VRC 321: A Phase I Open-Label Clinical Trial to Evaluate Dose, Safety, Tolerability, and Immunogenicity of an Influenza H1 Stabilized Stem Ferritin Vaccine, VRCFLUNPF099-00-VP, in Healthy Adults
Phase: PHASE1
Conditions: Influenza Infection
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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Version 3.0 
April 20, 2020 
 
VACCINE RESEARCH CENTER 
 
Protocol VRC 321 
(NIH 19-I-0032) 
 
A PHASE I OPEN-LABEL CLINICAL TRIAL TO EVALUATE DOSE, SAFETY, TOLERABILITY, AND 
IMMUNOGENICITY OF AN INFLUENZA H1 STABILIZED STEM FERRITIN VACCINE, VRC-
FLUNPF099-00-VP, IN HEALTHY ADULTS 
 
Vaccine Provided by 
National Institute of Allergy and Infectious Diseases (NIAID) 
Vaccine Research Center (VRC) 
Bethesda, Maryland  
 
Clinical Trial Sponsored by: 
National Institute of Allergy and Infectious Diseases (NIAID) 
Vaccine Research Center (VRC) 
Bethesda, Maryland 
BB-IND 18764 – held by VRC, NIAID, NIH 
 
Principal Investigator: 
Alicia Widge, M.D., M.S. 
 
 
VRC/NIAID/NIH 
Bethesda, MD 20892 
 
IRB Initial Review Date: August 6, 2018 
 
 

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TABLE OF CONTENTS 
TABLE OF ABBREVIATIONS ................................................................................................................... 6 
PRÉCIS ........................................................................................................................................................... 8 
 
INTRODUCTION AND RATIONALE ........................................................................................ 10 
 BACKGROUND ........................................................................................................................... 10 
 Rationale For Development Of Influenza H1ssF_3928 Vaccine, VRC-FLUNPF099-00-VP ....... 11 
 Human Experience with VRC-FLUNPF099-00-VP vaccine ........................................................ 12 
1.3.1 
Previous Human Experience with HA Ferritin vaccine (HA-F A/Sing) ........................... 12 
 Rationale for Study Product Dose .................................................................................................. 13 
 Rationale For Study Population ..................................................................................................... 13 
 Assessment Of Vaccine Immunogenicity ...................................................................................... 13 
 
STUDY PRODUCTS ...................................................................................................................... 13 
 VRC-FLUNPF099-00-VP ............................................................................................................. 13 
 VRC-PBSPLA043-00-VP, phosphate buffered saline (Diluent) ................................................... 14 
 Preclinical Studies with VRC-FLUNPF099-00-VP ...................................................................... 14 
 
STUDY OBJECTIVES ................................................................................................................... 14 
 Primary Objectives......................................................................................................................... 14 
 Secondary Objectives..................................................................................................................... 14 
 Exploratory Objectives .................................................................................................................. 14 
 
STUDY DESIGN AND CLINICAL PROCEDURES .................................................................. 14 
 Study Population ............................................................................................................................ 15 
4.1.1 
Inclusion Criteria .............................................................................................................. 15 
4.1.2 
Exclusion Criteria ............................................................................................................. 16 
 Clinical Procedures and Evaluations.............................................................................................. 17 
4.2.1 
Screening .......................................................................................................................... 17 
4.2.2 
Study Schedule .................................................................................................................. 18 
4.2.3 
Enrollment ........................................................................................................................ 18 
4.2.4 
Acceptable and Effective Methods of Birth Control ......................................................... 18 
4.2.5 
Vaccine Administration ..................................................................................................... 18 
4.2.6 
7-Day Solicited Reactogenicity and Follow-up ................................................................ 19 
4.2.7 
Follow-Up through End of Study ...................................................................................... 19 
4.2.8 
Mucosal Sample Collection .............................................................................................. 20 

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4.2.9 
Blood Sample Collection .................................................................................................. 20 
4.2.10 
Apheresis ........................................................................................................................... 20 
4.2.11 
Apheresis Eligibility Criteria ............................................................................................ 21 
4.2.12 
Concomitant Medications ................................................................................................. 21 
 Criteria for Dose Escalation and Dose Continuation ..................................................................... 21 
 Criteria for Discontinuing Study Injections or Protocol Participation ........................................... 22 
4.4.1 
Discontinuation of Study Injections .................................................................................. 22 
4.4.2 
Discontinuation from Protocol Participation ................................................................... 23 
 Criteria for Pausing and Resuming the Study ................................................................................ 23 
4.5.1 
Plan for Pausing the Study ............................................................................................... 23 
4.5.2 
Plan for Review of Pauses and Resuming the Study ......................................................... 23 
 
SAFETY AND ADVERSE EVENT REPORTING ..................................................................... 24 
 Adverse Events .............................................................................................................................. 24 
 Serious Adverse Events ................................................................................................................. 24 
 Adverse Event Reporting to the IND Sponsor ............................................................................... 25 
5.3.1 
IND Sponsor Reporting to the FDA .................................................................................. 25 
 Reporting to the Institutional Review Board ................................................................................. 26 
5.4.1 
Unanticipated Problem ..................................................................................................... 26 
5.4.2 
Protocol Deviation ............................................................................................................ 26 
5.4.3 
Non-Compliance ............................................................................................................... 27 
5.4.4 
Death ................................................................................................................................. 27 
5.4.5 
New Information ............................................................................................................... 27 
5.4.6 
Suspension or Termination of Research Activities ........................................................... 28 
5.4.7 
Expedited Reporting to the IRB ........................................................................................ 28 
5.4.8 
Annual Reporting to the IRB ............................................................................................. 28 
 
STATISTICAL CONSIDERATIONS .......................................................................................... 28 
 Overview ........................................................................................................................................ 28 
 Endpoints ....................................................................................................................................... 28 
6.2.1 
Primary Endpoints: Safety ................................................................................................ 28 
6.2.2 
Secondary Endpoints: Immunogenicity ............................................................................ 29 
6.2.3 
Exploratory Endpoints: Immunogenicity .......................................................................... 29 
 Sample Size and Accrual ............................................................................................................... 29 
6.3.1 
Power Calculations for Safety .......................................................................................... 29 
6.3.2 
Power Calculations for Immunogenicity .......................................................................... 31 
6.3.3 
Power for Comparison ...................................................................................................... 31 

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 Statistical Analysis ......................................................................................................................... 31 
6.4.1 
Analysis Variables ............................................................................................................ 31 
6.4.2 
Baseline Demographics .................................................................................................... 31 
6.4.3 
Safety Analysis .................................................................................................................. 31 
6.4.4 
Immunogenicity Analysis .................................................................................................. 32 
6.4.5 
Missing Data ..................................................................................................................... 32 
6.4.6 
Interim Analyses ............................................................................................................... 32 
 
PHARMACY AND VACCINE ADMINISTRATION PROCEDURES .................................... 33 
 Study Product ................................................................................................................................. 33 
 Study Product Presentation and Storage ........................................................................................ 33 
7.2.1 
Study Product Labels ........................................................................................................ 33 
7.2.2 
Study Product Storage ...................................................................................................... 33 
7.2.3 
Temperature excursions .................................................................................................... 34 
 Preparation of Study Products for Injection ................................................................................... 34 
7.3.1 
Preparation of VRC-FLUNPF099-00-VP for Needle and Syringe Administration .......... 34 
7.3.2 
Administration of Injections .............................................................................................. 34 
 Study Product Accountability ........................................................................................................ 34 
7.4.1 
Documentation .................................................................................................................. 34 
7.4.2 
Disposition ........................................................................................................................ 35 
 
HUMAN SUBJECT PROTECTIONS AND ETHICAL OBLIGATIONS ................................ 35 
 Institutional Review Board ............................................................................................................ 35 
 Subject Identification and Enrollment of Study Participants ......................................................... 35 
8.2.1 
Participation of Children .................................................................................................. 35 
8.2.2 
Participation of NIH Employees ....................................................................................... 35 
 Informed Consent .......................................................................................................................... 36 
 Subject Confidentiality .................................................................................................................. 36 
 Risks and Benefits ......................................................................................................................... 36 
8.5.1 
Risks of the VRC-FLUNPF099-00-VP vaccine ................................................................ 36 
8.5.2 
Risks of Specimen Collections .......................................................................................... 37 
8.5.3 
Risks of study vaccines on the fetus or nursing infant ...................................................... 37 
8.5.4 
Risks of New Diagnoses .................................................................................................... 37 
8.5.5 
Study Benefits .................................................................................................................... 37 
 Plan for Use and Storage of Biological Samples ........................................................................... 38 
8.6.1 
Use of Samples, Specimens and Data ............................................................................... 38 
8.6.2 
Storage and Tracking of Blood Samples and Other Specimens ........................................ 38 

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8.6.3 
Disposition of Samples, Specimens and Data at Completion of the Protocol .................. 38 
8.6.4 
Loss or Destruction of Samples, Specimens or Data ........................................................ 39 
 Compensation ................................................................................................................................ 39 
 Safety Monitoring .......................................................................................................................... 39 
8.8.1 
Protocol Safety Review Team ........................................................................................... 39 
 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................................. 40 
 Protocol Amendments and Study Termination .............................................................................. 40 
 Study Documentation and Storage ................................................................................................. 40 
 Data Collection, Data Sharing and Protocol Monitoring ............................................................... 40 
9.3.1 
Data Collection ................................................................................................................. 40 
9.3.2 
Data Sharing Plan ............................................................................................................ 41 
9.3.3 
Source Documents ............................................................................................................ 41 
9.3.4 
Protocol Monitoring Plan ................................................................................................. 41 
 Language ........................................................................................................................................ 41 
 Policy Regarding Research-Related Injuries ................................................................................. 41 
 
REFERENCES ................................................................................................................................ 42 
APPENDIX I: SCHEDULE OF EVALUATIONS ................................................................................... 44 
APPENDIX II: ASSESSMENT OF RELATIONSHIP TO VACCINE AND GRADING SEVERITY 
OF ADVERSE EVENTS ............................................................................................................................. 47 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
AdEDC 
Advantage Electronic Data Capture 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AoU 
assessment of understanding 
BMI 
body mass index 
CBC
complete blood count 
CDC 
Centers for Disease Control and Prevention 
cGMP 
current Good Manufacturing Practices 
dbGAP 
Database of Genotypes and Phenotypes 
DNA 
deoxyribonucleic acid 
DTM
Department of Transfusion Medicine 
FDA
Food and Drug Administration 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practices 
HA 
influenza hemagglutinin protein  
HIV
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HRPP 
Human Research Protection Program 
IB 
Investigator’s Brochure 
ICS
intracellular cytokine staining 
ILI 
influenza-like illness  
IM 
Intramuscular 
IND
investigational new drug application 
IRB 
Institutional Review Board 
IUD
intrauterine device 
LIMS 
Laboratory Information Management System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIV 
Monovalent Inactivated Vaccine 
MPA 
Medroxyprogesterone acetate 
MSD 
meso-scale delivery 
NA 
neuraminidase  
NAb 
Neutralizing antibody 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH
National Institutes of Health 
NIH CC 
NIH Clinical Center 
NSAID
nonsteroidal anti-inflammatory drug 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PI 
Principal Investigator 
PSRT 
Protocol Safety Review Team 
RBS 
receptor binding site 

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Abbreviation 
Term 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SARS 
Severe acute respiratory syndrome 
SUSAR 
serious and unexpected suspected adverse reaction 
TNF 
tumor necrosis factors 
TIV 
trivalent inactivated vaccine 
ULN 
upper limit of normal 
UP 
Unanticipated Problem 
VCMP 
Vaccine Clinical Materials Program 
 VIP 
Vaccine Immunology Program  
VRC 
Vaccine Research Center 
WBC 
white blood cell 
WHO 
World Health Organization 

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PRÉCIS 
 
Title: 
VRC 321, A Phase I Open-Label Clinical Trial to Evaluate the Dose, Safety, Tolerability 
and Immunogenicity of an Influenza H1 Stabilized Stem Ferritin Vaccine,  
                          VRC-FLUNPF099-00-VP, in Healthy Adults 
Study  
Design: 
This is a Phase I, open-label, dose escalation study to evaluate the dose, safety, 
tolerability, and immunogenicity of VRC-FLUNPF099-00-VP in two regimens. The 
hypotheses are that the vaccine is safe and tolerable and will elicit an immune response. 
The primary objective is to evaluate the safety and tolerability of the investigational 
vaccine in healthy adults. Secondary objectives are related to immunogenicity of the 
investigational vaccine and dosing regimen. 
Study  
Products:        The investigational vaccine, VRC-FLUNPF099-00-VP (H1ssF_3928), was developed by 
the Vaccine Research Center (VRC), National Institute of Allergy and Infectious 
Diseases (NIAID) and is composed of Helicobacter pylori non-heme ferritin assembled 
with influenza virus H1 haemagglutinin (HA) insert to form a nanoparticle displaying 
eight HA stabilized stem trimers from A/New Caledonia/20/1999 (H1N1) influenza. The 
vaccine is supplied in single-use vials at a concentration of 180 mcg/mL. H1ssF_3928 
will be administered intramuscularly (IM) in the deltoid muscle via needle and syringe. 
Subjects: 
Healthy adults between the ages of 18-70 years, inclusive. 
Study Plan:     The study will evaluate the safety, tolerability and immunogenicity of 1 or 2 doses of the 
H1ssF_3928 vaccine in a dose-escalation design. In Group 1, five subjects will receive a 
single low dose (20 mcg) of H1ssF_3928 on Day 0. For Group 1, the protocol requires 1 
vaccination visit, about 9 follow-up visits, and a telephone contact after vaccination.  
 
If the low dose is assessed as safe and well tolerated, enrollment will begin for Group 2A. 
Groups 2A, 2B, 2C, and 2D are stratified by age as shown in the vaccination schema. In 
Group 2A, subjects will receive a higher dose (60 mcg) of H1ssF_3928 on Day 0. If this 
higher dose is assessed as safe and well tolerated, subjects in Group 2A may receive a 
second vaccination at week 16 and enrollment can begin for Groups 2B, 2C, and 2D.  For 
Groups 2A, 2B, 2C, and 2D, the protocol requires 2 vaccination visits, about 11 follow-
up visits, and a telephone contact after each vaccination.  
For all groups, solicited reactogenicity will be evaluated using a 7-day diary card. 
Assessment of vaccine safety will include clinical observation and monitoring of 
hematological and chemical parameters at clinical visits throughout the study. 
 
VRC 321 Vaccination Schema
Group
Age Cohort
Subjects
Day 0
Week 16
1 
18-40 
5
20 mcg
2A 
18-40 
12
60 mcg
60 mcg 
2B
41-49 
12
60 mcg
60 mcg 
2C
50-59 
12
60 mcg
60 mcg 
2D 
60-70 
12
60 mcg
60 mcg 
Total 
53* 
*Enrollment up to 70 is permitted if additional
subjects are needed for safety or immunogenicity 
evaluations.

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Study  
Duration:  
Group 1: Subjects will be evaluated for 52 weeks following the vaccine administration 
and through an influenza season. 
                        Groups 2A, 2B, 2C, 2D: Subjects will be evaluated for 52 weeks following the last 
vaccine administration and through an influenza season. 
 
 
 
 
 

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 INTRODUCTION AND RATIONALE 
 BACKGROUND 
Influenza virus causes seasonal epidemics and pandemics at irregular intervals that result in 
significant morbidity and mortality. According to the World Health Organization (WHO), the 
annual global attack rate of influenza is estimated to be 5%–10% in adults and 20%–30% in 
children; worldwide these annual epidemics result in about 3 to 5 million cases of severe illness 
and about 250,000 to 500,000 deaths [1]. The US Centers for Disease Control and Prevention 
(CDC) estimates that a pandemic influenza outbreak costs the United States between $71 billion 
and $167 billion without counting the financial impact on commerce and society [2]. 
Influenza is an enveloped, negative single-stranded (-ss) ribonucleic acid (RNA) virus that 
belongs to the family Orthomyxoviridae. Of the five genera of influenza circulating in nature, 
only influenza A and B are known to cause epidemics in humans [3].  
Influenza A viruses consist of 8 RNA gene segments and are classified based on the antigenicity 
of their surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA). There are 18 
different HA subtypes (H1 through H18) and 11 NA subtypes known to exist, but only three HA 
subtypes (H1, H2, and H3) and two NA subtypes (N1 and N2) have caused significant human 
epidemics [4].  
The HA is the predominant viral antigen target for antibody neutralization [5]. HA glycoprotein 
consists of a globular head domain (which is highly variant in structure between HA subtypes) 
and a stem domain (which is highly conserved across HA subtypes) [6]. Most of the antibodies 
produced by the immune system after infection recognize the head domain, whereas the stem 
domain is recognized by a small population of antibodies [7-9]. The anti-head antibodies are 
very potent but are strain-specific while the anti-stem antibodies are less potent and are cross-
reactive across HA strains [10].  
Influenza exhibits genetic flexibility and antigenic variability because of its ability to go through 
antigenic “drift” (the gradual accumulation of mutations over time) and antigenic “shift” (the 
replacement of the hemagglutinin gene by reassortment during contemporaneous infection of a 
host by more than one influenza strain). The emergence of new influenza strains through 
continuous mutation and reassortment of circulating virus diminishes the effectiveness of annual 
influenza vaccines [11, 12]. 
Furthermore, in the United States, the current manufacturing process in egg-based systems can 
lead to lower yields and significant lag times due to virus strain identification and vaccine 
production, availability, and distribution [13, 14]. 
These limitations have raised the need for developing a universal influenza vaccine that can 
provide durable, cross-strain protection against different influenza viruses, with a rapid 
manufacturing process in which large vaccine quantities could be produced under well-
controlled conditions. A universal influenza vaccine would eliminate the need for annual 
reformulation and revaccination, and improve pandemic preparedness [15]. 
With the goal of developing a universal influenza vaccine, the Vaccine Research Center (VRC), 
National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health 
(NIH) has engineered and optimized a stabilized H1 influenza HA stem ferritin vaccine (VRC-
FLUNPF099-00-VP) that enhances the presentation of the HA stem to the immune system, 
potentially improving breadth against group 1 influenza strains.  

