Evaluation of Human Immune Responses to Influenza Virus Vaccination in Healthy Volunteers
Phase: PHASE4
Conditions: Influenza, Influenza Immunisation
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID CEIRS Protocol 14-0071 
 
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Evaluation of Human Immune Responses to Influenza Virus Vaccination in Healthy Volunteers 
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 Protocol Cover Page 
 
 
Official Title:  
Evaluation of Human Immune Responses to Influenza Virus Vaccination 
in Healthy Volunteers 
 
 
 
NCT Number: 
 
NCT02385123 
 
 
 
Document Date: 
June 4, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DMID CEIRS Protocol 14-0071 
 
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Evaluation of Human Immune Responses to Influenza Virus Vaccination in Healthy Volunteers 
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Evaluation of Human Immune Responses to Influenza Virus Vaccination in Healthy 
Volunteers 
 
DMID Protocol Number: 
14-0071 
 
Sponsored by: 
National Institute of Allergy and Infectious Diseases (NIAID) 
 
DMID Funding Mechanism: 
HHSN272201400004C, CEIRS 
 
 
CEIRS Principal Investigators: 
Walter A. Orenstein, MD 
Richard W. Compans, PhD 
 
CEIRS Center Coordinator: 
Erin- Joi Collins, MS, MPH, CPH 
 
Protocol Clinical Investigator: 
Aneesh Mehta, MD 
 
Protocol Research Investigator 
Rafi Ahmed, PhD, Emory University 
 
DMID Clinical Project Manager: 
Melinda Tibbals, RAC, CCRA 
 
Site Clinical Research Coordinator: 
Shine Thomas, BBA 
 
CEIRS Site Monitor: 
Jennifer C. Truell, MA, MPH 
 
Protocol Version  6.0 
 
June 4, 2020 
 
 
 
 
 
 

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Evaluation of Human Immune Responses to Influenza Virus Vaccination in Healthy Volunteers 
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Statement of Compliance 
 
The study will be carried out in accordance with Good Clinical Practice (GCP) as 
required by the following: 
• 
U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46) 
• 
21 CFR 312 
• 
ICH GCP E6 
• 
Completion of Human Subjects Protection Training 
• 
NIH Clinical Terms of Award 

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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 clinical study 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. 
 
 
Signed: __________________________________________  
Date________ 
              Aneesh K. Mehta, M.D. 
              Co-Investigator, Emory University, Emory-UGA CEIRS  
 
 
Signed: __________________________________________ 
Date: ________ 
              Rafi Ahmed, Ph.D 
              Co-investigator, Emory University, Emory-UGA CEIRS 
 
* The protocol should be signed by the local investigator who is responsible for the study 
implementation at his/her specific site. 
 
Principal Investigator (Administrative Site): 
 
Signed 
 
Date: 
 
 
Walter A. Orenstein, M.D.  
Principal Investigator, Emory University, Emory 
UGA CEIRS 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
Statement of Compliance ................................................................................................ i 
Signature Page ................................................................................................................ ii 
Table of Contents........................................................................................................ iii-v 
List of Abbreviations ..................................................................................................... vi 
Study Summary............................................................................................................... 1 
Schematic of Study Design ............................................................................................ 2 
 
1 
Key Roles .................................................................................................................. 3 
2 
Background Information and Scientific Rationale ................................................ 5 
2.1 
Background Information.................................................................................... 5 
2.2 
Scientific Rationale ............................................................................................ 6 
2.3 
Potential Risks and Benefits ............................................................................. 6 
2.3.1 Potential Risks .............................................................................................. 6 
2.3.2 Known Potential Benefits ............................................................................ 8 
3 
Objectives and Outcome Measures ........................................................................ 9 
3.1 
Study Objectives ................................................................................................ 9 
3.2 
Outcome Measures ............................................................................................ 9 
3.2.1 Primary Outcome Measures ........................................................................ 9 
3.2.2 Secondary Outcome Measures ................................................................... 9 
4 
Study Design ........................................................................................................... 11 
5 
Study Population .................................................................................................... 12 
5.1 
Inclusion Criteria .............................................................................................. 12 
5.2 
Exclusion Criteria ............................................................................................. 13 
5.3 
Handling of Withdrawals ................................................................................. 14 
5.4 
Termination of Study ....................................................................................... 14 
6 
Study Intervention Product.................................................................................... 15 
6.1 
Study Product Description .............................................................................. 15 
6.1.1 Acquisition .................................................................................................. 15 
6.1.2 Formulation, Packaging, and Labeling .................................................... 15 
6.1.3 Product Storage and Stability ................................................................... 15 
6.2 
Dosage, Preparation and Administration of Study Intervention Product ... 16 
6.3 
Accountability Procedures for the Study Intervention Product(s) .............. 16 
6.4 
Assessment of Participant Compliance with Study Intervention Product . 16 
6.5 
Concomitant Medications/Treatments ........................................................... 16 
7 
Study Schedule ....................................................................................................... 17 
7.1 
Screening (Day -1 to day -30) .......................................................................... 17 
7.2 
Enrollment/Baseline ......................................................................................... 17 

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7.3 
Follow-up and Final Visits ............................................................................... 18 
7.4 
Early Termination Visit .................................................................................... 19 
7.5 
Unscheduled Visit ............................................................................................ 19 
8 
Study Procedures and evaluations ....................................................................... 21 
8.1 
Clinical Evaluations ......................................................................................... 21 
8.2 
Laboratory Evaluations/Assays ...................................................................... 21 
8.2.1 Specimen Collection, Preparation, Handling and Shipping ................... 22 
8.3 
Procedures to be followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings ..................................................................... 23 
9 
Assessment of Safety ............................................................................................ 24 
9.1 
Specification of Safety Parameters ................................................................ 24 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ................................................................................................................. 24 
9.2.1 Adverse Events .......................................................................................... 24 
9.2.2 Serious Adverse Events ............................................................................ 26 
9.3 
Reporting Procedures and Safety Oversight ................................................. 27 
9.3.1  Reporting of Pregnancy .................................................................................. 28 
9.4 
Type and Duration of Follow-up of Participants after Adverse Events ....... 28 
9.5 
Halting Rules .................................................................................................... 28 
9.6 
Safety Oversight ............................................................................................... 28 
9.7 
Independent Safety Monitor (ISM) .................................................................. 28 
10 
Clinical monitoring ............................................................................................... 30 
10.1 
Site Monitoring Plan ...................................................................................... 30 
11 
Statistical considerations .................................................................................... 31 
11.1 
Study Hypothesis ........................................................................................... 31 
11.2 
Sample Size Considerations ......................................................................... 31 
11.3 
Planned Interim Analysis .............................................................................. 31 
11.4 
Final Analysis Plan ........................................................................................ 31 
12 
Source Documents and Access to Source Data/Documents ........................... 32 
13 
Quality Control and Quality Assurance ............................................................. 33 
14 
Ethics/Protection of Human Subjects ................................................................ 34 
14.1 
Ethical Standard ............................................................................................. 34 
14.2 
Institutional Review Board ............................................................................ 34 
14.3 
Informed Consent Process ........................................................................... 34 
14.3.1 Informed Consent/Assent Process (in Case of a Minor) ...................... 34 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) ..... 34 
14.5 
Participant Confidentiality ............................................................................. 35 
14.6 
Protocol Deviations ....................................................................................... 35 
14.7 
Study Discontinuation ................................................................................... 36 

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14.8 
Future Use of Stored Specimens .................................................................. 36 
15 
Data Handling and Record Keeping ................................................................... 37 
15.1 
Data Management Responsibilities .............................................................. 37 
15.2 
Data Capture Methods ................................................................................... 37 
15.3 
Types of Data .................................................................................................. 38 
15.4 
Timing/Reports ............................................................................................... 38 
15.5 
Study Records Retention .............................................................................. 38 
16 
Publication Policy ................................................................................................ 39 
17 
Literature References (in section 2.1) ................................................................ 40 
18 
Supplement/Appendices ..................................................................................... 41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
ACTSI 
AE 
Atlanta Clinical & Translational Science Institute 
Adverse Event 
CDC/VIS 
Centers for Disease Control and Prevention/Vaccine Information  
 
Statement 
CFR 
Code of Federal Regulations 
CIERS 
Center for Influenza Excellence in Research and Surveillance 
CoC 
Certificate of Confidentiality 
CPM 
Clinical Project Manager 
CRF 
Case Report Form 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH 
eCRF 
Electronic CRF 
FDA 
Food and Drug Administration 
FISMA 
Federal Information Security Management Act 
GCP 
Good Clinical Practice 
GCRC 
General Clinical Research Center of Emory University 
HA 
Hemagglutinin 
HHS 
Health and Human Services 
HI 
Hemagglutination Inhibition  
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IDS 
Investigational Drug Services 
IMGT 
Immunogenetics Information System 
IM 
Intramuscular 
IRB 
Institutional Review Board 
Ml 
Milliliter 
MO 
Medical Officer 
MOP 
Manual of Procedures 
NA 
Neuraminidase 
NGS 
Next Generation Sequencing 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH 
NIH 
National Institutes of Health 
NSAID 
Non-steroidal anti-inflammatory drug 
PHI 
Protected Health Information 
QIV 
Quadrivalent inactivated vaccine 
RedCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SMC 
Safety Monitoring Committee 
TIV 
Trivalent Inactivated Vaccine  
US 
United States 
VAERS 
Vaccine Adverse Event Reporting System 
WNL 
Within Normal Limits 

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Title: 
Evaluation of Human Immune Responses to Influenza Virus Vaccination in 
Healthy Volunteers 
 
Population: 
Male and female individuals aged 18-49; target enrollment is up to a total of 
70 subjects.  
 
