A Pragmatic Assessment of Influenza Vaccine Effectiveness in the DoD
Phase: PHASE4
Conditions: Influenza, Influenza-like Illness, Influenza Vaccines
Sponsor: Henry M. Jackson Foundation for the Advancement of Military Medicine

EIRB Protocol Template (Version 1.30)
1.0
General Information
*Please enter the full title of your study:
IDCRP-120 A Pragmatic Assessment of Influenza Vaccine Effectiveness in the DoD (PAIVED)
 
 
*Please enter the Protocol Number you would like to use to reference the protocol:
IDCRP-120 (v13.0, eIRB 1.30, 13DEC2022)
* This field allows you to enter an abbreviated version of the Protocol Title to quickly identify 
this protocol.
 
 
Is this a multi-site study (i.e. Each site has their own Principal Investigator)?
Yes
 
 
Does this protocol involve the use of animals?
Yes
No
 
 
2.0
Add Site(s)
2.1 List sites associated with this study:
Primary 
Dept?
Department Name
R and E - Uniformed Services University of the Health Sciences (USUHS)
 
3.0
Assign project personnel access to the project
3.1 *Please add a Principal Investigator for the study:
 
BURGESS, TIMOTHY H, MD, MPH
Select if applicable
Student
Site Chair
Resident
Fellow
 
3.2 If applicable, please select the Research Staff personnel:
 
A) Additional Investigators
AGAN, BRIAN K, MD 
 Associate Investigator
Collins, Limone C 
 Associate Investigator
G

Pollett, Simon David 
 Associate Investigator
Simons, Mark Paul, PhD, MSPH CDR 
 Associate Investigator
Williams, Alan LEWIS, MD 
 Associate Investigator
B) Research Support Staff
Becher, Dorothy Ann 
 Research Coordinator
Chapo, Elisa Wago 
 Research Coordinator
Fritschlanski, Mark Robert 
 Research Coordinator
Kosh, Lakeesha Jenielle 
 Research Coordinator
Nevo, Lev N/A, M.D. 
 Research Coordinator
Shaikh, Saira Yousaf 
 Research Coordinator
Spevak, Marianne V, BSHS 
 Team Member
3.3 *Please add a Protocol Contact:
 
BURGESS, TIMOTHY H, MD, MPH 
Becher, Dorothy Ann 
Chapo, Elisa Wago 
Collins, Limone C 
Fritschlanski, Mark Robert 
Kosh, Lakeesha Jenielle 
Nevo, Lev N/A, M.D. 
Shaikh, Saira Yousaf 
The Protocol Contact(s) will receive all important system notifications along with the Principal 
Investigator. (i.e. The protocol contact(s) are typically either the Protocol Coordinator or the 
Principal Investigator themselves).
3.4 If applicable, please select the Designated Site Approval(s):
 
Add the name of the individual authorized to approve and sign off on this protocol from your Site 
(e.g. the Site Chair).
4.0
 
Project Information
4.1  Is this a research study?
 Yes   
 No
4.2  What type of research is this?

Biomedical Research
Clinical trial (FDA regulated)
Behavioral Research
Educational Research
Psychosocial Research
Oral History
Other
Describe other:
Randomized open-label trial of FDA-licensed influenza vaccines.
4.3  Are you conducting this project in pursuit of a personal degree?
  Yes   
  No
4.5  Is this human subjects research (Activities that include both a systematic investigation designed to 
develop or contribute to generalizable knowledge AND involve a living individual about whom an 
investigator conducting research obtains data through intervention or interaction with the individual 
or identifiable private information.  Activities covered by 32 CFR 219.101(a) (including exempt 
research involving human subjects) and DoDI 3216.02)?
 Yes   
 No
4.6  Do you believe this human subjects research is exempt from IRB review?
  Yes   
  No
5.0
 
Personnel Details
5.1  List any Research Team members without EIRB access that are not previously entered in the protocol:
Name:
(Last, First, M.I.)
Fries, Anthony
Role on Protocol:
Associate 
Investigator
Phone Number:
 
937-938-2847
Email Address:
 
anthony.fries.
ctr@us.af.mil
Associated 
Institution:
 
USAFSAM
Name:
(Last, First, M.I.)
Macias, Elizabeth
Role on Protocol:
Associate 
Investigator
Phone Number:
 
937-938-3175
Email Address:
 
elizabeth.
macias@us.af.mil
Associated 
Institution:
 
USAFSAM
Name:
(Last, First, M.I.)

Seshadri, Srihari
Role on Protocol:
Associate 
Investigator
Phone Number:
 
703-681-5709
Email Address:
 
srihari.seshadri.
civ@mail.mil
Associated 
Institution:
 
IHB
Name:
(Last, First, M.I.)
Sheeler, Cindee
Role on Protocol:
Administrator
Phone Number:
 
301-816-8436
Email Address:
 
csheeler@idcrp.org
Associated 
Institution:
 
IDCRP
Name:
(Last, First, M.I.)
Bowers , Renee
Role on Protocol:
Administrator
Phone Number:
 
301-816-8458
Email Address:
 
rbowers@idcrp.org
Associated 
Institution:
 
IDCRP
Name:
(Last, First, M.I.)
Richard, Stephanie
Role on Protocol:
Epidemiologist
Phone Number:
 
301-816-8429
Email Address:
 
srichard@idcrp.org
Associated 
Institution:
 
IDCRP
Name:
(Last, First, M.I.)
Waickman, Adam
Role on Protocol:
Associate 
Investigator
Phone Number:
 
315-464-7653
Email Address:
 
waickmaa@upstate.
edu
Associated 
Institution:
 
SUNY Upstate 
Medical University
Name:
(Last, First, M.I.)
Williams, Maya
Role on Protocol:
Infectious Disease 
Directorate
Phone Number:
 
301-319-7446
Email Address:
 
maya.williams1.
mil@mail.
Associated 
Institution:
 
NMRC
Name:
(Last, First, M.I.)
Memoli, Matthew
Role on Protocol:
Phone Number:
 
301-443-5971
Email Address:
 
memolim@niaid.
nih.gov
Associated 
Institution:
 
NIAID

Site Investigator
Name:
(Last, First, M.I.)
Sundaram, Appuv
Role on Protocol:
Senior Scientist
Phone Number:
 
301-319-7199
Email Address:
 
appavu.k.
sundaram.
ctr@mail.mil
Associated 
Institution:
 
NMRC
Name:
(Last, First, M.I.)
Ewing, Daniel
Role on Protocol:
Lead Investigator
Phone Number:
 
301-319-9017
Email Address:
 
Daniel.f.ewing.
civ@mail.mil
Associated 
Institution:
 
Lead Investigator
Name:
(Last, First, M.I.)
Currier, Jeffrey
Role on Protocol:
Collaborator
Phone Number:
 
240-994-3911
Email Address:
 
jeffrey.r.currier.
civ@health.mil
Associated 
Institution:
 
Walter Reed Army 
Institute of 
Research (WRAIR)
Name:
(Last, First, M.I.)
Friberg-Robertson, 
Heather
Role on Protocol:
Collaborator
Phone Number:
 
301-319-9224
Email Address:
 
heather.l.friberg-
robertson.
civ@health.mil
Associated 
Institution:
 
Walter Reed Army 
Institute of 
Research (WRAIR)
5.2  
Will you have a Research Monitor for this study?
Yes 
No 
N/A 
Research Monitor Role:
If applicable, you may nominate an individual to serve as the Research Monitor:
No Users have been selected.
6.0
 
Data/Specimens
6.1  Does the study involve the use of existing data or specimens only (no interaction with human 

subjects)?
  Yes   
  No
7.0
 
Funding and Disclosures
7.1  Source of Funding:
Funding Source
Funding Type
Amount
DHP
:
Operations and 
Maintenance (O&M)
HU00012020082
2722000
Total amount of funding:
2722000
7.2  Do you or any other Investigator(s) have a disclosure of a personal interest or financial nature 
significant with sponsor(s), product(s), instrument(s) and/or company(ies) involved in this study?
  Yes   
  No
If Yes, complete and attach Conflict of Interest forms for all key personnel
8.0
 
Study Locations
8.1  Has another IRB/HRPP reviewed this study or will another IRB/HRPP be reviewing this study?
  Yes   
  No
IRB Name
Review Date
Determination
No records have been added
8.2  Is this a collaborative or multi-site study? (e.g., are there any other institutions involved?)
 Yes   
 No
8.3  Study Facilities and Locations:
Institution Site Name
Site Role
FWA or DoD 
Assurance 
Number
Assurance 
Expiration 
Date
Is there an 
agreement?
IRB Reviewing 
for Site
Navy
Naval 
Health 
Research 
Center
Laboratory 
analyses
FWA00013516
11/16
/2025
:
IAIR
:
USUHS 
IRB 
#1

Air 
Force
USAFSAM
Laboratory 
analyses
FWA00000609
08/29
/2023
:
IAIR
:
USUHS 
IRB 
#1
Navy
Navy 
Medical 
Research 
Center
Laboratory 
analyses
FWA00000152
06/05
/2024
:
IAIR
:
USUHS 
IRB 
#1
Army
Walter 
Reed 
Army of 
Institure 
Research
Laboratory 
analyses
FWA00000015
11/20
/2023
:
Other
:
USUHS 
IRB 
#1
Johns 
Hopkins 
University
Laboratory 
analyses
FWA00005752
10/01
/2023
:
Other
:
USUHS 
IRB 
#1
Other:
Other 
Institution Site
Site Role
FWA or DoD 
Assurance 
Number
FWA or DoD 
Expiration Date
Is there an 
agreement?
IRB Reviewing 
for Site
No records have been added
8.4  Are there international sites?
Attach international approval documents, if applicable, when prompted. Note: Ensure local 
research context has been considered
  Yes   
  No
8.5  Is this an OCONUS (Outside Continental United States) study?
  Yes   
  No
Select  the area of responsibility:
Have you obtained permission from that area of responsibility? (This is a requirement prior to 
study approval)
  Yes   
  No
9.0
 
Study Details
9.1  Abstract/ Summary:
Summarize the proposed study in 500 words or less, to include the purpose, the subject 
population, the study’s design type, and procedures
This four-year, pragmatic, prospective study will compare the effectiveness of the licensed egg-based 
inactivated influenza vaccine to the effectiveness of two other types of licensed vaccines, the cell-

culture based inactivated influenza vaccine and the recombinant influenza vaccine, in the prevention 
of laboratory-confirmed influenza infection in active duty members, military retirees, and other DoD 
beneficiaries.
Enrollment will be restricted to adults 18 years of age and older who are preparing to receive seasonal 
influenza vaccination at participating DoD sites. Subjects will receive one of the three licensed 
influenza vaccines types for evaluation of effectiveness. There is no exclusion for pregnancy, as none 
of these licensed products are contraindicated in pregnant women.
A total of 18,000 eligible subjects will be block randomized in 1:1:1 (cell-culture-based vaccine, the 
recombinant vaccine, or the egg-based vaccine) over four influenza seasons (2018-2019, 2019-2020, 
2020-2021, 2021-2022).
During the enrollment period subjects may opt-in or opt-out of a buccal swab and a same-day and 
post-vaccination self-collected blood sample.
Subjects who experience acute influenza-like illness symptoms during surveillance will be asked to 
complete a brief (5 min) online FLUPRO symptom severity questionnaire daily for 7 days. Additionally, 
subjects will complete an acute and a convalescent visit; these visits may be completed in person or 
virtually.
Those who choose to have an in-person acute visit will have either a self-collected Mitra kit or an 
intravenous blood draw (subject's choice), and two nasal swabs (one self-collected, one collected by 
study staff). The convalescent in-person visit procedures will consist of either a self-collected Mitra kit 
or an intravenous blood draw (subject's choice- preferably, consistent with the first visit).
Those who choose virtual visits will self-collect a nasal swab and a Mitra kit blood sample and send 
then to the appropriate location. At the convalescent visit, subjects will self-collect and send in a Mitra 
kit blood sample. 
At the first ILI visit study coordinators will record ILI history, hospitalizations status, and work days lost. 
At the second ILI visit during the convalescent phase of llness, coordinators will collect updated 
information on hospitalization status and work absences. This information will be collected at both the 
in-person and virtual visits.
All subjects will also be asked for permission to review their recorded medical encounters in order to 
ascertain whether they sought care for influenza-like illness. The test results will be for research 
purposes and will not be used to guide case management.
Immunogenicity substudy: Up to 1200 subjects (approximately 400/arm) from the main study will be 
enrolled in a vaccine immunogenicity substudy. Substudy participants will have blood drawn up to 30 
days prior to vaccination and then approximately one month post-vaccination in order to compare the 
effect of the vaccines on humoral and cellular immune responses.
End of study self-collected Mitra kit: Approximately 1,000 subjects who develop an ILI will be asked to 
collect and send in a self-collected Mitra blood kit. These individuals will be selected from the groups 
who completed the substudy or the same-day/post-vaccination blood sampling.
 
Study Period: Oct 2018 – Sep 2023
• Enrollment: Oct 2018 –Dec 2018, Sep 2019- Jan 2020, Sep 2020-Jan 2021, Sep 2021- Jan 2022
• Influenza-like illness (ILI) surveillance: Oct 2018 – May 2019, Sep 2019 – May 2020, Sep 2020-May 
2021, Sep 2021-May 2022
 • Analysis/Interpretation: May 2019 - Sep 2023
9.2  Key Words:
Provide up to 5 key words that identify the broad topic(s) of your study
influenza, vaccine, effectiveness, immunogenicity, antibody
9.3  Background and Significance:

Include a literature review that describes in detail the rationale for conducting the study. Include 
descriptions of any preliminary studies and findings that led to the development of the 
protocol.  The background section should clearly support the choice of study variables and 
explain the basis for the research questions and/or study hypotheses.  This section establishes 
the relevance of the study and explains the applicability of its findings
9.3.1 Influenza Vaccine Effectiveness
Globally, seasonal influenza epidemics cause three to five million severe cases and 300,000 to 
500,000 deaths annually according to the World Health Organization (1). A century after the 
1918 pandemic, influenza remains a leading cause of morbidity and a major threat to operational 
readiness in the United States Armed Forces. More than 90% of active duty personnel in the US 
receive influenza vaccinations annually (2)(Midterm vaccine effectiveness VRBPAC report - 
appendix #1). Despite high coverage, influenza-like illness frequently leads to clinical visits, 
missed duty days and hospitalizations. Findings from a recent study conducted by the Armed 
Forces Health Surveillance Branch(AFHSB) show that the number of incident hospitalizations for 
pneumonia and influenza averaged 1000 cases per year for active duty personnel between 2000 
and 2012 (3). Influenza alone accounted for nearly 14,000 days in hospital and 95,000 lost-duty 
days between 2011 and 2013 (4). The current 2017-2018 influenza season, with A(H3N2) as the 
predominate subtype, appears to be the worst in a decade. Infection rates for rivaled those of 
the 2009 H1N1 influenza pandemic (5). The overall percentage of influenza-positive respiratory 
specimens from active duty members and military beneficiaries is 17.4% and 25.6%, figures that 
highlight the significant burden of influenza in this population (6).
 
Seasonal strain-specific vaccination remains the foundation of influenza prevention and control. 
The effectiveness of seasonal influenza vaccines varies considerably by season and has generally 
been higher against influenza A(H1N1) pdm09 and B viruses than against A (H3N2) viruses, 
even when well-matched with circulating strains (7). The overall vaccine efficacy (VE) is 
estimated to be 19% in armed forces personnel, despite 90% vaccination coverage, while the 
overall VE is 51% in military beneficiaries assuming vaccine coverage of approximately 40% (2). 
In contrast, mid-season estimates of overall adjusted VE against influenza associated with 
medically attended acute respiratory infections the general United States population is 36% (8). 
The reasons for the disparities in VE are not yet known.
 