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VRC-FLUNPF099-00-VP (H1ssF_3928) is an investigational vaccine that has not been 
administered to humans before this study. The H1ssF_3928 vaccine may inform the development 
of a universal influenza vaccine and play an important role in the planning and preparation for 
future influenza pandemics [16].  
 RATIONALE FOR DEVELOPMENT OF INFLUENZA H1SSF_3928 VACCINE, VRC-
FLUNPF099-00-VP 
New vaccine platforms and production technologies directed toward the goal of a universal 
influenza vaccine include cell-culture-based manufacturing processes, novel live attenuated 
vaccines, recombinant proteins, recombinant DNA-based vaccines, and nanoparticles [13, 14]. 
Ferritin is a highly conserved, ubiquitous iron storage protein that is found in various species 
from Archaea, Eukarya, and Bacteria domains [17]. Ferritin particles can be used in vaccines for 
antigen presentation of influenza HA [18]. Ferritin self-assembles into a nearly-spherical 
nanoparticle, composed of 24 subunits organized in an octahedral symmetry with a hollow 
interior, that mimics the structure of the viral antigen and mediates the interaction with the 
immune system [18, 19]. The advantages of using ferritin as a vaccine platform to improve 
antigen presentation and immune stimulation against different strains of influenza viruses rely on 
the ability to obtain higher levels of protein quaternary structures and the capacity to display 
heterologous antigens on their surface [18, 20]. Furthermore, as the self-assembly process 
requires no energy and can be manufactured from simple expression vectors (without relying on 
egg-based systems), vaccine manufacturing timelines could be potentially shortened, improving 
the response to an influenza pandemic [18]. 
Investigators at the VRC, NIAID, NIH, Bethesda, MD, US, have identified a non-haem ferritin 
from Helicobacter pylori (H. pylori) as a protein able to display eight trimeric influenza HA 
spikes that mimic the physiological HA structure of A/New Caledonia/20/1999 (H1N1) 
influenza.  
Kanekiyo, et al. genetically fused the ectodomain of A/New Caledonia/20/1999 HA to H. pylori 
ferritin, creating a vaccine that antigenically resembles the native head and stem domains of the 
HA viral spikes on the surface of the ferritin spherical core [18].  In preclinical immunogenicity 
studies, this HA ferritin vaccine elicited two types of broadly neutralizing antibodies against the 
highly conserved HA stem and antibodies against the conserved receptor binding site (RBS) on 
the head of the viral HA. The HA stem and the RBS are structures of major interest for the 
development of a universal vaccine against influenza [21]. 
Yassine, et al. genetically fused the ectodomain of A/New Caledonia/20/1999 HA that lacks the 
immunodominant head domain to H. pylori ferritin, creating a synthetic ferritin that antigenically 
resembles the native stem domain of the HA protein on the surface of the ferritin spherical core 
[16]. In preclinical immunogenicity studies, this H1 HA stem ferritin vaccine conferred 
heterosubtypic protection against H5N1 influenza virus challenge in multiple animal models, 
indicating that vaccine-elicited HA stem–specific antibodies can protect against diverse group 1 
influenza strains [16].  
Both of these HA ferritin vaccines possess the desired structural properties and have 
demonstrated the capacity to enhance the breadth of neutralizing antibodies in pre-clinical 
studies when compared to the current commercial trivalent inactivated vaccine (TIV) containing 
the same 1999 H1N1 HA [18] [16]. Based on data reported with the HA stem ferritin vaccine in 

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animal studies (Section 2.3), it is expected that the H1ssF_3928 vaccine will be safe and 
immunogenic in this Phase I study in humans.  
 HUMAN EXPERIENCE WITH VRC-FLUNPF099-00-VP VACCINE  
This is the first clinical study to test the VRC-FLUNPF099-00-VP vaccine, and there is no 
previous human experience with this product. VRC-FLUNPF081-00-VP (HA-F A/Sing) was the 
first ferritin-based vaccine platform tested in a Phase I clinical trial, therefore human experience 
with HA-F A/Sing is provided below. 
1.3.1 Previous Human Experience with HA Ferritin vaccine (HA-F A/Sing) 
The first Phase I clinical trial (VRC 316; NCT03186781) using ferritin particles, HA-F A/Sing 
ferritin vaccine was opened to accrual in October 2017. The HA-F A/Sing vaccine is composed 
of H. pylori non-haem ferritin genetically fused to the influenza virus H2 HA to form a 
nanoparticle that antigenically resembles the native head and stem domains of the HA from 
A/Singapore/1/57 (H2N2) influenza.  
As of March 24, 2019, enrollment was complete and all 50 subjects have received at least one 
injection of the HA-F A/Sing vaccine. All injections with the HA-F A/Sing vaccine have been 
generally well tolerated.  
Maximum local reactogenicity in the 7 days after HA-F A/Sing administration was reported as 
mild local pain/tenderness by 7 of 47 (14.9 %) subjects. No other solicited local symptoms of 
swelling or redness were reported. No moderate or severe local symptoms have been reported.   
Regarding solicited systemic reactogenicity in the 7 days after product administration, 18 of 47 
(38.3%) subjects who received HA-F A/Sing had one or more systemic signs or symptoms, the 
most frequently reported AE was that of mild headache (13/47, 27.7%). Subjects also reported 
mild malaise (10/47, 21.3%), mild myalgia (8/47, 17.0%), moderate myalgia (1/47, 2.1%), mild 
chills (2/47, 4.3%), mild nausea (1/47, 2.1) and mild joint pain (2/47, 4.3%).  
One subject reported a severe fever that started on Day 4 after the first product administration, 
resolved within 1 day, and coincided with an influenza-like illness. 
Overall for the HA-F A/Sing vaccine groups, 22 of 47 (46.8%) subjects who received at least one 
administration of the vaccine have had at least one or more unsolicited AE, with maximum 
severity being Grade 1 (mild) for 12 subjects, Grade 2 (moderate) for 8 subjects, Grade 3 
(severe) for 1 subject and Grade 4 (life-threatening) for 1 subject.  
The most frequently reported unsolicited AEs were anaemia (8/47, 17.0%), with a maximum 
severity of Grade 2 for five subjects, and upper respiratory tract infection (5/47, 10.6%), with a 
maximum severity of Grade 2 for one subject.  
A severe AE of viral infection was reported by 1 subject 9 days after the initial study injection. 
The event was assessed as unrelated to study product and resolved with no residual effects three 
days after onset.  
As of March 24, 2019, 3 mild AEs were assessed as related to HA-F A/Sing vaccine and all 
resolved with no residual effects:  leukocytosis (1/47, 2.1%), blood alkaline phosphatase 
increased (1/47, 2.1%), and leukopenia (1/47, 2.1%) 
A  life-threatening SAE of myocardial infarction was reported by 1 subject at 117 days after the 
HA-F A/Sing  study product administration. The event was assessed as unrelated to study 
product and resolved with sequelae. 

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 RATIONALE FOR STUDY PRODUCT DOSE 
The VRC 316 study results as of March 18, 2018 showed that two dose levels (20 mcg as a 
single dose and 60 mcg as a repeat dose with a 16-week interval) of HA-F A/Sing were safe and 
well tolerated. In this study, H1ssF_3928 will be similarly evaluated at 20 mcg as a single dose 
and 60 mcg as a repeat dose with a 16-week interval. A 16-week interval between first and 
second doses is based on previous VRC studies suggesting that this interval may be optimal to 
develop an immune response to the vaccine regimen. 
 RATIONALE FOR STUDY POPULATION   
To assess safety, tolerability, and immunogenicity of the H1ssF_3928 vaccine, subjects 18-70 
years of age will be enrolled. In the higher dose group, subjects will be stratified by age into four 
groups (Groups 2A-2D) to evaluate how the immune responses to the H1ssF_3928 vaccine vary 
based on age and the likelihood of exposure to different influenza strains. 
 ASSESSMENT OF VACCINE IMMUNOGENICITY  
In this study, specimens to evaluate immunogenicity will be collected at baseline and at specified 
time points. The primary immunogenicity time point is two weeks after the first vaccination and 
assessed by measuring HA stem-specific antibody by pseudo-neutralization assay. Additional 
assessment of HA stem-specific antibody measured by pseudo-neutralization assay will be 
conducted on stored samples obtained throughout the study.  
Exploratory evaluations will include measurements of human ferritin antibody and H. pylori 
ferritin antibody. Additional exploratory evaluations may include the detection of antibody by 
MSD (Meso Scale Delivery) or neutralization assay, and exploratory B and T cell assays.  
Research samples for immunogenicity assays will be processed by the Vaccine Immunology 
Program (VIP) in Gaithersburg, MD, where many of the immunogenicity assays will also be 
performed. Some immunogenicity assays may be performed by VRC laboratories in Bethesda, 
MD, or by approved contract laboratories or research collaborators. 
Results from this study are expected to provide a foundation for development of a universal 
influenza vaccine candidate as well as show proof-of-concept for elicitation of antibody 
responses by influenza HA stem vaccination. 
 STUDY PRODUCTS 
The study products are manufactured under current Good Manufacturing Practice (cGMP) by the 
Vaccine Clinical Materials Program (VCMP) operated under contract by Leidos Biomedical 
Research, Inc., Frederick, MD.  
 VRC-FLUNPF099-00-VP 
The VRC-FLUNPF099-00-VP (H1ssF_3928) vaccine is composed of the HA stem domain from 
Influenza A/New Caledonia/20/1999 (H1N1) genetically fused to the ferritin protein from H. 
pylori. Purified H1ssF_3928 displays eight well-formed HA trimers that antigenically resemble 
the native H1 stem viral spikes.  
VRC-FLUNPF099-00-VP is a sterile, aqueous buffered solution.  Product is aseptically filled to 
a volume of 0.7 ± 0.1 mL into 3 mL single dose vials at a concentration of 180 mcg/mL.  The 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 14 of 54 
buffer consists of 20mM Sodium Phosphate, 100mM Sodium Chloride, 5% Sucrose and 0.01% 
PF-68 at pH 7.2. 
More details related to vaccine formulation, preparation, and preclinical studies performed with 
H1ssF_3928 can be found in the Investigator’s Brochure (IB). 
 VRC-PBSPLA043-00-VP, PHOSPHATE BUFFERED SALINE (DILUENT) 
VRC-PBSPLA043-00-VP will be the diluent for H1ssF_3928 and consists of sterile phosphate 
buffered saline (PBS) at pH 7.2, aseptically filled to 1.2 mL in a 3 mL glass vial for single use. 
 PRECLINICAL STUDIES WITH VRC-FLUNPF099-00-VP 
Non-clinical immunogenicity studies in mice and ferrets demonstrated that VRC-FLUNPF099-
00-VP administered IM was immunogenic as detected by ELISA and neutralization assay.  A 
dose toxicity study of VRC-FLUNPF099-00-VP was performed in New Zealand white rabbits to 
evaluate safety.  More details on this study and additional pre-clinical studies with VRC-
FLUNPF099-00-VP can be found in the IB.   
 STUDY OBJECTIVES 
 PRIMARY OBJECTIVES 
• To evaluate the safety and tolerability of the VRC-FLUNPF099-00-VP vaccine, 
administered as a single dose at 20 mcg IM via needle and syringe on Day 0 to healthy 
adults. 
 
• To evaluate the safety and tolerability of the VRC-FLUNPF099-00-VP vaccine, 
administered at 60 mcg IM via needle and syringe to healthy adults by repeat dosing on 
Day 0 and Week 16 for a total of 2 injections. 
 SECONDARY OBJECTIVES 
• To evaluate the antibody response to the VRC-FLUNPF099-00-VP vaccine administered 
as a single dose at 20 mcg IM via needle and syringe at two weeks after injection. 
 
• To evaluate the antibody response to the VRC-FLUNPF099-00-VP vaccine administered 
as repeat dosing at 60 mcg IM via needle and syringe at two weeks after each injection. 
 EXPLORATORY OBJECTIVES 
• To evaluate the specificity and functionality of vaccine-induced antibodies and the 
immune response at various timepoints throughout the study. 
 
• To evaluate the frequency, magnitude, and specificity of B-cell and/or T-cell responses at 
various time points throughout the study. 
 STUDY DESIGN AND CLINICAL PROCEDURES 
This is a Phase I, open-label, dose escalation study to evaluate the dose, safety, tolerability, and 
immunogenicity of the VRC-FLUNPF099-00-VP vaccine in two dose regimens in healthy 
adults. The study schema is shown in Table 1. The hypotheses are that the vaccine is safe, well-
tolerated, and will induce an antibody response to the stem of influenza virus subtype H1. The 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 15 of 54 
study will be conducted by the VRC Clinical Trials Program at a single site in the NIH Clinical 
Center (NIH CC), Bethesda, MD. 
Table 1: Study schema: 
VRC 321 Vaccination Schema 
Group 
Age  
Subjects 
Day 0  
Week 16   
1 
18-40 
5
20 mcg
 
2A
18-40 
12
60 mcg
60 mcg
2B
41-49 
12
60 mcg
60 mcg
2C
50-59 
12
60 mcg
60 mcg
2D
60-70 
12
60 mcg
60 mcg
Total 
53* 
*Enrollment up to 70 is permitted if additional
subjects are needed for safety or immunogenicity 
evaluations.
 STUDY POPULATION 
All inclusion and exclusion criteria must be evaluated for eligibility. 
4.1.1 Inclusion Criteria 
A subject must meet all of the following criteria: 
1. Healthy adults between the ages of 18-70 years inclusive  
2. Based on history and examination, in good general health and without history of any of 
the conditions listed in the exclusion criteria 
3. Received at least one licensed influenza vaccine from 2014 to the present 
4. Able and willing to complete the informed consent process 
5. If enrolled in Group 1: Available for clinic visits for 52 weeks after enrollment and 
through an influenza season 
6. If enrolled in Group 2A, 2B, 2C, or 2D: Available for clinic visits for 68 weeks after 
enrollment and through an influenza season 
7. Willing to have blood samples collected, stored indefinitely, and used for research 
purposes 
8. Able to provide proof of identity to the satisfaction of the study clinician completing the 
enrollment process  
9. Physical examination and laboratory results without clinically significant findings and a 
BodyMassIndex(BMI)≤40withinthe28 days before enrollment 
Laboratory Criteria within 28 days before enrollment 
10. White blood cells (WBC) and differential either within institutional normal range or 
accompanied by the site Principal Investigator (PI) or designee approval 
11. Totallymphocytecount≥800cells/mm3 
12. Platelets = 125,000 – 500,000/mm3 
13. Hemoglobin within institutional normal range 

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14. Serum iron either within institutional normal range or accompanied by the site PI or 
designee approval 
15. Serum ferritin within institutional normal range or accompanied by the site PI or designee 
approval 
16. Alanine aminotransferase (ALT) ≤1.25xinstitutionalupperlimitofnormal(ULN) 
17. Aspartate aminotransferase (AST) ≤1.25xinstitutionalULN  
18. Alkaline phosphatase (ALP) <1.1 x institutional ULN 
19. Total bilirubin within institutional normal range 
20. Serum creatinine≤1.1xinstitutional ULN 
21. Negative for HIV infection by an FDA-approved method of detection 
Criteria applicable to women of childbearing potential: 
22. Negative beta-human chorionic gonadotropin(β-HCG) pregnancy test (urine or serum) 
on the day of enrollment  
23. Agrees to use an effective means of birth control from at least 21 days prior to enrollment 
through the end of the study 
4.1.2 Exclusion Criteria 
A subject will be excluded if one or more of the following conditions apply: 
1. Breast-feeding or planning to become pregnant during the study.  
Subject has received any of the following substances: 
2. More than 10 days of systemic immunosuppressive medications or cytotoxic medications 
within the 4 weeks prior to enrollment or any within the 14 days prior to enrollment  
3. Blood products within 16 weeks prior to enrollment 
4. Live attenuated vaccines within 4 weeks prior to enrollment 
5. Inactivated vaccines within 2 weeks prior to enrollment  
6. Investigational research agents within 4 weeks prior to enrollment or planning to receive 
investigational products while on the study 
7. Current allergy treatment with allergen immunotherapy with antigen injections, unless on 
maintenance schedule 
8. Current anti-TB prophylaxis or therapy 
9. Previous investigational H1 influenza vaccine 
10. Previous investigational ferritin-based vaccine 
11. Receipt of a licensed influenza vaccine within 6 weeks before trial enrollment  
Subject has a history of any of the following clinically significant conditions: 
12. Serious reactions to vaccines that preclude receipt of study vaccinations as determined by 
the investigator  
13. Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema 

PRODUCT: VRC-FLUNPF099-00-VP 
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PROTOCOL DATE: APRIL 20, 2020 
Page 17 of 54 
14. Asthma that is not well controlled  
15. Diabetes mellitus (type I or II), with the exception of gestational diabetes 
16. Thyroid disease that is not well controlled 
17. Idiopathic urticaria within the past year 
18.  Autoimmune disease or immunodeficiency 
19. Hypertension that is not well controlled (baseline systolic > 140 mmHg or diastolic > 90 
mmHg) 
20. Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet 
disorder requiring special precautions) or significant bruising or bleeding difficulties with 
IM injections or blood draws 
21. Malignancy that is active or history of malignancy that is likely to recur during the period 
of the study. 
22. Seizure disorder other than 1) febrile seizures, 2) seizures secondary to alcohol 
withdrawal more than 3 years ago, or 3) seizures that have not required treatment within 
the last 3 years 
23. Asplenia, functional asplenia or any condition resulting in the absence or removal of the 
spleen 
24. Guillain-Barré Syndrome 
25. Any medical, psychiatric, social condition, occupational reason or other responsibility 
that, in the judgment of the investigator, is a contraindication to protocol participation or 
impairs a subject’s ability to give informed consent. 
 CLINICAL PROCEDURES AND EVALUATIONS 
Evaluation of this vaccine will include laboratory tests, medical history, physical assessment by 
clinicians, and subject self-assessment recorded on a diary card for 7 days after each injection. 
Potential adverse reactions will be further evaluated prior to continuing the vaccination schedule. 
The schedule of study evaluations is described in this section and shown in table format in 
Appendix I. 
4.2.1 Screening 
Screening for this study will be completed through the VRC’s screening protocol, VRC 500 
(NIH 11-I-0164, NCT01375530). Subjects will be recruited through Institutional Review Board 
(IRB)-approved advertising. The evaluations and sample collections that will be included in 
screening are a medical history, physical exam, laboratory tests needed to confirm eligibility, and 
pregnancy test for females of reproductive potential.  
If screening evaluations suggest a current concerning health condition or infection, such as 
hepatitis, then appropriate laboratory tests may be conducted to evaluate these conditions. 
Additional assessments of health may be conducted at screening based on clinical judgment. 
Screening evaluations for specific eligibility criteria (Section 4.1) must be completed within the 
time interval specified prior to enrollment for the given parameter and may be repeated, as 
needed, to confirm eligibility. Research blood samples will be collected during screening; 