Number of Sites: 
1  
 
Study Duration: 
6 years 
 
Participant Duration:  180 days (6 months) 
 
 
Objectives: 
Primary Objectives: 
To characterize HA-specific plasmablasts and memory B cells after influenza vaccination 
 
Secondary Objective: 
To investigate the longevity of humoral immunity to influenza virus in humans 
 
Study Summary: 
This is an open label single arm observational study of longitudinal immunologic responses to 
influenza vaccine in healthy adult subjects. This study will enroll males and non-pregnant females, 
18-49 years old.  The subjects will be screened at enrollment with a history and physical exam and 
laboratory testing to ensure they are healthy enough to participate. Qualifying subjects will be 
vaccinated with an FDA approved seasonal inactivated influenza vaccine (IIV) according to the 
package insert. Approximately 450 ml of blood will be collected for the research assays during the 
course of the study. Specifically, 16 ml will be collected for screening; 48ml will be collected at 
enrollment; 96ml will be collected at visit days 7 and 14; and 64 ml will be collected at  28, 90, and 
180 days post vaccination.  
 
Due to the COVID-19 pandemic, all non-essential research was halted in mid-March 2020. New 
enrollments were placed on hold for this study. Follow-up visits were also halted, which impacted 
the timing of participants’ subsequent follow-up visits. For this study, there are participants whose 
Day 180 visits were impacted. We will request an expansion of the study window for the 
participants whose visits were impacted. Additional details regarding this are detailed further in the 
protocol. None of the other visits were impacted. 
 
The study will enroll 10 healthy volunteers per vaccination season in years 1, 2, and 4. For years 5 
and 6, we anticipate enrolling a maximum of 20 participants for a total enrollment of up to 70 

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subjects. Individuals who complete the study will be given the option to re-enroll in subsequent 
years as long as they continue to meet all inclusion/exclusion criteria. Re-enrolling subjects will be 
re-consented, given new subject identifiers, and counted towards the enrollment number goal for 
each year of participation.  
 
 
 
 
Schematic of Study Design: 
       
                                                               
 
 
 
 
 
Clinical Group 
 
 
Numbers 
                           Blood Draws 
 
Timepoint (day) 
Screen  
            0 
 
7 
 
14 
 
28 
 
90 
 
180 
Healthy 
Controls 
receiving  
inactivated 
influenza 
vaccine 
10/year 
Years 1, 
2, and 4 
Maximum 
of 
20/year 
for Years 
5 and 6 
 16 ml            48ml  
96ml 
96ml 
64ml 
64ml 
64ml 
Post 
DMID/IRB 
approved 
Flyers in IRB 
app approved 
Administer 
influenza 
vaccine 
Collect 
blood for 
research 
assays at 
the 
designated 
Perform 
mechanistic 
studies  
Title: Graph of Study Design 
Data analysis and 
publication 
Telephone 
screen of 
potential 
subjects  
Invite qualifying 
subjects to 
come for 
Screening/ 
enrollment visit 
Screen and 
enroll eligible 
subjects 

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1 
KEY ROLES 
DMID Representatives: 
 
 
 DMID Medical Officer: 
 Trinka Coster, MD, MS 
 DMID/NIAID/NIH  
 
 Clinical Project Manager: 
Melinda Tibbals, RAC, CCRA 
DMID/NIAID/NIH  
 
 
 
 Scientific Lead: 
 
 
 Diane J. Post, Ph.D. 
 
 
 DMID/NIAID/NIH 
 
Study Site:  
 
 
 
 Aneesh K. Mehta, MD 
 
 
 Emory University, Atlanta 
 Assistant Professor of Medicine 
 Assistant Professor of Surgery 
 Assistant Director of Transplant Infectious Diseases  
 
 Associate Chief of Service – ID, EUH/WWH/EUOSH 
 Emory University School of Medicine 
 
 
 101 Woodruff Circle, WMRB 2101 
  
 
 Atlanta, GA 30322 
 Tel:  404-727-8435 
Fax: 404-712-2278 
Email: aneesh.mehta@emory.edu  
 
 
 
 
 
 
 Co-Investigator (Research Project Leader) 
 
 
 Rafi Ahmed, Ph.D. 
 
 
 Emory University, Atlanta, Georgia 
 
 
 Director, Emory Vaccine Center;  
 Georgia Research Alliance Eminent Scholar In Vaccine Research 
 Professor, Microbiology & Immunology, Emory, University 
 1510 Clifton Road, Atlanta, GA  30322 
 Tel:  404-727-4700 
 Fax:  404-727-8250 
 Email:  ra@microbio.emory.edu 
 
 

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 Clinical Laboratory: 
 Emory Medical Laboratories, Emory University Hospital (Main Lab) 
 1364 Clifton Road, NE, Atlanta, GA  30322 
 
 Research Laboratory: 
 Dr. Rafi Ahmed’s Laboratory 
 Emory University Dental School Building 
 1462 Clifton Road, NE Room 412 
 Atlanta, GA  30322 
 Tel: 404-727-4700 
 
 
 
 
 
 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
2.1 
Background Information  
 
Annual influenza virus epidemics by subtype A viruses (H1N1 and H3N2), and/or influenza B 
viruses have been shown to cause substantial morbidity and mortality, exacting an average of 
36,000 deaths and more than 200,000 hospitalizations in the US alone (1).  
 
To combat this important public health threat, two types of inactivated influenza vaccines have 
been approved by the FDA: 1) a trivalent, inactivated vaccine (TIV); and 2) a quadrivalent 
inactivated vaccine (QIV). The TIV vaccine contains the hemagglutinin (HA) and neuraminidase 
(NA) proteins corresponding to the three influenza viruses predicted to be in circulation during the 
influenza season (two A strains and one B), and the quadrivalent type contains the HA and NA for 
an additional B strain. These vaccines induce predominantly HA-specific and NA-specific 
antibodies that are capable of virus neutralization. Antibodies to HA are critical to provide immune 
protection to the host against influenza virus infection, as this protein plays a key role in virus entry 
to initiate the replication cycle in the cell. A live attenuated vaccine has also been approved but this 
study will use only inactivated influenza vaccine. 
 
Currently, the Advisory Committee on Immunization Practices of the CDC recommends that 
everyone aged 6 months or older in the United States receive the influenza vaccine on an annual 
basis (2). The recommendation for annual vaccination, regardless of previous vaccination history, 
is in part due to the constantly changing nature of the influenza strains in circulation.  Through the 
processes of antigenic drift and antigenic shift, the viral HA protein is constantly changing to evade 
the antibody response.  This requires that the formulation of the influenza vaccine must be updated 
each season.  However, when the vaccine formulation remains unchanged from year to year, re-
vaccination is still recommended because antibody levels decline over the course of a year (3). 
 
In recent years it has become apparent that a significant fraction of the human antibody response 
to influenza targets highly conserved neutralizing epitopes on the virus (4).  This raises the 
possibility that an optimally designed vaccine could elicit a broad immunity to the virus.  If long 
lived antibody responses could be generated against these neutralizing epitopes through 
immunization, it could eliminate the need for yearly re-vaccination.  The development of such a 
vaccine will therefore require an understanding of the factors that lead to the generation of long-
lived antibody responses. 
 
 
 
 

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2.2 
Scientific Rationale  
 
The challenge of developing a broadly protective influenza vaccine stems from three main factors: 
first, the ever-evolving nature of influenza viruses which allows the virus to overcome pre-existing 
immunity; second, the fact that the majority of vaccine-elicited neutralizing antibodies are directed 
against epitopes within the hypervariable region of the HA globular head which facilitates the 
emergence of antibody-escape viral variants; and third, the apparent short half-life of vaccine-
mediated protection, in some instances, even against matched virus strains, raising issues about 
the longevity of vaccine induced immune responses. Therefore, an ideal influenza vaccine should 
feature two improvements over the existing ones; it should be able to elicit neutralizing antibody 
responses against conserved HA epitopes to provide broad protection against diverse influenza 
virus strains and it should be able to induce long-lived antibody responses. 
 