There are multiple factors that may contribute to suboptimal influenza vaccine effectiveness. 
These include prior influenza exposure and vaccination history could influence subsequent 
responses to seasonal influenza vaccines. Furthermore, host factors such as age and coexisting 
conditions affect vaccine effectiveness (1, 7). It may also be due the timing of vaccination, 
vaccine failure, or some other undetermined factors related to transmission or virulence of 
influenza in this population. Another factor that may alter the effectiveness of influenza vaccines 
is the substrate used to produce them. In the United States, most influenza-vaccine viruses are 
propagated in eggs, although some are produced either in cell culture or by a recombinant 
protein expression system. Residue changes in the vaccine virus hemagglutinin protein, the 
antigen responsible for virus attachment and a target of neutralizing antibodies that arise during 
passage in eggs have been suggested to confer antigenic differences that may result in 
decreased vaccine effectiveness in specific circumstances (9, 10). Additional studies are needed 
to assess whether VE against circulating influenza viruses vary by vaccine formulation, including 
comparisons between egg-based and non-egg-based vaccines.
 
9.3.2 Immune Responses to Seasonal Influenza Vaccines
Antigenic relatedness (match) between vaccine and circulating virus strains greatly affects 
influenza vaccine effectiveness. Determining which strains to include in new vaccines requires 
global coordination among organizations that provide i) surveillance of circulating influenza 
strains, ii) antigenic analyses of emerging strains in comparison to vaccine viruses, and iii) 
evaluation of human post-vaccination antibody responses to determine whether antibodies are 
reactive with recent virus isolates. The latter analysis requires panels of sera drawn from 
subjects up to 30 days before and 21-35 days after influenza vaccination.
 
Egg-adaptive mutations in vaccine strains used to formulate past influenza vaccines may have 
reduced VE by altering antigenicity (3) and immunogenicity (4). Influenza viruses that are 
isolated in cells and used for vaccine manufacture have the potential to overcome this problem. 
Until the current 2017-2018 influenza season, the Madin-Darby canine kidney (MDCK)-cell-
culture based inactivated influenza vaccine, Flucelvax, used egg-based viruses as seeds. This 
year, Flucelvax used a wild type, cell-culture based virus as its H3N2 vaccine seed and did not 
contain egg-adaptive mutations. The effect of this change on vaccine immunogenicity and 
antibody reactivity is currently unknown. Similarly, the recombinant HA influenza vaccine, 
FluBlok, does not use egg-adapted viruses. Therefore, we are now in a good position to compare 
how these egg-adaptive mutations affect antibody responses and HI and neutralization titers to 
matched- and mismatched-vaccine strains. Sera collected from individuals vaccinated with egg-
based and cell-culture-based influenza vaccines provide the opportunity to compare the potential 
effectiveness of these vaccines against circulating viruses.

 
Due to a lack of appropriate sera panels, there is currently insufficient information on whether 
the cell-culture-based influenza vaccines that lack egg-adaptive mutations induce antibodies that 
react more broadly with circulating strains than egg-based influenza vaccines. Therefore, sera 
panels from individuals vaccinated with different influenza vaccine formulations are needed to aid 
antigenic analyses of all vaccine formulations. As a secondary objective, we propose to collect 
pre- and post-immunization sera from subjects at DoD clinics who have received either egg- or 
cell-culture -based influenza vaccines to investigate potential differences in antibody responses 
to these vaccines types.
 
9.3.3 Scientific Merit
We propose to conduct a prospective study to compare immune responses and effectiveness of 
immunization to prevent influenza acquisition in DEERS-eligible adults (≥18 years and older) 
receiving egg-based, cell-culture-based, or recombinant inactivated influenza vaccines. This 
study will be conducted at selected military treatment facilities in a well-described military 
population comprised of individuals with both high (active duty personnel) and moderate 
(military retirees/beneficiaries)  vaccination coverage. The study results would provide new and 
important information on the immune responses and vaccine effectiveness by vaccine 
formulation. Publication in a high impact journal is likely as this information may have important 
influenza vaccination policy implications for both the military and the US population at large. The 
immunogenicity data may inform the development of effective universal influenza vaccines.
 
9.4  
Objectives/Specific Aims/Research Questions:
Describe the purpose and objective(s) of the study, specific aims, and/or research questions
/hypotheses
Primary Aim:
 
Specific Aim #1: Comparison of the relative effectiveness (prevention of laboratory-confirmed 
influenza illness) of three types of licensed seasonal influenza vaccines.
 
Research Question: Is either the cell-culture based vaccine or the recombinant vaccine more 
effective than egg-based vaccine?
There are two hypotheses of interest based on influenza attack rates (AR):
 
Assuming relative VE of 30% => 1 – AR /AR
 = 0.3  
1
egg
 
 Therefore 1- 0.3 = AR /AR
 = RR therefore 0.7=
=RR (AR =attack rate in either cell-
1
egg
AR /AR
1
egg
1
culture based or recombinant vaccine)
 
   Ho: RR=1 vs HA: RR< 1; p=0.025;  
   The RR to be tested is defined as: 1) RR1=ARcell / ARegg and 2) RR2=ARrecombinant / ARegg
 
Endpoint:
 
Influenza attack rates in the egg-based, cell-culture-based, and recombinant protein influenza 
vaccines arms of the study in the 2018-2019, 2019-2020,
 seasons. 
 2020-2021, and 2021-2022
 
Secondary Aim
 
Specific Aim #2: (Immunogenicity substudy) Determine whether cell-culture-based, egg-based 
and recombinant influenza vaccines give comparable HI and PVN titers to egg- and cell-matched 
vaccine antigens. An outcome of this objective is the potential to determine whether cell-culture-
based vaccine antigens can provide broader coverage of circulating viruses than egg-based 
vaccine antigens. 
Research Question: Is the proportion of subjects who seroconvert in either the cell-culture based 
or recombinant vaccine arm of the study greater in the either that in the egg-based vaccine arm 
of the study?
There are two hypotheses of interest for Specific Aim 2, based on the seroconversion rates (SCR)
H : RR=1 vs H : RR>1; p=0.025;
0
A
 The RR to be tested is defined as: 1) RR1=SCRcell / SCRegg and 2) RR2=SCRrecombinant / 
SCRegg

 
Endpoints:
Humoral responses: HAI titer, anti-NA titer, virus-neutralizing titer
Cellular responses (exploratory): frequency of antigen-specific CD4 and CD8 cells, B cells
 
SA 2.1:  To obtain post-vaccination sera panels to determine breadth of reactivity to circulating 
strains.
 
SA 2.2: To identify individuals who responded to H1N1, H3N2, B/Victoria and B/Yamagata 
vaccine components.
 
SA 2.3: To evaluate differences in serum reactivity between egg-, cell-culture-based and 
recombinant antigens.
 
SA 2.4: Compare the breadth of the antibody response elicited by egg, cell-culture-based and 
recombinant vaccines to circulating strains.
 
SA 2.5:  To examine the breadth of reactivity against past strains
 
Exploratory Aims
 
Specific Aim #3: To determine if the impact of the influenza vaccine on disease burden and the 
attributable healthcare costs differs by product type. 
Influenza-like Illness (ILI) case definition: ILI will be defined as:
Cough or sore throat AND
Feverish/chills OR Muscle/body aches or fatigue
Endpoints
Incidence of PCR-confirmed influenza cases
Frequency of influenza-confirmed hospitalization
Frequency of influenza-like illness
Work days lost due to influenza
Work days lost due to influenza-like illness
Healthcare costs/utilization attributable to influenza
Healthcare cost/utilization attributable to influenza-like illness
 
Specific Aim #4: To evaluate the association host single nucleotide polymorphisms (SNPs) and 
immune responses to the influenza vaccine, influenza acquisition and influenza severity
Frequency of SNPs by influenza status and by influenza severity
Frequency of SNPs by geometric mean titer (GMT) cutoff
Frequency of SNPs by mean fold rise (MFR) cutoff
Frequency of SNPs by  influenza status
Frequency of SNPs by influenza severity classification
Tertiary Aim
Specific Aim #5 Assess the burden of COVID-19 and explore the inter-relationship between 
influenza and COVID-19
Research questions: What is the burden of COVID-19 in the PAIVED cohort? What is the burden 
of co-infection with influenza and COVID-19 and how does it impact the severity of infection 
when compared with influenza-only or COVID-19-only infection? Which symptoms differentiate 
COVID-19 from influenza?
Endpoints:
Incidence of COVID-19, incidence of co-infection with influenza
Severity of COVID-19, symptoms associated with COVID-19 infection (compared with 
influenza, other respiratory viruses)
 
9.5  Study Design:
Describe study design in one to two sentences (e.g., prospective, use of existing records/data
/specimens, observational, cross-sectional, interventional, randomized, placebo-controlled, 

cohort, etc.). Specify the phase – Phase I, II, III, or IV – for FDA-regulated investigational drug 
research
This pragmatic, prospective study will assess the relative effectiveness of the licensed egg-based 
inactivated influenza vaccine to the effectiveness of two other licensed vaccines, the cell-culture-
based inactivated influenza vaccine and the recombinant influenza vaccine, in the prevention of 
laboratory-confirmed influenza infection in active duty members, military retirees and 
beneficiaries over four consecutive influenza seasons. Subject recruitment will take place at 
military treatment facilities (MTFs). Subjects will be  adults ≥ 18 years old who are DEERS-
eligible for care in the MHS. At enrollment, following the provision of informed consent, study 
staff will collect data on subject demographics and medical history (co-morbidities, history of 
influenza, and history of influenza vaccination). In contrast to standard practice, where vaccine 
selection is guided by individual preference or vaccine availability, study subjects will be 
randomly allocated by study investigative team to receive one of the three types of vaccine.
 
All subjects will be give the option to participate in a buccal swab collection for host genomic 
studies during the enrollment period. Subjects participating in the immunogenicity substudy will 
have their blood drawn up to 30 days prior to influenza vaccination and again at day 21-35 post-
vaccination to assess changes in immune responses to the vaccines. Those not participating in 
the substudy may opt in to have blood collected on the day of vaccination and post-vaccination 
using a Mitra device.
 
Subjects will undergo surveillance for influenza-like illness (ILI) during the influenza season, 
beginning 4 weeks post-vaccination and ending when nationwide influezna activity has returned 
to baseline (typically at the end of May).  During this period, automated weekly email or text 
messages will be sent to subjects asking them if they have experienced ILI symptoms in the past 
7 days. Subjects who meet the ILI case definition will be asked to complete an online 7-day 
symptom severity questionnaire and to schedule an ILI acute and convalescent virtual visit  with 
a study coordinator, ascertain a  self-collected nasal swab and self-collected blood samples. At 
the acute ILI virtual visit  study coordinators will record subjects ILI history, hospitalization 
status, and work absences. The convalescent virtual ILI visit will take place approximately 28 
days after answering "yes" to the surveillance survey (trigger"). Information on hospitalization 
status, and work absences will be updated at this visit.
 
Subjects will be monitored through as many ILI episodes as they experience, though subjects 
will only be compensated for the first 3 episodes. ILI episodes must be separated by at least 30 
days. Information on ILI health care utilization and cost for data will be abstracted from the 
Military Health System Data Repository (MDR) database by IDCRP study staff at the end of each 
influenza season.
 
Up to 18,000 eligible subjects (or 6,000 subjects distributed evenly between the 3 study 
arms) will be block randomized in 1:1:1 (cell-culture-based vaccine, the recombinant vaccine, or 
the egg-based vaccine).
 
The study will compare the effectiveness of three types of FDA-licensed influenza 
vaccines used in DoD populations to prevent influenza acquisition. The vaccines are 
listed below: 
 
Licensed cell culture-based influenza vaccine:
Flucelvax Quadrivalent (Seqirus) (15µg HA/strain)
Licensed recombinant vaccines:
Flublok Quadrivalent (Protein Sciences) (45µg HA/strain)
Licensed egg-culture based influenza vaccines:
Fluarix Quadrivalent (GlaxoSmithKline) 15µg HA/strain
OR 
FluLaval Quadrivalent (ID Biomedical Corp. of Quebec) 15µg HA/strain
OR
Afluria Quadrivalent (Seqirus) 15µg HA/strain
 
Randomization Process:
Eligible subjects at each site will be randomized to receive a single dose of cell culture-based vaccine 
versus recombinant vaccine versus one of three standard dose egg-based vaccines.
 
Subjects will be randomized in a 1:1:1 ratio to one of 3 vaccine formulations offered. Block 
randomization will be used in order to reduce bias and achieve balance in the allocation of subjects to 
treatment arms. An IDCRP biostatistician not involved in the study will generate a series of 
randomization vaccine codes. The roster for each site will be sent to the study staff, who, after 
enrolling the subject, will use the list to determine which vaccine each subject will receive. The 
vaccine allocations will be made sequentially using the roster.

Study Timeline
Study Day/Follow-up Interval
Pre-
Vax
Baselin
e
Post-Vax
Surveillanc
e
ILI
 
Day 
-30 
to 0
Day 0
Day 21-35
 
Weekly
(throughou
t the flu 
season)
ILI
Vi
sit 
1
 
ILI-Day 
28±7 
from 
trigger 
date 
 
Eligibility assessment
Res
earc
h
Researc
h
 
 
 
 
Informed Consent & HIPAA Authorization
Res
earc
h
Researc
h
 
 
 
 
Randomization
 
Researc
h
 
 
 
 
Vaccination
 
Standar
d of 
Care
 
 
 
 
9.6  Target Population:
Describe the population to whom the study findings will be generalized
U.S. military active duty members, midshipman, recruits, retirees, students, and their adult 
beneficiaries, along with U.S. adult population.
9.7  Benefit to the DoD:
State how this study will impact or be of benefit to the Department of Defense
If there are significant differences in either the immunogenicity or 
effectiveness between vaccines, influenza vaccination policy in the U.S. 
military may change to provide better protection against influenza. 
Conversely, if the differences in immunogenicity or vaccine effectiveness are 
minimal, the current immunization recommendations should not change. 
This study has the potential to provide high visibility to military infectious 
disease research, given the importance and global relevance of the research 
question being addressed
10.0
 
Study Procedures, Data Management, and Privacy
10.1  Study Procedures:
Describe step-by-step how the study will be conducted from beginning to end
Receipt of egg-based, cell-culture-based, or recombinant influenza vaccination is a requirement for 
study participation. All study assessments will be performed by members of the investigative team 
who are specifically designated to perform such activities in a clinical setting (according to site 
practices, local law, and as designated on the appropriate study documents). Study procedures will be 
performed in a clinical setting at participating MTFs (e.g., immunization clinic) or other clinical setting 
where vaccines are being administered in accordance with each site’s vaccination policy.
 
