VRC 317: A Phase I Randomized, Open-Label Clinical Trial to Evaluate Dose, Safety, Tolerability and Immunogenicity of a Stabilized Prefusion RSV F Subunit Protein Vaccine, VRC-RSVRGP084-00-VP (DS-Cav1), Alone or With Alum Adjuvant, in Healthy Adults
Phase: PHASE1
Conditions: Respiratory Syncytial Virus
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Official Title: A Phase I Randomized, Open-Label Clinical Trial to Evaluate Dose, Safety,
Tolerability and Immunogenicity of a Stabilized Prefusion RSV F Subunit Protein
Vaccine, VRC-RSVRGP084-00-VP (DS-Cav1), Alone or with Alum Adjuvant in
Healthy Adults
ClinicalTrials.gov Identifier: NCT03049488
Document Type:
• 
Redacted Final Version of the Study Protocol (Statistical Analysis Considerations located in
Section 6 of the Protocol)
• 
Redacted Final Version of IRB-approved Informed Consent
Document/Date:
• 
Protocol Version 7.0: August 23, 2019
• 
Version 7.0 IRB-approved Informed Consent: September 9, 2019

 
 
 
 
VACCINE RESEARCH CENTER 
 
Protocol VRC 317 
(NIH 17-I-0058) 
 
A PHASE I RANDOMIZED, OPEN-LABEL CLINICAL TRIAL TO EVALUATE DOSE, 
SAFETY, TOLERABILITY AND IMMUNOGENICITY OF A STABILIZED PREFUSION 
RSV F SUBUNIT PROTEIN VACCINE, VRC-RSVRGP084-00-VP (DS-CAV1), 
ALONE OR WITH ALUM ADJUVANT, IN HEALTHY ADULTS  
 
Vaccine Provided by: 
National Institute of Allergy and Infectious Diseases  
Vaccine Research Center  
Bethesda, Maryland 
Clinical Trial Sponsored by: 
National Institute of Allergy and Infectious Diseases  
Vaccine Research Center  
Bethesda, Maryland 
IND Sponsored by: 
National Institute of Allergy and Infectious Diseases  
Vaccine Research Center  
Bethesda, Maryland 
 
IND 17256 - held by VRC 
 
 
 
Principal Investigator: 
Grace Chen, MD, MPH 
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
Bethesda, MD 20892 
IRB Initial Review Date:  December 5, 2016 
 
Version 7.0 
August 23, 2019 

Product: VRC-RSVRGP084-00-VP 
 
Protocol VRC 317, Version 7.0 
 August 23, 2019 
 
TABLE OF CONTENTS 
 
ABBREVIATIONS .........................................................................................................................6
PRÉCIS 
 ......................................................................................................................................8
1.
INTRODUCTION ........................................................................................................9
1.1.
Rationale for Evaluation of DS-Cav1 .........................................................................10
1.2.
Rationale for Use of Aluminum–Based Adjuvant ......................................................11
1.3.
Previous Human Experience .......................................................................................11
1.4.
Assessment of Immunogenicity ..................................................................................12
2.
STUDY PRODUCTS .................................................................................................12
2.1.
VRC-RSVRGP084-00-VP .........................................................................................13
2.2.
Aluminum Hydroxide Suspension - Adjuvant ...........................................................13
2.3.
Preclinical Toxicology Studies of VRC-RSVRGP084-00-VP ...................................13
3.
STUDY OBJECTIVES ..............................................................................................13
3.1.
Primary Objectives .....................................................................................................13
3.2.
Secondary Objectives .................................................................................................13
3.3.
Exploratory Objectives ...............................................................................................13
4.
STUDY DESIGN AND CLINICAL PROCEDURES ...............................................14
4.1.
Eligibility Criteria .......................................................................................................15
4.1.1.
Inclusion Criteria ........................................................................................................15
4.1.2.
Exclusion Criteria .......................................................................................................15
4.2.
Clinical Procedures and Evaluations ..........................................................................16
4.2.1.
Screening ....................................................................................................................17
4.2.2.
Enrollment ..................................................................................................................17
4.2.3.
Product Administration ...............................................................................................17
4.2.4.
Post-Injection Follow-Up and Diary Card ..................................................................18
4.2.5.
Follow-Up through End of Study ...............................................................................18
4.2.6.
Concomitant Medications ...........................................................................................19
4.3.
Dose Continuation and Dose Escalation Plans ...........................................................19
4.4.
Criteria for Discontinuing Subject Participation ........................................................20
4.4.1.
Discontinuation from Study Injections .......................................................................20
4.4.2.
Discontinuation from Protocol Participation ..............................................................21
4.5.
Criteria for Pausing and Resuming the Study .............................................................21