Generation of immunological memory is the hallmark of adaptive immune responses. Influenza 
vaccines work by activating antigen-specific B cells to proliferate and differentiate into 
plasmablasts (PBs) that secrete protective antibodies and memory B cells (MBCs) that can rapidly 
proliferate and differentiate into PBs upon re-encountering the immunizing antigen. A subset of the 
plasmablasts migrate to the bone marrow and become long-lived plasma cells (LLPCs) secreting 
antigen-specific antibodies for protracted periods of time. Memory B cells and long-lived PCs 
provide a remarkably stable immunological memory that can persist over 50 years after 
vaccination in humans. It remains unclear what factors direct the differentiation of activated, 
antigen-specific B cells into either memory B cells or plasmablasts and long-lived plasma cells. 
Studies in mice have suggested that the B cell repertoire in the memory B and the long-lived 
plasma cell compartments differ in terms of antigen-binding affinity and breadth. In this study, we 
will address the fundamental question of what determines the fate (plasmablasts vs. memory B 
cells) of antigen-specific B cells following vaccination in humans.  
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
The physical risk of drawing blood is local pain and bruising at the site of venipuncture.  Qualified 
phlebotomists or designee will draw blood samples.  Care will be taken to obtain these specimens 
in a safe and hygienic manner.  A small number of people experience lightheadedness or fainting. 
There is a slight risk of infection. Repeated blood drawing may be associated with iron deficiency 
anemia. To avoid this risk, no more than 432 ml of blood will be obtained over a period of 180 
days.  
 
The side effects from inactivated influenza vaccine are generally mild. They include soreness at 
injection site (10-64% of subjects) that lasts <2 days. When the vaccine is given, the subject may 
feel a slight pain and burning during the injection.  Fever, malaise and myalgia can occur after 
vaccination with inactivated influenza vaccine. These reactions begin 6-12 hours after vaccination 

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and can persist for 1-2 days. Allergic reactions rarely occur after influenza vaccination and are 
generally caused by residual egg proteins. Persons with a history of egg allergy will be excluded 
from study participation.  Associated with the 1976 swine influenza vaccine, there is a slight risk of 
Guillain-Barre syndrome with the administration of the seasonal inactivated influenza vaccine.  
Persons with a history of Guillain-Barre syndrome will be excluded from study participation. 
Occasionally, recipients of unadjuvanted licensed, inactivated influenza virus vaccines may 
develop influenza-like reactions, such as fever, feverishness (chills/shivering/sweating), fatigue 
(tiredness), malaise (general unwell feeling), myalgia (body aches/muscular pain), arthralgia (joint 
pain), headache, and/or nausea.  Some subjects may develop reactions at the injection site, 
including 
pruritus 
(itching), 
ecchymosis 
(bruising), 
erythema 
(redness), 
induration 
(hardness)/swelling, pain, and/or tenderness.  With unadjuvanted licensed, inactivated influenza 
virus vaccines most of these reactions peak in intensity in the first 24 hours after vaccination and 
usually disappear without treatment within 1 or 2 days.  Analgesics (e.g., acetaminophen, or 
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. 
Acute and potentially life-threatening allergic reactions are also possible.  Very rarely, occurring in 
about 1 in 4 million people given a vaccination, there can be a serious allergic reaction to a 
vaccine.  These reactions can manifest as skin rash (hives), swelling around the mouth, throat or 
eyes (angioedema), difficulty breathing (bronchospasm), a fast pulse (tachycardia), or loss of blood 
pressure (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 fatal reaction (death), although researchers do not 
expect this to occur. 
In addition, post-marketing surveillance indicates the following adverse events of special interest 
(AESI) as potential risks for the seasonal influenza vaccines: neuritis, convulsions, severe allergic 
reactions, syncope, encephalitis, thrombocytopenia, vasculitis, and Guillain-Barré syndrome.  
Reports of these reactions were rare; however, exact incidence rates cannot be precisely 
calculated. 
During the swine influenza (H1N1) vaccine campaign of 1976, some recipients developed a 
paralytic illness called Guillain-Barré syndrome (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 (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, 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 inactivated influenza vaccines since 1976 has shown a 

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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 H1N1 vaccine was associated with a small but significant risk of GBS in persons 50 
years and older (46).  An active, population-based surveillance study conducted during the 2009-
2010 influenza season found less than 1 excess GBS case per million doses of 2009 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 2009 monovalent H1N1 vaccination (incidence rate ratio = 2.41, 95% confidence 
interval: 1.14, 5.11; attributable risk = 2.84 per million doses administered, 95% confidence 
interval: 0.21, 5.48) (50).  An international collaboration study also supported a conclusion of an 
association between 2009 H1N1 vaccination and GBS (51).  It is unknown if the administration of 
the inactivated A/H7N9 vaccine to be used in this study will result in the incidence of GBS that was 
seen with the 1976 vaccine product as the mechanism leading to this response has not been 
completely elucidated. 
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 subjects’ PHI.  All records will be kept in a locked file cabinet or 
maintained in a locked room at the participating VTEU sites.  Electronic files will be password 
protected.  Only people who are involved in the conduct, oversight, monitoring, or auditing of this 
study will be allowed access to the PHI that is collected.  Any publications from this study will not 
use information that will identify subjects by name.  Organizations that may inspect and/or copy 
research records maintained at the participating sites for quality assurance and data analysis 
include groups, such as National Institute of Allergy and Infectious Diseases (NIAID) and Food and 
Drug Administration (FDA). 
There may be other unknown risks, discomforts, or side effects. 
2.3.2 Known Potential Benefits 
There is no guarantee of benefit to subjects who will enroll in this protocol. However, seasonal 
influenza vaccine is considered beneficial to most subjects, as it generally provides protective 
immunity against the influenza strains within the vaccine.  If vaccine is administered after flu 
season, there is no benefit to the subject.  Data from this study may yield a better understanding of 
the current body of knowledge describing human infections with influenza viruses. 

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3 
OBJECTIVES AND OUTCOME MEASURES 
3.1 
Study Objectives 
Primary Objectives: 
To characterize HA-specific plasmablasts and memory B cells after influenza vaccination 
 
Secondary Objective: 
To investigate the longevity of humoral immunity to influenza virus in humans 
 
3.2 
Outcome Measures 
3.2.1 Primary Outcome Measures 
 
• 
Determine the percentage of subjects achieving seroconversion, defined as the percentage 
of subjects with either a pre-vaccination HI titer < 1:10 and a post-vaccination HI titer > 1:40 
or a pre-vaccination HI titer > 1:10 and a minimum four-fold rise in post-vaccination HI 
antibody titer (day 0, 28). 
3.2.2 Secondary Outcome Measures  
 Investigation of the longevity of humoral immunity to influenza virus in humans will be 
performed by: 
• 
Measuring influenza hemagglutinin stem-specific and head-specific memory B-cells and 
serum antibody levels at days 0, 28, and 180.  
• 
For serum antibody responses directed against the HA head or stem regions, we will 
determine the endpoint IgG titers at days 0, 28 and 180 after vaccination. 
For memory B cells, we will determine the frequency of HA head- or stem-specific IgG-
secreting memory B cells per total IgG-secreting cells at days 0, 28 and 180 after 
vaccination. 
• 
Plasmablast responses against either the HA head or stem antigens will be determined by 
direct ex vivo ELISPOT at day 7 after vaccination. 
 
• 
Expression of human influenza-specific monoclonal antibodies from Day 7 plasmablasts and 
assessing their functional by ELISA, HAI, and virus neutralization assays. 
 
 

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3.2.3 Exploratory Outcome Measures  
Characterization of HA-specific plasmablasts and memory B cells after influenza vaccination will 
be performed using samples from the following timepoints: 
• 
Sequencing of antibodies from single cell sorted plasmablasts and deep immunoglobulin 
sequencing of RNA from bulk sorted plasmablasts and plasma cells will be carried out using 
day 7 samples, and the following assays will be performed: 
• 
Cloning of human influenza-specific monoclonal antibodies and analysis of strain 
specificity by ELISA, HAI, and virus neutralization assays. 
• 
Sequence analysis of influenza-specific antibodies to characterize patterns in VDJ 
usage, CDR3 region length, and numbers of replacement vs. silent mutations. 
 
• 
Protein sequencing of serum antibodies which bind to vaccine antigens at different 
timepoints (day 0, 28, 180) post vaccination. 
• 
Define the gene expression profile of HA-specific plasmablasts and memory B cells (day 7) 
• 
Examine the clonal diversity of HA-specific plasmablasts and memory B cells (day 7) 
 
 
Investigation of the longevity of humoral immunity to influenza virus in humans will be performed 
by: 
▪ 
Identifying which plasmablast clones persist to late time points and examine whether the 
same plasmablast clones are re-amplified after vaccination. 
▪ 
Examining associations between specific antibody features (hypermutation level, antigen 
binding affinity, cross reactivity to previous vaccine strains) and the likelihood of long-term 
persistence in each compartment. 
Using proteomics directed cloning to identify the dominant B-cell clones producing influenza-
specific and hemagglutinin stalk-specific antibodies in the serum of vaccine recipients and infected 
subjects.   
 

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4 
STUDY DESIGN 
Longitudinal assessment of the study participants will be made at every study visit.  Assessments 
will be performed at day 0, 7, 14, 28, 90 and 180 days after immunization as outlined in the 
Schedule of Events (appendix A). Participants will be monitored by the study nurse for the 
presence of both expected reactions to vaccination and for unexpected adverse reactions for 15 
minutes following vaccination. Subject enrollment will be contingent upon the availability of the 
seasonal flu vaccine and will end upon expiration of the product.   
 