Detailed Description of Assessments
 
 

Demographics, enrollee interview, medical 
history (comorbidity/chronic diseases, 
influenza vaccination history, influenza 
history)
Res
earc
h
Researc
h
 
 
 
 
Blood sample
Res
earc
h
(Sub
stud
y 
Only
)
Researc
h
(Option
al 
same-
day 
Mitra)
 
Research
(Only for 
substudy and 
optional post-
vax Mitra)
 
 
Re
se
ar
ch
Research
Cheek cell (Buccal) swab (opt in)
 
Researc
h- 
optional
 
 
 
 
Acute ILI  Surveillance
 
 
 
Research
 
 
FLU-PRO 7-day Symptom Severity 
Survey via email
 
 
 
 
Re
se
ar
ch
 
Nasal specimen (self collection )
 
 
 
 
Re
se
ar
ch
 
ILI history (IH)
 
 
 
 
Re
se
ar
ch
 
Hospitalization (status, duration) and other 
AEs
 
 
 
 
Re
se
ar
ch
Research
Duty/work days lost related to ILI episode 
(RW)
 
 
 
 
Re
se
ar
ch
Research
 
 Medical history/demographic interview may occur prior to or following randomization/vaccination
 
Enrollment: Virtual or in-person
Sites will follow their MTF specific guidelines for consenting. Subjects may enroll in the study through 
e-consent or paper consent ICDs. E-consent links will be sent out to previous enrolled subjects and 
the use of through the use of QR codes for those enrolling electronically. Anyone e-enrolling will first 
complete a e-screening tool that will only allow those who meet the enrollment criteria to be enrolled. 
Potential subjects will review and sign the ICD with the clinical research coordinator(s) (CRCs) or may 
email/call study staff with questions, prior to signing an e-consent. Prior to any subject procedure 
being completed, study staff will confirm the subject signed the e-consent in real-time in REDCap. If 
REDCap is not available (due to connectivity issues, etc.), the subject will sign a paper copy of the 
consent with the study staff prior to any subject procedure being completed. 
 
The following procedures will take place:
Administration of informed consent
Subject informed consent, and HIPAA authorization, and California Subject’s Bill of 
Rights (if applicable).
The clinical research coordinator(s) will review the informed consent document with the 
subject. The Principal Investigator will review and document compliance of the 
informed consent document within 30 days of consent.
Potential subjects may be given an electronic copy of the informed consent document, 
educational items, and electronic briefs for review prior to study day 0. 
Contact information (source: patient-completed questionnaire)
Demographics (source: patient-completed quiestionnaire) 
age
sex
weight

height
ethnicity
race
DEERS status (active duty, retiree, beneficiary)
Military rank (active duty only)
Subject may opt-in for a same-day and post vaccination self-collected blood sample using a 
Mitra Device. If they opt-in, their first sample will be taken the same day as their vaccination 
and their second sample will be taken 14-30 days later. Subjects may be asked to provide an 
end of study mitra kit. 
Immunogenicity substudy subjects only
Study Day -30-0
Venipuncture blood draw (approximately 40 mL)
Study Day 21-35
Venipuncture blood draw (approximately 40 mL)
 
Acute Influenza-like Illness Surveillance 
The main study will rely on the identification/ascertainment of individuals with acute ILI. During the ILI 
surveillance period, subjects will receive an automated email or text message (via REDCap platform) 
at 1 week intervals asking them if they have experienced ILI in the preceding 7 days. Subjects will get 
a reminder email or text 72 hours later and again 24 hours later  if they have not responded to the 
weekly ILI surveillance. Influenza-like Illness (ILI) will be defined as:
Cough OR sore throat AND
Feverish/Chills OR Body aches/fatigue
 
The email or text messages (sent on a weekly basis) will also remind subjects to contact their medical 
provider should they experience any of the emergency signs described on the CDC’s influenza 
website (
, (Kellerman AL et al.  Web-
https://www.cdc.gov/h1n1flu/homecare/warningsigns.htm
based self-triage of influenza-like illness during the 2009 H1N1 influenza pandemic. Ann Emerg Med. 
2010 Sep;56(3):288-294). They are:
Difficulty breathing or shortness of breath
Pain or pressure in the chest or abdomen
Sudden dizziness
Confusion
Severe or persistent vomiting (vomiting that goes on)
Flu-like symptoms that improve but then return with fever and worse cough
Collection of ILI symptom presence and severity data for a sequential 7-day period using the FLUPRO 
questionnaire
 
Email or text messages responses from subjects who report symptoms meeting the ILI case definition 
will trigger an email or text message to a study coordinator, who will then contact the subject to 
schedule a virtual acute ILI visit. Subjects who respond to the email/text message stating that they are 
experiencing ILI symptoms will be sent a web link to a 7-day ILI severity questionnaire that will record 
the severity of ILI symptoms that they experienced in the past 24-72 hours in the online questionnaire. 
They will also receive daily email/text reminders to enter the symptom severity information for the past 
24 hours for each of the remaining six days.
 
ILI surveillance in military trainees/recruits
 
Internet/email/text message access is not available to military recruits/trainees, and therefore they will 
not complete the FLUPRO questionnaire should they develop ILI symptoms. As such, at enrollment 
they will be guided to report to sick call should they develop acute ILI symptoms during the study 
follow-up period. Study coordinators will be on hand at the appropriate medical clinic to obtain acute 
ILI Visit Day 1 data and specimen collection. A convalescent ILI visit  is not required for military recruits
/trainees. ILI Visits have the option of taking place virtually or in-person  
 
VIRTUAL ILI VISIT PROCEDURES
 
Acute ILI Visit #1 : visit during an acute phase of ILI episode 

Subjects who develop ILI symptoms will undergo the following procedures:
Self-collected nasal swab specimen.
Self-collected blood sample (40 µL)
ILI History
If hospitalized:
ILI hospitalization status
Number of days hospitalized (if hospitalized for care)
Number of work/duty days absent related to ILI episode
Visit #2- Convalescent Visit (21-35 post trigger): visit during convalescent phase of ILI episode 
Subjects who develop ILI symptoms will undergo the following procedures:
Self- collected blood sample (40 µL)
If hospitalized
ILI  hospitalization status
Number of days hospitalized (if hospitalized for care)
Total number of work/duty days absent related to ILI episode
IN-PERSON VISIT PROCEDURES
 
Visit #1- Acute ILI Visit
Subjects who develop ILI symptoms will undergo the following procedures:
Self-collected nasal swab specimen.
CRC collected nasal swab specimen
In-clinic self-collected blood sample (40 µL) or intravenous blood draw (16 mL) (subject's 
choice)
ILI History
If hospitalized
ILI hospitalization status
Number of days hospitalized (if hospitalized for care)
Number of work/duty days absent related to ILI episode
Visit #2- Convalescent Visit (21-35 post trigger) 
In-clinic self-collected blood sample (40 µL) or intravenous blood draw (16 mL) (subject's choice, 
consistent with the first visit, if possible)
If hospitalized
ILI  hospitalization status
Number of days hospitalized (if hospitalized for care)
Total number of work/duty days absent related to ILI episode
ILI Healthcare utilization and costs
Data on health care utilization and costs attributed to ILI episode will be abstracted from the MDR at 
the end of each influenza season.
 
Deviations: 
Missed nasal specimens (in-person and/or self-collected) and self-collected blood samples (in-person 
and/or self-collected) will be considered protocol deviations
 
Collection of the Human Biological Specimens/Specimen processing:
Blood:
All subjects who develop ILI during the current influenza season will provide specimens as part 
of the acute ILI visit and convalescent ILI visit  . Recruits/trainees with an ILI will not be 
required to provide convalescent blood samples. Blood may be collected via venipuncture in 
clinic (16 mL per timepoint) or with a Mitra kit (40 µL per timepoint).  Up to 16 mL will be 
collected at each of these visits; up to 96 mL total over the course of follow up.
Subjects may opt-in for a day of vaccination and post vaccination self-collected blood sample 
(40 µL per timepoint).
: Subjects in the substudy will undergo phlebotomy up 
Immunogenicity substudy subjects only
to 30 days prior to vaccination and again 21-35 days post-vaccination to assess changes in 
humoral and cell-mediated immunity in response to influenza vaccination. Approximately 40 

mL will be collected at each of these two visits and the end of study self-collected blood 
sample; approximately 80 mL over the course of the study.  A sample of the stored serum 
samples will be shipped to the FDA CBER, or other partner, laboratories for analysis. Subjects 
who participate in the substudy will not be selected to provide the optional same-day/post-vax 
blood samples.
Approximately 1,000 subjects who report at least one ILI during the surveillance period AND 
are participating in either the substudy or the day of vaccination/post vaccination blood 
samples may be asked to complete an end of study mitra kit (40 µL). This is being conducted 
in order to estimate the influenza seroconversion rate in this population and to evaluate 
whether we can determine if influenza cases are missed during surveillance.
Nasal Swabs:
For virtual appointments, there will be one self-collected nasal swab collected for each ILI case. For in-
person visits there will be one self-collected nasal swab and one in-clinic nasal swab for each ILI 
case. Self-collected nasal (mid-turbinate) swabs are collected once ILI symptoms are identified, 
through the ILI Surveillance Survey. An additional a in-clinic swab (mid-turbinate) will be taken for 
subjects who have in-person visits. Labelled specimens will be shipped to Naval Health Research 
Center (NHRC) or U.S. Air Force School of Aerospace Medicine (USAFSAM). Specimens received at 
laboratories will be logged into a project database and labeled according to the lab’s standard 
procedures. A link to the Study ID will be maintained. Specimens will be assessed using sensitive 
molecular detection methods for detection of influenza, as well as other respiratory viruses and 
bacteria of interest.
Buccal Swabs:
Host-Genetic Analysis: One buccal cheek swab will be collected on the day of vaccination from those 
subjects that opt-in to assess the association between host genetic polymorphisms on respiratory 
infection acquisition and on immune responses to vaccination.
Salivary Antibody Evaluation:
At the US Naval Academy, saliva collected by oral swabs will be evaluated for antibodies to SARS-
CoV-2 and other respiratory viruses (e.g. influenza A/B) using multiplex microbead immunology 
assays. Differences between antibody types and magnitudes between serum and saliva will be 
evaluated over the duration of study participation.  See USNA Site-Specific Protocol for further details.
 
10.2  Data Collection:
Describe all the data variables, information to be collected, the source of the data, how the data 
will be operationally measured, and approvals needed for use of information from DoD databases
Data Collection
Study data will be derived from source documents and then transcribed onto electronic CRFs 
(eCRFs). Study data may also be entered directly on the eCRFs as original observations and thus 
have the dual function of source document and data capture form at the study site. In the case 
where a source documentation is not completed on the CRF directly, the transcriptions will occur 
on an ongoing basis during the study in accordance with Good Clinical Practice (GCP) guidelines 
by study staff delegated this task on the Delegation/Responsibilities Log. Study staff should 
maintain in the regulatory files a list of CRFs that serve the dual purpose of source 
documentation and CRF.
  
DCC programmers will pull MDR records on enrolled subjects at the end of the influenza season (o
r end of study, as applicable) in an attempt to confirm relevant health information, such as comorbidities, 
prescription medications, history of influenza and other vaccination history of influenza and other respiratory 
infections (i.e., influenza, SARS-CoV-2, and other respiratory pathogen test results), healthcare utilizations and 
 Evaluations mandated by this research protocol will have no impact on standard of 
costs associated with ILI.
care assessment and treatment. 
 
Names and email will be collected prior to enrollment using the MHS Portal J6 email list. This will 
allow access to send recruitment materials along with e-consents to potential study participants.
 
Demographics: Following administration of informed consent, collected demographic data will 
include but not be limited to age, sex, DEERS status, and military rank.
 

Past Medical History:  Information on subjects’ past medical history will be captured at or after enro
llment. The information collected will focus on comorbidities, history of influenza and other respiratory infections 
(e.g., SARS CoV-2), and history of influenza and other vaccinations. Medical history information will be 
collected via electronic or paper questionnaires, or through an MDR pull. Coordinators will review the subjects’ 
questionnaire responses for completeness. Health information from up to five years prior to a subject’s study 
enrollment may contribute to the MDR record data pull.
 
FluPRO daily symptom questionnaire information will be entered into a REDCap web form on a 
URL provided by the DCC. Subjects will be provided a direct link to access the website and enter 
their study data. 
 
FLUPRO Questionnaire: Subjects who report ILI symptoms which meet the study case definition 
for ILI will be sent a link to a web-based version of the 7-day FLUPRO Questionnaire. FLUPRO is 
a tool designed to evaluate patient-reported ILI symptoms and their severity. Subjects will be 
responsible for entering the symptoms for 7 consecutive days beginning with the day they 
reported meeting the ILI case definition. Subjects who experience ILI symptoms may be 
compensated for up to three new ILI episodes per season. ILI episodes must be separated by at 
least 30 days.
 
ILI history: ILI history will be captured at the ILI Visit 1. Information recorded includes date of 
ILI onset, duration of illness, number of reduced/limited activity due to illness, and number of 
school/work days missed.
 
Concomitant Medications:  If any over the counter fever reducers and pain reducing medications 
are being taken at the time of enrollment it will be noted by the subject on the enrollment form. 
Any prescribed medications taken throughout the subject's participation in the study, to include: 
antibiotic, influenza antiviral, antiemetic, antihistamine, antipyretic, bronchodilator, 
decongestant, systemic steroid, or other immunomodulator will be gathered through an MDR pull.
                                                                                                                                            
      
Hospitalization status: At the ILI Visit 1, subjects will be asked if ILI episode resulted in 
hospitalization (in-patient). If the episode resulted in hospitalization, information on duration of 
hospitalization and severity (e.g. ICU status and oxygen administration as proxies for severity). 
This information will be updated at the ILI Visit 2 Day 28 visit.
 
Return to Work: Information on the total number of days from illness onset that subjects were 
not able to perform their normal activities is recorded at the ILI Vist 1 and updated at the ILI 
visit 2.
 
Data Management Plan
Procedures and policies related to data collection, completion of forms/logs, and the 
management and use of data after collection are outlined in the current version of the Data 
Management Plan (DMP).
   
Study Records Retention
The PI at each site is responsible for retaining all essential documents listed in the International 
Conference on Harmonization (ICH)/ Good Clinical Practice (GCP) Guidelines. All essential 
documentation for all study subjects are to be maintained by the investigator in a secure storage 
facility according to each military treatment facility’s requirement. These records are also to be 
maintained in compliance with IRB, state, and federal medical records retention requirements, 
whichever is longest. All stored records are to be kept confidential to the extent provided by 
federal, state, and local law.
 