PRODUCT: VRC-FLUNPF099-00-VP 
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PROTOCOL DATE: APRIL 20, 2020 
Page 18 of 54 
although generally collected in the 28 days prior to enrollment; a particular interval of time prior 
to enrollment for collection of these samples is not required. 
The informed consent form (ICF) will be reviewed and counseling related to pregnancy 
prevention will be provided. 
Subjects who are not up to date on standard vaccinations may receive these, if available, during 
their participation in the screening protocol or at a later date during study participation. As part 
of the informed consent process, an Assessment of Understanding (AoU) is completed on the 
day the subject is scheduled to enroll prior to signing the VRC 321 protocol ICF. Incorrect 
answers will be explained to the subject, who will sign the ICF only after the study clinician is 
satisfied with the subject’s understanding of the study. 
4.2.2 Study Schedule  
The Schedule of Evaluations in Appendix I provides details on the study schedule, the permitted 
windows for completing the visits, and the evaluations to be performed at each visit. The visit 
schedule is based on intervals of time after each study injection (Appendix I). The clinicians will 
discuss the target dates and timing of the study vaccination(s) and sample collections with each 
subject before completing enrollment to help ensure that subjects can comply with the projected 
schedule. 
After enrollment, deviations from the visit windows are discouraged and will be recorded as 
protocol deviations but are permitted at the discretion of the PI (or designee) in the interest of 
completing the vaccination schedule and obtaining subject safety and immunogenicity 
evaluations. 
4.2.3 Enrollment 
The study has staged enrollment with required interim safety reviews, as described in Section 
4.3, for dose escalation, continuing enrollment, and second product administration. The first 
three subjects of Groups 1 and 2A will be enrolled with no more than one subject per day.  
Subjects will be stratified by age into Group 2A, 2B, 2C, and 2D.   
The pharmacy database will be set up prior to opening the study to accrual. The group 
assignment is known to the staff and subject before completing the electronic enrollment into the 
study on Day 0. Any subject who receives at least one study injection will be expected to 
continue with follow-up through the end of the study. 
4.2.4 Acceptable and Effective Methods of Birth Control 
Women of reproductive potential are required to agree to use an acceptable and effective method 
of birth control beginning 21 days prior to enrollment and continuing through end of study. 
Acceptable and effective methods of birth control for women of reproductive potential in this 
study include: abstinence (no sex) with male partners, birth control pills or patch, condoms, 
Medroxyprogesterone acetate (MPA) injection, diaphragm or cervical cap, intrauterine device 
(IUD), Implant (Nexplanon®), NuvaRing®, partner has vasectomy, or use of spermicides. 
4.2.5 Vaccine Administration  
All study injections will be completed according to the assigned group and will be administered 
IM in the deltoid muscle.  Scheduled blood collection must be completed before vaccinations. 

PRODUCT: VRC-FLUNPF099-00-VP 
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PROTOCOL DATE: APRIL 20, 2020 
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On the injection day (prior to injection), study subjects will be clinically evaluated and samples 
will be collected as per Schedule of Evaluations (Appendix I). A subject who arrives at the clinic 
with fever or evidence of an acute illness that precludes administration of the vaccine may be 
rescheduled within the allowed study visit window. 
Pregnancy test results for women of reproductive potential must be obtained on each injection 
day prior to the study injection and the results must be negative to proceed. 
When choosing an arm for injection, clinicians should consider whether there is an arm injury, 
local skin problem or significant tattoo that precludes administering the injection or will interfere 
with evaluating the arm after injection.  
Subjects enrolled in Group 1will be observed for a minimum of 1 hour following the injection. 
Vital signs (temperature, blood pressure, pulse and respiratory rate) will be collected at least 1 
hour after the injection, prior to subject departure from the clinic.  
Subjects enrolled in Group 2A, 2B, 2C, and 2D will be observed for a minimum of 30 minutes 
following each injection; vital signs will be collected after at least 30 minutes.  
For all subjects, the injection site will be inspected for evidence of local reaction following the 
observation period.  
In keeping with the NIH CC policy and good medical practice, acute medical care will be 
provided to subjects for any immediate allergic reactions or other injury resulting from 
participation in this research study.  
4.2.6 7-Day Solicited Reactogenicity and Follow-up 
Subjects will be given a “Diary Card” to use as a memory aid, on which they can record 
temperature and symptoms daily for 7 days after each injection. Subjects will be trained and 
encouraged to use the secure electronic database but will have the option to complete a paper 
diary card. When the diary card parameters are recorded directly by the subject in the electronic 
database, the subject’s electronic record will be the source for these data. When collected on 
paper, the paper diary card will be the source document. When neither paper nor electronic diary 
is available from the subject, the study clinician will document the source of reactogenicity 
information recorded in the study database. 
The solicited signs and symptoms on the diary card will include the following parameters: 
unusually tired/feeling unwell, muscles aches (other than at injection site), headache, chills, 
nausea, joint pain, and pain/tenderness, redness, swelling, skin lesions at injection site. Subjects 
will also record the day’s highest measured temperature and measurement of largest diameter for 
redness and swelling at injection site.  
Follow-up on subject well-being will be performed by telephone on the first day following all 
injections and by clinic visits as shown in the Schedule of Evaluations (Appendix I). 
Events following any study injection that may require clinical evaluation include rash, urticaria, 
feverof38.5˚C(Grade2)orhigherlastinggreaterthan24hours,orsignificantimpairmentinthe
activities of daily living. Additionally, other clinical concerns may prompt a study visit based on 
the judgment of a study clinician. 
4.2.7 Follow-Up through End of Study 
Group 1: Study follow-up will continue via clinical visits through 52 weeks after the study 
injection and through an influenza season. 

PRODUCT: VRC-FLUNPF099-00-VP 
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PROTOCOL DATE: APRIL 20, 2020 
Page 20 of 54 
Groups 2A, 2B, 2C, and 2D: Study follow-up will continue via clinical visits through 52 weeks 
after the last study injection and through an influenza season. 
4.2.8 Mucosal Sample Collection 
Throughout the study, nasopharyngeal swabs for diagnostic purposes will be requested from 
subjects who meet criteria for influenza-like illness (ILI) as defined in Section 5.1. 
4.2.9 Blood Sample Collection 
At intervals throughout the study, blood will be drawn for safety and immunologic assays. Blood 
will be drawn from the arm veins of subjects by standard phlebotomy procedures. Total blood 
volume drawn from each subject will not exceed the NIH CC guidelines. 
4.2.10 Apheresis 
Group 2 subjects will be offered apheresis as an optional procedure at Visit 09 in order to collect 
blood cells of special interest for research. The apheresis procedure will be carried out by trained 
Department of Transfusion Medicine (DTM) medical staff using automated cell separator 
devices.  
Apheresis performed for this protocol will be performed solely for research purposes. All study 
subjects will be treated according to standard DTM whole blood and apheresis donation policies 
and procedures. Prior to the scheduling apheresis, the subject must have a venous assessment 
performed by the DTM staff.  
In order to undergo apheresis procedures, a subject must meet the apheresis eligibility criteria as 
described in Section 4.2.11 and have no medical contraindications, as determined by the DTM 
staff.  A VRC study clinician will complete a checklist for apheresis eligibility before referring a 
subject for the procedure.    
Prior to beginning the apheresis procedure, a study clinician may request in advance that other 
laboratory samples be collected as needed to monitor the well-being of the subject or if needed 
by a research laboratory.  In addition, for women of reproductive potential, a pregnancy test by 
blood or urine will be performed by a VRC study clinician within 72 hours prior to the apheresis 
procedure. Results must be negative to proceed with apheresis.   
The Dowling Apheresis Clinic staff at the NIH CC routinely performs a hemoglobin test prior to 
initiating apheresis, per DTM Apheresis Clinic standard policies. If a subject is found to have a 
hemoglobin value less than permitted by the Apheresis Clinic, then the apheresis will not be 
initiated, and the ordering provider will be notified.  
In this study, the procedure will require two antecubital venous access sites and will involve 
processing 1 to 4 liters of whole blood. The expected mononuclear cell yield is approximately 
0.5 to 1.0 x 109 cells per liter processed, and the apheresis device can process about 2 to 3 liters 
per hour. Thus, 1 to 2 hours are required to process 1 to 4 liters of blood and obtain about 1 to 4 
x 109 leukocytes. The packed red cell loss during the procedure is the equivalent of a 6 mL blood 
draw; this is the volume that will be used for the purposes of calculating cumulative blood draw 
when apheresis is performed. 
During or following an apheresis visit, if there is any concern about the well-being of the subject, 
the DTM clinic may conduct appropriate medical evaluations by history-taking, physical 
examination, laboratory tests, and/or other testing. 

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PROTOCOL DATE: APRIL 20, 2020 
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Research blood samples will be processed and stored at VIP or a collaborating research 
laboratory. Stored samples may be used later to further evaluate immune responses and to 
elucidate genetic factors associated with immune response. 
4.2.11 Apheresis Eligibility Criteria 
Subject must meet all of the following criteria:  
1. Afebrile (temperature < 37.50C) 
2. Weight≥110pounds 
3. Adequate bilateral antecubital venous access 
4. Hemoglobin > 12.5 g/dL for females; > 13.0 g/dL for men 
5. Platelets > 150,000 K/uL 
6. No cardiovascular instability as indicated by a) history of medically significant cardiac 
arrhythmia within the last 12 months, or b) ischemic cardiovascular disease within the last 12 
months, or c) heart rate outside of the 50 - 100 beats/minute interval (on 3 successive 
readings), or d) blood pressure greater than 180 mmHg (systolic) or 100 mmHg (diastolic) on 
3 successive readings 
7. No current lung or kidney disease  
8. No known coagulation disorder 
9. No sickle cell disease  
10. No active or chronic hepatitis  
11. No intravenous injection drug use in the past 5 years  
12. Not breast feeding 
13. Negative beta-humanchorionicgonadotropin(β-HCG) pregnancy test (urine or serum) 
performed by a VRC study clinician within 72 hours prior to the apheresis procedure  
4.2.12 Concomitant Medications 
Only routine prescription medications will be entered in the database at the time of enrollment.  
Subsequently, the only concomitant medications that will be recorded or updated in the database 
are those associated with an AE requiring expedited reporting or the development of a new 
chronic condition requiring ongoing medical management. Anti-viral medications taken during 
influenza or influenza-like illnesses will be recorded in the database. Receipt of a FDA-approved 
vaccine at any time during the study will be recorded in the database (clinicians should work 
with subjects regarding the timing of licensed vaccines relative to study injection). Otherwise, 
concomitant medications taken throughout the study will be recorded in the subject’s study chart 
and general medical record for general medical documentation but will not be recorded in the 
database.   
 CRITERIA FOR DOSE ESCALATION AND DOSE CONTINUATION  
There will be one dose escalation review and two dose continuation reviews in this study. The 
Protocol Safety Review Team (PSRT, Section 8.8) will conduct an interim safety data review 
before dose escalation or repeat dosing may occur. The PSRT must assess the data as showing no 