Due to the COVID-19 pandemic, all non-essential research was halted in mid-March 2020. New 
enrollments were placed on hold for this study. Follow-up visits were also halted, which 
impacted the timing of participants’ subsequent follow-up visits. For this study, there are 
participants whose Day 180 visits were impacted. We will request an expansion of the study 
window for the participants whose Day 180 visits were impacted. Additional details regarding 
this are detailed further in the protocol. None of the other visits were impacted. 
The clinical study is designed to characterize the specific immunologic response to influenza 
vaccination of humans using commercially available influenza vaccine. This study will compare 
and contrast the response of individual components of the immune system using licensed 
seasonal inactivated influenza vaccine. This vaccine is FDA approved for protection against 
influenza infection but may have different effects on different components of the immune system. 
The enrollment goal is up to a total of 70 subjects. The subjects will have blood drawn at 
designated time points to have ex-vivo analysis of specific immunologic responses measured. 
Blood will be drawn at screening, day 0, 7, 14, 28, 90 and 180 study visits. 
 
Due to the COVID-19 pandemic, there are participants whose Day 180 visits were impacted. We 
are requesting that the window for the day Day 180 visit be expanded by 90 days. Day 180 is the 
final visit/study endpoint for this study.  
 

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5 
STUDY POPULATION 
 
The study will enroll 10 healthy volunteers per vaccination season in years 1, 2, and 4, to analyze 
the immune response to influenza vaccination in healthy individuals.  For years 5 and 6, we 
anticipate enrolling a maximum of 20 participants, to analyze the immune response to influenza 
vaccination in healthy individuals.   
Total enrollment goal is up to a total of 70 subjects. Individuals who complete the study will be 
given the option to re-enroll in subsequent years as long as they continue to meet all 
inclusion/exclusion criteria. Re-enrolling subjects will be re-consented, given new subject 
identifiers, and counted towards the enrollment number goal for each year of participation.  
 
• 
Males and non-pregnant females confirmed to be non-pregnant immediately prior to 
vaccination, aged 18 - 49, inclusive. 
 
• 
Study subjects will be drawn from existing populations of students, staff, faculty, or 
volunteers at Emory University or other eligible healthy adults who may hear of the study by 
word of mouth. 
 
• 
Study subjects will be recruited via word of mouth and placement of recruitment flyers in 
key locations on campus. Social media messaging via Facebook and Twitter will also be 
used in an effort to increase the number of enrollees into this study. 
5.1 
Inclusion Criteria 
For inclusion into the study, a subject must satisfy all of the following criteria: 
1.  Male or female subjects between 18 and 49 years of age, inclusive 
2. 
Subjects capable of providing written informed consent prior to initiation of any study 
procedures. Subjects able to understand and comply with planned study procedures and 
be available for all study visits 
3. Screening labs within normal limits per the local laboratory normal ranges or considered to 
be not clinically significant by the investigator1.  Normal laboratory ranges are as listed 
below:  
A. Hematology:   
- 
Hemoglobin: Male- 12.9-16.1 gm/dL, Female- 11.4-14.4 gm/dL 
- 
White blood cells (WBC): Male- 4.2-9.2/uL, Female- 4-10/uL 
- 
Platelet count: 150-400/uL 
B. Chemistries:  
- 
Kidney function:Glomerular filtration rate (GFR)     >/= 60 mL/min/1.73 m2; 
 
 

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- 
 Liver enzymes: Albumin   >/= 3.5 g/dL; ALT <66 U/L; AST  <62 U/L  
4. Subjects who have not received the seasonal influenza vaccine in the current flu season 
and are not suspected to have had an influenza infection in the current flu season.  
5.  Female subjects of child bearing potential must have a negative urine pregnancy test at 
the screening visit, enrollment visit and all subsequent study visits longer than 14 days 
since the last pregnancy test.  
5.2 
Exclusion Criteria 
Subjects with any of the following will be excluded from the study:  
1. Known infection with HIV, HCV, or HBV. This information will be obtained verbally 
from the patient. 
2. If female, active pregnancy or breast-feeding or plans to become pregnant during 
study participation. 
3. Chronic medical conditions that cause immunodeficiency or that require 
medications which could alter immune function such as immunosuppressants  and 
immunoenhancers.  
4. Have any medical disease or condition that, in the opinion of the site principal 
investigator or appropriate sub-investigator, is a contraindication to study 
participation. This includes any chronic medical disease or condition, defined as 
persisting 3 months (defined as 90 days) or longer, 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 study 
 
5. Have an acute illness, as determined by the site principal investigator or 
appropriate sub-investigator, within 72 hours prior to study vaccination. An acute 
illness which is nearly resolved with only minor residual symptoms remaining is 
allowable if, in the opinion of the site principal investigator or appropriate sub-
investigator, the residual symptoms will not interfere with the ability to assess 
safety parameters as required by the protocol. 
 
6. Persons taking anticoagulants, long-term aspirin therapy, or long-term systemic 
steroids (greater than 3 months in the past 12 months and any within 30 days). 
7. Have known hypersensitivity or allergy to eggs, egg or chicken protein or other 
components of the study vaccine; 
8. Have a known latex allergy; 

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9. Have a history of severe reactions following previous immunization with licensed 
influenza virus vaccines 
10.Have a history of Guillain-Barre syndrome 
11.Subjects who had or are suspected to have had an influenza infection in the 
current influenza season 
12.Subjects who, at screening, have abnormal vital signs and/or physical exam, 
including a temperature ≥ 38.0 C, Systolic blood pressure ≤90 or≥160 mmHg, 
pulse ≤ 60 or > 110 beats per minute, new rash, signs of infection. 
13.Subjects who have already received the seasonal influenza vaccine in the current 
influenza vaccination season. 
5.3 
Handling of Withdrawals 
Subjects are free to withdraw from the study at any time.  Subjects are provided a revocation form 
at enrollment with withdrawal procedures clearly explained. Subjects who have developed an 
adverse event or serious adverse event will be followed for safety purposes. Subjects who develop 
any exclusion criteria will not continue to have blood drawn.  Subjects may be taken off the study 
without their consent if the study doctor determines that it is in his or her best interest not to 
continue to participate in the study, if the subject is unable to complete the required study 
procedures, or if the study is stopped by the Institution, the sponsor, or the Food and Drug 
Administration (FDA) or other health authorities.  If the subject is removed from the study, the 
Principal Investigator or designee will contact the participant to discuss the study stopping 
procedures.   
 
Participants who withdraw, or are withdrawn or terminated from the study, or are lost to follow-up 
after study enrollment visit will not be replaced.  
 
5.4 
Termination of Study  
The sponsor reserves the right to terminate the study at any time for clinical or administrative 
reasons.    
 

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6 
STUDY INTERVENTION PRODUCT 
6.1 
Study Product Description 
Each flu season, the vaccine used in this study will be a licensed seasonal inactivated 
influenza vaccine that is approved by the FDA for the current flu season. The vaccine 
product used will depend upon supply stocked by the Emory University Hospital 
Investigational Drug Services (IDS). These vaccines are typically provided in pre-filled 
syringes (clear syringe plunger rod), 0.5 ml.  If pre-filled syringes are not available from the 
manufacturer, the study product will be provided in a latex free vial, 5 ml, one vial per 
carton. 
6.1.1 Acquisition  
The licensed vaccine will be provided by the Emory University Hospital Investigational Drug 
Pharmacy and will be stored in a secure temperature-monitored refrigerator in a secure, 
limited access storage area. 
6.1.2 Formulation, Packaging, and Labeling 
The vaccine used in this study is the licensed seasonal inactivated influenza vaccine and 
will be supplied by Emory University Hospital Investigational Drug Services (IDS) in a pre-
filled syringe placed in a clear plastic bag labeled with the DMID protocol number, study ID, 
and dosing instructions per the prescription signed by Dr. Mehta or a designee.   
6.1.3 Product Storage and Stability 
Per the package insert from the manufacturer, the seasonal inactivated influenza vaccine 
will be stored at 2-8 degrees C (35-45 degrees F) in a study specific designated location in 
a refrigerator at the Emory University Hospital Investigational Drug Services.  The 
refrigerator temperature is monitored via the Temp Trak system, an electronic temperature 
monitoring system that records temperatures every five minutes 24 hours a day.   The 
refrigerator is set to alarm at 2.5 degrees C or 7.5 degrees C. If there is a deviation in 
temperature, the Temp Trak system will notify the Emory IDS pharmacist via an alarm 
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6.2 
Dosage, Preparation and Administration of Study Intervention Product 
Upon receipt of the signed prescription, an Emory IDS pharmacist will prepare the study 
drug and, per standard operating procedure, will have a 2nd pharmacist double check the 
study prescription with the study product and label before dispensing the drug to the clinical 
research nurse for administration.  An Emory IDS pharmacist or pharmacy technician will 
walk over the study product to the clinic procedure area and then deliver it to the research 
coordinator. The pharmacist or pharmacy technician will hand the subject’s medication to 
the clinical research nurse who will then verify the correct protocol, subject name and study 
ID, study product, dosing instructions per signed prescription, and study product expiration 
date using a checklist. 
A vaccine dose of 0.5 mL will be administered by qualified personnel at the GCRC 
intramuscularly (IM) in the subject’s preferred arm per the manufacturer’s instructions.   
6.3 
Accountability Procedures for the Study Intervention Product(s) 
The Emory Investigational Drug Service will maintain and monitor the inventory of the 
influenza vaccine per their standard operating procedures (SOPs). 
6.4 Assessment of Participant Compliance with Study Intervention Product  
Each participant will be assessed for compliance with the influenza vaccination via his or 
her receipt of 0.5ml of vaccine without immediate reaction.  
6.5 
Concomitant Medications/Treatments 
 