DCC
Access to study files at DCC (eCRFs) is restricted to staff members given specific study related 
tasks to perform.  The files are maintained on controlled-access servers in accordance with DCC 
standard procedures.
10.3  At any point in the study, will you request, use, or access data from a DoD Database or the Military 
Health System (MHS)?
 Yes   
 No
10.4  Review the definitions below and respond to the following two questions.  If you are not sure of the 
answers, email 
 for assistance.
DHA.PrivacyBoard@mail.mil
   The 
 is 
Military Health System (MHS)
defined as all DoD health plans and DoD health care providers that are organized under the 

management authority of, or in the case of covered individual providers, assigned to or employed by, 
  
the Defense Health Agency (DHA), the Army, the Navy, or the Air Force  
 
MHS workforce members
are employees, volunteers, trainees, and other persons whose conduct, in the performance of work 
  
for the MHS, is under the direct control of the MHS, whether or not they are paid by the MHS.  MHS 
 are persons or entities that provide a service to the MHS and require protected 
business associates
health information (PHI) to provide the service.
Are you an MHS workforce member?
Yes, I am an MHS workforce member 
No, I am not an MHS workforce member 
Are you an MHS business associate?
Yes, I am an MHS business associate 
No, I am not an MHS business associate 
10.5  Have you consulted with an MHS data expert to determine the data elements required for your study?
Consulting with a data expert often saves time later in the compliance process because the data 
expert can advise on the data available in the numerous MHS information systems, the quality of 
that data and the methods for encrypting and collapsing data.  To schedule a consult with an 
MHS data expert, send an email to: (
)
dha.ncr.pcl.mbx.privacyboard@mail.mil
Yes, then complete the questions below according to the data consult 
No, then complete the questions below according to the best of your knowledge 
10.6  Indicate how you will request data from the MHS.  Select all that apply.
Talking with MHS health care providers or MHS health plans about specific research 
participants
Obtaining MHS hard copy records specific to research participants
Obtaining data from an MHS information system(s)
10.7  If you are obtaining data from an MHS information system(s), indicate whether you plan to receive a 
data extract or whether you plan to access an MHS information system directly to create a data set.
A data extract is when the MHS or a contractor provides the data set directly to the 
researcher.  When receiving a data set through data extract, the researcher may indicate 
whether the data elements should be provided as is, encrypted or collapsed.  In contrast to a 
data extract, access to an information system means that the researcher may directly access an 
MHS information system and create a data set for the research study
Data Extract
Access
10.8  Do you intend to use only de-identified data from the MHS in your research study?
There are different two methods for de-identifying data pursuant to HIPAA:
1) Safe Harbor Method: Removing all of the identifiers listed in Table 1 below, provided that the 
researcher does not have actual knowledge that the remaining data can be used alone or in 
combination with other information to identify the individual who is the subject of the information
2) Statistical Method: An expert, with appropriate knowledge of and experience with generally 
accepted statistical and scientific principles and methods for rendering information not 
individually identifiable, determines that the data is not individually identifiable
  Yes   
  No
10.9  Indicate the MHS information system(s) from which you will seek to obtain data

If you do not know which system(s) contains the data elements you need, refer to the Guide for 
DoD Researchers on Using MHS Data or request guidance from an MHS data expert at: DHA.
.
PrivacyBoard@mail.mil
 
Below is a list of commonly used MHS systems. If the system from which you seek to obtain 
data is not listed below, list the name of the system in the “Other MHS Systems” category below
PHI Systems:
MHS Information System
Requesting Data
:
AHLTA
:
Yes
:
CHCS
:
Yes
:
ESSENTRIS
:
Yes
:
MDR
:
Yes
PII-Only Systems:
MHS Information System
Requesting Data
MHS Genesis
:
Yes
Information System
Requesting Data
No records have been added
10.10  Do you intend to merge or otherwise associate the requested data with data from any sources 
outside of the MHS, including other DoD systems that are not part of the MHS?
Yes, will merge data  
No, will not merge data 
10.11  Indicate the data elements about research participants or relatives, employers, or household 
 that you will request from MHS hard copies or from MHS 
members of the research participants
information systems.   If you answered “yes” to question 10.9 above, also indicate non-MHS data 
elements about research participants or relatives, employers, or household members of the 
 that you will have access to in any form or medium.
research participants
Data Element(s)
MHS
Non-MHS Systems
MHS Hard Copies
1. Names
2. Postal address 
with only town, 
city, state and zip 
code
3. Postal address 
with all geographic 
subdivisions smaller 
than a state, 
including street 
address, city, 
county, precinct, 

zip code and their 
equivalent 
geocodes, except 
for the initial three 
digits of a zip code 
if, according to the 
current publicly 
available data from 
the Bureau of 
Census: 1) the 
geographic unit 
formed by 
combining all zip 
codes with the 
same three initial 
digits contains 
more than 20,000 
people; and 2) the 
initial three digits of 
a zip code for all 
such geographic 
units containing 
20,000 or fewer 
people is changed 
to 000
4. Dates including 
all elements 
(except year) 
directly related to 
an individual, 
including birth date, 
admission date, 
discharge date, and 
date of death
5. Ages over 89 
and all elements of 
dates (including 
year) indicative of 
such age, unless 
you will only 
request a single 
category of “age 90 
or older”
6. Telephone 
numbers
7. Fax numbers
8. Electronic mail 
addresses
9. Social Security 
numbers (SSNs)
10. Medical record 
numbers

11. Health plan 
beneficiary numbers
12. Account 
numbers
13. Certificate
/license numbers
14. Vehicle 
identifiers and 
serial numbers, 
including license 
plate numbers
15. Device 
identifiers and 
serial numbers
16. Web Universal 
Resource Locators 
(URLs)
17. Internet 
Protocol (IP) 
address numbers
18. Biometric 
identifiers, 
including finger and 
voice prints
19. Full-face 
photographic 
images and any 
comparable images
20. Any other 
unique identifying 
number, 
characteristic, or 
code (DEERs ID, 
EDIPN, Rank)
If you are obtaining SSNs, provide a justification as to why and explain why a substitute cannot 
be used
Participants receiving >$600 in compensation in one calendar year must fill out a W9 in order to 
receive 
 at the end of the year for IRS tax reporting purposes. Social security numbers are 
a 1099
collected for this reason alone.
10.12  Do you believe it is possible for the MHS data to become identifiable because of triangulation, a 
small cell size, or any unique data element(s)?

Triangulation means using different data elements that are not themselves identifiable but that 
when combined can be used to identify an individual. For example, triangulation would use rank 
and race together to determine the identity of an individual with a particular health condition.
 
Small cell size means that there is only a small number of eligible individuals that satisfy the 
category description. Guidance for acceptable cell size is available from the Centers for Medicare 
and Medicaid Services. For example, the rank category of four star generals with a particular 
diagnosis may be less than 30, so the rank category may need to be expanded to include lower 
ranks.
 
A unique data element includes any unique features that are not explicitly enumerated in the 
categories of data in rows 1 – 20 of the table above (in Section 10.10), but that could be used to 
identify an individual. Unique data elements include characteristics that are not themselves 
identifying, such as the rank of general or admiral, or a race or gender, but within the context of 
other information could be identifiable.
Yes, I believe there is a reasonable possibility the MHS data will become identifiable 
No, I believe there is no reasonable possibility the MHS data will become identifiable 
10.13  HIPAA Privacy Rule and Use of Protected Health Information in Research:
N/A – will not use or disclose protected health information (PHI) 
HIPAA Authorization will be obtained 
Use of a limited data set where a data use agreement will be obtained 
Waiver/alteration of HIPAA Authorization is being requested 
10.14  Managing Data (Data Management and/or Sharing Plan) and/or Human Biological Specimens for 
this Study:
Include in this section the plan for acquiring data (both electronic and hard copy), access during 
the study, data/specimen storage and length of time stored, shipment/transmission, and the 
plan for storage and final disposition at the conclusion of the study. Describe any data 
agreements in place for accessing data within and/or outside of your institution (e.g., Data 
Sharing Agreement, Data Use Agreement, Business Agreements, etc.)
The only electronic links between the subject’s name, DoD ID, SSN, and Study ID number will be on 
tracking spreadsheets at the clinical sites used for collecting information on ILI cases, as needed, from 
electronic medical records and will only be accessed by authorized study staff. During the study, 
source documents will be held in a secure cabinet with restricted access. Team members with access 
to the documents are counseled on the importance of maintaining the confidentiality of subjects’ 
medical records and trained on human subjects’ protection and HIPAA. All staff involved in this study 
have completed the required human subjects’ protection and ethics training. In all electronic records 
used for data analysis, the subjects are not referenced by name, but only Study ID number. This 
method is designed to protect study subjects’ medical information. All measures are put in place to 
protect the privacy of all subjects. The study will utilize passwords and firewalls to maintain 
confidentiality of data accessed via computer. The summary report generated from the interviews and 
completed questionnaires will not contain any subject identifying information.
 
To determine whether an individual has been enrolled previously at another study site, study staff at 
all sites will have the ability to query IDCRP data management systems to locate an individual. The 
data management systems are secure and can only be accessed by authorized individuals using a 
unique user ID/password combination.
 
The REDCap data entry system includes a server accessible by standard web browsers and device-
based applications. The server is hosted, maintained, and kept secure by the Henry M Jackson 
Foundation IT department. REDCap data is encrypted using 64-bit DES technology, and the REDCap 
server is configured to accept HTTPS connections only.
 
Tablets will be configured as follows:
The internal hard drive or folders containing study data will 
 encrypted
be
Username/password will be required to log on to the tablet

Study data transmission will employ a secure transmission 
 (i.e SSL)
protocol,
 
Email and cell phone number collection:
Subject e-mails
will be collected in REDCap accessed on a tablet using 
 and cell phone numbers 
a secure wireless connection or on a computer using a secure landline connection, to the 
Infectious Disease Clinical Research Program Data Coordination Center. Emails and cell 
phone numbers may also collected on paper source documents and transcribed into tablets.
Study data will be stored on the tablet hard drive only when the tablet is in offline mode; both 
the hard drive and the data folders are encrypted
The tablet will periodically be uplinked via a secure 
 at which time the study data will 
connection
be transferred securely to the central study database
 
FluPRO daily symptom questionnaire:
No personally identifying information will be collected in the questionnaire
FluPRO daily symptom questionnaire information will be entered into a REDCap form via a 
URL provided by the DCC directly to the subject; the URL will be unique to the specific subject 
and questionnaire.
Salivary Sample Analysis will be performed at Johns Hopkins University (JHU).  JHU will receive only 
coded samples and data, labeled by study ID.  
10.15  Managing Data (Data Management and/or Sharing Plan) and/or Human Biological Specimens for 
Future Research:
If the study involves collecting, storing, or banking human specimens, data, or documents 
(either by the Investigator or through an established repository) for FUTURE research, address. 
How the specimens/data will be used, where and how data/specimens will be stored (including 
shipping procedures, storage plan, etc.), whether and how consent will be obtained, procedures 
that will fulfill subjects’ request as stated in the consent, whether subjects may withdraw their 
data/specimens from storage, whether and how subjects may be recontacted for future research 
and given the option to decline, whether there will be genetic testing on the specimens, who will 
have access to the data/specimens, and the linkage, the length of time that data/specimens will 
be stored and conditions under which data/specimens will be destroyed.
Research use of data collected through this protocol will be coded and will not contain identifiers. 
Any DHA-derived PHI will be de-identified. Access
highly limited. Much of the 
 to these data will be 
subsequent research using the materials collected under the auspices of this study will be 
accomplishable through approved exempt or 
human use sub-studies. All research using the 
non-
materials collected under this protocol will be conducted in accordance with an IRB-reviewed 
protocol. Data and tissue samples released for research use will be labeled by Subject ID only; 
data will be shared without any identifiers or links to individuals. The DCC will not share 
identifying 
 with 
 without explicit IRB approval.
information
investigators
11.0
 
Statistical/Data Analysis Plan
11.1  Statistical Considerations:
List the statistical methods to be used to address the primary and secondary objectives, specific 
aims, and/or research hypotheses.  Explain how missing data and outliers will be handled in the 
analysis.  The analysis plan should be consistent with the study objectives.  Include any sub-
group analyses (e.g., gender or age group).  Specify statistical methods and variables for each 
analysis.  Describe how confounding variables will be controlled in the data analysis
The statistical plans discussed below are not final or definitive. They will need to evolve as the flu 
seasons develop and we communicate with other ILI study centers and the sponsors. In case of 

a severe epidemic, they may have to change substantially. Detailed statistical protocols will need to 
be created for the specific studies that will fulfill secondary objectives. The statistical considerations 
below for the secondary objectives will serve as starting points for the more detailed statistical plan .
 
Primary Aim
 
Specific Aim #1: Comparison of the effectiveness (prevention of laboratory-confirmed influenza 
illness) of three types of licensed seasonal influenza vaccines.
 
: Is either the cell-culture based vaccine or the recombinant vaccine more effective 
Research question
than egg-based vaccine? There are two hypotheses of interest based on influenza attack rates (AR):
Vaccine Effectiveness (VE)= (
) x100% = (1-AR /AR )x 100%=(1-RR) x100%
AR  – AR
0
1
1
0
                AR0
when AR  is placebo,   VE~= vaccine efficacy or via Nauta (“absolute vaccine efficacy”) when AR  is 
0
0
the egg-based vaccine then the VE~= 
vaccine efficacy.
relative 
We want relative VE of 33% => 1 – AR /AR
  = 0.33 ,  therefore 1- 0.33 = AR /AR
 = RR 
1
egg
1
egg
therefore 0.67 =RR (AR1 = attack rate in either cell-culture based or recombinant vaccine)
 
We have simplified the primary hypotheses for the study and have opted for two pairwise comparisons 
rather a single three-way comparison. There are two hypotheses of interest based on influenza attack 
rates (AR):
 H : RR=1 vs H : RR < 1; alpha=0.025;
0
A
The RR to be tested is defined as: 1) RR1=AR
 / AR
 and 2) RR2=AR
 / AR
cell
egg
recombinant
egg
Text: Statistics in Clinical Vaccine Trials by Jozef Nauta.
 
1. Endpoint:
Influenza attack rates in the egg-based, cell-culture-based, and recombinant protein influenza 
vaccines arms of the study in the 2018-2019, 2019-2020, 2020-2021, and 2021-2022 seasons. 
 
2. Ascertainment of primary outcome:
Laboratory-confirmed influenza as ascertained by a sensitive and specific assay is needed to 
assess effectiveness. The best assay is RT-PCR from nasopharyngeal swab specimens 
(various assay platforms); one particular antigen detection assay has similar sensitivity and 
performance characteristics, but numerous available rapid antigen detection tests for influenza 
are poorly sensitive and have poor negative predictive value, thus risking false-negative results 
if relied upon for outcome. There is heterogeneity across MHS clinical laboratories with respect 
to the type of test that is employed. A key factor is that individuals must present for care to 
have outcome ascertainment. Thus, follow-up methodology will involve strategies to increase 
likelihood of presentation for evaluation of incident ILI following vaccination.
 
3. Statistical analysis:
Incidence rates: To determine incidence, we will use the number of enrolled laboratory-
confirmed influenza cases by vaccine formulation as the numerator. For the denominator, we 
will use the number of enrolled subjects by vaccine formulation.  We estimate that 
approximately 30- 40 percent  of the subjects and will develop ILI symptoms. Of this group, 
perhaps 30 percent  will seek care, with symptom severity the leading predictor for seeking 
care. We realize that there is no effective way in a large study to avoid the potential for bias in 
case ascertainment due to differences in symptom severity. As a pragmatic study, our goal is 
not to eliminate bias but to minimize the impact of bias , by using a broad but 
standardized  case definition and by providing incentives for symptomatic individuals to be 
assessed. We can also use symptom severity data from the FLUPRO questionnaire to explore 
the extent to which symptom severity scores differs by region.
 
The ability of the study to detect a difference in effect is proportionate to the incidence of the 
outcome. A total of 172 influenza cases were reported among the 10,771 subjects enrolled in 
first three years of the study (2018-2021). The influenza attack rate has ranged from 0% in third 
season (COVID-19 pandemic), to 2.5% in the second season, with an overall attack rate 1.6% 
The observed attack rates are lower than baseline attack rates of 5% and 3% that formed the 
basis of sample size calculations for the first three years of the study. Consequently, the power 
to detect significant differences in VE between vaccine arms has been too low to due to the low 
attack rates. For the fourth year of the study is to increase the enrollment target from 15,000 to 
18,00 to enhance power to detect significant differences in VE between attack rates are lower.
 

 
 
Secondary Aims:
 
Specific Aim #2:  
Determine whether cell-culture-based and egg-based influenza vaccines give comparable HI 
and PVN titers to egg- and cell-matched vaccine antigens. An outcome of this objective is the 
potential to determine whether cell-culture-based vaccine antigens can provide broader 
coverage of circulating viruses than egg-based vaccine antigens.
 
