days prior to day 1 of the study. 
&Vital signs assessed on Day 1 (Visit 1) before 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. 
() Targeted physical examination and vital signs if indicated based on review of complete or interim 
medical history. 
@Must be performed on all female subjects of childbearing potential within 24 hours prior to each study 
vaccination and results must be negative and known prior to each study vaccination. 
+Complete medical history by interview of subjects to be obtained on Day 1 (Visit 01) prior to the first 
study vaccination and interim medical history by interview of subjects to be obtained at follow-up visits 
after study vaccination. 
 
Study Visit Number 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
Study Day +/- Window (days) 
D1 
D8+1 
D15 
+/-2 
D29 
+/-3 
D100 
+/-14 
D180  
+/-14 
D365 
+/-30 
Obtain Informed Consent# 
X* 
 
 
 
 
 
 
Review Eligibility Criteria 
X* 
 
 
 
 
 
 
Medical History+ 
X* 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X*% 
X 
X 
X 
 
 
 
Vital Signs  
(Oral Temperature, Pulse Rate, 
and BP) 
X*&$ 
(X$) 
(X$) 
(X$) 
(X$) 
(X$) 
(X$) 
Height and Weight 
X* 
 
 
 
 
 
 
Targeted Physical Examination 
X* 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Urine Pregnancy Test 
X*@ 
 
 
 
 
 
 
Study Vaccination 
X 
 
 
 
 
 
 
20-minute Evaluation Period 
After Study Vaccination 
X 
 
 
 
 
 
 
Venous Blood Collection for 
Study Assays 
X 
X 
X 
X 
X 
X 
X 
Memory Aid review 
 
X 
 
 
 
 
 
Adverse events Grade 2 and 
above 
X 
X 
X 
X 
 
 
 
Serious adverse events  
X 
X 
X 
X 
X 
X 
X 

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Appendix B: Adverse Events Grading4 
 
 
INJECTION SITE REACTIONS 
 
Grade 
 
0 
1 
2 
3 
Swelling 
None 
Mild 
induration/swelling 
2.5-5cm; does not 
interfere with 
activity 
 
Moderate 
induration/swelling 
5.1-10cm; limiting 
instrumental activities 
of daily living 
Severe induration/swelling  
>10 cm; limiting self-care 
activities of daily living 
Redness 
None 
Mild erythema  
2.5-5cm; does not 
interfere with 
activity 
Moderate erythema 
5.1-10cm; limiting 
instrumental activities 
of daily living 
Severe erythema >10cm;  
limiting self-care activities of 
daily living 
Pain  
None 
Mild pain; does not 
interfere with 
activity 
Moderate pain; 
limiting instrumental 
activities of daily 
living 
Severe pain; limiting self-care 
activities of daily living 
 
 
GENERAL ADVERSE REACTIONS 
 
Grade 
 
0  
1 
2 
3 
Fatigue  
None 
Fatigue relieved by 
rest 
Fatigue not relieved by rest; 
limiting instrumental activities of 
daily living 
Fatigue not relieved by rest, 
limiting self-care activities of daily living 
Body ache 
(myalgia) 
None 
Mild pain 
Moderate pain; limiting 
instrumental activities of daily living 
Severe pain; limiting self-care 
activities of daily living 
Chills  
None 
Mild sensation of 
cold; shivering; 
chattering of teeth 
Moderate tremor of the entire body; 
narcotics indicated 
Severe or prolonged, not responsive to 
narcotics 
Nausea 
None 
Loss of appetite 
without alteration in 
eating habits 
Oral intake decreased without 
significant weight loss, dehydration 
or malnutrition 
Inadequate oral caloric or fluid 
intake; tube feeding, TPN, or hospitalization 
indicated 
Diarrhea 
None 
Increase of <4 stools 
per day 
over baseline 
Increase of 4 - 6 stools per day 
over baseline; limiting instrumental 
activities of daily living 
Increase of >6 stools per day 
over baseline;  
hospitalization indicated; limiting self-care 
activities of daily living 
Headache 
None 
Mild pain 
Moderate pain; limiting instrumental 
activities of daily living 
Severe pain; limiting self-care activities of 
daily living 
Joint pain 
(arthralgia)  
None 
Mild pain 
Moderate pain; limiting instrumental 
activities of daily living 
Severe pain; limiting self-care activities of 
daily living 
Fever* 
None 
100.4 - 102.2 
degrees F 
102.3 - 104.0 degrees F 
>104.0 degrees F 
*   Oral temperature; no recent hot or cold beverages or smoking