Subjects with chronic medical conditions or taking medications that are prohibited 
according to Section 5.2 Exclusion Criteria will be excluded from study participation.  The 
medication history will be reviewed and updated at every study visit to ensure that subjects 
are not taking the medications prohibited for study participation. Subjects will be allowed to 
take anti-pyretics (e.g. acetaminophen) and/or non-steroidal anti-inflammatories (NSAIDs; 
e.g. ibuprofen) after vaccination if desired by subject.  

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7 
STUDY SCHEDULE 
7.1 
Screening (Day -1 to day -30)  
Potential participants will be screened for eligibility within 30 days prior to the administration 
of the study product. Screening period begins at screening visit and continues through 
enrollment visit. Qualified subjects will be scheduled for enrollment visit 1-day post 
screening visit through 30 days post screening visit.  At screening, the following activities 
will be performed: 
• 
Participants will be provided with a description of the study (purpose and study 
procedures) and asked to read and sign the informed consent form. The informed 
consent form will be signed prior to performing any study procedures, including any 
screening procedures. 
• 
Complete medical history will be obtained by interview of participants to assure 
eligibility, including history of prior influenza vaccinations.  
• 
All concomitant medications will be recorded on the appropriate data collection 
form. 
• 
Demographic information will be collected from the participant. 
• 
Eligibility criteria will be reviewed.  
• 
A urine pregnancy test will be performed on all female participants of childbearing 
potential and must be negative. 
• 
Approximately 16 ml (about 1 tablespoon) of venous blood will be collected for 
chemistry and hematology performed by the site laboratory. The results will be 
provided by the site laboratory and be reviewed by the principal investigator.  
• 
Targeted physical exam, including height, weight and vital signs (oral or axillary 
temperature, pulse, blood pressure.). 
7.2 
Enrollment/Baseline 
 
 
 
Day 0 – Baseline and vaccination 
• 
Reconfirm participant’s willingness to take part in the study prior to performing any 
study procedures. 
• 
Eligibility criteria, including results of all clinical screening laboratory evaluations, will 
be reviewed to assure continued eligibility prior to vaccination. 
• 
All concomitant medications taken since the screening visit will be recorded on the 
appropriate data collection form. 
• 
Vital signs, including oral or axillary temperature, pulse, and blood pressure, will be 
obtained to assure eligibility.  
• 
In the event that the enrollment visit exceeds 14 days from screening visit, a urine 
pregnancy test will be performed for all females of childbearing potential, to confirm 
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• 
Approximately 48 ml of blood (3 tbsp) will be drawn from the subject prior to 
vaccination 
• 
A seasonal inactivated influenza vaccine will be administered by an intramuscular 
injection into the deltoid muscle of the subject's preferred arm.   
• 
The subject will be monitored for 15 minutes after vaccination to ensure that no 
acute reactions occur. 
• 
Due to the COVID-19 pandemic, all non-essential research was halted in mid-March 2020. 
New enrollments were placed on hold for this study.  
 
7.3 
Follow-up and Final Visits 
 
Follow-up visits: Days 7, 14, 28, 90, 180. 
• 
Study participants will be asked to return for five follow up visits, with the respective window 
periods, per the table below: 
 
Time point 
Day 
7 
14 
28 
90 
180 
Window 
+/- 1 
+/- 2 
+/- 3 
+/- 10 
+/- 14 (a 90 
day window 
expansion is 
being 
requested) 
 
 
 
 
 
 
Blood Volume 
96mL 
96mL 
64mL 
64mL 
64mL 
 
• 
Medical history will be reviewed and updated as appropriate. 
• 
All concomitant medications taken since the previous study visit will be recorded on the 
appropriate data collection form. Previously recorded medications will be updated as 
appropriate. 
• 
Study personnel will discuss with participants and assess and record all AE/SAEs. 
Previously recorded AE/SAEs will be updated as appropriate. 
• 
Approximately the amount of venous blood, as indicated by the table above, will be 
collected for research assays.    
• 
Targeted physical exam will be done only as dictated by a change in medical history. 
• 
A urine pregnancy test will be performed on all female participants of childbearing potential  

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for any visit longer than 14 days from the last pregnancy test.. 
• 
Follow-up visits were also halted, which impacted several participants’ Day 180 
follow-up visit.  
• 
We are requesting that the windows for the Day 180 visit be extended by 90 days.  
• 
Extending the window for the Day 180 follow-up visits would allow samples from 
participants whose visits were halted at this time point to be collected once the 
Emory restrictions regarding COVID-19 are lifted and staff can reasonably collect 
samples, dependent upon when the University and applicable Unit and School 
allow. The scientists feel that the samples, even if a few months late, will greatly 
help evaluate the longevity of the responses to flu vaccines. 
• 
Study activities will not be changed, just the timing of the Day 180 visit. 
 
7.4 
Early Termination Visit 
There are no special or routine evaluations to be done at an early termination visit; subjects will not 
be asked to come in for an additional visit if they decide to end their participation in the study or the 
study is terminated. If the study is terminated early, the subject will be informed via telephone of 
the reason for early termination.   
7.5 
Unscheduled Visit 
Unscheduled visits are not anticipated with this study, but may occur at any time during the study. 
Any of the following activities may be performed: 
• 
Medical history will be reviewed and updated as appropriate. 
• 
All concomitant medications taken since the study visit will be recorded on the appropriate 
data collection form. Previously recorded medications will be updated as appropriate. 
• 
Study personnel will discuss with participants and assess and record all AE/SAEs. 
Previously recorded AE/SAEs will be updated as appropriate. 
• 
Vital signs, including oral or axillary temperature, pulse, blood pressure and will be 
obtained. 
• 
A targeted physical examination will be performed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or 
sub-investigator. 

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• 
Approximately 10 mL of venous blood will be collected for chemistry and/or hematology 
performed by the local or site laboratory if deemed necessary by Dr. Mehta or a designee. 
• 
A urine pregnancy test will be performed on all female participants of childbearing potential.  
 

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8 
STUDY PROCEDURES AND EVALUATIONS 
8.1 
Clinical Evaluations 
• 
Clinical interview of subject at screening to include:  
o Demographics: age, date of birth, gender, ethnicity, race  
o History of allergies: food, drug, environmental, specifically solicit if any allergy to 
vaccines or eggs 
o History of influenza vaccination, and previous reactions, if any 
o History of Guillain-Barre syndrome 
o History of medications taken within the past 90 days to include prescription and over 
the counter medications, specifically solicit if any blood thinners or 
immunosuppressive agents have been used 
o History of any vaccinations within the past year 
o Acute or chronic medical conditions as reported by subject 
• 
Vital signs (blood pressure, pulse, temperature, height, weight) 
• 
Targeted physical exam  
• 
Collection of blood for clinical laboratory tests at screening visit (16 ml) 
• 
Collection of research blood samples at study visits: day 0 (48 ml), 7, 14 (96 ml), 28, 90 
and 180 (64 ml).  
• 
Administration of licensed seasonal inactivated influenza vaccine by the clinical research 
nurse at Day 0 
• 
Clinical health assessment at follow up study visit to include inquiry regarding any illness, 
any change in medication, and any overall health changes since last study visit. 
• 
A urine pregnancy test will be performed on all female participants of childbearing potential 
and must be negative. 
 