Research Question:Is the proportion of subjects who seroconvert in either the cell-culture 
based or recombinant vaccine arm of the study   greater than in the egg-based vaccine arm of 
the study.
 
 
There are two hypotheses of interest for Specific Aim 2, based on the seroconversion rates 
(SCR)
H : RR=1 vs H : RR < 1; p=0.025;  The RR to be tested is defined as: 1) RR1=SCRcell / 
0
A
SCRegg and 2) RR2=SCRrecombinant / SCRegg
 
1. Endpoints:
Humoral responses: HAI titer, anti-NA titer, virus-neutralizing titer
Cellular responses (exploratory): frequency of antigen-specific CD4 and CD8 cells, B 
cells
 
 
SA 2.1: To obtain post-vaccination sera panels to determine breadth of reactivity to circulating 
strains.
This will be accomplished by recruiting consenting adults to an IRB-approved study conducted 
during a routine influenza vaccination campaign, collecting sera up to 30 days before and 21-
35 days after vaccination with egg- or cell-culture-based or recombinant influenza vaccines. 
The samples will be de-identified and shipped to partner laboratories for aliquoting, storage, 
and antigenic analyses. We intend the study to be conducted during early vaccination 
campaigns performed at DoD facilities. 
 
SA 2.2: To identify individuals who responded to H1N1, H3N2, B/Victoria and B/Yamagata 
 This will be accomplished by testing pre- and post-vaccination sera for 
vaccine components.
HA inhibition (HI) and pseudovirus microneutralization (PVN) antibody titers. Individuals who 
had a 4-fold or greater response against each matched antigen in the vaccine will be 
considered responders (i.e. if egg-based vaccine, the test will be conducted against egg-based 
antigen). The study will be designed to identify responders to egg- and cell-culture-based 
vaccines for each vaccine antigen (H1N1, H3N2, B/Yamagata and B/Victoria). For H3N2 
strains that do not hemagglutinate, only PVN titers will be determined. The sera collected post-
vaccination from responders will be aliquoted and distributed to laboratories performing assays 
to evaluate the breadth of antibody reactivity.
 
SA 2.3: To evaluate differences in serum reactivity between egg- , cell-culture-based and 
recombinant antigens.
We will test pre- and post-vaccination sera against antigens with sequences corresponding to 
the “other” platform. We will compare PVN antibody titers against egg- and cell-culture-based 
antigens for all strains included in the vaccine, and calculate the response rate (i.e. percent of 
individuals in each arm with a 4-fold or greater titer response) of each arm of the study against 
egg and cell antigens. The results from this test will indicate whether antibodies elicited in 
response to egg- and cell-culture-based vaccines are specific for the immunogen.
 
SA 2.4: Compare the breadth of the antibody response elicited by egg, cell-culture-based and 
recombinant vaccines to circulating strains.
To determine the breadth of antibody reactivity, post-vaccination serum PVN titers will be 
measured against cell-culture-based vaccine and emerging circulating virus antigens 
representing most clades from each subtype. Only cell-based sequences will be used in this 
analysis because these are representative of the original human isolate sequences. We 

propose to include the HAs of at least 6-10 recent virus isolates per subtype/lineage. PVN titers 
against recent virus isolates that are >4 fold different from the homologous vaccine antigen will 
be considered low reactors (LRs). The breadth of reactivity will be scored by calculating the 
number of LRs identified for each study subject, e.g., sera that react to all antigens will be given 
a score of 100%, sera that react to no antigens will be given a score of 0% and sera that react 
to 4 of 10 antigens will be given a score of 40%. The overall breadth of reactivity for each study 
Arm will be calculated as the average breadth of reactivity for all persons in the Arm. If the 
difference between the groups is not significant, additional antigens within the subtype/lineage 
but that are known to be antigenically-distinct, may be tested.
 
.
SA 2.5:  To examine the breadth of reactivity against past strains
Recent studies demonstrate a back-boost effect following vaccination, i.e. increased antibody 
titers against influenza antigens from past vaccines or infections. The human immune 
responses are therefore impacted by prior vaccination history or infection. To retain the 
possibility of performing additional tests that examine the back-boost effect, left over sera will 
be stored for future additional investigations of how pre-existing breadth of antibody reactivity to 
past influenza strains influences responses to current influenza vaccines.
 
:
Exploratory Aims
Specific Aim #3: To determine if the impact of the influenza vaccine on disease burden and the 
attributable healthcare costs differs by product type.
An analysis of the impact of ILI and SARI on health care utilization will allow a more detailed 
estimation of the burden of infections caused by these pathogens in military populations. The 
collection and analysis of health care utilization information will be useful for informing priorities 
for ARI control and will serve as a basis for the comparison of the effectiveness of different ILI 
control measures to enhance Force Health Protection.
 
Endpoints:
Incidence of PCR-confirmed influenza cases
Frequency of influenza-confirmed hospitalization
Frequency of influenza-like illness
Work days lost due to influenza
Work days lost due to influenza-like illness
Healthcare costs/utilization attributable to influenza
Healthcare cost/utilization attributable to influenza-like illness
Specific Aim #4: To evaluate the association host single nucleotide polymorphisms (SNPs) on 
the immune responses to the influenza vaccine and on influenza severity
 
Endpoints:
Frequency of SNPs by seroconversion status
Frequency of SNPs by geometric mean titer (GMT) cutoff
Frequency of SNPs by mean fold rise (MFR) cutoff
Frequency of SNPs by  influenza status
Frequency of SNPs by influenza severity classification
11.2  Sample Size:
18000
11.3  Total number of subjects requested (including records and specimens):
18000
11.4  If you are recruiting by study arm, please identify the arms of the study and how many subjects will 
be enrolled in each arm
Arm 1: cell-culture based, 6,000.
Arm 2: recombinant influenza vaccine, 6,000.

Arm 3: egg-based influenza vaccine, 6,000.
Sub-study: Approximately 1,200 subjects total recruited from the main study population.
11.5  Please provide a justification for your sample size
Main Study
Based on an alpha of 0.025 (1-sided) and a power of 0.80, a sample size of 18,000 (6,000 per arm) 
subjects has the power to detect a 33% difference in effectiveness between egg-based vaccine and 
two other vaccine preparations, assuming an influenza incidence of 2.3% in the egg-based arm and 
1.54% in the cell-culture-based and recombinant arms. It assumes that 15% of subjects will be lost to 
follow-up. 
Substudy
Based on an alpha of 0.025 (1-sided) and a power of 0.80, a sample size of 1,200 subjects  (400/arm) 
has the power to detect a 22% relative difference in seroconversion rate if there is a 50% 
seroconversion at day 28 among the egg-based vaccine recipients. It assumes that 15-20% of 
subjects will be lost to follow-up.
11.6  Data Analysis Plan:
See section 11.1
12.0
 
Participant Information
12.1  Subject Population:
The study is comprised of DEERS-eligible adults (active duty, retirees and beneficiaries) 
vaccinated (at an MTF) (will be vaccinated) with one of the licensed egg-based, cell-culture-
based or recombinant influenza vaccines during the 2018-2019, 2019-2020, 2020-2021, 2021-
2022 influenza seasons in the United States. Subjects enrolled in the study during 2018-2019, 
2019-2020, and/or 2020-2021 may also be enrolled in the 2021-2022 season.
12.2  Age Range:
Check all the boxes that apply. if the age range of potential subjects (specimens, records) does 
not match the range(s) selected, please specify in the text box.
0-17
18-24
25-34
35-44
45-54
55-64
65-74
75+
12.3  Gender:
Male
Female
Other

12.4  Special categories, check all that apply
Minors /Children
Students
Employees - Civilian
Employees - Contractor
Resident/trainee
Cadets /Midshipmen
Active Duty Military Personnel
Wounded Warriors
Economically Disadvantaged Persons
Educationally Disadvantaged Persons
Physically Challenged (Physical challenges include visual and/or auditory impairment)
Persons with Impaired Decisional Capacity
Prisoners
Pregnant Women, Fetuses, and Neonates
Non-English Speakers
International Research involving Foreign Nationals - Headquarters Review is necessary
You must also consider the requirements of DoDI 3216.02, Enclosure 3, paragraphs 7.e. and 12.
You must also consider the requirements of DoDI 3216.02, Enclosure 3, paragraph 7.e.
12.5  Inclusion Criteria:
Order 
Number
Criteria
1 
Eligible for care in DoD facilities (DEERS eligible)
 
2 
Greater than or equal to 18 years of age
 
3 
At a participating MTF site for the purpose of receiving a seasonal influenza 
vaccination.
 
4 
Able to speak English and able to provide informed consent
 
5 
Able to receive and respond to texts and/or emails, or a military recruit
 
12.6  Exclusion Criteria:
Order 
Number
Criteria
1 
Adults intending to receive or who have received the current season's FluMist 
vaccine (LAIV).
 
2 
Adults who have already received a Flu Vaccine within the current season
 
3 
Individual who cannot receive a flu vaccine or standard dosing due to another 
medical condition
 
4 
Allergic to gentamicin, polymyxin, and/or neomycin
 
Individuals who fail to meet the inclusion criteria

5 
 
13.0
 
Recruitment and Consent
13.1  Please describe the recruitment process, including how subjects will be identified and selected for 
the study.
Identification and Selection of Subjects:
Potential subjects may be encouraged using recruitment flyers that may be posted at the sites in 
areas such as acute care clinics, ward workrooms, the emergency room, the commissary, the 
post exchange and/or base exchange and outside MTFs (e.g. shipyard, military bases, branch 
clinics etc.) as appropriate (if accessible at the MTF (i.e., MAMC). Print advertisements may be 
placed in the command newspaper at each participating MTF. Sites may choose to disseminate 
the flyer via email to targeted audiences (e.g. house staff/attending physicians) or via the web 
using social media networks (i.e. Facebook). In addition, a recruitment poster/flyer may be 
provided to patients during intake by clinic staff to inform potential enrollees about the study. All 
advertisements will include information summarizing the study enrollment criteria, dates and 
locations for enrollment, and indicate that participation in research is voluntary.
 
 
All recruitment material will be reviewed and approved by the IRB prior to use.
 
 
Eligibility Assessment Process:
 
 
Any person eligible to receive care at one of the participating DoD inpatient facilities or 
outpatient clinics, and who meets all inclusion criteria and exclusion criteria is eligible for 
participation in the study. Eligibility for care is determined by the Defense Enrollment Eligibility 
Reporting System (DEERS). This will include individual active duty service members, retired 
military, and their eligible dependents. Attempts will be made to enroll subjects of all genders 
and racial and ethnic origins. Coordinators will confirm DEERS eligibility based on CAC, military 
identification and military health care documents.
 
Recruitment Process: 
 
Electronic Enrollment:
 
Potential subjects can be sent consents, educational and recruitment material via email 30 days 
prior to vaccination day up to two times prior to vaccination day.
 
E-consent links and QR codes will be given via email or in-person for potential subjects to sign 
up for the study. Subjects will receive a screening questionnaire and instruction sheet to ensure 
they understand the procedures, are eligible for the study, and have contact information for the 
staff if they have questions.
 
 
In-person recruitment:
 
Recruitment and consent in the MTFs may take place up to 30 days prior to randomization and 
vaccination. Research protocol briefs may be given on a regular basis by the site PIs or a 
member of the study team to training programs and to the inpatient/outpatient health care staff 
in their primary care clinics as well as the emergency room staff. Following the medical briefing, 
a study investigator will give a 10-minute briefing that outlines the proposed research study. No 
officers in the chain of command will be present during the briefing or the consent process. It will 
be made clear during the briefing that enrollment is completely voluntary and that enrolling, or 
failing to enroll, will in no way affect their standing. Any healthcare worker who was not present 
at the briefing, will be given the opportunity to participate once they have received study 
information and are given the opportunity to ask questions.
 

After the investigator’s briefing, there will be a 10-minute period (more time will be allowed if 
needed) for any questions potential subjects may wish to ask publicly. They will also be given the 
opportunity to ask additional questions in private. Questions on the nature of the study, the 
means by which it is to be accomplished, and the risks to the subjects will be addressed. Any 
questions that cannot be answered will be referred to the site PI. No study procedures will occur 
prior to the subject giving informed consent.
                                               
Active duty members
Recruitment and enrollment of active duty members in groups, may take place outside MTFs (e.
g. military units, shipyard, etc.), or at command briefings for recruits. Following the medical 
briefing, a study investigator will give a 10-minute briefing that outlines the proposed research 
study. No officers in the chain of command will be present during the briefing or the consent 
process. It will be made clear during the briefing that enrollment is completely voluntary and 
that enrolling, or failing to enroll, will in no way affect their standing.
                                               
Beneficiaries
Prior (via electronically) or when beneficiaries arrive at the MTF (in person) to receive their 
influenza vaccination, the immunization or study staff are able to make beneficiaries aware of 
the study and may provide them with recruitment materials describing the study. Individuals 
who are interested learning more about the study will be directed to speak with a study staff 
team member. Beneficiaries will be given the opportunity to ask questions in private. Questions 
on the nature of the study, the means by which it is to be accomplished, and the risks to the 
subject will be addressed. Any questions that cannot be answered will be referred to the site PI. 
No study procedures will occur prior to the subject giving informed consent.
 
Immunogenicity Substudy: Substudy participants are recruited from subjects enrolled in the 
main study. Participation in the main study is a requirement for substudy enrollment. The study 
team will focus on recruitment and enrollment into the immunogenicity sub-study in the weeks 
preceding the start of vaccination. The recruitment strategy for the sub-study will be similar to 
the main study utilizing a combination of flyers, outreach in MTF clinics to target beneficiaries, 
group briefings for MTF health care works and offsite military units (e.g. sailors assigned to ships 
in dry dock, trainees at the Medical Education and Training Campus (METC), etc). Using a similar 
recruitment and enrollment strategy to the main (VE) study will allow for a similar composition of 
subjects between the sub-study and overall cohort. Subjects recruited during the ‘pre-
vaccination window’ will be enrolled and complete the pre-vaccination blood draw, and then 
return for randomization and vaccination at the ‘vaccination or Day 0’ visit. Once the sites start 
vaccination visits, recruitment and enrollment efforts will prioritize the main (VE) study, although 
sites can continue enrollment in the immunogenicity sub-study in order to meet enrollment 
targets.  Enrollments into the immunogenicity sub-study will be stratified by site but not by any 
other parameters (e.g. day of week, every 3rd enrollment etc). Of note, individuals must be 
enrolled in the main study (VE) in order to participate in the sub-study. Individuals who agree to 
participate in the sub-study will be required to complete the main study consent document 
(PAIVED ICD) in addition to the sub-study consent document (PAIVED Sub-Study ICD). 
13.2  Compensation for Participation:
FLUPRO Questionnaire:
Subjects who develop ILI symptoms will receive $10 for their best effort in completing the 7 day 
entries, at the ILI Visit 1.
 
Blood Collection:
$10 per self-collected blood sample
$50 per venipuncture
Under 24 USC 30, payment to Federal Employees and Active Duty military personnel for 
participation in research while on duty is limited to blood donation and may not exceed $50 per 
blood draw. They may not receive any other payment or non-monetary compensation for 
participation in a research study unless they are off duty or on leave during the time they are 
participating in the protocol. 
 
Nasal swab:
Individuals will be compensated $10 per each of the nasal specimens.
 