PRODUCT: VRC-FLUNPF099-00-VP 
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PROTOCOL DATE: APRIL 20, 2020 
Page 22 of 54 
significant safety concerns before enrollment of the next dose level and repeat dosing at the same 
level may proceed. 
Enrollment will begin in Group 1 (20 mcg of VRC-FLUNPF099-00-VP) with no more than one 
subject enrolled per day. Two weeks after vaccination of the third subject, there will be an 
interim safety review of available data for three subjects to determine whether to continue 
enrollment in Group 1 and to proceed to the next dose level. If the 20 mcg dose of VRC-
FLUNPF099-00-VP is assessed as safe, enrollment can continue for Group 1 and begin for 
Group 2A. 
In Group 2A (60 mcg of VRC-FLUNPF099-00-VP), enrollment will continue with no more than 
one subject enrolled per day. Two weeks after vaccination of the third subject, there will be an 
interim safety review of the available data for three subjects to determine whether to proceed to 
Groups 2B, 2C, and 2D. If the 60 mcg dose of VRC-FLUNPF099-00-VP is assessed as safe, 
enrollment can continue for Group 2A and begin for Groups 2B, 2C, and 2D. Additionally, if the 
60 mcg dose is assessed as safe, all Group 2 subjects may receive the second vaccination at week 
16. 
Additional subjects may be enrolled into a group in order to have the requisite data for at least 3 
subjects, if first vaccinations are not completed or there are discontinuations from the study 
before there are sufficient data to conduct the dose escalation and continuation review for that 
group. 
The IRB will be provided with documentation of the safety review process and notification of 
the dose escalation. Consultation with the IRB and FDA, if needed, as per study pause criteria 
(Section 4.5) will occur if indicated by the review. One outcome of a dose escalation review may 
be to recommend evaluation of additional subjects at the current dose level and reassess for 
safety before proceeding to a higher dose level and repeat dosing at the same dose level.  
 CRITERIA FOR DISCONTINUING STUDY INJECTIONS OR PROTOCOL PARTICIPATION 
Decisions by the PI or designee to discontinue study injections or protocol participation for a 
subject will be made with these criteria. 
4.4.1 Discontinuation of Study Injections 
A subject will be discontinued from receiving study product for the following reasons: 
1. Subject voluntarily withdraws 
2. Pregnancy 
3. Grade 3 unsolicited AE assessed as possibly, probably or definitely related to study 
product  
4. Grade 4 AE assessed as related to study product 
5. Immediate hypersensitivity reaction associated with study product 
6. Intercurrent illness that is not expected to resolve prior to the next scheduled study 
injection 
7. Treatment with systemic glucocorticoids (e.g., prednisone or other glucocorticoid) or 
other immunomodulators (other than nonsteroidal anti-inflammatory drugs [NSAIDs]), 
with the exception that study injections may continue per investigator discretion if the 
next dose occurs at least 2 weeks following completion of glucocorticoid treatment 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 23 of 54 
8. The study PI assesses that it is not in the best interest of the subject to continue the 
vaccination schedule 
Group 2 subjects who do not receive the second injection as scheduled are expected to continue 
follow-up according to the Schedule of Evaluations for Group 1 subjects, except that research 
sample collections will be discontinued for pregnant women or others in which it is 
contraindicated.  
4.4.2 Discontinuation from Protocol Participation 
A subject will be discontinued from protocol participation for the following reasons: 
1. Subject voluntarily withdraws 
2. Subject develops a medical condition that is a contraindication to continuing study 
participation 
3. The IND Sponsor or regulatory authority stops the protocol 
4. The IND Sponsor or PI assesses that is it not in the best interest of the subject to continue 
participation in the study or that the subject’s compliance with the study is not sufficient 
 CRITERIA FOR PAUSING AND RESUMING THE STUDY 
4.5.1 Plan for Pausing the Study 
The PI and Protocol Safety Review Team (PSRT) will closely monitor and analyze study data as 
they become available and will make determinations regarding the presence and severity of AEs. 
The administration of study injections and new enrollments will be paused and the IND Sponsor 
will be promptly notified according to the following criteria: 
• One (or more) subject experiences a SAE or Grade 4 AE assessed as related to study 
product. 
• Two (or more) subjects experience the same Grade 3 unsolicited AE assessed as 
possibly, probably or definitely related to study product. 
• Three (or more) subjects experience the same Grade 2 or higher laboratory 
abnormality assessed as possibly, probably or definitely related to study product. 
• One (or more) subject experiences ulceration, abscess, or necrosis at the injection site. 
Self-limited solicited reactogenicity that is not an SAE will not be counted towards pause 
criteria. 
4.5.2 Plan for Review of Pauses and Resuming the Study 
The IND Sponsor, with participation by the PI and PSRT, will conduct the review and make the 
decision to resume, amend or close the study and notify the IRB accordingly.  As part of the 
pause review, the reviewers will also advise on whether the study needs to be paused again for 
any subsequent AEs of the same type.  The pause criterion for the SAE will continue to apply. 
The administration of study injections and new enrollments would resume only if review of the 
events that caused the pause resulted in a recommendation to permit further study injections and 
enrollments. Safety data reports and changes in study status will be submitted to relevant 
regulatory authorities in accordance with Section 5 and institutional policy. 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 24 of 54 
 SAFETY AND ADVERSE EVENT REPORTING 
 ADVERSE EVENTS 
Adverse Event (AE) - Any untoward medical occurrence in a human subject, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the subject’s participation in research, whether or not 
considered related to the subject’s participation in the research. In the context of FDA-required 
reporting, an AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
Each AE will be graded according to the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, Food and Drug 
Administration Guidance – September 2007 (Appendix II). The following guidelines will be used 
to determine whether or not an AE is recorded in the study database: 
• Solicited AEs (i.e., reactogenicity parameters as defined in Section 4.2.6) will be 
recorded without attribution assessments by the subject on paper or an electronic diary 
card for 7 days after each injection. If the paper diary card is completed by subject, data 
will be transcribed by a clinician into the study database. Clinicians will follow and 
collect resolution information for any reactogenicity symptoms that are not resolved 
within 7 days. 
• All unsolicited AEs will be recorded with attribution assessments in the study database 
from receipt of the first study injection through completion of the 4 week visit that 
follows each study injection. At other periods between injections and following the 4 
week post-injection visit after the second vaccination through the last study visit, only 
SAEs (Section 5.2), new chronic medical conditions, and influenza or ILI will be 
recorded.  
• Cases of influenza or influenza-like illness (ILI) will be evaluated as follows: 
ILI is defined as fever (temperature of 1000F [37.80C] or greater) and a cough and/or sore 
throat in the absence of a known cause other than influenza. Collection of nasopharyngeal 
swabs will be used for laboratory confirmation of influenza by polymerase chain reaction 
(PCR) in subjects who meet criteria for ILI.  The severity of illness in subjects with 
laboratory confirmed influenza illness will be recorded on a case report form rather than 
on an AE form.  
 SERIOUS ADVERSE EVENTS 
The term “Serious Adverse Event” (SAE) is defined in 21 CFR 312.32 as follows: “An adverse 
event or suspected adverse reaction is considered serious if, in the view of either the investigator 
or the sponsor, it results in any of the following outcomes: Death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 25 of 54 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.” 
“Life-threatening” refers to an AE that at occurrence represents an immediate risk of death to the 
subject. It does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. Similarly, a hospital admission for an elective procedure 
is not considered a SAE. 
 ADVERSE EVENT REPORTING TO THE IND SPONSOR 
AEs that meet SAE criteria must be reported and submitted by the clinical site on an expedited 
basis to the IND Sponsor, VRC/NIAID/NIH, according to sponsor guidelines as follows:  
• Results in death; 
• Is life threatening (places the subject at immediate risk of death from the event as it 
occurred); 
• Results in inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 
• Results in a congenital anomaly/birth defect in the offspring of a study subject; OR 
• Based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition (examples of such events include allergic bronchospasm requiring intensive 
treatment in the emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse). 
In addition, any event, regardless of severity, which in the judgment of an investigator  
represents a SAE, may be reported on an expedited basis. 
An investigator must communicate an initial SAE report within 24 hours of site awareness of 
occurrence to the IND Sponsor data entry into the database, which triggers an alert to the IND 
Sponsor MO. Within 3 working days, a written summary by the investigator should be submitted 
to the IND Sponsor. 
In order for the IND Sponsor to comply with regulations mandating sponsor notification of 
specified SAEs to the FDA within 7 or 15 calendar days, the investigator must submit additional 
information as soon as it is available.   
5.3.1 IND Sponsor Reporting to the FDA 
The IND Sponsor is responsible for making the determination of which SAEs are “serious and 
unexpected suspected adverse reactions” (SUSARs) as defined in 21 CFR 312.32. The following 
definitions apply: 
• Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the study product caused the AE. 
• Unexpected Adverse Event means an AE that is not listed in the IB or is not listed at the 
specificity or severity that has been observed.   
All SUSARs (as determined by the IND Sponsor) will be reported to the FDA as IND Safety 
Reports per 21 CFR 312.32 as soon as possible but not exceeding 7 calendar days for unexpected 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 26 of 54 
fatal or life-threatening events, and not exceeding 15 calendar days for other qualifying events. 
IND Safety Reports will also be provided to the IRB. 
The IND Sponsor will also submit an IND Annual Report of the progress of the investigation to 
the FDA as defined in 21 CFR 312.33. 
 REPORTING TO THE INSTITUTIONAL REVIEW BOARD 
The following information is consistent with NIH IRB Policy 801: Reporting Research Events, Version 1, 
effective July 1, 2019.  
Reportable Event - An event that occurs during the course of human subject research that requires 
notification to the IRB. 
For the purposes of this policy, reportable events include the following: 
• 
Unanticipated Problems (UPs) involving risks to subjects or others 
• 
Non-compliance (including major protocol deviations and noncompliance that is not related to a 
protocol deviation) 
• 
Deaths related or possibly related to research activities 
• 
New information that might affect the willingness of subjects to enroll or continue participation in 
the study 
5.4.1 Unanticipated Problem 
An unanticipated problem (UP) is defined as any incident, experience, or outcome that meets all 
three of the following criteria: 
• Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; and 
• Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); and 
• Suggests that the research places subjects or others (which may include research staff, 
family members or other individuals not directly participating in the research) at a greater 
risk of harm (including physical, psychological, economic, or social harm) related to the 
research than was previously known or expected. 
A UP must be reported within 7 calendar days of an investigator becoming aware of the actual or 
suspected UP. 
5.4.2 Protocol Deviation  
A protocol deviation (PD) is defined as any change, divergence, or departure from the IRB-
approved study procedures in a research protocol and are further characterized as major and 
minor as follows: 
• Major Deviations – Deviations from the IRB approved protocol that have, or may have 
the potential to, negatively impact, the rights, welfare or safety of the subject, or to 
substantially negatively impact the scientific integrity or validity of the study.  
• Minor Deviations – Deviations that do not have the potential to negatively impact the 
rights, safety, or welfare of subjects or others, or the scientific integrity or validity of the 
study. 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 27 of 54 
For the reporting purposes, failure of subjects to comply with the research protocol does not 
represent non-compliance unless that failure is due to an action or omission of a member of the 
research team, for example, the failure to give adequate instruction to the subject. 
A major deviation must be reported within 7 calendar days of an investigator becoming aware of 
an actual or suspected deviation. Although PDs are also non-compliance, these should only be 
reported once as deviations. Major deviations resulting in death must be reported within 24 hours 
of the occurrence of the event or of any member of the study team becoming aware of the death. 
Researchers are responsible for monitoring their studies throughout the year for adherence to the 
IRB approved protocol. The purpose of this monitoring is to identify major deviations and to 
look for trends in minor deviations that may indicate a systemic issue in how the study is being 
conducted that could potentially negatively impact the rights, safety, or welfare of participants or 
the study’s ability to produce scientifically valid results. A series of minor deviations pointing 
toward a more global issue that could affect the rights, safety or welfare of the participant or 
affect the validity of the study should be reported as a major deviation. In all other instances, a 
summary of minor deviations should be provided to the IRB at the time of continuing review. 
5.4.3 Non-Compliance  
Non-compliance is the failure of investigator(s) to follow the applicable laws, regulations, or 
institutional policies governing the protection of human subjects in research, or the requirements 
or determinations of the IRB, whether intentional or not. 
Non-compliance may be unintentional (e.g. due to lack of understanding, knowledge, or 
commitment), or intentional (e.g. due to deliberate choice to ignore or compromise the 
requirements of any applicable regulation, organizational policy, or determination of the IRB). 
Non-compliance is further characterized as serious or continuing as follows: 
• Serious non-compliance – Non-compliance, whether intentional or not, that results in 
harm or otherwise materially compromises the rights, welfare and/or safety of the subject. 
Non-compliance that materially effects the scientific integrity or validity of the research 
may be considered serious non-compliance, even if it does not result in direct harm to 
research subjects. 
• Continuing non-compliance – A pattern of recurring non-compliance that either has 
resulted, or, if continued, may result in harm to subjects or otherwise materially 
compromise the rights, welfare and/or safety of subjects, affect the scientific integrity of 
the study or validity of the results. The pattern may comprise repetition of the same non-
compliant action(s), or different noncompliant events. 
Any actual or suspected non-compliance by any investigator or entity associated with the 
protocol must be reported to the IRB by the PI/designee within 7 calendar days of any 
investigator or individual associated with the protocol first becoming aware. 
5.4.4 Death 
Any death of a research subject that is possibly, probably or definitely related to the research must be 
reported within 24 hours of an investigator becoming aware of the death. 
5.4.5 New Information 
New information that might affect the willingness of a subject to enroll or remain in the study should be 
reported within 7 calendar days of an investigator first becoming aware. 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 28 of 54 
5.4.6 Suspension or Termination of Research Activities 
Any suspension or termination of research activities, including holds on new enrollment, placed upon the 
research by the study sponsor, NIH or IC leadership, or any regulatory agency must be reported within 7 
calendar days of an investigator becoming aware. 
5.4.7 Expedited Reporting to the IRB 
Death related to research must be reported within 24 hours. 
The following will be reported within 7 calendar days of investigator awareness:  
• Actual or suspected UPs; 
• Actual or suspected non-compliance; 
• Actual or suspected Major PDs; 
• SAEs that are actual or suspected UPs; 
• New information that might affect the willingness of a subject to enroll or remain in the 
study; 
• Suspension or termination of research activities, including holds on new enrollment, 
placed upon the research by the study sponsor, NIH or IC leadership, or any regulatory 
agency. 
5.4.8 Annual Reporting to the IRB 
The following will be reported to the NIAID IRB in summary at the time of Continuing Review: 
• Summary of UPs and non-compliance; 
• AEs, including SAEs, that are not UPs, as a narrative summary statement indicating 
whether these events were within the expected range; 
• Minor PDs (aggregate summary); 
• Any trends or events which in the opinion of the investigator should be reported. 
 STATISTICAL CONSIDERATIONS 
 OVERVIEW 
This is a Phase I, open-label, dose escalation study to evaluate the dose, safety, tolerability, and 
immunogenicity of VRC-FLUNPF099-00-VP in two dose regimens.  Study objectives can be 
found in Section 3. 
 ENDPOINTS 
6.2.1 Primary Endpoints: Safety 
Assessment of product safety will include clinical observation and monitoring of hematological 
and chemical parameters. Reactogenicity will be closely monitored for 7 days after each 
injection and safety evaluated by clinical visits for 52 weeks following the last vaccine 
administration and through an influenza season. See Section 4.2 and Appendix I for details and 
specified time points. The following parameters will be assessed for all study groups: 
• Occurrence of solicited local reactogenicity symptoms for 7 days after each injection 
• Occurrence of solicited systemic reactogenicity symptoms for 7 days after each injection 
• Change from baseline in safety laboratory measures 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 29 of 54 
• Occurrence of AEs of all severities through the 4 week post-injection visit 
• Occurrence at any time throughout the study of SAEs or new chronic medical conditions 
that require ongoing medical management. 
6.2.2 Secondary Endpoints: Immunogenicity 
The principal immunogenicity endpoints will be assessed by measuring HA-stem specific 
antibody by pseudo-neutralization assay at:  
• Group 1: Baseline (Week 0/Visit 02) and Week 2 (Visit 04) after vaccination, and 
• Groups 2A-2D: Baseline (Week 0/Visit 02) and Week 2 (Visit 04) after the first 
vaccination, and at Week 16 (Visit 07) and Week 18 (Visit 09) after the second 
vaccination 
6.2.3 Exploratory Endpoints: Immunogenicity  
Exploratory immunogenicity evaluations may include the detection of antibody by MSD or 
microneutralization assay, and exploratory B and T cell assays. 
 SAMPLE SIZE AND ACCRUAL 
Recruitment will target 53 healthy adult participants 18 to 70 years of age, though up to 70 
participants may be enrolled if deemed necessary for safety or immunogenicity evaluations.  
Enrollment will be spread over multiple groups. Group 1 will target 5 healthy adults 18 to 40 
years of age. Groups 2A, 2B, 2C, and 2D will target 12 healthy adult participants each, with each 
study group corresponding to a different age range. 
6.3.1 Power Calculations for Safety 
The goal of the safety evaluation for this study is to identify safety concerns associated with 
injections of the investigational vaccine. Primary sample size calculations for safety are 
expressed in terms of the ability to detect serious adverse experiences. Other sample size 
calculations for comparing the two vaccination groups on adverse experiences are similar to the 
calculations for immunogenicity (Section 6.4.3). 
The ability of the study to identify SAEs will be expressed in terms of the probability of 
observing a certain number of SAEs. Useful values are the minimum true rate such that the 
probability of observing at least one event is at least 90%, and the maximum true rate such that 
the probability of not observing any event is at least 90%.  
For Group 1 (dose-escalation) within each group (n=5), there is a 90% chance to observe at least 
1 SAE if the true rate is at least 0.369 and over 90% chance to observe no SAE if the true rate is 
less than 0.021. 
For Groups 2A, 2B, 2C, 2D within each group (n=12), there is greater than a 90% chance to 
observe at least 1 SAE if the true rate is at least 0.175 and over a 90% chance to observe no SAE 
if the true rate is no more than 0.009. 
If Groups 2A, 2B, 2C, 2D are combined (N=48), there is greater than a 90% chance to observe at 
least 1 SAE if the true rate is at least 0.047 and greater than a 90% chance to observe no SAE if 
the true rate is no more than 0.002 
Probabilities of observing 0 or more than 1 SAE within each group are presented in Table 6-1 
for a range of possible true event rates and different sample sizes. These calculations provide a 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 30 of 54 
complete picture of the sensitivity of this study design to identify potential safety problems with 
the vaccine. 
Table 6-2 gives the upper and lower bounds for 95% exact binomial confidence intervals of the 
true SAE rate at all possible numbers of events within each group (n=5 and n=12).  
For Group 1 (n=5): If none of the 5 participants receiving the vaccines experience SAEs, the 
95% exact 2-sided upper confidence bound for the SAE rate is 0.52. 
For Groups 2A, 2B, 2C, 2D (n=12): If none of the 12 participants receiving the vaccines 
experience SAEs, the 95% exact 2-sided upper confidence bound for the SAE rate is 0.265. 
 
Table 6-1: Probability of Events for Different Safety and Immunogenicity Scenarios 
 
Group 1 (dose-escalation): 
N=5 
Groups 2A, 2B, 2C, 2D: 
N=12 
Groups 2A, 2B, 2C, 2D 
combined: N=48 
True 
Event 
Rate 
Pr  
(observing 
0 event) 
Pr  
(observing 
more than 1 
event) 
Pr  
(observing 
0 event) 
Pr  
(observing 
more than 1 
event) 
Pr  
(observing 0 
event) 
Pr  
(observing 
more than 1 
event) 
0.01 
0.951 
0.001 
0.886 
0.006 
0.617 
0.083 
0.02 
0.904 
0.004 
0.785 
0.023 
0.379 
0.249 
0.05 
0.774 
0.023 
0.540 
0.118 
0.085 
0.699 
0.1 
0.590 
0.081 
0.282 
0.341 
0.006 
0.960 
0.15 
0.444 
0.165 
0.142 
0.557 
<0.001 
0.996 
0.2 
0.328 
0.263 
0.069 
0.725 
<0.001 
>0.999 
0.3 
0.168 
0.472 
0.014 
0.915 
<0.001 
>0.999 
0.4 
0.078 
0.663 
0.002 
0.980 
<0.001 
>0.999 
0.5 
0.031 
0.812 
<0.001 
0.997 
<0.001 
>0.999 
Table 6-2: 95% Confidence Intervals for the True Rate at All Possible Observed Rates 
within a Group (n=5 and n=12) 
 
Group 1: N=5 
95% Confidence Interval 
 
 
Group 2A, 2B, 2C, 2D: N=12 
95% Confidence Interval 
Observed 
Rate 
Lower Bound 
Upper Bound 
 
Observed 
Rate 
Lower Bound 
Upper Bound 
0/5 
0 
0.522 
 
0/12 
0 
0.265 
1/5 
0.005 
0.716 
 
1/12 
0.002 
0.385 
2/5 
0.053 
0.853 
 
2/12 
0.021 
0.484 
3/5 
0.147 
0.947 
 
3/12 
0.055 
0.572 
4/5 
0.284 
0.995 
 
4/12 
0.099 
0.651 
5/5 
0.478 
1 
 
5/12 
0.152 
0.723 
 
 
 
 
6/12 
0.211 
0.789 
 
 
 
 
7/12 
0.277 
0.848 
 
 
 
 
8/12 
0.349 
0.901 
 
 
 
 
9/12 
0.428 
0.945 
 
 
 
 
10/12 
0.516 
0.979 
 
 
 
 
11/12 
0.615 
0.998 
 
 
 
 
12/12 
0.735 
1 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 31 of 54 
6.3.2 Power Calculations for Immunogenicity 
Table 6-1 gives the probabilities of observing 0 or more than 1 response over a range of 
underlying response rates and different sample sizes.  
Table 6-2 is applicable to the immunogenic response rates and gives the exact 95% confidence 
interval of the true response rate over possible number of responses out of the 5 and 12 subjects.  
6.3.3 Power for Comparison 
As exploratory analyses, we will conduct pairwise comparisons between Groups 2A, 2B, 2C, and 
2D of the study for possible differences in immunogenicity; a simple comparison on the positive 
response rate will be used. Table 6-3 gives the power of Fisher’s exact test to compare the 
schedules over a range of possible response rates. It indicates that a comparison between the 
groups is not powered by the study design with 12 samples per group. 
Table 6-3: Power to Detect Difference in Response Rates between Any Group by Fisher’s 
Exact Test, Where Both Groups are of Size n=12  
 
Group Y (N=12) 
Group Z (N=12) 
 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
0.1 
 
2 
9 
23 
42 
64 
0.2 
2 
 
3 
9 
21 
39 
0.3 
9 
3 
 
4 
9 
21 
0.4 
23 
9 
4 
 
4 
10 
0.5 
42 
21 
9 
4 
 
4 
0.6 
64 
39 
21 
10 
4 
 
 STATISTICAL ANALYSIS  
All statistical analyses will be performed using Statistical Analysis System (SAS), R, or S-Plus 
statistical software. No formal multiple comparison adjustments will be employed for safety 
endpoints or secondary endpoints. 
6.4.1 Analysis Variables 
The analysis variables consist of baseline variables and safety variables for primary and 
secondary objective analyses. 
6.4.2 Baseline Demographics 
Baseline characteristics including demographics and laboratory measurements will be 
summarized using descriptive statistics. 
6.4.3 Safety Analysis 
6.5.3.1 Reactogenicity 
The number and percentage of participants experiencing each type of reactogenicity sign or 
symptom will be tabulated by severity. For a given sign or symptom, each participant’s 
reactogenicity will be counted once under the maximum severity for all assessments. 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 32 of 54 
6.5.3.2 Adverse Events 
AEs are coded into Medical Dictionary for Regulatory Activities (MedDRA) preferred terms. 
The number and percentages of participants experiencing each specific AE will be tabulated by 
severity and relationship to treatment. For the calculations in these tables, each participant’s AE 
will be counted once under the maximum severity or strongest recorded causal relationship to 
treatment. 
A complete listing of AEs for each participant will provide details including severity, 
relationship to treatment, onset, duration and outcome. 
6.5.3.3 Local Laboratory Values 
Boxplots, violin plots, or beeswarm plots of local laboratory values will be generated for baseline 
values and for values measured during the course of the study. Each plot will show the 1st 
quartile, the median, and the 3rd quartile. Outliers, or values outside the boxplot, will also be 
plotted. If appropriate, horizontal lines representing boundaries for abnormal values will be 
plotted. 
6.4.4 Immunogenicity Analysis 
The statistical analysis for immunogenicity will employ the intent-to-treat principle whereby all 
data from enrolled subjects will be analyzed according to the group assignment. However, if 
during immune assessment on stored samples, a subject is found to have a positive antibody 
response at baseline, the vaccine immune responses assessment for these subjects will not be 
included in the final immunogenicity analysis. If needed, a per-protocol analysis will be 
performed as secondary analysis where subjects will be analyzed according to their actual 
vaccination scheme if it is different from the assigned or up to the last visit in the study if there 
are early dropouts. The study is not designed to power the comparison in immune responses 
between vaccine dosages. 
If assay data are qualitative (i.e., positive or negative) then analyses will be performed by 
tabulating the frequency of positive response for each assay at each time point that an assessment 
is performed. Binomial response rates will be presented with their corresponding exact 95% 
confidence interval estimates. 
Some immunologic assays have underlying continuous or count-type readout that is often 
dichotomized into responder/non-responder categories. For these assays, graphical and tabular 
summaries of the underlying distributions will be made. These summaries may be performed on 
transformed data (e.g., log transformation) for ease of interpretation. 
6.4.5 Missing Data 
Missing responses will be assumed to be missing completely at random. Analyses will include 
all samples available at each study time point. Based on experience from previous trials, we 
expect missing data to be rare. Regardless, in the event of missing data, we will report the 
occurrence and extent of missingness. We will also provide plausible explanations for the 
missingness mechanism, should such information be available. 
6.4.6 Interim Analyses 
Safety Reviews: The PSRT will review safety data routinely throughout the study. The study 
will utilize both electronic database features and reviews by designated safety review personnel 
to identify in a timely manner if any of the safety pause rules of the study are met.  