8.2 
Laboratory Evaluations/Assays 
The participating laboratories are Emory Medical Laboratories. 
The following clinical laboratory evaluations will be performed in the study: 
• 
Urine Pregnancy Test for women of childbearing potential  

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• 
Hematology:  hemoglobin, white blood cells (WBC), platelet count.[ Acceptable ranges: 
WBC: Male-  4.2-9.1/uL, Female- 4-10/uL; Hemoglobin: Male- 12.9-16.1/dL, Female- 
11.4-14.4/dL; Platelet 150-400/uL] 
• 
Chemistries:  creatinine, liver enzymes [Acceptable ranges: calculated Glomerular 
filtration rate (GFR) >/= 60 mL/min/1.73 m2; Albumin    >/= 3.5 gm/DL;  ALT   <66 u/L; 
AST   <62 u/L] 
 
Research Laboratory Assays: 
• 
Innate responses in the blood and mucosal sites: The serum analyses of cytokines and 
chemokines associated with innate immunity will be determined by multiplex analysis,, 
including IP-10, Th1 cytokines (IFN-g, TNF, IL-2), Th2 (IL-4, IL-5, IL-13) and regulatory (IL-
10) cytokines. Flow cytometric analysis of innate cell populations (dendritic cell subsets, 
monocyte subsets, NK cell subsets and innate lymphoid cells) will be performed using 
antibody panels routinely in use in the research laboratory 
• 
B cell and CD4 T cell responses: The following influenza virus-specific responses will be 
analyzed in the blood after vaccination:  
• 
Serum antibody: We will measure the HAI titers, neutralizing antibody responses, 
and the influenza-specific serum antibody levels (IgG, IgA, and IgM) using ELISA at 
all time-points. 
• 
Plasmablasts: The influenza-specific plasmablast response will be quantitated using 
both ELISPOT and flow cytometry at day 7 post-vaccination.   
• 
Memory B cells: The kinetics of the IgG memory B cell influenza-specific response 
will be quantitated using an established assay. 
• 
CD4 T cells: The HA-specific CD4 T cell responses will be quantitated at each time 
point by ex vivo stimulation using overlapping HA peptides or HA protein of the 
different influenza strains present in the vaccine. The following cytokines will be 
analyzed using ICS or ELISPOT: Th1 cytokines (IFNg, TNF-a, and IL-2); Th2 
cytokines (IL-4 and IL-10); and TFH cytokines (IL-21 and IL-4).  We will put a specific 
focus on analyzing CD4 T follicular helper (TFH) responses since these cells 
specialize in B cell help and are critical for the formation and maintenance of 
germinal centers. The germinal center reaction, in turn, is necessary for the 
generation of high affinity antibody responses and memory B cells. In addition, TFH 
cells secrete the cytokine IL-21 that is essential for generating long-lived plasma 
cells and sustaining antibody responses. Therefore the generation of long-term 
humoral immunity is critically dependent on CD4 TFH cells.  
8.2.1 Specimen Collection, Preparation, Handling and Shipping 
Samples will be drawn, labeled and logged by a skilled clinical research nurse or phlebotomist, 
under the supervision of the principal investigator and in accordance with site specific SOPs. 
Checklists will be utilized to verify appropriate sample collection, transportation, processing, and 
storage.  

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Subjects consented to participate in this study will also be asked to consent to storage of any 
unused blood for future assays. If new studies are identified, the de-identified samples of subjects 
who have consented to storage of their unused blood will be utilized.   
 
 
8.3 
Procedures to be followed in the Event of Abnormal Laboratory Test Values 
or Abnormal Clinical Findings  
For subjects with values in the clinically significant range, the lab abnormalities will be 
explained to the study participant by the principal investigator or a designee. The designee 
may be clinical study personnel (Clinical Research Coordinator, Study Coordinator or 
Research Nurse) as indicated on the Delegation of Authority log. The subject will be given a 
copy of his or her abnormal lab report and instructed to follow up with his or her primary health 
care provider or health clinic.  Abnormal clinical values obtained from screening labs, which 
are done prior to treatment, will be considered to render the subject a screen failure and will 
not considered to be adverse events. Any subject with Lab values outside of clinical range will 
be informed of the value and referred to their PCP for follow up. 
 

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9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
Only FDA approved, licensed seasonal inactivated influenza vaccine will be administered in this 
protocol as standard of care during influenza vaccine season, following the manufacturers’ 
instructions and safety precautions. 
 
For the purposes of this study, reportable adverse events are limited to any occurrence or 
worsening of an undesirable or unintended sign, symptom or disease that is specifically associated 
with a study procedure that is not part of the normal standard of care for the participant.  As 
previously mentioned, there are minimal risks associated with venipuncture for obtaining research 
related labs. Foreseeable adverse events associated with venipuncture are: mild, temporary 
discomfort at the venipuncture site, bruising, and phlebitis. Very rarely, subjects may experience 
“vaso-vagal syndrome” during phlebotomy. Vaso-vagal reactions may include diaphoresis, nausea, 
syncope and rarely loss of consciousness.   
 
Anticipated adverse events related to administration of the inactivated influenza vaccine include: 
localized erythema, induration, swelling, itching and/or pain at the injection site, mild fever, 
myalgia, headache and malaise following vaccination. Since immunization with flu vaccine 
annually is offered as standard of care to healthy adults to prevent influenza infection, these 
anticipated reactions to the vaccine will not be considered reportable adverse events. Illness 
requiring hospitalization as deemed related to vaccination will be reported as an adverse event. 
Any adverse event listed by the vaccine manufacturer as a contraindication to further doses of the 
vaccine will be considered an adverse event for the study. 
 
9.2 Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
9.2.1 Adverse Events 
Any adverse events occurring as a result of obtaining blood samples will require clinical review, 
monitoring and treatment as needed until resolution or stabilization, and assessment for severity 
and relatedness. Subjects will be asked about final resolution of symptoms upon completion of 
each visit. 
 
Adverse Event:   

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ICH E6 defines an AE as any untoward medical occurrence in a subject or clinical investigation 
participant administered a pharmaceutical product regardless of its causal relationship to the study 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of medicinal 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.  
All AEs including local and systemic reactions not meeting the criteria for “serious adverse events” 
will be captured on the appropriate CRF.  Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship to study product (assessed only by 
those with the training and authority to make a diagnosis, which would include MD, PA, Nurse 
Practitioner, DO, or DDS), and time of resolution/stabilization of the event.  All AEs occurring while 
on study will be documented appropriately regardless of relationship.  All AEs will be followed to 
stabilization or 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 it deteriorates at any time during the study, it will 
be recorded as an AE. 
All AEs will be graded for severity and relationship to study product.  
FDA defines an AE as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
Severity of Event:  All AEs will be assessed by the clinician using a protocol defined grading 
system.  For events not included in the protocol defined grading system, than the following 
guidelines will be used to quantify intensity.  
• 
Mild:  events require minimal or no treatment and do not interfere with the subject’s daily 
activities. 
• 
Moderate:  events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe:  events interrupt a subject’s usual daily activity and may require systemic drug therapy 
or other treatment. Severe events are usually incapacitating. 
• 
Life threatening:  any adverse drug experience that places the subject or subject, in the view of 
the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that had it occurred in a more severe form, might have caused death. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of intensity to be performed.  Adverse events characterized as intermittent will 
require documentation of onset and duration of each episode. 
Relationship to Study Products:  The clinician will assess an AE's relationship to influenza 
vaccine as part of the documentation process, but it is not a factor in determining what is or is not 
reported reported.  All AEs will have their relationship to study product assessed using the terms:  
related or not related using the following guidelines: 

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• 
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between 
the study product and the adverse event. 
• 
Not Related – There is not a reasonable possibility that the study product caused the event. 
 
Adverse events will be followed until resolved or considered stable. Any adverse event listed by 
the vaccine manufacturer as a contraindication to further doses of the vaccine will be considered 
an adverse event for the study. Any adverse event listed in the VAERS Table of Reportable Events 
Following 
Vaccination 
 
found 
using 
the 
following 
link 
http://vaers.hhs.gov/resources/VAERS_Table_of_Reportable_Events_Following_Vaccination.pdf 
that occurs within the specified time period after vaccination or, if  in the judgment of the PI, any 
unexpected reaction to the vaccine will be reported to VAERS with a copy faxed or emailed to the 
DMID CPM and MO at time of VAERS reporting. These reports will be made using the timelines 
outlined at  
https://vaers.hhs.gov/resources/VAERS_Table_of_Reportable_Events_Following_Vaccination.pdf.  
All adverse events that meet the reporting requirements of the Institutional Review Board will be 
reported to the IRB within 10 days of the investigator learning of the event as delineated by the 
requirements listed on the Emory IRB website at: http://www.irb.emory.edu/documents/AE-PD-
UPchart.pdf. These events will also be faxed or emailed to the Clinical Project Manager at time of 
IRB reporting. Per these guidelines, these adverse events would include those that are 
unanticipated, related to the study intervention and involve risk to the study participant  
All Adverse events not meeting the reporting requirements of the Emory IRB will be reported to the 
clinical project manager periodically in monthly clinical reports and to the IRB periodically at annual 
continuing reviews.  
 
9.2.2 Serious Adverse Events 
Serious Adverse Event (SAE): Serious Adverse Events will be collected from the time the 
participant begins the study until study completion, or until the participant withdraws from the 
study. SAE’s will be documented on the Adverse Event form and reported to the DMID CPM and 
MO. 
• 
All deaths and life-threatening events, regardless of relationship will be recorded on 
the SAE form and sent by fax to DMID CPM and MO within 24 hours of site awareness 
of the death or life-threatening event. 
• 
All other SAEs, regardless of relationship will be recorded on the SAE form and sent 
by fax within 72 hours of becoming aware of the event.  
 