Participants may be compensated for up to three new ILI episodes per season. ILI episodes must 
be separated by at least 30 days. Recruits/trainees may be compensated if permitted per 

a.  
b.  
c.  
d.  
military policy.In the event that a mitra kit or self-collected nasal swab is collected by a subject 
but the study staff does not receive it a subject may be compensated and can be compensated 
for a replacement.
13.3  Please describe the pre-screening process. If no pre-screening, enter Not Applicable in the text editor
For potential subjects who a e-consenting, there will be a pre-screen eligibility questionnaire.
13.4  Consent Process:
Are you requesting a waiver or alteration of informed consent?
 Yes   
 No
What type?
Waiver of documentation of informed consent
Waiver or alteration of informed consent
Please explain why your study is eligible for the requested waiver
We are requesting an alteration of informed consent to a short form consent. Since we are 
looking to enroll a very large sample during a very short time, use of a short form consent will 
make the consent process more efficient, thereby giving staff members more time to answer any 
questions that the subjects may have. The short informed consent has all of the required 
elements. 
Please explain the consent process:
ICD and Assent Regulatory Requirements:
 
The Informed Consent Document (ICD) will be reviewed and approved by the IRB prior to 
initiation of the study. The ICD Form contains a full explanation of the possible advantages, 
risks, and alternatives to participation, and availability of treatment in the case of injury. 
 
An ICD, in compliance with applicable DoD regulations, 32 CFR 219, the Belmont Principles, the 
Health Insurance Portability and Accountability Act (HIPAA) Authorization, and California Subject’
s Bill of Rights (if applicable) will be signed by the subject or representative before any study-
related procedures are initiated for each subject. The investigator will retain the ICD and 
authorization form as part of the study records. Only PIs, research physicians, clinical 
coordinators, research assistants, and site managers listed in Personnel and Collaborators 
Protocol Attachment will present the protocol in lay terms to the subjects. As part of the 
informed consent process, study staff will describe study procedures, risks of the study, and 
alternative to participation to the potential subject either in person or electronically. All subjects 
will be given the opportunity to ask questions. Any question that cannot be answered by the 
study staff will be referred to the principal investigator (PI) and/or research physicians. Study 
staff will make all effort to answer questions to the subjects to satisfaction prior to granting 
consent. Informed consent includes the principle that it is critical the subject be informed about 
the potential risks and benefits.  This information will allow the subject to make a personal risk 
versus benefit decision and understand the following general principles:
 
Participation is entirely voluntary,
Subjects may withdraw from participation at any time,
Refusal to participate involves no penalty, and
The individual is free to ask any questions that will allow him/her to understand the 
nature of the protocol.
 
Study staff will clearly state that enrollment in the study is completely voluntary. At the end of 
the discussion, all subjects will be provided an electronic copy or the paper consent form, the 
HIPAA authorization form, and the California Subject’s Bill of Rights (if applicable) to carefully 
read and review before considering whether or not to participate.
 
Should the protocol be modified, the subjects consent document will be revised, as needed, to 
reflect the changes to the protocol. If the subject is directly affected by the change, and it is 
directed by the IRB, each subject will be re-consented per the previously defined process and 

subjects will be offered a copy of the newly signed and dated ICD. The approved revision will be 
read, signed, and dated by the subject subjects.
 
Informed Consent Process - Enrollment
 
In response to a flyer or other print advertisement, a potential subject may call the study 
coordinator for more information regarding the study. The study coordinator will explain the 
study and/or ask the individual or group to come to the MTF for further discussion and possible 
enrollment. Following the recruitment procedures, those interested subjects will be offered the 
consent form and authorization forms to sign or paper or electronically. In accordance with DoD 
regulations, if a military member is interested in volunteering, their informed consent process 
will not take place in the presence of uniformed personnel in their chain of command or in the 
presence of a superior officer. At the time of consent, HIPAA authorization will also be obtained. 
 
Study staff will be available to answer any questions an individual may have before deciding 
whether or not to participate in the study. When each individual has determined that they are 
interested in participating, they will sign the appropriate consent form in front of the designated 
study staff (listed in the Personnel and Collaborators Attachment).   Each subject will have the 
ability to opt-in for a buccal swab and for same-day/post-vaccination self-collected blood 
samples. Subjects will elect to opt into this procedure in a designated area of the consent form 
and will do so without penalty or loss of entitlements.  A copy of the signed ICD will be offered to 
the subject and the original document will be retained by the investigative team.
 
A subject is considered to be enrolled when they have signed a consent form and HIPAA 
authorization form (and California Bill of Rights, if applicable). 
 
Substudy enrollment:
Study staff listed in the Personnel and Collaborators Attachment will ensure that each potential 
enrollee of the substudy is presented with the Substudy ICD .  This ICD will be explained by the 
consenting study staff member and the potential participant will be able to ask any questions 
they may have.  If a subject chooses to participate, the substudy ICD  will be signed after the 
main ICD is completed and before any substudy procedures are done. Substudy participants will 
be offered a copy of their signed substudy ICD.
 
  
Participation Log
If individuals agree to participate, identifiers and the study ID, will be recorded in the 
participation log on a secure computer.  Completed study procedures will be documented in the 
electronic participation log. 
 
13.5  DoDI 3216.02 requires an ombudsman to be present during recruitment briefings when research 
involves greater than minimal risk and recruitment of Service members occurs in a group setting. If 
applicable, you may nominate an individual to serve as the ombudsman.
N/A 
Propose ombudsman 
13.6  Withdrawal from Study Participation:
Explain the process for withdrawal and specify whether or not the subjects will be given the 
opportunity to withdraw their data their data/specimens in the event they wish to withdraw from 
the study
A subject may voluntarily end participation in the study at any time.  If a subject withdraws, the 
investigator will make a reasonable effort to determine the reason for the subject’s withdrawal 
from the study. Telephone calls, registered letters, and/or e-mail correspondence will be 
considered reasonable effort for subjects whom are deemed lost to follow up. “Lost to follow-up” 
is defined as a subject who 
received a randomly allocated vaccine 
enrolled in the study and 
but did not respond to any ILI surveillance, or a subject who reported ILI symptoms but then did 
not complete any ILI visit or ILI-related procedure
  
s.
Subjects who withdraw because of study-related AEs will be followed to resolution of AE or as 
long as reasonably possible.  In the event of a continuing study-related AE, the information will 
be provided to the Institutional Review Board (IRB).
 

For the immunogenicity sub-study, “lost to follow-up” is a sub-study subject who did not 
complete the two blood draws and will be reported to the IRB during continuing review. All data 
and specimens collected up to the time of withdrawal will be reported and retained. 
14.0
 
Risks and Benefits
14.1  
Risks of Harm:
Identify all research-related risks of harm to which the subject will be exposed for each research 
procedure or intervention as a result of participation in this study.  Consider the risks of breach 
of confidentiality, psychological, legal, social, and economic risks as well as physical risks.  Do 
not describe risks from standard care procedures; only describe risks from procedures done for 
research purposes
FDA-approved influenza vaccines are made by a number of manufacturers and are classified as 
either “live attenuated” or “inactivated” influenza vaccines. This study will compare the relative 
effectiveness of three inactivated influenza vaccine formulations, an egg-based, a cell-culture-
based, and a recombinant. The live attenuated vaccine (i.e. Flumist) will not be evaluated in this 
study. There are 3 separate egg-based vaccines being studied. To date, there is no published 
data to suggest that there are "clinically significant" differences in the rate of adverse events 
following immunization (AEFI). The CDC/ACIP’s current guidance to providers is to administer 
any licensed, age-appropriate influenza vaccine with no preference expressed for one vaccine 
over another. Active duty members are required to receive an annual influenza vaccination and 
voluntary for retirees and beneficiaries. Approximately 90% of active duty members and 
healthcare workers and 40% of beneficiaries are vaccinated each season.
 
We contend that the PAIVED study meets the standard for a minimal risk study for the following 
reasons: the Centers for Disease Control and Prevention (CDC) and its Advisory Committee on 
Immunization Practices (ACIP) recommend that all patients 6 months of age and older be 
vaccinated annually against influenza. Moreover, the ACIP's current guidance to providers is to 
administer any licensed, age-appropriate influenza vaccine (Inactivated influenza vaccines (IIV), 
Recombinant influenza vaccine (RIV), or live attenuated influenza vaccine (LAIV4) with no 
preference expressed for one vaccine over another (Appendices 2-4). A summary of the common 
adverse effects following immunization (AEFI) associated with influenza vaccines to be used the 
study is presented in Appendix 5. To date, there no published data to suggest that there are 
"clinically significant" differences in the rate of adverse events following immunization (AEFI) 
with the various products and no nationally authoritative body has seen a need to preferentially 
avoid one vaccine's side effects for another product. Thus, it is well within the standard of care to 
give any patient any of the FDA-approved vaccines. It should be noted that among the products 
to be administered have different excipients (Fluarix contains gentamicin and Afluria contains 
neomycin and polymyxin) so participants with who are allergic to these medications would have 
an increased risk of an adverse event, consequently, allergies to gentamicin, neomycin and 
polymyxin has been added to the study exclusion criteria.
 
This 
 is designed to follow individuals who have allocated to 
comparative effectiveness study
receive one of three FDA licensed types influenza vaccine formulations in order to evaluate their 
relative impact of on risk of influenza acquisition and immune responses. Given that all the 
vaccines represent the standard of care and will be administered in accordance with ACIP 
recommendations, to those who are not allergic to vaccine components, the only increased risk 
to subjects in the study would be related to the risk of a blood draw (syncope, bruise, etc.) as 
well as any remote risk of PII compromise. 
 
 
1. Rare (Event rate < 1%)
Secondary infection and syncope from vasovagal reactions occur from blood collection in 
rare cases. Nasal swabs could trigger symptomatic nose bleeds in rare cases.
2. Less Likely (1% greater or equal Event Rate 5%)
Nasal swabs may abrade or irritate mucosal surfaces already inflamed due to respiratory 
infections, leading to discomfort and minimal local bleeding.

1.  
2.  
3.  
3. Likely (5% greater or Equal Event Rate < 5%)
Bruising and bleeding may occur as a result of blood collection procedure. Nasal swabbing 
for viral diagnostics 
and cheek swabbing for obtaining shed buccal cells (for future study of genetic 
polymorphisms) may cause local discomfort.
4. More likely (Event rate less or equal to 10%)
No known risks
 
Risk of Phlebotomy
The primary risks of phlebotomy include local discomfort, occasional bleeding or bruising of the 
skin at the site of needle puncture, and rarely hematoma, infection, or fainting.
At the time of enrollment and at Day 21-35, each subject in the immunogenicity substudy will be 
asked about participation in other research studies to ensure that blood draws do not exceed the 
following amounts for all research protocols combined: 10.5 mL/kg or 550 mL, whichever is 
smaller, over any 8-week period for adults. Subjects will also be asked to collect a minimal 
amount of blood for both  ILI visits along with an opt-in pre and post vaccination using a small 
finger prick.
 
For assessment of risk in this class of subjects we look to the DHHS IRB Guidebook Chapter VI – 
Special Classes of Subjects. Section B of that chapter speaks to the risk of phlebotomy in 
pregnant women:
 Obtaining this modest phlebotomy and nasal specimens from pregnant women should conform 
to the specific requirements of 45 CFR 46, section 207.
Risk of Nasal and Buccal Specimen Collection
 
Nasal swabbing for pathogen diagnostics may cause brief, local discomfort. While less likely, 
obtaining a nasal swab may trigger sneezing, coughing, or a gag reflex, which is slightly more 
likely in subjects who are already suffering from these symptoms. Rarely, nasal swabs could 
trigger a symptomatic nosebleed.
Cheek swabbing for obtaining shed buccal cells (for future study of genetic 
polymorphisms) may cause local discomfort.
 
Any adverse event resulting from blood collection procedures will be managed according to 
standard clinical procedures.
 
Confidentiality Breach
Another risk of participation in this study is that someone may accidently release information 
from the subject’s medical records without the subject’s permission. However, the investigators 
make every effort to protect subject’s confidentiality and privacy by careful handling of records 
and data. Furthermore, the data base is secured by only using codes (subject’s identification 
number and PIN), and not names or other individual. Extensive security measures have been 
taken to protect this information.
 
      4. Risk Associated with Each Vaccine
 
See Appendix 5 - comparison of vaccine side effects.
14.2  
Measures to Minimize Risks of Harm (Precautions, safeguards):
For each research procedure or intervention, describe all measures to minimize and/or eliminate 
risk of harms to subjects and study personnel
Blood/Nasal swab collection
Any adverse events resulting from blood collections and/or nasal swab procedures will be 
managed according to standard clinical procedures. Expected adverse events that are not 
serious, but are directly related, are reported at continuing review. Steps to minimize and 

mitigate risks of participation are described in the appropriate, and respective, sections of the 
protocol.
 
Data Management
Data will be handled in accordance to the protocol and all applicable SOPs. The Flu Pro 
questionnaire will be used electronically. Subject’s information will only be recorded using the 
subject’s study number and their PIN number. The subject's study number and a PIN number are 
used by participants to access the electronic Flu Pro Diary. The subject study number is given to 
the participant by the clinical research coordinator. The PIN is a four digit number that is auto-
generated in RedCAP and recorded by the subject so they may return at a later time to complete 
the Flu Pro Diary. Both are unique and non-identifying numbers.
 
Once the subject received instructions they will respond to each question. They will be able to 
review and modify his/her answers before completion/closure of the questionnaire. Upon 
completion/closure of the questionnaire, a notification message will be presented confirming this 
and the subject will no longer have access to that day’s questionnaire. Study personnel at the 
site will be able to access the electronic FluPRO questionnaire data; only DCC personnel will be 
able to access and manage the questionnaire data.
 
Specimens label study identification codes will be sent to participating labs. No PHI will be 
transferred. Transmittal logs will be sent via secure file transfer.Details are outlined in the Data 
Management section of the protocol.
14.3  
Confidentiality Protections (for research records, data and/or specimens):
Describe in detail the plan to maintain confidentiality of the research data, specimens, and 
records throughout the study and at its conclusion (e.g., destruction, long term storage, or 
banking). Explain the plan for securing the data (e.g., use of passwords, encryption, secure 
servers, firewalls, and other appropriate methods). If data will be shared electronically with 
other team members/collaborators outside the institution, describe the method of transmission 
and safeguards to maintain confidentiality. Explain whether this study may collect information 
that State or Federal law requires to be reported to other officials or ethically requires action, e.
g., child or spouse abuse
The investigator will ensure that the subject’s anonymity is maintained.  Subjects will not be 
identified in any publicly released reports of this study.  All data collected in this study will be 
strictly confidential in accordance with local, state, and federal law. 
 