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 33 of 54 
Immunogenicity Review:  Analyses of immunogenicity may be performed when pseudo-
neutralization assay of samples collected 2 weeks after each vaccination are conducted. This may 
occur prior to completion of safety follow-up visits or collection of data for secondary and 
exploratory immunogenicity endpoints. Such an analysis would constitute the final analysis for 
the primary immunogenicity endpoint, so sample size adjustments are not required. Reports 
providing results by study group may be provided to VRC solely for the purpose of informing 
decisions related to future trials in a timely manner. The results should in no way influence the 
conduct of the VRC 321 trial in terms of early termination or later safety or immunogenicity 
endpoint assessments. Analyses of secondary and exploratory immunogenicity assays may also 
be performed as data become available. 
 PHARMACY AND ADMINISTRATION PROCEDURES  
The study groups and study agent dosing schedule are shown in Table 1 in Section 4. Refer to 
the IB for further information about the investigational study products.   
 STUDY PRODUCT 
The study includes one investigational vaccine described as follows: 
• VRC-FLUNPF099-00-VP at 180 mcg/mL. Vials contain 0.7 ± 0.1 mL of a clear, 
colorless, isotonic buffered (pH=7.2) sterile solution. The formulation buffer consists of 
20mM Sodium Phosphate, 100mM Sodium Chloride, 5% Sucrose, and 0.01% PF-68. 
Vials are intended for single use only and do not contain a preservative. Vials must not be 
refrozen or reused after thawing. 
 
• VRC-PBSPLA043-00-VP (PBS), diluent, is a clear, colorless, sterile solution at pH 7.2, 
aseptically filled to a volume of 1.2 mL in a 3 mL glass vial. Vials are intended for single 
use only and do not contain preservative. Vials must not be refrozen or reused after 
thawing. 
 STUDY PRODUCT PRESENTATION AND STORAGE 
7.2.1 Study Product Labels 
At the time of study product delivery to the pharmacy, labels on study products VRC-
FLUNPF099-00-VP and VRC-PBSPLA043-00-VP will have specific product information (e.g., 
product description, VRC product number, lot number, fill volume, concentration, fill date, 
storage condition). Labels will contain an Investigational Use Statement (“Limited by Federal 
Law to Investigational Use”) and manufacturer information. 
7.2.2 Study Product Storage 
VRC-FLUNPF099-00-VP (H1ssF_3928): Vials will be shipped within the recommended 
temperature range using appropriate shipping configurations to the study pharmacist or designee. 
Vials of vaccine are stored until use at -35°C to -15°C in a qualified, continuously monitored, 
temperature-controlled freezer. As freezer temperatures may fluctuate, a temperature range of -
45°C to -10°C is acceptable. Storage below -45ºC is not permitted because of the stopper 
limitation. 
VRC-PBSPLA043-00-VP (PBS): Vials are stored until use at the target temperature of -35°C to 
-15°C in a qualified, continuously monitored, temperature-controlled freezer. As freezer 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 34 of 54 
temperatures may fluctuate, a temperature range of -45°C to -10°C is acceptable based upon 
historic stability data from studies of similar products. 
7.2.3 Temperature excursions  
If deviations in storage temperature occur from the normal allowance for the pharmacy freezer, 
the site pharmacist or designee must report the storage temperature excursion promptly to the PI 
and IND Sponsor. The excursion must be evaluated and investigated, and action must be taken to 
restore and maintain the desired temperature limits. Pending the outcome of the investigation, the 
IND Sponsor will notify the pharmacist if continued clinical use of the product is acceptable. 
 PREPARATION OF STUDY PRODUCTS FOR INJECTION  
This section describes how the site pharmacist will prepare study injections. Clinician 
instructions on how to select an arm and administer an injection are in Section 4.2.5. Refer to the 
group assignment for the study subject to prepare the correct dose.  
For all study groups, the prepared syringe must be labeled with the subject identifier and the date 
and time after which the preparation may not be used. Filled syringes should be kept at room 
temperature and out of direct sunlight until product administration. All injections must be 
administered within 4 hours after removing the vaccine vial from the freezer. 
7.3.1 Preparation of VRC-FLUNPF099-00-VP for Needle and Syringe Administration 
Subjects will receive the vaccine via needle and syringe injection. The following instructions 
apply for VRC-FLUNPF099-00-VP preparation. More information on vaccine preparation is 
available in the IB. 
Group 1 (20 mcg): 
1. Thaw 1 vial of H1ssF_3928 at room temperature (15 to 30º C) until all ice crystals have 
melted.  Swirl gently to mix. 
2. Thaw 1 vial of PBS diluent at room temperature (15 to 30º C) until all ice crystals have 
melted.  Swirl gently to mix. 
3. Withdraw 0.11 mL of H1ssF_3928 into the syringe. 
4. Withdraw 0.2 mL of PBS into the same syringe. 
5. Invert syringe 5x to mix. 
Group 2A, Group 2B, Group 2C, and Group 2D (60 mcg): 
1. Thaw 1 vial of H1ssF_3928 at room temperature (15 to 30º C) until all ice crystals have 
melted.  Swirl gently to mix. 
2. Withdraw 0.33 mL of H1ssF_3928 into the syringe. 
7.3.2 Administration of Injections 
Refer to Section 4.2.5. Product labeling and IM injection procedures will be performed 
consistent with institutional policies and standard procedures. 
 STUDY PRODUCT ACCOUNTABILITY 
7.4.1 Documentation 
The study pharmacist or designee will be responsible for maintaining an accurate record of the 
codes, inventory, and an accountability record of the investigational study products supplies for 
this study. Electronic documentation as well as paper copies will be used. 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 35 of 54 
7.4.2 Disposition 
The empty vials, the partially-used vials, and any unused, unopened vial that has been removed 
from freezer will be discarded on the same day as removal from freezer in a biohazard 
containment bag and incinerated or autoclaved per facility policy. Any unopened vials that 
remain at the end of the study will be discarded or returned at the discretion of the VRC in 
accordance with policies that apply to investigational products. Partially used vials or expired 
prepared doses cannot be administered to other subjects nor used for in vitro experimental 
studies and will be discarded as indicated above. 
 HUMAN SUBJECT PROTECTIONS AND ETHICAL OBLIGATIONS 
This research study will be conducted in compliance with the protocol, International Council for 
Harmonisation Good Clinical Practices (ICH-GCP) guidance, and all applicable regulatory 
requirements. 
 INSTITUTIONAL REVIEW BOARD 
A copy of the protocol, ICF, other written subject-facing information, and any advertising 
material will be submitted to the NIAID IRB for written approval prior to use. 
The PI must submit and, where necessary, obtain approval from the IRB for all subsequent 
protocol amendments and changes to the ICF. The PI will notify the IRB of events that occur on 
study as described in Section 5.4. 
The investigator will be responsible for obtaining IRB approval of the annual Continuing Review 
throughout the duration of the study. 
 SUBJECT IDENTIFICATION AND ENROLLMENT OF STUDY PARTICIPANTS  
Study subjects will be recruited through on-site and off-site advertising done for the screening 
protocol, VRC 500 (11-I-0164). All study activities will be carried out at the NIH CC. Effort will 
be made to include women and minorities in proportions similar to that of the community from 
which they are recruited. 
8.2.1 Participation of Children 
Children are not eligible to participate in this clinical trial because the investigational vaccine has 
not been previously evaluated in adults. If the product is assessed as safe and immunogenic, 
other protocols designed for children may be conducted in the future. 
8.2.2 Participation of NIH Employees 
NIH employees and members of their immediate families may participate in this protocol. NIH 
staff may be a vulnerable class of subjects. The VRC will follow the Guidelines for the Inclusion 
of Employees in NIH Research Studies and will give each employee a copy of the “NIH 
Information Sheet on Employee Research Participation” and a copy of the “Leave Policy for 
NIH Employees Participating in NIH Medical Research studies.” 
Neither participation nor refusal to participate will have an effect, either beneficial or adverse, on 
the participant’s employment or work situation. The NIH information sheet regarding NIH 
employee research participation will be distributed to all potential subjects who are NIH 
employees. The employee subject’s privacy and confidentiality will be preserved in accordance 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 36 of 54 
with NIH CC and NIAID policies. For NIH employee subjects, consent will be obtained by an 
individual who is independent of the employee’s team. If the individual obtaining consent is a 
co-worker to the subject, independent monitoring of the consent process will be included through 
the Bioethics Consultation Service. Protocol study staff will be trained on obtaining potentially 
sensitive and private information from co-workers or subordinates. 
 INFORMED CONSENT 
The study ICF describes the investigational product to be used and all aspects involved in 
protocol participation. 
Before a subject’s participation in the study, the investigators must obtain written informed 
consent from the subject, after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study and before any protocol-specific procedures or study products 
are administered. 
An IRB-approved AoU, intended to assist in the evaluation of the subject’s understanding of this 
study, is administered as part of the consent process. 
The acquisition of informed consent will be documented in the subject’s medical records, as 
required by 21 CFR 312.62, and the ICF will be signed and personally dated by the subject and 
by the person who conducted the informed consent discussion. The original, signed ICF will be 
placed in the medical record and a copy of the signed ICF will be provided to the subject. 
 SUBJECT CONFIDENTIALITY 
The investigator must ensure that the subject’s anonymity is maintained and will ensure that no 
information identifying the subject will be released to any unauthorized party. Subjects will not 
be identified in any reports on this study. All records will be kept confidential to the extent 
provided by federal, state and local law. Medical records are made available for review when 
required by the FDA or other authorized users, such as the vaccine manufacturer, only under the 
guidelines set by the Federal Privacy Act. Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study. The investigator is obligated to inform the subjects that the above-named representatives 
will review their study-related records without violating the confidentiality of the subjects. 
Stored study research samples are labeled by a code (such as a number) that only the study team 
can link to the subject. The requirement to maintain subject confidentiality is discussed in the 
study ICF. 
 RISKS AND BENEFITS  
8.5.1 Risks of the VRC-FLUNPF099-00-VP vaccine 
This is the first study in humans of the investigational vaccine, VRC-FLUNPF099-00-VP. This 
product is derived from H. pylori ferritin and not human ferritin, for this reason it is not expected 
to interfere with iron storage, transport or iron serum levels [18]. 
Potential side effects resulting from IM injection include stinging, arm discomfort, redness of the 
skin or mild bruising at vaccine injection sites.   
Subjects may exhibit general signs and symptoms associated with administration of a vaccine, 
including fever, chills, rash, aches and pains, nausea, headache, dizziness and fatigue.  These 
side effects will be monitored, but are generally short term, mild to moderate severity and 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 37 of 54 
usually do not require treatment. 
In another VRC study of a similar ferritin vaccine (VRC 316), only 23.4% of participants were 
noted to have occasional asymptomatic and self-limited changes in laboratory tests such as mild 
leukocytosis, mild leukopenia, and mild increase in ALP as of March 24, 2019. 
There may be other unknown side effects. 
8.5.2 Risks of Specimen Collections 
• Blood drawing: The risks of blood sample collection are minimal and consist of mild 
discomfort at the sample collection site. The procedure may cause pain, bruising, 
fainting, and, rarely, infection at the site where the blood is taken. 
• Apheresis: The procedure may cause pain, bruising, and discomfort in the arms where the 
needles are placed. It may also cause chills, nausea, heartburn, mild muscle cramps and 
tingling sensation around the mouth or in the fingers, however this can usually be 
relieved by slowing or temporarily interrupting the apheresis procedure or taking a 
calcium containing antacid, such as Tums®. Other possible side effects are anxiety, 
vomiting and lightheadedness. Temporary lowering of the blood pressure may develop. 
There is the rare possibility of infection, fainting or seizure. Very rarely a nerve problem 
at the needle placement site may occur. Also, very rarely, a machine malfunction may 
occur, resulting in the loss of about one unit of blood. There may be additional risks of 
apheresis that are unknown at this time. 
• Mucosa samples: Collection of samples by nasopharyngeal swabs rubbed over the 
mucosal surfaces may cause momentary discomfort and, in some cases, minor bleeding. 
8.5.3 Risks of study vaccines on the fetus or nursing infant 
We do not know the possible effects of the study vaccine on the fetus or nursing infant. Women 
of reproductive potential will be required to agree to use an effective method of birth control 
beginning 21 days prior to enrollment and continuing through end of study.  
Because this is a research study, women of reproductive potential will be tested for pregnancy 
prior to administration of each study injection and asked to notify the site immediately upon 
learning of a pregnancy during this study. In the case of pregnancy, subjects will no longer 
receive additional vaccine but will continue to be followed for safety. Research sample 
collections will be discontinued for pregnant women. The subject will be contacted to ask about 
the outcome of a pregnancy that begins during the study. 
8.5.4 Risks of New Diagnoses 
It is possible that the standard medical tests performed as part of this research protocol will result 
in new diagnoses. Depending upon the medical findings and consequences of being provided 
with the new medical information about health status, the study subject may view this aspect of 
study participation as either a risk or a benefit. Any such information will be shared and 
discussed with the subject and, if requested by the subject, will be forwarded to the subject’s 
primary health care provider for further workup and management. 
8.5.5 Study Benefits  
Study subjects will not receive direct health benefit from study participation. This protocol is not 
designed to provide treatment for any condition. Others may benefit from knowledge gained in 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 38 of 54 
this study that may aid in the development of an H1 (or universal) influenza virus vaccine. The 
investigational vaccine is not expected to provide protection from influenza. 
 PLAN FOR USE AND STORAGE OF BIOLOGICAL SAMPLES 
The plan for use and storage of biological samples from this protocol is as outlined in the 
following sections. 
8.6.1 Use of Samples, Specimens and Data 
Samples, specimens and data collected under this protocol may be used to conduct protocol 
related safety and immune response evaluations, exploratory laboratory evaluations related to the 
type of infection the study product was designed to prevent, exploratory laboratory evaluations 
related to vaccine or infectious disease research in general and for research assay validation. 
Genetic testing may be performed in accordance with the genetic testing information that is 
included in the study ICF. HLA testing may be done in association with identifying factors 
linked with the immune response development or progression of infections.  
Additional optional genetic testing, including transcriptome sequencing may be done on 
collected specimens in an effort to assess the expression of genes involved in the immune 
response to vaccination.  
Results of genetic testing may have psychological implications for patients such as revelations 
regarding future health risks, incurable conditions, and/or information contradictory to stated 
biological relationships. Genetics counseling and advice will be available from the NIH to help 
subjects at all study sites with the implications of findings, where appropriate.  
Following genetic testing, the data will be shared in a controlled-access public database for other 
investigators to benefit from it (e.g. the Database of Genotypes and Phenotypes dbGAP). 
However, no personal identifiable information will be shared in this process as the results will 
only be shared with a code. Other optional analysis, including proteome, lipidome, metabolome, 
and exosome may be done on collected specimens to evaluate some proteins, lipids, metabolites, 
and low molecular weight molecules involved in the immune response to vaccination.  
8.6.2 Storage and Tracking of Blood Samples and Other Specimens 
All of the stored study research samples are labeled by a code that only the site can link to the 
subject. Samples are stored at the VIP, Gaithersburg, MD or VRC laboratories in Building 40, 
Bethesda, MD, which are both secure facilities with limited access. Data will be kept in 
password-protected computers. Only investigators or their designees will have access to the 
samples and data. Samples will be tracked in the Laboratory Information Management System 
(LIMS) database or using another software designed for this purpose (e.g., Freezerworks). 
8.6.3 Disposition of Samples, Specimens and Data at Completion of the Protocol  
In the future, other investigators (both at NIH and outside) may wish to study these samples 
and/or data. IRB approval must be sought prior to any sharing of samples. Any clinical 
information shared about those samples would similarly require prior IRB approval. The 
research use of stored, unlinked or unidentified samples may be exempt from the need for 
prospective IRB review and approval. Exemption requests will be submitted in writing to the 
NIH Office of Human Subjects Research, which is authorized to determine whether a research 
activity is exempt. 