A Serious Adverse Event is defined as an AE meeting one of the following conditions: 
• 
Death during the period of protocol defined surveillance 
• 
Life Threatening Event (defined as a subject at immediate risk of death at the time of the 
event) 

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• 
An event requiring inpatient hospitalization or prolongation of existing hospitalization during 
the period of protocol defined surveillance  
• 
Results in congenital anomaly or birth defect 
• 
Results in a persistent or significant disability/incapacity. 
• 
Any other important medical event that may not result in death, be life threatening, or require 
hospitalization, may be considered a serious adverse experience when, based upon 
appropriate medical judgment, the event may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed above.  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. 
Events not considered to be serious adverse events are hospitalizations for the:  
• 
routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.  
• 
treatment, which was elective or pre-planned, for a pre-existing condition that is unrelated 
to the indication under study and did not worsen 
• 
treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions 
of serious given above and not resulting in hospital admission 
 
 
All SAEs will be followed until satisfactory resolution or until the PI or co-investigator deems the 
event to be chronic or the subject to be stable. All SAEs will be reported to the Vaccine Adverse 
Event Reporting System (VAERS). 
 
The DMID Medical Officer will review and assess the SAE for regulatory reporting and potential 
impact on the study subject safety and protocol conduct. 
 
 
9.2.3 Other Adverse Events (If applicable)  
Not Applicable  
9.3 
Reporting Procedures and Safety Oversight  
This is a minimal risk study.  Due to its nature very few, if any, serious adverse events are likely 
to be chronologically or causally related to study procedures, and any adverse events that do 
occur are likely to be mild, transient, and self-limiting. Therefore, adverse events, including 
serious adverse events, will be collected and reported to the IRB/IEC and  DMID except for 
anticipated reactions noted in Section 9.2.1, an Independent Safety Monitor will not be required, 
and a formal Safety Monitoring Committee will not be constituted. All Adverse events will be 
communicated to the DMID and to the IRB as delineated by Emory Internal Review Board 
reporting requirements stated in section 9.2.1 and 9.2.2.      
 

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9.3.1  Reporting of Pregnancy 
A negative urine pregnancy testing is required for all women of childbearing potential prior to 
participating in the study. A urine pregnancy test will be performed at the screening visit and 
subsequently at any visit if the visit occurs +14 days after the last pregnancy test visit.  If a subject 
becomes pregnant after enrollment in the study or reports it to the research team, the pregnancy 
will be reported as stated in section 9.3. Pregnant subjects will be withdrawn from the study and 
pregnancy will be followed for safety monitoring monthly to the point of pregnancy outcome. 
 
9.4 
Type and Duration of Follow-up of Participants after Adverse Events 
Clinical studies at Emory University are compliant with ICH E6 guidelines for Good Clinical 
Practice.  
Adverse events will be documented and reported according to the DMID and Emory IRB 
policies (as described in section 9.2.1 and 9.3). All AEs and SAEs will be followed until 
resolved, return to baseline or stable as determined by the study team.  The occurrence of 
AEs and the status of existing AEs will be assessed at each study visit and events are 
recorded in the regulatory binder.  Subjects will be encouraged to contact study staff of any 
health changes that may occur between study visits.  An unscheduled visit or telephone 
follow-up may occur depending on the adverse event. 
9.5 
Halting Rules 
This is a minimal risk study. It is not anticipated that there will be a need to halt the study due to 
SAEs. The study will be halted if the following occurs: 
• 
One or more participants have laryngospasm, bronchospasm, or anaphylaxis associated 
with study procedure and occurring within 72 hours post study procedure;  
• 
Any SAE associated with study product or procedure; 
• 
Two or more participants experience the same or similar severe or life-threatening AE 
judged to be associated with study procedure.   
 
9.6 
Safety Oversight  
Serious and severe adverse events will be reported to DMID. DMID has the authority to stop 
study enrollment, vaccinations and procedures if AEs are reported that meet halting criteria.    
9.7 
Independent Safety Monitor (ISM) 
Not Applicable.  

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10 
CLINICAL MONITORING  
Purpose: to protect the rights and well-being of human subjects in this study; to ensure that data 
are accurate, complete and verifiable from source documents; to ensure that conduct is in 
compliance with the currently approved protocol/amendments, with Good Clinical Practice, and 
with regulatory requirements. 
10.1 
Site Monitoring Plan 
 
Site monitoring will be conducted using the DMID tools provided to ensure that human subject 
protection, study procedures, laboratory procedures, and data collection processes are of high 
quality and meet sponsor, GCP/ICH, and regulatory guidelines, and that the study is conducted in 
accordance with the protocol and sponsor standard operating procedures. DMID, the sponsoring 
agency, or its designee will conduct site-monitoring visits as defined in the CQMP. 
 
A protocol-specific Clinical Quality Management Plan (CQMP) has been approved for this study by 
DMID which provides details for site monitoring. The Quality Assurance (QA) plan will be 
implemented by a weekly review of source documents by the CRC to determine adherence to 
protocol requirements. The Quality Control (QC) plan will be implemented by daily observation and 
documentation of the site’s work processes by study staff, to ensure that accepted procedures are 
followed. 
 
Site visits may 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, sample tracking log, CRFs, informed consent forms, medical and laboratory 
reports, and protocol compliance. Study monitors will meet with investigators to discuss any 
problems and actions to be taken and document visit findings and discussions.  Emory University 
IRB and other regulatory agencies may conduct study monitoring visits.  
 
 
 
 
 
 

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11 
STATISTICAL CONSIDERATIONS 
For this study we will assess immunologic responses in the periphery (blood). These responses 
contain a variety of immunologic assays with different types of response output. Hence our primary 
data analytic strategy will be the use of longitudinal data analysis methods to determine the 
temporal course of a given response measurement and factors associated with heterogeneity in 
that temporal course. Study outcomes will be measured using numerical data from laboratory 
assays including flow cytometry and ELISPOT assays. A detailed data management system will 
utilize general linear mixed models for continuous responses to assess differences among time 
points. 
 
11.1 
Study Hypothesis 
 
To investigate the longevity of humoral immunity to influenza virus in humans. Our overarching 
hypothesis is that an understanding of how long-term humoral immunity to influenza virus is 
generated and maintained is essential for the development of a “universal” vaccine against 
influenza virus. This aim will be accomplished by measuring the total influenza-specific, memory B-
cells and serum antibody levels over extended periods following vaccination. 
 
11.2 
Sample Size Considerations 
In our preliminary studies, we found that vaccine-elicited plasmablasts that are specific to the stalk 
region of HA (the broadly protective region) were induced in 20% of subjects after receiving the 
annual inactivated trivalent influenza vaccine. This analysis was done on only 20 subjects and we 
would like to test the consistency of our observation with a larger sample size of 50. 
11.3 
Planned Interim Analysis  
                  Not Applicable  
11.4 
Final Analysis Plan  
 
We will be utilizing the paired Student’s t-test to determine whether the observed increase in serum 
antibody titers from baseline to 4 weeks after vaccination is significant or not. We do not anticipate 
any major change in our analysis strategy. For all of this analysis we will work the Emory/UGA 
CEIRS Data Management Team headed by Dr. Hertzberg using the approved Data Management 
Plan for this contract. 
 

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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
The site will maintain appropriate medical and research records for this study in compliance with 
ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects.  The site will permit authorized representatives of the DMID, its 
designees, and appropriate regulatory agencies to examine (and when required by applicable law, 
to copy) clinical records for the purposes of quality assurance reviews, audits 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, pharmacy dispensing records, recorded data from automated instruments, x-rays, 
and subject files kept at the laboratories involved in the study.  CRFs will serve as source 
documents.  Laboratory reports will serve as source documents for lab results required at 
screening. All study documents will be secured by key and/or password protection. 
 

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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
A Clinical Quality Management Plan (CQMP) has been approved by DMID, for the overall Center 
and for this specific protocol.  The site will conduct the study, generate data and maintain 
documentation in compliance with the protocol, the CQMP, ICH-GCP and all applicable regulatory 
requirements.  All source documents will be reviewed by the study team.  Adverse events will be 
assessed for severity and graded in accordance with that scale (mild, moderate, severe, life-
threatening) and causality and reviewed by the PI or designee.  Study staff will be trained to use 
the clinical data collection program RedCap which includes tools for QA/QC.  The clinical PIs will 
supervise and oversee the clinical staff on this study, and the center PI will supervise the 
administrative personnel.  During the study, the site will maintain complete and accurate 
documentation for the study. The Investigator is responsible for ensuring the accuracy, 
completeness, legibility and timeliness of the data submitted. Research data resulting from this 
study will be reported to the CEIRS Data Processing and Coordinating Center (DPCC) as defined 
in the contract agreement. 
. 
The Quality Assurance (QA) plan will be implemented by a weekly review of source documents by 
the CRC to determine adherence to protocol requirements.  
 
The Quality Control (QC) plan will be implemented in real time during study procedures to ensure 
and document the site’s work processes by study staff, to ensure that accepted procedures are 
followed. 
 
Clinical Quality Management assessment will be will be approached as an ongoing, interactive tool 
that will address the current version of the protocol. 
 