The only electronic links established between the subject name, DOD ID#, and the Study ID 
number will be on tracking spreadsheets at the clinical sites used for collecting information on ILI 
cases as applicable from the electronic medical record and will only be accessed by authorized 
study staff. During the study, source documents will be held in a secured cabinet with restricted 
access. Team members with access to the documents are counseled on the importance of 
confidentiality of subject medical records, and trained on human subjects’ protection and HIPAA. 
All staff involved in this study have completed the required human subjects protection and ethics 
training. In all electronic records for data analysis, the subject is not referenced by name, but 
only Study ID number. This method is designed to protect the privacy of study subject medical 
information. All source documents will be held at the study site in the research spaces in secured 
cabinets with restricted access. All measures are in place to protect the privacy of all 
subjects.  The study will utilize passwords and firewalls to maintain confidentiality of data 
accessed via computer. The summary report generated from the interviews and completed 
questionnaires will not contain any subject identifying information. 
14.4  
Potential Benefits:
Describe any real and potential benefits of the research to the subject and any potential benefits 
to a specific community or society
If the individuals in the research are considered experimental subjects (per 10 USC 980), and 
they cannot provide their own consent, the protocol must describe the intent to directly benefit 
all subjects

1. Benefits of participation in the study
 
This no greater than minimum risk study provides no direct benefit to the subject. If the study 
results show that there are significant differences in the either the immunogenicity or 
effectiveness between vaccines then they would have important implication for influenza 
vaccination policy in the US military. Conversely, if the findings showed that the differences in 
immunogenicity or vaccine effectiveness were minimal, they would provide evidence in support 
of current immunization recommendations.  This study has the potential to provide high visibility 
to military infectious disease research given the importance and global relevance of the research 
question being addressed.
14.5  
Privacy for Subjects:
Describe the measures to protect subject’s privacy during recruitment, the consent process, and 
all research activities, etc.
Following group study briefings, potential subjects will have the opportunity to have their 
questions and concerns addressed by study staff member and to complete the consent form in a 
private setting. Please see Section 14.3 for additional details about maintaining a subject’s 
privacy throughout the study.
14.6  
Incidental or Unexpected Findings:
Describe the plan to address incidental findings and unexpected findings about individuals from 
screening to the end of the subject’s participation in the research. In cases where the subject 
could possibly benefit medically or otherwise from the information, state whether or not the 
results of screening, research participation, research tests, etc., will be shared with subjects or 
their primary care provider. State whether the researcher is obligated or mandated to report 
results to appropriate military or civilian authorities and explain the potential impact on the 
subject
Vaccine Effectiveness Study:  Achieving this objective involves the collection self-reported data 
(e.g. demographics, chronic/co-morbid conditions, etc.) and data abstracted from medical 
records (history of influenza, history of influenza vaccination, etc.), recording respiratory illness 
symptoms, and the analysis of nasal specimens for diagnosing influenza.  Of these, only the 
diagnosis of influenza has the potential to impact case management. However, the results of the 
laboratory will not be known until the data collection phase of the study has been completed, and 
therefore, will not have the potential to improve the management of influenza cases.
 
Immunogenicity substudy: Laboratory analyses conducted for the substudy are specifically 
focused on HAI testing and immune responses to influenza vaccination. As such, the results may 
identify an influenza vaccine failure but have little scope to reveal an otherwise unknown life-
threatening condition. However, in the event that a life-threatening immune abnormalities are 
detected in a study subject, the test results will be reported to the study team and the site PI, 
who would notify the subject’s provider. The site PI would also follow-up with the subject.
 
De-identified study results will be reported in the aggregate and submitted for publication in a 
peer reviewed journal.
15.0
 
Study Monitoring
15.1  Your study requires either Data and Safety Monitoring Plan (DSMP) or a Data and Safety Monitoring 
Board (DSMB).

DSMP 
DSMB 
Both 
Not Applicable 
A DSMP should describe the plan to monitor the data to verify that the data are collected and 
analyzed as specified in the protocol. Include who will conduct the monitoring, what will be 
monitored, and the frequency of monitoring. It should also include the plan to ensure the safety 
of subjects
This study is a comparison of the effectiveness of licensed influenza vaccines. These reviews will 
occur annually, dururing periods of low influenza activity when no enrollment is occurring.
 
Quality Assurance (QA) will be conducted at least once per site per year by a QA Reviewer(s)by 
someone who is not involved in the day-to-day collection of data or study procedures. QA will 
occur, as durings off season times. Only subjects that have not been previously checked in a 
prior QA review will be included in each annual QA review. The reviewer(s) will document any 
and all of their site-specific QA findings using the QA Checklist and Summary Cover Sheet. The 
findings should be posted on the PAIVED study portal on the IDCRP Intranet prior to the roll-out 
of the new Flu vaccine administration dates/ILI season.  Any protocol deviations arising from QA 
review/visits will be reported to the ID IRB according to the protocol.
 
An independent Data Monitoring Committee appointed by the PI will conduct an interim review 
after one year to assess whether an early signal or trend exists that could affect equipoise.  The 
DMC will be comprised of subject matter experts in influenza, epidemiology and statistics.  The 
DMC will receive and review study reports from the PI at the one year point and at other times 
as deemed appropriate.
Describe the composition of your DSMB and how frequently it meets. Explain who will be 
responsible for ensuring data accuracy and integrity, how often interim data be reviewed - and 
by whom - and who will perform aggregate analysis of data and adverse events. 
The 
includes independent experts that do not have direct 
Data Monitoring Committee (DMC) 
involvement in the conduct of the study and have no significant conflicts of interests. They will 
review the study prior to initiation and yearly thereafter, unless otherwise recommended by the 
Committee. The DMC may convene additional reviews as necessary. The DMC will review the 
study data to evaluate efficacy, study progress, and conduct of the study.  The DMC will be 
responsible for conducting an interim analysis of the results comparing the vaccines for the 
primary endpoint using data from the first year of the trial (2018-2019). The results of the 
interim will be used to assess whether there is substantive evidence showing clinically 
meaningful differences in effectiveness exist between cell-culture-based, the recombinant 
licensed influenza and egg-based vaccines to  warrant early termination of the study. Such a 
level of evidence would also facilitate more precise comparison of effects in patient subgroups 
and for secondary endpoints.  Although application of this guideline is focused on influenza 
acquisition, if a similar level of evidence is achieved first in comparing severity between 
randomized arms, then termination of the study might also be considered.
 
Safety Monitoring Plan:
The USU IDCRP is providing the funds for this research. The IDCRP is a DoD program based at 
the USU with funding through an interagency agreement with the National Institutes of Health 
(NIH) National Institute of Allergy and Infectious Diseases (NIAID). As part of the NIAID support 
of this program, Office of Clinical Research Policy and Regulatory Operations (OCRPRO), Division 
of Clinical Research, NIAID and Regulatory Compliance and Human Subjects Protection Program 
(RCHSPP), Leidos Biomedical Research, Inc. personnel typically provide study monitoring for 
IDCRP to assure that appropriate regulations, the approved protocol, and NIAID Intramural 
Clinical Monitoring Guidelines are followed.
 
The Principal Investigator and the Chief of Quality Management will perform internal safety 
monitoring as needed. The internal monitors, may inspect all documents and records maintained 
by the site, including but not limited to medical records (office, clinic, or hospital) and pharmacy 
records for the subject in this study. The PI will obtain, as part of the informed consent, 
permission for monitoring or regulatory authorities to review, in confidence, any records 
identifying individuals in this clinical study.
 
Additionally, the Quality Management processes will be utilized to ensure regulatory and protocol-
specific responsibilities 
. This process is outlined below.
are met
 
The Clinical Quality Management Plan (CQMP) establishes the quality management guidelines for 
tasks to PAIVED. Quality Control (QC) activities will be conducted for each subject's study visit 

by an individual at the study site who did not complete the study visit, such as another Clinical 
Research Coordinator (CRC) or the Site Manager (SM). Quality Assurance (QA) activities will be 
conducted annually by a QA Reviewer who is not involved in the day-to-day collection of data or 
study procedures. Following each QA Annual Review Visit, the QA Reviewer will complete a QA 
Annual Summary Report that will be uploaded to the Intranet and an overall QM study status 
summary will be shared with IDCRP Leadership. Any protocol deviations or reportable events 
arising from QC and QA reviews and/or visits will be reported to the USUHS IRB according to the 
protocol.
 
Leidos reviewed this project and it was determined that this study does not require independent 
data and safety monitoring.
16.0
 
Reportable Events
16.1  Reportable Events:
Consult with the research office at your institution to ensure requirements are met
 
• Describe plans for reporting expected adverse events. Identify what the expected adverse 
events will be for this study, describe the likelihood (frequency, severity, reversibility, short-
term management and any long-term implications of each expected event)
 
• Describe plans for reporting unexpected adverse events and unanticipated problems. Address 
how unexpected adverse events will be identified, who will report, how often adverse events and 
unanticipated problems will be reviewed to determine if any changes to the research protocol or 
consent form are needed and the scale that will be used to grade the severity of the adverse 
event
Reportable Events
A unanticipated problem (UP) may only involve exposure of a subject or others to an unexpected 
risk or the risk may culminate in a subject or another individual actually experiencing a harm 
that is generally described as an adverse event in clinical research or an adverse outcome in 
behavioral or social science research. UP that are directly related to study procedures will be 
reported within 48 hours to the IRB.
 
An adverse event is defined as any complaint of illness or injury that occurs during the period of 
study participation. These are recorded and inspected by the supervising physician investigator 
to determine severity and relatedness to participation (definite, probable, possible, or unlikely). 
The physician investigator is responsible for directly managing or coordinating management of 
adverse events following routine clinical practice. Because this is proposed to be a minimal risk 
study, the reporting of adverse events is limited to an analysis at the time of annual reporting.
 
UPs involving risk to the subject or others, adverse events, and serious adverse events will be 
reported only if they are directly related to study procedures (e.g., phlebotomy, nasal swab 
collection, etc. ) or determined by the study site investigator to be an event requiring reporting 
to the IRB. Stable chronic conditions which are present prior to enrollment and do not worsen 
are not considered adverse events or serious adverse events even if they meet the standard 
definition, and will be accounted for in the subject’s medical history. They will not be reported as 
adverse events or serious adverse events.
 
Expected adverse events which are not serious are reported on the Annual Progress Report 
(APR) during the continuing review of the protocol. APR is mostly due in a 12-month cycle, the 
anniversary month of the protocol’s initial approval or due in lesser than 12-month cycle as 
determined by the IRB for continuing review and approval.
 
A serious adverse event is any illness or injury occurring during the period of study participation 
that:
1) requires the subject to be admitted to a hospital
2) Causes permanent injury to the subject
3) Causes the death of a study subject
 
Serious Adverse Events:

The PI, within 48 hours, will report serious adverse events (SAE) directly relating to study 
procedures occurring in subjects enrolled at their site. This is accomplished by submitting an 
adverse event report memorandum to the IRB.
 
Unexpected (but not serious) adverse events occurring in subjects enrolled at a study site which, 
in the opinion of the PI, are possibly related to study procedures will be reported by the PI within 
10 working days to the IRB using the same procedure.
 
A summary of all serious or unexpected adverse events also will be included in the APR.
Reporting Protocol Deviations
 
The PI or designee will be responsible for identifying and reporting all deviations, which are 
defined as isolated occurrences involving a procedure that did not follow the study protocol or 
study-specific procedure. Investigators will report protocol deviations to the USU ID IRB within 
10 business days that:
1) Relate to subject safety
2) Relate to the informed consent process
3) Are any other protocol deviations which, in the opinion of the PI, should be promptly reported 
to the IRB
 
Subject non-compliance with collection of nasal swabs will be considered a deviation. A log of all 
deviations will be reported annually in the continuing review report to the IRB and in the Final 
Study Report.
Adverse Events (AE)
Expected adverse events that are not serious, but are directly related, are reported at continuing 
review.
Expected adverse events that are not serious and not related will not be recorded or reported. A 
continuing review report is mostly due in a 12-month cycle, the anniversary month of the 
protocol’s initial approval or due in lesser than 12-month cycle, as determined by the IRB for 
continuing review and approval. An adverse event is any untoward or unfavorable medical 
occurrence in a human subject, including any abnormal sign (e.g., abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the subject’s participation 
in the research, whether or not considered related to the research.
 
Expected non-serious adverse events related to study procedures (e.g. phlebotomy, nasal swab 
collection, etc.) conducted by a study staff member will be reported to the IRB at continuing 
review.
 
Please note:  Known side effects of the FDA-licensed influenza vaccines (CDC. Flu Vaccine Safety 
Information. 
)  will 
 be 
https://www.cdc.gov/flu/protect/vaccine/general.htm
not
reported as Adverse Events. The risks of side effects of the flu vaccine are generally mild and go 
away on their own within a few days.
 
Common side effects from the influenza vaccine include:
 
Soreness, redness, and/or swelling from the shot
Headache
Fever
Nausea
Muscle aches
The influenza vaccine, like other injections, can occasionally cause fainting.
 
A few research studies have found a possible small association of injectable influenza vaccine 
with Guillain-Barré syndrome (GBS). Overall, these studies estimated the risk for GBS after 
vaccination as fewer than 1 or 2 cases of GBS per one million people vaccinated. Other studies 
have not found any association. GBS also, rarely, occurs after acute influenza infection. Even 
though GBS following flu illness is rare, GBS is more common following influenza infection than 
following influenza vaccination. GBS has not been associated with FluMist, the nasal spray 
vaccine.  (CDC. Flu Vaccine Safety Information. https://www.cdc.gov/flu/protect/vaccine/general.
htm)
 
Serious Adverse Event (SAE)
This is a no greater than minimum risk study. We will not be monitoring subjects’ medical 
records for events following the standard of care vaccination. 
 
Unexpected Adverse Event
An AE is unexpected if it is not listed in the Package Insert (for the influenza vaccine) or is not 
listed at the frequency or severity that has been observed. All serious adverse events or 

1.  
2.  
3.  
reportable events will be reported to the IRB in 15 calendar days or sooner if mandated by local 
regulation.
 
Unanticipated Problem that is not an Adverse Event (UPnonAE)
An unanticipated problem that does not fit the definition of an adverse event, but which may, in 
the opinion of the investigator, involve risk to the subject, affect others in the research study, or 
significantly impact the integrity of research data. Such events would be considered a non-
serious UP. For example, we will report occurrences of breaches of confidentiality, or accidental 
destruction of study records.
Protocol Deviation
 
Any change, divergence, or departure from the IRB approved study procedures in a research 
protocol. Protocol deviations are designated as serious or non-serious and further characterized 
as:
1. Those that occur because a member of the research team deviates from the protocol;
2. Those that are identified before they occur, but cannot be prevented;
3. Those that are discovered after they occur; Non- serious deviations will be reported at the 
time of continuing review.
 
Deviations that require prompt reporting are:
Those that relate to the informed consent process;
Those that relate to subject safety;
Any other deviation in which the PI feels should be promptly reported
 
Serious Protocol Deviation
A deviation that meets the definition of a Serious Adverse Event or compromises the safety, 
welfare or rights of subjects or others.
 
Documenting, Recording, and Reporting Adverse Events
All AEs and all SAEs occurring from the time the informed consent is signed through Day 28 will 
be documented, recorded, and reported.
 
At each contact with the subject, information regarding AEs will be elicited by appropriate 
questioning and examinations and will be:
 
immediately documented in the subject’s medical record/source document,
recorded on the Adverse Event Case Report Form (AE CRF) and reported as outlined below
 
If a diagnosis is clinically evident (or subsequently determined), the diagnosis rather than the 
individual signs and symptoms will be recorded as the AE.
 
Assessment of Adverse Event
The Investigator will evaluate all AEs with respect to Seriousness (criteria listed above), Severity 
(grading), and Causality (relationship to study agent and relationship to research) according to 
the following guidelines.
 
Severity
The Investigator will grade the severity of each AE according to the National Institutes of Health, 
“Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events” Version 
2.1, March 2017, which can be found at: http://rsc.tech-res.com/docs/default-source/safety
/daids-ae-grading-table-mar2017.pdf
 
Causality
Causality (likelihood that the event is caused by the study agent(s)) or research study 
participation will be assessed considering the factors listed under the following categories:
 
Definitely Related

reasonable temporal relationship
follows a known response pattern
evidence to suggest a causal relationship
is no alternative etiology
 
Probably Related
reasonable temporal relationship
follows a suspected response pattern (based on similar agents)
No evidence of a more likely alternative etiology.
 