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PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 39 of 54 
At the time of protocol termination, samples will remain in the VIP facility or VRC laboratories 
or, after IRB approval, transferred to another repository. Regulatory oversight of the stored 
samples and data may be transferred to a stored samples protocol as part of the IRB-approved 
termination plan. Data will be archived by the VRC in compliance with requirements for 
retention of research records, or after IRB and study sponsor approval, it may be either destroyed 
or transferred to another repository. 
8.6.4 Loss or Destruction of Samples, Specimens or Data 
The NIH Intramural Protocol Deviation definition related to loss of or destruction of samples or 
data will be followed. Any loss or unanticipated destruction of samples (for example, due to 
freezer malfunction) or data (for example, misplacing a printout of data with identifiers) that 
compromises the scientific integrity of the study will be reported to the IRB in accordance with 
institutional policies. The PI will also notify the IRB if the decision is made to destroy the 
remaining samples. 
 COMPENSATION 
Subjects will be compensated for time and inconvenience in accordance with the standards for 
compensation of the NIH Clinical Research Volunteer Program. The compensation per visit will 
be $275 for visits that include injections and $175 for clinic visits that include a blood draw. Any 
visit that includes mucosal sample collection will result in an additional $50 in compensation. 
The compensation for any clinic visit that does not include a blood draw or mucosal sample 
collection will be $75. The compensation for timely completion of the electronic diary card will 
be $25. Compensation will be $250 for apheresis, if performed. The total compensation for the 
subject is based on the number of study clinic visits, injections completed and if optional 
research blood collections are performed.  
Subjects will receive compensation by direct deposit within approximately 1 or 2 weeks after 
each completed visit. Compensation may need to be reported to the Internal Revenue Service 
(IRS) as taxable income. 
The approximate total compensation is as follows: 
 
Group 
Without Apheresis 
With Apheresis 
Group 1 
$1,875 
NA 
Group 2A 
Group 2B 
Group 2C  
Group 2D 
$2,525 
$2,600 
 SAFETY MONITORING  
8.8.1 Protocol Safety Review Team 
Close cooperation between the designated members of the Protocol Team will occur to evaluate 
and respond to individual AEs in a timely manner. The VRC designated Safety Officer for the 
day conducts a daily safety review of clinical data per VRC Standard Operating Procedures. The 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 40 of 54 
PSRT, comprised of the PI, Associate Investigators, Study Coordinator, Protocol Specialists, and 
other Study Clinicians, will review the summary study safety data reports on a weekly basis 
through 4 weeks after the last subject receives the final study injection. After this time, the PSRT 
will monitor the safety data reports on a monthly basis through completion of the last study visit.   
 ADMINISTRATIVE AND LEGAL OBLIGATIONS 
 PROTOCOL AMENDMENTS AND STUDY TERMINATION 
Agreement from the PI must be obtained for all amendments to the protocol and the informed 
consent document. All study amendments will be submitted to the IRB for approval. 
The VRC, NIAID IRB, Office of Human Research Protections, study PI, and FDA reserves the 
right to terminate the study. The PI will notify the IRB in writing of the study’s completion or 
early termination. 
 STUDY DOCUMENTATION AND STORAGE 
The PI will maintain a list of appropriately qualified persons to whom trial duties have been 
delegated. 
Source documents are original documents, data, and records from which the subject’s data are 
obtained. These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, and correspondence.  
The PI and staff are responsible for maintaining a comprehensive and centralized filing system of 
all study-related (essential) documentation, suitable for inspection at any time by representatives 
from the VRC, IRB, FDA, and/or applicable regulatory authorities. Elements include but not 
limited to: 
• Subject files containing completed informed consent forms, and supporting copies of 
source documentation (if kept) 
• Study files containing the protocol with all amendments, Investigator Brochures, copies 
of all correspondence with the IRB and VRC 
In addition, all original source documentation must be maintained and be readily available. 
All essential documentation will be retained by the institution for the same period of time 
required for medical records retention. The FDA requires study records to be retained for up to 
two years after marketing approval or refusal (21 CFR 312.62). No study document will be 
destroyed without prior written agreement between the VRC and the PI.  
 DATA COLLECTION, DATA SHARING AND PROTOCOL MONITORING 
9.3.1 Data Collection 
Clinical research data will be collected in a secure electronic web-based clinical data 
management system (CDMS) through a contract research organization, The Emmes Company, 
LLC (Rockville, MD). Extracted data without patient identifiers will be sent to the Protocol 
Statistician for statistical analysis. 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 41 of 54 
9.3.2 Data Sharing Plan 
Data generated in this study will be shared as de-identified data in the government-funded public 
repository, www.ClinicalTrials.gov.  Data may be shared prior to publication at approved public 
presentations or for collaborative development and will be shared at the time of publication or 
within 1 year of the primary completion date.  
9.3.3 Source Documents  
The site will maintain appropriate medical and research records for this trial, in compliance with 
ICH-GCP, regulatory and institutional requirements for the protection of confidentiality of 
subjects. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include but are not limited to medical records, 
laboratory reports, pharmacy records and other research records maintained for the clinical trial. 
9.3.4 Protocol Monitoring Plan 
Site investigators will allow the study monitors, the NIAID IRB, and the FDA to inspect study 
documents (e.g., consent forms, drug distribution forms, and case report forms) and pertinent 
hospital or clinic records for confirmation of the study data. 
Site visits by study monitors will be made in accordance with the study monitoring plan to 
monitor the following: study operations, the quality of data collected in the research records, the 
accuracy and timeliness of data entered in the database, and to determine that all process and 
regulatory requirements are met. Study monitoring visits will occur as defined by the IND 
Sponsor approved monitoring plan. 
 LANGUAGE 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood by the subject.  
 POLICY REGARDING RESEARCH-RELATED INJURIES 
The NIH CC will provide short-term medical care for any injury resulting from participation in 
this research. In general, the NIH, the NIH CC, or the U.S. Federal Government will provide no 
long-term medical care or financial compensation for research-related injuries. 
 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 42 of 54 
 REFERENCES 
1. 
WHO. Influenza (Seasonal) Fact Sheet. 2009; Available from: 
http://www.who.int/mediacentre/factsheets/fs211/en/index.html. 
2. 
Meltzer, M.I., N.J. Cox, and K. Fukuda, The economic impact of pandemic influenza in 
the United States: priorities for intervention. Emerg Infect Dis, 1999. 5(5): p. 659-71. 
3. 
Subbarao, K., B.R. Murphy, and A.S. Fauci, Development of effective vaccines against 
pandemic influenza. Immunity, 2006. 24(1): p. 5-9. 
4. 
CDC. Types of Influenza Viruses. 2014  4/15/2014]; Available from: 
http://www.cdc.gov/flu/about/viruses/types.htm. 
5. 
Taubenberger, J.K. and J.C. Kash, Influenza virus evolution, host adaptation, and 
pandemic formation. Cell Host Microbe, 2010. 7(6): p. 440-51. 
6. 
D C Wiley, a. and J.J. Skehel, The Structure and Function of the Hemagglutinin 
Membrane Glycoprotein of Influenza Virus. Annual Review of Biochemistry, 1987. 
56(1): p. 365-394. 
7. 
Ekiert, D.C., et al., Antibody recognition of a highly conserved influenza virus epitope. 
Science, 2009. 324(5924): p. 246-51. 
8. 
Throsby, M., et al., Heterosubtypic neutralizing monoclonal antibodies cross-protective 
against H5N1 and H1N1 recovered from human IgM+ memory B cells. PLoS One, 2008. 
3(12): p. e3942. 
9. 
Corti, D., et al., A neutralizing antibody selected from plasma cells that binds to group 1 
and group 2 influenza A hemagglutinins. Science, 2011. 333(6044): p. 850-6. 
10. 
Harris, A.K., et al., Structure and accessibility of HA trimers on intact 2009 H1N1 
pandemic influenza virus to stem region-specific neutralizing antibodies. Proc Natl Acad 
Sci U S A, 2013. 110(12): p. 4592-7. 
11. 
Tripp, R.A. and S.M. Tompkins, Virus-vectored influenza virus vaccines. Viruses, 2014. 
6(8): p. 3055-79. 
12. 
CDC. Vaccine Effectiveness - How Well Does the Flu Vaccine Work? 2016 11/14/2016; 
Available from: https://www.cdc.gov/flu/about/qa/vaccineeffect.htm. 
13. 
Lambert, L.C. and A.S. Fauci, Influenza vaccines for the future. N Engl J Med, 2010. 
363(21): p. 2036-44. 
14. 
Krammer, F. and P. Palese, Advances in the development of influenza virus vaccines. Nat 
Rev Drug Discov, 2015. 14(3): p. 167-82. 
15. 
Neuzil, K.M. and R.A. Bright, Influenza vaccine manufacture: keeping up with change. J 
Infect Dis, 2009. 200(6): p. 835-7. 
16. 
Yassine, H.M., et al., Hemagglutinin-stem nanoparticles generate heterosubtypic 
influenza protection. Nat Med, 2015. 21(9): p. 1065-70. 
17. 
Bai, L., et al., Genome-wide comparison of ferritin family from Archaea, Bacteria, 
Eukarya, and Viruses: its distribution, characteristic motif, and phylogenetic 
relationship. Naturwissenschaften, 2015. 102(9-10): p. 64. 

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PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 43 of 54 
18. 
Kanekiyo, M., et al., Self-assembling influenza nanoparticle vaccines elicit broadly 
neutralizing H1N1 antibodies. Nature, 2013. 499(7456): p. 102-6. 
19. 
Yamashita, I., K. Iwahori, and S. Kumagai, Ferritin in the field of nanodevices. Biochim 
Biophys Acta, 2010. 1800(8): p. 846-57. 
20. 
Zhao, L., et al., Nanoparticle vaccines. Vaccine, 2014. 32(3): p. 327-37. 
21. 
Krammer, F., P. Palese, and J. Steel, Advances in universal influenza virus vaccine design 
and antibody mediated therapies based on conserved regions of the hemagglutinin. Curr 
Top Microbiol Immunol, 2015. 386: p. 301-21. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 44 of 54 
APPENDIX I: SCHEDULE OF EVALUATIONS 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 45 of 54 
 
VRC 500 
VRC  321 Schedule of Evaluations: Group 1 
Visit Number 
*01 
02 
02A 
03 
04 
05 
06 
07 
09 
11 
12 
13 
Week of Study 
-4 to 0 
W0 
W1 
W1 
W2 
W4 
W12 
W16 
W18 
W28 
W40 
W52 
Day of Study 
-28 to 0 
1D0 
D1 
D6 
D14 
D28 
D84 
D112 
D126 
D196 
D280 
D364 
Clinical 
Tube 
 
 
 
 
 
*VRC 500 Screening Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
VRC 321 AoU; Consent 
 
 
X 
 
 
 
 
 
 
 
 
 
 
2Physical exam for eligibility, height /weight/ vitals at screening; 
vital signs and targeted exam (as needed) other visits. 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history targeted to eligibility at screening; then interim 
medical history 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
3Study Product Administration: Group 1 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Phone evaluation (clinic visit as needed) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Begin diary card 
 
 
X 
 
 
 
 
 
 
 
 
 
 
4Pregnancy test: urine or serum 
 
X 
X 
 
 
 
X 
 
 
 
 
X 
X 
4Pregnancy prevention counseling/ Reproductive Information Form 
 
X 
X 
 
 
 
X 
 
 
 
 
X 
X 
CBC with differential 
EDTA 
3 
3 
 
 
3 
3 
 
 
 
 
3 
3 
Iron and serum ferritin 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Total bilirubin, AST, ALT, and ALP  
GLT 
4 
4 
 
 
4 
4 
 
 
 
 
4 
4 
Creatinine 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
5HLA type 
EDTA 
 
 
 
 
 
 
 
 
 
20 
 
 
HIV Ab/Ag Combo (other tests, if needed) 
EDTA 
3 
 
 
 
 
 
 
 
 
 
 
 
Research Samples 
 
 
 
 
 
 
H. pylori ferritin antibody and human ferritin antibody 
SST 
X 
 
 
 
 
X 
 
 
 
 
 
 
Serum  
SST 
32 
16 
 
16 
16 
16 
16 
16 
16 
16 
16 
16 
PBMC and plasma  
EDTA 
80 
80 
 
680 
80 
80 
80 
80 
40 
80 
80 
80 
Daily Volume (mL) 
 
122 
103 
0 
96 
103 
103 
96 
96 
56 
116 
103 
103 
Max. Cumulative Volume (mL) 
 
122 
225 
225 
321 
424 
527 
623 
719 
775 
891 
994 
1,097 
* VRC 500: Screening evaluations must be no more than 28 days prior to Day 0 to be used for eligibility (negative pregnancy test from Day 0 must be used for eligibility). If clinical assessment on Day 0 suggests 
significant changes may have occurred since screening, then physical examination & laboratory studies done on Day 0 are used for eligibility. 
1 Day 0=day of enrollment and first vaccine injection. Day 0 evaluations prior to first injection are the baseline for assessing adverse events subsequently. 
2 Screening visit includes physical exam with vital signs. At other visits, physical exam is done if indicated. Otherwise only blood pressure (BP), pulse, temperature, and respiration are required. 
3 Study Product Administration: Group 1 will receive H1ssF_3928 20 mcg IM at Day 0. Complete post vaccination evaluations (BP, pulse, temperature, respiration and injection site assessment) at 1 hour or longer 
after injection. 
4 Negative pregnancy test results must be confirmed for women of reproductive potential prior to each study injection. 
5 HLA type blood sample is collected once at any time-point in the study and is shown as a Visit 05 evaluation for convenience; however, if HLA type is already available in the medical record, it does not need to 
be repeated. HLA type may also be obtained from a frozen sample. 
6 Visit 03: Two tubes of PBMC collected in EDTA tubes will be sent to Building 40, while the remainder of the blood collected will be sent to VIPVITL. 
Visit windows: Schedule Visits 02A - 13 with respect to Day 0 per the following visit windows: Visit 02A (+1 day). Visit 03 (±1 day). Visits 04, 05, 09 (±2 days). Visits 07 (± 7 days). Visit 06 (±14 days). Visits 11, 
12 and 13 (± 14 days).  
 

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PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 46 of 54 
VRC 500 
VRC  321 Schedule of Evaluations: Groups 2A, 2B, 2C, 2D 
Visit Number 
*01 
02 
02A 
03 
04 
05 
06 
07 
07A 
08 
09 
10 
11 
12 
13 
14 
Week of Study -4 to 0 
W0 
W1 
W1 
W2 
W4 
W12 
W16 
W17 
W17 
W18 
W20 
W28 
W40 
W52 
W68 
Day of Study -28 to 0 
1D0 
D1 
D6 
D14 
D28 
D84 
D112 
D113 
D118 
D126 
D140 D196 D280 D364 D476 
Clinical 
Tube 
 
 
 
 
 
 
 
 
*VRC 500 Screening Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VRC 321 AoU; Consent 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2Physical exam for eligibility, height /weight/ vitals at 
screening; vital signs and targeted exam (as needed) 
other visits. 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Medical history targeted to eligibility at screening; then 
interim medical history 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
3Study Product Administration: Group 2A-2D 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Phone evaluation (clinic visit as needed) 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Begin diary card 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4Pregnancy test: urine or serum 
 
X 
X 
 
 
 
X 
 
X 
 
 
8[X] 
X 
 
X 
X 
X 
4Pregnancy prevention counseling/ Reproductive 
Information Form 
 
X 
X 
 
 
 
X 
 
X 
 
 
8[X] 
X 
 
X 
X 
X 
CBC with differential 
EDTA 
3 
3 
 
 
3 
3 
 
3 
 
 
 
3 
 
3 
3 
3 
Iron and serum ferritin 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Total bilirubin, AST, ALT, and ALP 
GLT 
4 
4 
 
 
4 
4 
 
4 
 
 
 
4 
 
4 
4 
4 
Creatinine 
 
X 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
5HLA type 
EDTA 
 
 
 
 
 
 
 
 
 
 
 
 
20 
 
 
 
HIV Ab/Ag Combo (other tests, if needed) 
EDTA 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Samples 
 
 
 
 
 
 
 
 
 
 
H. pylori ferritin antibody and human ferritin antibody 
SST 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum  
SST 
32 
16 
 
16 
16 
16 
16 
16 
 
16 
16 
16 
16 
16 
16 
16 
PBMC and plasma  
EDTA 
80 
80 
 
680 
80 
80 
80 
80 
 
80 
7120 or 
Apheresis (6) 
80 
80 
80 
80 
80 
Daily Volume (mL) 
 
122 
103 
0 
96 
103 
103 
96 
103 
0 
96 
136 
103 
116 
103 
103 
103 
Max. Cumulative Volume (mL) 
 