 
 

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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the US National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the 
ICH E6; 62 Federal Regulations 25691 (1997).   
14.2 
Institutional Review Board 
The Emory University IRB will review and provide approval of this protocol and the associated 
informed consent documents, recruitment materials and procedures as required by OHRP and 
local requirements before subject enrollment.  The Emory University IRB currently holds and will 
maintain a US FWA issued by OHRP for the entirety of the study.  Any amendments to the 
protocol or consent materials will be approved before they are placed in use.  An independent 
ethics committee may review the study at any time. 
 
14.3 
Informed Consent Process 
Informed consent will be initiated prior to the individual’s agreeing to participate in the study and 
continuing throughout the individual’s study participation.  Extensive discussion of risks and 
possible benefits of participation in this study will be provided to the subjects.  Consent forms 
describe in detail the study procedures and risks, and written documentation of informed consent is 
required prior to enrollment in the study.  Consent forms are IRB approved and the subject will be 
asked to read and review the document. Upon reviewing the document, the research nurse will 
explain the research study to the subject and answer any questions that may arise. The subjects 
will sign the informed consent document prior to being enrolled in the study.  They will have ample 
opportunity to discuss the study or think about it prior to agreeing to participate.  The subjects may 
withdraw consent at any time throughout the course of the study.  A copy of the informed consent 
document will be given to the subjects for their records.  The rights and welfare of the subjects will 
be protected by emphasizing to them that the quality of their medical care is not adversely affected 
if they decline to participate in, or withdraw from, this study. 
 
14.3.1 Informed Consent/Assent Process (in Case of a Minor) 
Not applicable 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
Not applicable 

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14.5 
Participant Confidentiality 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence.  No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
The study monitor or other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study.  The 
clinical study site will permit access to such records.  A representative from the Emory IRB may 
also have access to the subject’s record. 
To protect privacy, the NIH has provided a Certificate of Confidentiality, CoC.  With this CoC, the 
participating sites cannot be forced to release information that may identify the participant, even by 
a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings.  The participating sites will use the CoC to resist any demands for information that 
would identify the participant, except as explained below. 
The CoC cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of federally funded projects, like this study or 
local laws, such as for reporting of communicable diseases. 
A CoC does not prevent the participant from voluntarily releasing information about themselves or 
their involvement in this research.  If any person or agency obtains a written consent to receive 
study information, then the participating sites may not use the CoC to withhold that information.   
The CoC does not prevent the participating sites from reporting without the participant’s consent, 
information that would identify the subject as a participant in the study regarding matters that must 
be legally reported including: child and elder abuse, sexual abuse, or wanting to harm themselves 
or others. 
14.6 
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 principal 
investigator, or other study personnel.  As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
All protocol deviations, as defined above, must be addressed in study subject source documents.  
A completed copy of the Protocol Deviation Form must be maintained in the Regulatory File as 
well as in the subject's chart. 
It is the responsibility of the principal investigator and other study personnel to use continuous 
vigilance to identify and report deviations.  The principal investigators and other study personnel 
are responsible for knowing and adhering to their IRB/IEC requirements.  Only protocol deviations 
that are related to subject safety and/or eligibility will be reported to the local IRB/IEC per its 

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guidelines.  Line listings of protocol deviations that are reported to the IRB/IEC will be submitted to 
DMID on a quarterly basis. 
14.7 
Study Discontinuation 
If the study is discontinued, participants will be contacted via telephone and in writing.  Due to the 
nature of this study, subjects are not required to come in for a final visit in the event of study 
closure and it is not anticipated that an enrolled study participant will require continued follow-up 
after study closure. 
 
14.8 
Future Use of Stored Specimens 
 
Subjects who consent to participate in the study will be asked, as part of the informed consent 
process, to agree to or refuse his/her specimen to be used for future research as noted in the 
protocol and consent form. This decision can be changed at any time by the participant without 
penalty.  

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15 
DATA HANDLING AND RECORD KEEPING 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported.  All source documents will be completed in a neat, legible manner to ensure 
accurate interpretation of data using black ink to ensure clarity of reproduced copies.  When 
making changes or corrections, the original entry will be crossed out with a single line, initialed and 
dated. The original text will not be erased, overwritten, or altered with correction fluid or tape on the 
original. 
 
15.1 
Data Management Responsibilities 
 
All source documents and laboratory reports will be reviewed by the clinical team and data entry 
staff, who will ensure that they are accurate and complete.   
Data collection is the responsibility of the clinical study staff at the site under the supervision of the 
clinical PIs.  During the study, the investigators will maintain complete and accurate documentation 
for the study. Research data resulting from this study will be reported to the CEIRS Data 
Processing and Coordinating Center (DPCC) as defined in the contract agreement. 
15.2 
Data Capture Methods 
Both paper and electronic recording of data will be used in this study. Paper data will be scanned 
and electronically uploaded to a central clinical database (RedCap) that is password-protected, 
HIPAA compliant and FISMA compliant.  
 
Exposure data will be captured on CRFs after interviewing the participants. Laboratory data will be 
recorded on CRFs upon completion of the laboratory analysis. All CRFs will be used as source 
documents and all data will be entered into one clinical database, RedCap. CRFs may be used as 
source documents if they represent data collected for the study and are where data were initially 
recorded. 
 
If data are obtained at a later date (i.e., after the study visit) and are recorded on the CRF as 
source documentation, it will be signed/initialed and dated. 
 
If data are transcribed from another source onto the CRF, the CRF is not considered to be the 
original source document and it will not be used as source documentation.  
 
As detailed in the CEIRS contract, overall CEIRS data sharing will adhere to the following 
schedule:  
• 
Basic research data: provided to Data Processing Coordinating Center within 2 
months post publication 

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15.3 
Types of Data 
 
Data for this study will include safety assessments and research laboratory assays data. 
 
15.4 
Timing/Reports 
 
The final report will include a comprehensive analysis of the data. 
15.5 
Study Records Retention 
 
Records and documents pertaining to the conduct of this clinical study, including CRFs, source 
documents, and consent forms will be retained by the investigator for at least 2 years following the 
date of completion of the study. No study records will be destroyed without prior authorization by 
DMID. These documents will be retained for a longer period, however, if required by local 
regulations.  
 

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16 
PUBLICATION POLICY 
Following completion of the study, the research investigators will publish data as defined in the 
contract and as directed by the CO and COR. 

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17 
LITERATURE REFERENCES (in section 2.1) 
 
(1) Thompson, WW; Shay, DK; Weintraub, E; Brammer, L; Cox, N, et al. Mortality associated with 
influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179–86.3. 
 
(2) Centers for Disease Control and Prevention (CDC). Prevention and control of seasonal 
influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices-
-United States, 2013-2014.MMWR Recomm Rep. 2013 Sep 20;62(RR-07):1-43. 
 
(3) Künzel W, Glathe H, Engelmann H, Van Hoecke C.  Kinetics of humoral antibody response to 
trivalent inactivated split influenza vaccine in subjects previously vaccinated or vaccinated for the 
first time. Vaccine. 1996 Aug;14(12):1108-10 
 
(4) Pica N, Palese P. Toward a universal influenza virus vaccine: prospects and challenges. 
Annu Rev Med. 2013;64:189-202.. 
 

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18 
SUPPLEMENT/APPENDICES 
 
Appendix A: Schedule of Events  
 
 
 
Procedures 
Screening 
(day -30 
thru -1) 
Day 0 
Day 7 
Day 14 
Day 28 
Day 90 
Day 
180 
Unsch. 
Visit 
Study Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical HX/ 
Medication HX 
X 
 
 
 
 
 
 
 
Height/Weight 
X 
 
 
 
 
 
 
 
Targeted 
Physical Exam 
X 
 
 
 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical/Baseline 
labs: Hgb, Hct, 
Plts, GFR, LFT’s 
X 
 
 
 
 
 
 
X 
AE/SAE 
Assessment 
 
 
X 
X 
X 
X 
X 
X 
Conmeds 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
Testing  
X 
X 
 
X 
X 
X 
X 
X 
Enrollment 
 
     X 
 
 
 
 
 
 
Peripheral blood  
draw for 
research 
immunity testing 
 
X 
X 
X 
X 
X 
X 
 
Administration of 
Influenza 
Vaccine 
 
X 
 
 
 
 
 
 
 *  For oral temperature, participants must not eat or drink anything hot or cold, or smoke within 10 
minutes prior to taking temperature 
** for women of child-bearing potential for whom enrollment visit occurs >14 days after     
screening visit  
Appendix B: Informed Consent Form (See attached)  

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Appendix C:  Study Flow Chart 
 
 
 
 
 
 
 
 
 
 
Screening/enrollment 
Post flyers 
 Screening labs to 
Emory Medical Lab 
Subject samples to Dr. 
Ahmed’s research lab 
Regulatory and 
essential docs/data to 
central database 
Ongoing QA/QC by site staff 
DMID oversight/site visits 
Subject visits follow 
defined time points 
Hard copies to 
regulatory binder