Possibly Related
reasonable temporal relationship
little evidence for a more likely alternative etiology
 
Unlikely Related
does not have a reasonable temporal relationship
OR
good evidence for a more likely alternative etiology
 
Not Related
does not have a temporal relationship
OR
definitely due to an alternative etiology
 
Note: Other factors should also be considered for each causality category when appropriate.
Causality assessment is based on available information at the time of the assessment of the AE.
The investigator may revise the causality assessment as additional information becomes 
available.
17.0
 
Equipment/non-FDA Regulated Devices
17.1  Does the study involve the use of any unique non-medical devices/equipment?
  Yes   
  No
18.0
 
FDA-Regulated Products
18.1  Will any drugs, dietary supplements, biologics, or devices be utilized in this study?
Drugs
Dietary Supplements
Biologics
Devices
N/A
18.2  Drugs, Dietary Supplements and Biologics/Vaccines details:

Are drug(s) in this research being used in accordance to the approved labeling?
Are drug(s) in this research being used in a manner other than its approved labeling?
Enter Dietary Supplements and Biologics/Vaccines in the Drug Information table. Complete all 
relevant fields in the table (“Protocol Drug Details” screen). If the question is not relevant, leave 
the question blank and/or do not change the default selection.
View 
Details
Drug Name
FDA Approved
A new drug or a 
new use of 
approved drug:
IND Number
Trade Drug 
Name:
Flucelvax 
Quadrivalent 
(Seqirus)
Generic Drug 
Name:
Investigational 
Drug Name:
Yes 
No 
 
Trade Drug Name:
Flucelvax Quadrivalent (Seqirus) 
Generic Drug Name:
 
Investigational Drug Name:
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic:
Seqirus  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new 
use of an already approved 
drug
No  
Is an IND necessary
No  
IND Number
 
Who holds the IND:
N/A  
IND details:
 
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption:
 
Are you currently using this 
IND in another research 
project?
No  
If yes, list the IRB Number(s):
 
Dose Range:
 
Frequency:
 
Route of administration:
 
Will the investigational 
pharmacy be dispensing?
No  
If the source is not a FDA 
licensed facility, provide details 
regarding the purity, quality, 
stability and sterility of the 
investigational drug/biologic:
 
Identify who will be preparing 
the investigational drug
/biologic for administration and 
describe in detail how it will be 
prepared:
 

Indication(s) under 
Investigation:
 
Where will the drug be stored
 
Drug Storage Restrictions 
(including temperature, etc.):
 
Administration Instructions:
 
Possible Untoward Effects, 
Their Symptoms & Treatment:
 
Potential or Actual Antidotes 
for Excessive or Adverse Drug 
Effect:
 
Contraindications and 
Interactions, If Known:
 
Investigators Authorized to 
Prescribe:
 
Trade Drug 
Name:
Flublok® 
QIV (45µg 
HA/strain)
Generic Drug 
Name:
Investigational 
Drug Name:
Yes 
No 
 
Trade Drug Name:
Flublok® QIV (45µg HA/strain) 
Generic Drug Name:
 
Investigational Drug Name:
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic:
Protein Sciences  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new 
use of an already approved 
drug
No  
Is an IND necessary
No  
IND Number
 
Who holds the IND:
N/A  
IND details:
 
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption:
 
Are you currently using this 
IND in another research 
project?
No  
If yes, list the IRB Number(s):
 
Dose Range:
 
Frequency:
 
Route of administration:
 
Will the investigational 
pharmacy be dispensing?
No  
If the source is not a FDA 
licensed facility, provide details 
regarding the purity, quality, 
 

stability and sterility of the 
investigational drug/biologic:
Identify who will be preparing 
the investigational drug
/biologic for administration and 
describe in detail how it will be 
prepared:
 
Indication(s) under 
Investigation:
 
Where will the drug be stored
 
Drug Storage Restrictions 
(including temperature, etc.):
 
Administration Instructions:
 
Possible Untoward Effects, 
Their Symptoms & Treatment:
 
Potential or Actual Antidotes 
for Excessive or Adverse Drug 
Effect:
 
Contraindications and 
Interactions, If Known:
 
Investigators Authorized to 
Prescribe:
 
Trade Drug 
Name:
Flulaval® 
QIV (15 µg 
HA/strain)
Generic Drug 
Name:
Investigational 
Drug Name:
Yes 
No 
 
Trade Drug Name:
Flulaval® QIV (15 µg HA/strain) 
Generic Drug Name:
 
Investigational Drug Name:
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic:
ID Biomedical Corp. of Quebec  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new 
use of an already approved 
drug
No  
Is an IND necessary
No  
IND Number
 
Who holds the IND:
N/A  
IND details:
 
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption:
 
Are you currently using this 
IND in another research 
project?
No  
If yes, list the IRB Number(s):
 
Dose Range:
 

Frequency:
 
Route of administration:
 
Will the investigational 
pharmacy be dispensing?
No  
If the source is not a FDA 
licensed facility, provide details 
regarding the purity, quality, 
stability and sterility of the 
investigational drug/biologic:
 
Identify who will be preparing 
the investigational drug
/biologic for administration and 
describe in detail how it will be 
prepared:
 
Indication(s) under 
Investigation:
 
Where will the drug be stored
 
Drug Storage Restrictions 
(including temperature, etc.):
 
Administration Instructions:
 
Possible Untoward Effects, 
Their Symptoms & Treatment:
 
Potential or Actual Antidotes 
for Excessive or Adverse Drug 
Effect:
 
Contraindications and 
Interactions, If Known:
 
Investigators Authorized to 
Prescribe:
 
Trade Drug 
Name:
Fluarix QIV 
(15 µg HA
/strain)
Generic Drug 
Name:
Investigational 
Drug Name:
Yes 
No 
 
Trade Drug Name:
Fluarix QIV (15 µg HA/strain) 
Generic Drug Name:
 
Investigational Drug Name:
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic:
GlaxoSmithKline  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new 
use of an already approved 
drug
No  
Is an IND necessary
No  
IND Number
 
Who holds the IND:
N/A  
IND details:
 
If FDA Approved and an IND is 
not required, Please provide a 
 

rationale for exemption:
Are you currently using this 
IND in another research 
project?
No  
If yes, list the IRB Number(s):
 
Dose Range:
 
Frequency:
 
Route of administration:
 
Will the investigational 
pharmacy be dispensing?
No  
If the source is not a FDA 
licensed facility, provide details 
regarding the purity, quality, 
stability and sterility of the 
investigational drug/biologic:
 
Identify who will be preparing 
the investigational drug
/biologic for administration and 
describe in detail how it will be 
prepared:
 
Indication(s) under 
Investigation:
 
Where will the drug be stored
 
Drug Storage Restrictions 
(including temperature, etc.):
 
Administration Instructions:
 
Possible Untoward Effects, 
Their Symptoms & Treatment:
 
Potential or Actual Antidotes 
for Excessive or Adverse Drug 
Effect:
 
Contraindications and 
Interactions, If Known:
 
Investigators Authorized to 
Prescribe:
 
Trade Drug 
Name:
Afluria QIV 
(15 µg HA
/strain)
Generic Drug 
Name:
Investigational 
Drug Name:
Yes 
No 
 
Trade Drug Name:
Afluria QIV (15 µg HA/strain) 
Generic Drug Name:
 
Investigational Drug Name:
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic:
Seqirus  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new 
use of an already approved 
drug
No  

Is an IND necessary
No  
IND Number
 
Who holds the IND:
N/A  
IND details:
 
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption:
 
Are you currently using this 
IND in another research 
project?
No  
If yes, list the IRB Number(s):
 
Dose Range:
 
Frequency:
 
Route of administration:
 
Will the investigational 
pharmacy be dispensing?
No  
If the source is not a FDA 
licensed facility, provide details 
regarding the purity, quality, 
stability and sterility of the 
investigational drug/biologic:
 
Identify who will be preparing 
the investigational drug
/biologic for administration and 
describe in detail how it will be 
prepared:
 
Indication(s) under 
Investigation:
 
Where will the drug be stored
 
Drug Storage Restrictions 
(including temperature, etc.):
 
Administration Instructions:
 
Possible Untoward Effects, 
Their Symptoms & Treatment:
 
Potential or Actual Antidotes 
for Excessive or Adverse Drug 
Effect:
 
Contraindications and 
Interactions, If Known:
 
Investigators Authorized to 
Prescribe:
 
18.4  Reporting Requirements for FDA-regulated research under IND and IDE:
Describe the process for complying with FDA regulatory requirements for adverse event 
reporting and adverse device effects reporting to the sponsor
18.5  Sponsor (organization/institution/company):
N/A
If applicable, provide sponsor contact information:

1.  
2.  
3.  
4.  
5.  
6.  
7.  
8.  
9.  
19.0
 
Research Registration Requirements
19.1  ClinicalTrials.gov Registration:
Registration is not required 
Registration pending 
Registration complete 
“NCT” number:
NCT03734237
19.2  Defense Technical Information Center Registration (Optional):
Registration is not required 
Registration pending 
Registration complete 
20.0
 
References and Glossary
20.1  References:
References:
 
Influenza. Atlanta: Centers for Disease Control and Prevention (https://www.cdc.gov
).
/flu/index.htm
DoD AFHSB.2018 VRBPAC DoD Influenza Surveillance Rpt.1Mar2018.  https://www.
health.mil/Military-Health-Topics/Health-Readiness/Armed-Forces-Health-
 Publications/Influenza-Summary- and- Reports.
Surveillance-Branch/Reports-and
Update: pneumonia-influenza and severe acute respiratory illnesses, active component, U.
S. Armed Forces, July 2000-   June 2012. MSMR. 2012;19(9):11-15.
Sanchez JL, Cooper MJ, Myers CA, Cummings JF, Vest KG, Russell KL, et al. Respiratory 
Infections in the U.S. Military: Recent Experience and Control. Clinical microbiology 
reviews. 2015;28(3):743-800.
CDC. FluView. 2017-2018 Influenza Season Week 13 ending March 31, 2018. https://w
ww.cdc.gov/flu/weekly/index.htm
AFHSB. Seasonal Influenza Summary:Northern Command--Week 13 (04 Mar-07 Apr 
2018). https://www.health.mil/Military-Health-Topics/Health-Readiness/Armed-
Forces-Health-Surveillance-Branch/Reports-and-Publications/Influenza-
.
Summary-and-Reports
Paules CI, Sullivan SG, Subbarao K, Fauci AS. Chasing Seasonal Influenza - 
 for a 
TheNeed
Universal Influenza Vaccine. N Engl J Med. 2018 Jan 4;378(1):7-9.
Flannery B, Chung JR, Belongia EA, et al. Interim Estimates of 2017–18 Seasonal 
Influenza Vaccine Effectiveness — United States, February 2018. MMWR Morb Mortal Wkly 
Rep 2018;67:180–185.
 Zost SJ, Parkhouse K, Gumina ME, et al. Contemporary H3N2 influenza viruses have a 
glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. 
Proc Natl Acad Sci U S A 2017;114:12578–83.

10.  
11.  
12.  
13.  
14.  
Wu NC, Zost SJ, Thompson AJ, et al. A structural explanation for the low effectiveness of 
the seasonal influenza H3N2 vaccine. PLoS Pathog 2017; 13(10): e1006682
Skowronski et al., Low 2012-13 influenza vaccine effectiveness associated with 
 
mutation
in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PLoS 
One. 2014 9(3):e92153. 
: 10.1371/journal.pone.0092153.
doi
Cobey S. et al., Poor immunogenicity, not vaccine strain egg adaptation, may explain the 
low H3N2 influenza vaccine effectiveness in 2012-13. Clin Infect Dis. 2018. 
: 10.1093
doi
/cid/ciy097.
Wang, W., et al., Establishment of retroviral pseudotypes with influenza hemagglutinins 
from H1, H3, and H5 subtypes for sensitive and specific detection of neutralizing 
antibodies. J Virol Methods, 2008. 153(2): p. 111-9.
Wang, W., et al., Characterization of lentiviral pseudotypes with influenza H5N1 
hemagglutinin and their performance in neutralization assays. J Virol Methods, 2010. 165
(2): p. 305-10.
20.2  Abbreviations and Acronyms:
AE                           Adverse Event
AFHSB                   Armed Forces Health Surveillance Branch
AHLTA                   Armed Forces Health Longitudinal Technology Application
ARD                       Acute Respiratory Disease
ARI                         Acute Respiratory Infection
BAMC                   Brooke Army Medical Center
BMI                        Body Mass Index
CBC                        Complete Blood Count
CDC                        Centers for Disease Control and Prevention
CRC                        Clinical Research Coordinator
CRF                       Case Report Form
DCC                        Data Coordination Center
DHHS                     Department of Health and Human Services
DNBI                      Disease and Non-Battle Injury
DoD                       Department of Defense
eCRF                      Electronic Case Report Form
ELISA                     Enzyme Linked Immunosorbent Assay
FHP                        Force Health Protection
FSH                       Fort Sam Houston
GC-MS                  Gas chromatography-mass spectrometry
GCP                       Good Clinical Practice
GEIS                       Global Emerging Infections Surveillance and Response System
HIPAA                     Health Insurance Portability and Accountability Act
IHB                         Immunization Healthcare Branch
ICD                         Informed Consent Document
ICU                         Intensive Care Unit
IDCRP                    Infectious Disease Clinical Research Program
IDSA                      Infectious Diseases Society of America
IFN                         Interferon
IL                             Interleukin
ILI                           Influenza-like Illness
IRB                         Institutional Review Board
LAIV                       Live attenuated influenza vaccine
MCP                      Macrophage Chemo-attractant Protein
MIP                        Macrophage Inflammatory Protein
MAMC                  Madigan Army Medical Center
MDR                      Military Health System Data Repository
MTF                       Military Treatment Facility
NHRC                    Naval Health Research Center
NIAID                    National Institute of Allergy and Infectious Diseases
NIH                    National Institutes of Health
NMCP                   Naval Medical Center Portsmouth
NMCSD                Naval Medical Center San Diego
NMRC                   Naval Medical Research Center
OCRPRO               Office of Clinical Research Policy and Regulatory Operations (formerly RCHSPB)
OHRP                    Office for Human Research Protections
PCC                        Program Coordination Center

PCR                        Polymerase Chain Reaction
PI                            Principal Investigator
PPM                      Personal Protective Measures
RA                          Research Assistant
RCHSPP                Regulatory Compliance and Human Subjects Protection Program
RCT                      Randomized Controlled Trial
RR                           Relative Risk (measured as a risk ratio, odds ratio, hazards ratio, etc.)
rRT-PCR                Real-time reverse transcriptase polymerase chain reaction
SAE                     Serious Adverse Event
SARI                       Severe Acute Respiratory Illness
SIQ                         Sick in Quarters
SOIV                      Swine-Origin Influenza Virus
SOP                        Standard Operating Procedure
SPL                         Specimen Processing Laboratory
SSN                        Social Security Number
Study ID               Study Identification Number
US                          United States
USU                       Uniformed Services University of the Health Sciences
VE                           Vaccine efficacy
WAMC                  Womack Army Medical Center
WRAIR                  Walter Reed Army Institute of Research
WRNMMC          Walter Reed National Military Medical Center