122 
225 
225 
321 
424 
527 
623 
726 
727 
822 
958 
1,061 1,177 1,280 1,383 1,486 
* VRC 500: Screening evaluations must be no more than 28 days prior to Day 0 to be used for eligibility (pregnancy test from Day 0 must be used for eligibility). If clinical assessment on Day 0 suggests significant changes may 
have occurred since screening, then physical examination & laboratory studies done on Day 0 are used for eligibility. 
1 Day 0=day of enrollment and first vaccine injection. Day 0 evaluations prior to first injection are the baseline for assessing adverse events subsequently. 
2 Screening visit includes physical exam with vital signs. At other visits, physical examination is done if indicated. Otherwise only blood pressure (BP), pulse, temperature, and respiration are required. 
3 Study Product Administration: Groups 2A-2D will receive H1ssF_3928 60 mcg IM at Day 0 and Week 16. Complete post vaccination evaluations (BP, pulse, temperature, respiration and injection site assessment) at 30 minutes 
or longer after each injection for Group 2A-2D. 
4 Negative pregnancy test results must be confirmed for women of reproductive potential prior to each study injection and prior to apheresis. 
5 HLA type blood sample is collected once at any time-point in the study and is shown as a Visit 05 evaluation for convenience; however, if HLA type is already available in the medical record, it does not need to be repeated. HLA 
type may also be obtained from a frozen sample. 
6 Visit 03: Two EDTA tubes for PBMC collected will be sent to Building 40, while the remainder of the blood collected will be sent to VIP. 
7 If optional Apheresis occurs, ONLY draw 16 mL in SST (DO NOT draw 120 ml in EDTA tubes). 
 8For women of reproductive potential, pregnancy test must be negative within 72 hours prior to apheresis procedure. 
Visit windows: Schedule Visits 02A - 07 with respect to Day 0; Schedule Visits 07A - 13 with respect to Visit 07. The following visit windows apply: Visits 02A and 07A (+1 day). Visits 03 and 08 (±1 day). Visits 04 and 09 (±2 days). 
Visits 05 and 10 (±2 days). Visits 06 and 11 (±14 days). Visit 07 (±14 days). Visits 12, 13 and 14 (±14 days). 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 47 of 54 
APPENDIX II: ASSESSMENT OF RELATIONSHIP TO VACCINE AND GRADING 
SEVERITY OF ADVERSE EVENTS

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 48 of 54 
Assessment of Relationship of an Adverse Event to Study Vaccine:  
 
The relationship between an AE and the vaccine will be assessed by the investigator on the basis 
of his or her clinical judgment and the definitions below. 
• Definitely Related. The AE and administration of study agent are related in time, and 
a direct association can be demonstrated. 
• Probably Related. The AE and administration of study agent are reasonably related 
in time, and the AE is more likely explained by study agent than other causes.  
• Possibly Related. The AE and administration of study agent are reasonably related in 
time, but the AE can be explained equally well by causes other than study agent. 
• Not Related. The AE is clearly explained by another cause not related to the study 
product.  
For purposes of preparing summary data reports in which AE attributions are simplified to 
“Related” or “Not Related”, in this protocol, the “Definitely, Probably and Possibly” attributions 
above will be mapped to the “Related” category, while the “Unlikely/Probably Not Related” and 
“Not Related” attributions above will be mapped to the “Not Related” category. The definitions 
that apply when these two attribution categories alone are used are as follows: 
• Related – There is a reasonable possibility that the AE may be related to the study 
product(s). 
• Not Related – There is not a reasonable possibility that the AE is related to the study 
product(s). 
Grading the Severity of Adverse Events: 
The FDA Guidance for Industry (September 2007): “Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” is the basis for the 
severity grading of AEs in this protocol. Several modifications were made to the table as follows: 
• “Emergency room visit” is not automatically considered a life-threatening event; these 
words have been removed from any “Grade 4” definition where they appear in the table 
copied from the guidance document. 
• Laboratory value shown as a “graded” value in the table that is within the institutional 
normal range will not be severity graded or recorded as an AE. 
• Severity grading for hemoglobin decrease on the basis of the magnitude of decrease from 
baseline is not applicable at the Grade 1 level; only absolute hemoglobin will be used to 
define Grade 1. 
• Severity grading for Grade 4 local reaction to injectable product (Erythema/Redness and 
Induration/Swelling) refer to necrosis or exfoliative dermatitis “requiring medical 
attention.” 
• Bruising or skin lesion associated with study injection will be assessed using the same 
severity grading as for erythema/redness. 
 
 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 49 of 54 
When not otherwise specified, the following guidance will be used to assign a severity grade: 
• Grade 1 (Mild): No effect on activities of daily living 
• Grade 2 (Moderate): Some interference with activity not requiring medical intervention 
• Grade 3 (Severe): Prevents daily activity and requires medical intervention  
• Grade 4 (Potentially Life-threatening): Hospitalization; immediate medical 
intervention or therapy required to prevent death. 
• Grade 5 (Death): Death is assigned a Grade 5 severity. Only the single AE that is 
assessed as the primary cause of death should be assigned “Grade 5” severity. 
 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials 
Modified from FDA Guidance - September 2007 
 
A. Tables for Clinical Abnormalities  
 
Local Reaction to  
Injectable Product  
Mild 
 (Grade 1)  
Moderate 
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Pain  
Does not 
interfere  
with activity  
Repeated use of 
non-narcotic 
pain reliever > 
24 hours or 
interferes with 
activity  
Any use of 
narcotic pain 
reliever or 
prevents daily  
activity  
Hospitalization  
Tenderness  
Mild discomfort 
to touch  
Discomfort with 
movement  
Significant  
discomfort 
at 
rest  
Hospitalization  
1,2Erythema/Redness   2.5 – 5 cm  
5.1 – 10 cm  
> 10 cm  
Necrosis or  
exfoliative 
dermatitis 
requiring 
medical 
attention  
3 Induration/Swelling   2.5 – 5 cm and 
does 
not 
interfere  
with activity  
5.1 – 10 cm or  
interferes with  
activity  
> 10 cm or  
prevents daily  
activity  
Necrosis 
requiring 
medical 
attention  
 
4 Vital Signs 
Mild  
(Grade 1)  
Moderate 
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
5Fever (°C)  
            (°F)  
38.0 – 38.4  
100.4 – 101.1  
38.5 – 38.9  
101.2 – 102.0  
39.0 – 40  
102.1 – 104  
> 40  
> 104  

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 50 of 54 
4 Vital Signs 
Mild  
(Grade 1)  
Moderate 
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Tachycardia - beats 
per  
minute 
 
101 – 115  
116 – 130  
> 130  
Hospitalization 
for arrhythmia  
6Bradycardia - beats 
per Minute 
50 – 54  
45 – 49  
< 45  
Hospitalization 
for arrhythmia  
Hypertension 
(systolic) - mm Hg  
141 – 150  
151 – 155  
> 155  
Hospitalization 
for malignant  
hypertension  
Hypertension 
(diastolic) - mm Hg  
91 – 95  
96 – 100  
> 100  
Hospitalization 
for malignant  
hypertension  
Hypotension 
(systolic) – mm Hg  
85 – 89  
80 – 84  
< 80  
Hospitalization 
for hypotensive 
shock  
Respiratory Rate – 
breaths per minute  
17 – 20  
21 – 25  
> 25  
Intubation  
 
1. In addition to grading the measured local reaction at the greatest single diameter, the measurement 
should be recorded as a continuous variable.  
2. Bruising or skin lesion associated with study injection will be assessed using the same severity 
grading as for erythema/redness. 
3. Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
4. Subject should be at rest for all vital sign measurements.  
5. Oral temperature; no recent hot or cold beverages or smoking.  
6. When resting heart rate is between 60 – 100 beats per minute. Use clinical judgment when 
characterizing  
 
Bradycardia among some healthy subject populations, for example, conditioned athletes. 
 
Systemic 
(General)  
Mild  
(Grade 1)  
Moderate 
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Nausea/vomiting  
No interference  
with activity or 1 – 
2  
episodes/24 hours  
Some 
interference  
with activity or > 
2  
episodes/24 
hours  
Prevents daily  
activity, requires  
outpatient IV  
hydration  
Hospitalization 
for hypotensive 
shock  
Systemic 
(General)  
Mild  
(Grade 1)  
Moderate 
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 51 of 54 
Diarrhea  
2 – 3 loose stools 
or 
< 400 gms/24 
hours 
4 – 5 stools or  
400 – 800 
gms/24  
hours  
6 or more watery  
stools or  
> 800gms/24 
hours or requires  
outpatient IV  
hydration  
Hospitalization  
Headache  
No interference 
with activity  
Repeated use of 
non-narcotic 
pain  
reliever > 24 
hours or some 
interference  
with activity  
Significant; any  
use of narcotic  
pain reliever or  
prevents daily  
activity  
Hospitalization  
Fatigue  
No interference 
with activity  
Some 
interference  
with activity  
Significant;  
prevents daily  
activity  
Hospitalization  
Myalgia  
No interference 
with activity  
Some 
interference  
with activity  
Significant;  
prevents daily  
activity  
Hospitalization  
Illness or clinical 
adverse  
event (as defined  
according to 
applicable  
regulations)  
No interference 
with activity  
Some 
interference  
with activity not  
requiring 
medical  
intervention  
Prevents daily  
activity and  
requires medical  
intervention  
Hospitalization  
 
 
 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 52 of 54 
B. Tables for Laboratory Abnormalities  
 
The laboratory values provided in the tables below serve as guidelines and are dependent upon 
the institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate. 
 
Serum *  
Mild  
(Grade 1)  
Moderate  
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4) ** 
Sodium – Hyponatremia 
mEq/L 
132 – 134  
130 – 131  
125 – 129  
< 125  
Sodium – Hypernatremia 
mEq/L 
144 – 145  
146 – 147  
148 – 150  
> 150  
Potassium – Hyperkalemia 
mEq/L 
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6  
Potassium – Hypokalemia 
mEq/L 
3.5 – 3.6  
3.3 – 3.4  
3.1 – 3.2  
< 3.1  
Glucose – Hypoglycemia 
mg/dL  
65 – 69  
55 – 64  
45 – 54  
< 45  
Glucose – Hyperglycemia  
Fasting – mg/dL  
Random – mg/dL  
 
100 – 110  
110 – 125  
 
111 – 125  
126 – 200  
 
>125  
>200  
Insulin 
requirements or 
hyperosmolar 
coma  
Blood Urea Nitrogen  
BUN mg/dL  
23 – 26  
27 – 31  
> 31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires 
dialysis  
Calcium – hypocalcemia 
mg/dL  
8.0 – 8.4  
7.5 – 7.9  
7.0 – 7.4  
< 7.0  
Calcium – hypercalcemia 
mg/dL  
10.5 – 11.0  
11.1 – 11.5  
11.6 – 12.0  
> 12.0  
Magnesium – 
hypomagnesemia mg/dL  
1.3 – 1.5  
1.1 – 1.2  
0.9 – 1.0  
< 0.9  
Phosphorous – 
hypophosphatemia mg/dL  
2.3 – 2.5  
2.0 – 2.2  
1.6 – 1.9  
< 1.6  
CPK – mg/dL  
1.25 – 1.5 x 
ULN***  
>1.5 – 3.0 x 
ULN  
>3.0 –10 x 
ULN  
> 10 x ULN  
Albumin – 
Hypoalbuminemia g/dL  
2.8 – 3.1  
2.5 – 2.7  
< 2.5  
--  
Total Protein – 
Hypoproteinemia g/dL  
5.5 – 6.0  
5.0 – 5.4  
< 5.0  
--  
Alkaline phosphate –  
increase by factor  
1.1 – 2.0 x 
ULN  
2.1 – 3.0 x 
ULN  
> 3.0 – 10 x 
ULN  
> 10 x ULN  

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 53 of 54 
Serum *  
Mild  
(Grade 1)  
Moderate  
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4) ** 
Liver Function Tests –
ALT, AST increase by 
factor  
1.1 – 2.5 x 
ULN  
> 2.6 – 5.0 x 
ULN  
> 5.1 – 10 x 
ULN  
> 10 x ULN  
Bilirubin – when 
accompanied by any 
increase in Liver Function 
Test  
increase by factor  
1.1 – 1.25 x 
ULN  
> 1.26 – 1.5 x 
ULN  
> 1.51 – 
1.75 x ULN  
> 1.75 x ULN  
Bilirubin – when Liver 
Function Test is normal; 
increase by factor  
1.1 – 1.5 x 
ULN  
1.6 – 2.0 x 
ULN  
2.0 – 3.0 x 
ULN  
> 3.0 x ULN  
Cholesterol  
201 – 210  
211 – 225  
> 226  
---  
Pancreatic enzymes – 
amylase, lipase  
1.1 – 1.5 x 
ULN  
1.6 – 2.0 x 
ULN  
2.1 – 5.0 x 
ULN  
> 5.0 x ULN  
* The laboratory values provided in the tables serve as guidelines and are dependent upon 
institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in 
characterization of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For 
example, a low sodium value that falls within a Grade 3 parameter (125-129 mE/L) should be 
recorded as a Grade 4 hyponatremia event if the subject had a new seizure associated with the 
low sodium value. 
***ULN” is the upper limit of the normal range. 
 
 
 

PRODUCT: VRC-FLUNPF099-00-VP 
PROTOCOL: VRC 321, VERSION 3.0 
PROTOCOL DATE: APRIL 20, 2020 
Page 54 of 54 
Hematology *  
Mild  
(Grade 1)  
Moderate  
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life  
Threatening 
(Grade 4)  
Hemoglobin (Female) - 
gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0  
Hemoglobin (Female)  
decrease from baseline 
value - gm/dL  
not 
applicable 
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
Hemoglobin (Male) - 
gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
< 8.5  
Hemoglobin (Male)  
decrease from baseline 
value – gm/dL  
not 
applicable  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
WBC Increase - cell/mm
3 
10,800 – 
15,000  
15,001 – 
20,000  
20,001 – 25, 
000  
> 25,000  
WBC Decrease - cell/mm
3 
2,500 – 
3,500  
1,500 – 2,499  
1,000 – 
1,499  
< 1,000  
Lymphocytes Decrease - 
cell/mm
3 
750 – 1,000  500 – 749  
250 – 499  
< 250  
Neutrophils Decrease - 
cell/mm
3 
1,500 – 
2,000  
1,000 – 1,499  
500 – 999  
< 500  
Eosinophils - cell/mm
3 
650 – 1500  
1501 - 5000  
> 5000  
Hypereosinophilic  
Platelets Decreased - 
cell/mm
3 
125,000 – 
140,000  
100,000 – 
124,000  
25,000 – 
99,000  
< 25,000  
PT – increase by factor  
(prothrombin time)  
1.10 x 
ULN**  
> 1.11 – 1.20 x 
ULN  
1.21 – 1.25 
x ULN  
> 1.25 ULN  
PTT – increase by factor 
(partial thromboplastin 
time)  
1.10 – 1.20 
x ULN  
1.21 – 1.4 x 
ULN  
1.4 – 1.5 x 
ULN  
> 1.5 x ULN  
Fibrinogen increase - 
mg/dL  
400 – 500  
501 – 600  
> 600  
--  
Fibrinogen decrease - 
mg/dL  
150 – 200  
125 – 149  
100 – 124  
< 100 or 
associated with 
gross bleeding  
or disseminated 
intravascular 
coagulation (DIC)  
* The laboratory values provided in the tables serve as guidelines and are dependent upon 
institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate. 
**ULN” is the upper limit of the normal range. 

PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/20/2020
Page 1 of 14
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Alicia Widge, MD, MS
STUDY TITLE: VRC 321: A Phase I Open-Label Clinical Trial to Evaluate Dose, Safety, 
Tolerability, and Immunogenicity of an Influenza H1 Stabilized Stem Ferritin Vaccine, 
VRCFLUNPF099-00-VP, in Healthy Adults
STUDY SITE: NIAID/VRC
Cohort: Healthy volunteer
Consent Version:  3.0, April 20, 2020
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: Alicia Widge, MD, MS; 301-761-7968; alicia.widge@nih.gov 
Study Coordinator: Floreliz Mendoza, RN; 301-451-8715; mendozaf@mail.nih.gov
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
This is the first study in people of this experimental vaccine for prevention of H1 influenza (flu). 
“Experimental” means that the study vaccine has not been approved by the Food and Drug 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/20/2020
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CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Administration (FDA). The FDA allows this vaccine to be used for research purposes only. We do 
not know if this vaccine works. The main purpose of this study is to see if the experimental vaccine 
is safe and if there are any side effects. We also want to study immune responses to this vaccine.
STUDY VACCINE
Vaccines are given to teach the body to prevent or fight an infection. In this study, we are testing 
one experimental vaccine that was developed by the Vaccine Research Center (VRC) at the NIH: 
H1 Stabilized Stem Ferritin vaccine, VRC-FLUNPF099-00-VP. In this consent form, the study 
vaccine will be called the “H1 Ferritin vaccine.”
This vaccine is intended to help the body to make an immune response to H1 flu, which is a strain 
of flu that infects humans.
Most vaccines are made of proteins that are injected into a muscle. Proteins are natural substances 
that the body uses as building blocks. This vaccine is made in the laboratory with two proteins: 
one protein from the H1 flu virus and one protein from a type of bacteria called Helicobacter pylori 
(H. pylori). These two proteins have been modified in the laboratory. When combined, they make 
a particle that looks like the outside of the H1 flu virus. The body’s immune system may respond 
to this particle. There is no virus or bacteria in the vaccine, so you cannot get an H1 flu infection 
or H. pylori infection from this vaccine.
We do not know if the H1 Ferritin vaccine will protect you from flu. 
ELIGIBILITY
You are eligible to take part in this study because you have completed the screening process and 
are:

18-70 years old

In general good health without significant medical problems as determined at screening

Willing to get the experimental vaccine

Willing to donate blood samples for future research

Willing to use birth control from at least 21 days prior to enrollment through the end of 
the study, if female and able to become pregnant

Must have received a licensed influenza (flu) vaccine at least once since January 1, 2014.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/20/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
STUDY PLAN
About 53 people will take part in this study at the NIH Clinical Center in Bethesda, MD. 
If you are enrolled in Group 1, you will get one vaccination and remain in the study for about one 
year. 
If you are enrolled in Groups 2A, Group 2B, Group 2C, or Group 2D you will get two vaccinations 
and remain in the study for about one year and three months.
You will get the experimental vaccine by injections (shots) in the upper arm muscle. This is called 
an intramuscular “IM” injection. We will use a needle and syringe to give you the H1 Ferritin 
vaccine. We will check you for any side effects from the vaccine. 
We will tell you if we learn anything new during this study that might cause you to change your 
mind about staying in the study. At the end of the study, we will tell you when study results may 
be available and how to learn about them.
There will be two different doses of vaccine given in this study, a lower dose (20 mcg) and a higher 
dose (60 mcg).
Group 1 will get the lower dose of the H1 Ferritin vaccine one time on the day of enrollment. If 
there are no safety concerns at this dose after 2 weeks of follow-up, we will start enrolling people 
to get the higher dose.
Groups 2A, 2B, 2C, 2D will get the higher dose of the H1 Ferritin vaccine on the day of the 
enrollment and about 4 months later (week 16). Groups are based on age. This is done so that 
researchers may compare the immune response of people of different ages. 
The table below shows the study plan: 
Group
Age 
Subjects
Day 0
Week 16  
1
18-40
5
20 mcg
2A
18-40
12
60 mcg
60 mcg
2B
41-49
12
60 mcg
60 mcg
2C
50-59
12
60 mcg
60 mcg
2D
60-70
12
60 mcg
60 mcg
Total
53
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/20/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
STUDY PROCEDURES
If you agree to take part in the study and are enrolled in:
Group 1: you will have 1 vaccination visit, 1 phone follow-up, and 9 follow-up clinic visits. 
Groups 2A, 2B, 2C, 2D: you will have 2 vaccination visits, a phone follow-up after each 
vaccination, and 11 follow-up clinic visits.
If you are a woman who can get pregnant, we will do a pregnancy test before each injection. The 
test must show that you are not pregnant before you can get the injection.
Each vaccination visit will take about 4 to 6 hours. Most follow-up clinic visits will take about 1 
to 2 hours; the optional apheresis visit will take 2 to 4 hours.
If you are enrolled in Group 1 you will need to stay in the clinic for at least 1 hour after your 
vaccination. If you are enrolled in Group 2A, 2B, 2C, or 2D, you will need to stay in the clinic for 
at least 30 minutes after each vaccination. 
After each vaccination, the clinic staff will call to check on you. Also, after each vaccination, you 
will need to complete a diary card for 7 days. The purpose of the diary card is to record any 
symptoms that you may have for data analysis and not because of any risk of getting the flu from 
this vaccine. We will give you a thermometer to record your temperature even if you feel well. We 
will also give you a ruler to measure any skin changes at the injection site.  You will get a password 
to a secure website where you can enter this data online. If you do not have access to the internet, 
you can use a paper diary card instead.
If you have any symptoms or feel unwell, you should tell a clinic nurse or doctor as soon as 
possible. You can reach the staff by phone 24 hours a day. If you have symptoms, you may be 
asked to come to the clinic for a checkup. It is very important that you follow the instructions from 
the clinic staff. 
At each visit, we will check you for any health changes or problems. We will ask you how you are 
feeling and if you have taken any new medications. We will draw your blood at each visit, taking 
about 6 to 14 tubes of blood per visit. We will tell you right away if any of your test results show 
a health problem. Some blood samples will be used for research only so that we can study your 
immune response to the vaccine. Results of these research tests are not used to check your health 
and will not be given to you.
Mucosal Swab: It is very important to report symptoms including fever of 1000 F or higher, runny 
nose, sore throat, headache, feeling more tired than usual or muscle aches. This group of symptoms 
may be the flu or a flu-like illness. You will need to come to the clinic so that we can do a nose 
and throat swab. We will use a thin disposable swab to collect this sample. Each swab is new and 
sterile and is safe for use in sensitive parts of the body.
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Consent to Participate in a Clinical Research Study
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Apheresis: For subjects enrolled in Group 2A, Group 2B, Group 2C, and Group 2D, after your 
last study injection, we would like to collect your blood by a method called “apheresis.” This 
procedure is optional and choosing not to take part in it will not affect your study participation.
To be eligible for apheresis:

You must not have an unstable heart as indicated by your medical history and test results

You must not have blood pressure greater than 180/100

You must not have a known blood clotting disorder

You must not be pregnant or breast feeding

You must not have a condition that the attending physician or the apheresis clinic staff 
considers a reason to not do an apheresis procedure.
Before apheresis, we will check your weight, pulse and blood pressure. We will ask questions 
about your general health and medical history.  If you are a woman who can get pregnant, we will 
do a pregnancy test before the apheresis procedure. The test must show that you are not pregnant.
During the procedure, you will lie on a recliner, couch, or hospital bed. The procedure requires 
that a needle be placed into a vein in both arms using a sterile method. The kits used to collect 
apheresis samples are sterile, single-use, disposable sets that are not in contact with any person’s 
bodily fluids other than yours. No blood products are given to you during these procedures. The 
apheresis is done at the NIH Clinical Center, and a physician from the NIH Department of 
Transfusion Medicine will be available in or near the apheresis area at all times.
In the apheresis procedure, blood is removed through a needle in the vein of one arm, spun in a 
machine that separates the desired blood components (white blood cells) and then the rest of your 
blood is returned to you through a needle in the other arm. Citrate, a medication to prevent blood 
from clotting, is added to the blood while in the machine to prevent it from clotting.
The purpose of this procedure is to allow us to get and study a larger number of white blood cells 
that cannot be collected by simple blood drawing. The number of white blood cells collected is a 
small fraction of the total amount in your body. The body quickly replaces cells that have been 
removed. The Blood Bank of the NIH Clinical Center and other blood banks use similar procedures 
every day to collect blood samples from donors and as a form of therapy for some diseases. 
However, we will not use your samples for transfusion or therapy. The procedure will take 
approximately 1-3 hours.
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Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
MONITORING OF THE STUDY
This study will be monitored by a group of physicians and scientists at NIH. This group will review 
the study information and will pay close attention to any reactions. If there are serious side effects, 
study injections may be delayed or canceled.
GENETIC TESTING
Some of the blood drawn from you during this study will be used for genetic tests. Some genetic 
tests are done in research studies to see if genetic differences in people cause different types of 
immune responses. Your blood sample used in these genetic tests will not have your name on it 
and the results will not be in your medical record except for Human Leukocyte Antigen (HLA) 
typing results. These tests are not used to check your health and we will not tell you the results. 
A special genetic test, called HLA typing, is done by the NIH Clinical Center medical laboratory. 
These results will be in your medical record, but they will not be used to check your health. Any 
genetic testing, including HLA testing, is for research purposes only. Any genetic information 
collected or learned about you will be kept confidential. Medical records, including HLA test 
results are kept securely. We will not give any genetic information that is in your medical record 
to anyone without your permission.
STORED SAMPLES
We will collect blood samples from you during the study. We will keep these samples for future 
research indefinitely to learn more about flu virus, vaccines, the immune system, and other 
research questions. Results from research with your samples will not be in your medical record or 
reported to you.
Labeling of Stored Samples: Your stored samples will be labeled by a special code or number 
and not your personal information. Only the study team can link this code to you. Any identifying 
information about you (like name or date of birth) will be kept as confidential as allowable by law.
Risks of Stored Samples: There is a risk of unplanned release of information from your medical 
record. The chance that this information will be given to an unauthorized person without your 
permission is very small. Possible problems with the unplanned release of information include 
discrimination when applying for insurance or employment. Similar problems may occur if you 
give information about yourself or agree to have your medical record released.
Future studies: In the future, other investigators at NIH or outside of NIH may wish to study your 
stored samples. When your stored samples are shared, they will be marked with a code. Your 
samples will not have any identifying information on them. Some information about you, like your 
gender, age, health history, or ethnicity may be shared with other researchers. Any future research 
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
studies using your samples will be conducted in a way that protects the rights and privacy of study 
participants.
Your stored samples will only be used for research and will not be sold. The research done with 
your materials may be used to develop new products in the future, but you will not receive payment 
for such products.
Making your Choice: You cannot take part in this study if you do not want us to collect or store 
your blood samples. If you agree to take part in this study, you must also agree to let us keep any 
of your samples and data for future research.
If you decide not to take part in this study, you may still take part in other studies at NIH.
POSSIBLE STUDY RISKS
Possible risks of injections: Temporary stinging, pain, redness, soreness, itchiness, swelling, or 
bruising. 
Possible risks of any vaccine: Fever, chills, rash, aches and pains, nausea, headache, dizziness, 
and feeling tired and/or unwell. These types of reactions are usually greatest within the first 24 
hours after vaccination and typically last 1 to 3 days. Over-the-counter medicine, like 
acetaminophen (Tylenol) or ibuprofen, may be used to help these symptoms. 
Very rarely, a serious allergic reaction with symptoms like hives, trouble breathing, or sudden 
weakness may occur shortly after any vaccination. This is called “anaphylaxis” and may be life-
threatening. While you are waiting in the clinic after the vaccination, we will monitor you for 
anaphylaxis. Treatment for anaphylaxis will be given right away if it occurs.
Possible risks of the H1 Ferritin vaccine: The H1 Ferritin vaccine has not been given to people 
before. It may have unknown risks. It has been tested in mice and rabbits. The vaccine did not 
cause any unusual side effects and met the safety criteria to be tested in humans.
Possible risks of blood drawing: Pain, bleeding, bruising, feeling lightheaded, and fainting. 
Rarely, infection may occur at the site where the blood is taken.
Possible risks of mucosal sample collection: Samples collected by rubbing swabs over mucosal 
surfaces in the mouth or in the nose can cause brief discomfort, or a little bleeding.
Possible risks of apheresis: Apheresis is generally safe and side effects are rare. Pain, bruising or 
discomfort at the needle placement site may occur. Sometimes apheresis causes a tingling 
sensation around the lips, nose and mouth, coolness all over and slight nausea. This can usually be 
relieved by slowing or temporarily stopping the apheresis or taking an antacid with calcium pill, 
like Tums®. Other possible side effects are anxiety, vomiting and lightheadedness. Temporary 
lowering of the blood pressure may develop. There is the rare possibility of infection, fainting or 
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
seizure. Very rarely a nerve problem at the needle placement site may occur. Also, very rarely, a 
machine malfunction may occur and result in the loss of about one unit (one pint) of blood.
There are theoretical risks from re-infusion of the blood after processing by the machine such as 
infection or an adverse reaction to the blood components. However, this has not been seen in many 
thousands of volunteers who have undergone this or similar procedures to date. There may be other 
risks of apheresis that are unknown at this time.
Unknown safety risks: There may be side effects from the study vaccines - even serious or life-
threatening ones- that we do not yet know about. Please tell the study staff about any side effect 
you think you are having. This is important for your safety.
Possible risks of genetic testing: Unplanned release of information that could be used by insurers 
or employers to discriminate against you or your family; discovering a gene that suggests risk of 
disease for you or your family; discovering unknown family relationships.
Possible risks of data sharing:  Information in the shared databases could be linked back to you 
and used to discriminate against you or your family.  State and federal laws provide some 
protections against genetic and pre-existing conditions discrimination.
Possible risks during pregnancy: We do not know how the experimental vaccines may affect a 
fetus or nursing infant. Therefore, women who can become pregnant must have a negative 
pregnancy test before each injection and agree to use effective birth control beginning at least 21 
days before the first injection until the end of the study. We will discuss effective methods of birth 
control with you. 
You must tell the clinic staff right away if you become pregnant or think that you might be pregnant 
during the study. If you are pregnant, you will not get any more vaccinations. You will be asked 
to continue with follow-up visits so that we can check your health. We will ask you the outcome 
of the pregnancy.
Possible other risks: We do not know if the study vaccine will change how your body responds 
to flu virus infections in the future.
You may not donate blood at a blood bank while taking part in this study. You may not donate 
blood for one year after the last experimental vaccine injection.
POSSIBLE BENEFITS
This study is not designed to benefit you. We do not know if the vaccines will work. The study is 
not designed to protect you from flu. You and others may benefit in the future from the information 
that will be learned from the study. The study visits are used to check your health for research 
purposes, not to provide health care. However, we will tell you right away if any of your test results 
show a possible health problem.
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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/20/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
REASONS FOR STOPPING STUDY INJECTIONS
You may not get all of your planned study vaccinations. Reasons for this may include:
You don’t keep appointments or follow procedures
You get a serious illness that needs ongoing medical care.
You have a serious side effect, thought to be due to the study vaccine.
You become pregnant.
You need to get treatment with a medication that affects your immune system (such as 
a steroid like prednisone).
The study is stopped by regulatory agencies, the study sponsor or study investigators. 
If this happens, we will tell you why.
If you agree to take part in this study, it is important for you to keep all of your appointments. Your 
participation in this study is completely voluntary. You can choose to stop taking part in the study 
at any time. There is no penalty or loss of benefits if you choose to leave the study.
If you are not able to get the second injection (for Groups 2A, Group 2B, Group 2C, and Group 
2D), we will adjust your schedule but will ask that you still have study visits. It is important that 
we continue to check your health even if you do not get a second injection.
ALTERNATIVES
This study is not designed to treat or prevent any disease. You may choose to not take part in this 
study. You may be eligible for other studies. 
CONFLICT OF INTEREST
The NIH research staff is checked yearly for conflicts of interest. You may ask the research team 
for more information. This study may have investigators who are not NIH employees. Non-NIH 
investigators are expected to follow the principles of the Protocol Review Guide but are not 
required to report their personal financial holdings to the NIH. 
The NIH, including some members of the VRC scientific staff, developed the investigational 
vaccines being used in this research study. The results of this study could play a role in whether 
the FDA will approve the vaccine for sale at some time in the future. If approved, the future sale 
of the vaccine could lead to payments to NIH and some NIH scientists. By U.S. law, government 
scientists are required to receive such payments for their inventions. You will not get any money 
from the development or sale of the product. 
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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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Version Date: 04/20/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will be compensated for your time and inconvenience by the NIH Clinical Research Volunteer 
Program. It is possible that you may have some expenses that are not covered by the compensation 
provided.
The compensation is $275 for each vaccination visit. You will get $25 total for the timely 
completion of all 7 days of an electronic diary. You will get $175 for each scheduled follow-up 
visit that includes a research blood draw. You will get $75 for all other clinic visits that do not 
include research blood draws or mucosal sample collection. You will get $250 for apheresis 
procedure. You will get an additional $50 for any visit that also includes a nose and throat swab.
If you are enrolled in Group 1, the total compensation for completion of all study visits is about 
$1,875.
If you are enrolled in Groups 2A, 2B, 2C, or 2D, the total compensation for completion of all study 
visits is about $2,525 without apheresis and about $2,600 with apheresis.
If you are unable to finish the study, you will receive compensation for the visits and for the parts 
you completed.  
With few exceptions, study compensation is considered taxable income that is reportable to the 
Internal Revenue Service (IRS). A “Form 1099-Other Income” will be sent to you if your total 
payments for research participation are $600 or more in a calendar year. If you have unpaid debt 
to the federal government, please be aware that some or all of your compensation may be 
automatically reduced to repay that debt on your behalf.
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
This study does not offer reimbursement for, or payment of, travel, lodging or meals. 
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
There are no costs to you for taking part in this study. We will not charge you or your insurance 
carrier for any health evaluations or services. You or your health insurance will have to pay for all 
costs for medical care that you get outside this study. It is possible that you may have some costs 
that are not covered by the study compensation we give you.
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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
HUMAN DATA SHARING
To advance science, it is helpful for researchers to share information they get from studying 
humans by putting it into shared scientific databases. Researchers can then study the information 
combined from many studies to learn even more about health and diseases.
If you agree to take part in this study, some of your data will be put into one or more scientific 
databases. We will remove identifying information like your name, address, and birth date. The 
data may then be used for future research and shared broadly for research purposes.
Only researchers who are approved to access the database may be able to see and use your 
information. You will not get any direct benefits from future research that uses your data and 
information.
You may stop participating in this study at any time and withdraw permission for your individual 
data, specimens, and health information to be used for additional or future research. You may ask 
to have your research data destroyed. However, it may not be possible to withdraw or delete data 
once they have been shared with other researchers.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor VRC or their agent(s) 
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
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NIH-2977 (4-17)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Alicia Widge, 
M.D., MS alicia.widge@nih.gov 301-761-7968. Other researchers you may call are: [Floreliz 
Mendoza, RN, at 301-451-8715. You may also call the NIH Clinical Center Patient Representative 
at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you have a research-
related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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Consent to Participate in a Clinical Research Study
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Alicia Widge, MD, MS
STUDY TITLE:  VRC 321: A Phase I Open-Label Clinical Trial to Evaluate Dose, Safety, 
Tolerability, and Immunogenicity of an Influenza H1 Stabilized Stem Ferritin Vaccine, 
VRCFLUNPF099-00-VP, in Healthy Adults
STUDY SITE:  NIAID/VRC
Cohort: Healthy volunteer 
Supplementary Consent Version:  3.0, April 20, 2020
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: Alicia Widge, MD, MS:
Study Coordinator: Floreliz Mendoza, RN;
Supplementary consent for extended genetic testing (optional)
You agreed to participate in VRC 321 study for testing of an investigational vaccine to prevent H1 
influenza (flu) virus infection. This additional consent covers optional genetic testing that you may 
agree to. If you do not agree to this additional testing, you still can participate in the VRC 321 
study.
There is a new type of genetic test that lets us look at the expressions of genes, called transcriptome 
sequencing. This test lets us look at the genes that are actively expressed at any given moment. 
However, it does not measure the amount of protein produced. Also, this new genetic test is still 
in development and researchers are working on understanding the data and how that data can be 
utilized in various clinical applications, such as in medicine to help prevent disease. 
This test may take a long time to understand, and we may not have any news to give you about it. 
Since we are looking for genes that control infection or immune response, we will not report to 
you or your doctors anything that we find that is not related to infection or immunity. However, if 
we find something in your DNA that we think is urgent to deal with because of your health, we 
will confirm the result and then tell you about it. We think this sort of problem will be very rare.
Genetic Data Sharing
Following genetic testing for transcriptome sequencing, your sequence data may be shared in a 
controlled access public database, for other investigators to benefit from it. However, no personal, 
identifiable information will be shared in this process, as the shared results will be coded with no 
link back to you.
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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act.  In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your record without your permission, for example, if it is 
requested by Congress. Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting,  to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 04/20/2020
Page 3 of 4
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Alicia Widge, 
M.D., MS alicia.widge@nih.gov 
 Another researcher you may call is: Floreliz 
Mendoza, RN, at
  You may also call the NIH Clinical Center Patient Representative 
at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you have a research-
related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 04/20/2020
Page 4 of 4
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process with a non-English speaking subject and this English consent form has been approved 
by the IRB for use as the basis of translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
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