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4.5.1.
Criteria for Pausing the Study.....................................................................................21
4.5.2.
Plan for Review of Pauses and Resuming Rules ........................................................21
5.
SAFETY AND ADVERSE EVENTS ........................................................................21
5.1.
Adverse Events ...........................................................................................................21
5.2.
Serious Adverse Events ..............................................................................................22
5.2.1.
Serious Adverse Event Definition ..............................................................................22
5.2.2.
Reporting Serious Adverse Events to the IND Sponsor .............................................22
5.2.3.
IND Sponsor Reporting to the FDA ...........................................................................23
5.3.
Reporting to the Institutional Review Board ..............................................................23
5.3.1.
Unanticipated Problem ...............................................................................................23
5.3.2.
Non-Compliance .........................................................................................................24
5.3.3.
Protocol Deviation ......................................................................................................24
5.3.4.
Death ...........................................................................................................................25
5.3.5.
New Information .........................................................................................................25
5.3.6.
Suspension or Termination of Research Activities ....................................................25
5.3.7.
Expedited Reporting to the IRB .................................................................................25
5.3.8.
Annual Reporting to the NIAID IRB ..........................................................................26
6.
STATISTICAL CONSIDERATIONS AND SAMPLE ANALYSIS ........................26
6.1.
Overview .....................................................................................................................26
6.2.
Endpoints ....................................................................................................................26
6.2.1.
Primary Endpoints: Safety ..........................................................................................26
6.2.2.
Secondary Endpoints: Immunogenicity ......................................................................27
6.2.3.
Exploratory Endpoints ................................................................................................27
6.3.
Sample Size and Accrual ............................................................................................27
6.3.1.
Power Calculations for Evaluation of Safety ..............................................................27
6.3.2.
Power Calculations for Evaluation of Immunogenicity .............................................28
6.4.
Statistical Analysis ......................................................................................................28
6.4.1.
Baseline Demographics ..............................................................................................28
6.4.2.
Safety Analysis ...........................................................................................................28
6.4.3.
Analysis of Immune Responses ..................................................................................28
6.4.4.
Missing Data ...............................................................................................................29
6.4.5.
Interim Analyses .........................................................................................................29
6.4.6.
Randomization of Treatment Assignments ................................................................29

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7.
PHARMACY PROCEDURES ...................................................................................29
7.1.
Study Products ............................................................................................................29
7.2.
Study Product Presentation and Storage .....................................................................30
7.2.1.
Labels ..........................................................................................................................30
7.2.2.
Storage ........................................................................................................................30
7.3.
Preparation of Study Products for Administration .....................................................31
7.3.1.
Preparation of VRC-RSVRGP084-00-VP (non-adjuvanted) .....................................31
7.3.2.
Preparation of VRC-RSVRGP084-00-VP with Adjuvant ..........................................32
7.4.
Study Product Administration ....................................................................................33
7.5.
Study Product Accountability .....................................................................................33
7.5.1.
Documentation ............................................................................................................33
7.5.2.
Disposition ..................................................................................................................33
8.
HUMAN SUBJECTS PROTECTION .......................................................................33
8.1.
Institutional Review Board .........................................................................................33
8.2.
Subject Recruitment and Enrollment ..........................................................................34
8.2.1.
Participation of Children .............................................................................................34
8.2.2.
Participation of Site Employees ..................................................................................34
8.3.
Informed Consent .......................................................................................................34
8.4.
Subject Confidentiality ...............................................................................................35
8.5.
Risks and Benefits ......................................................................................................35
8.5.1.
Risks ...........................................................................................................................35
8.6.
Plan for Use and Storage of Biological Samples ........................................................36
8.6.1.
Use of Samples, Specimens and Data .........................................................................36
8.6.2.
Storage and Tracking of Blood Samples and Other Specimens .................................36
8.6.3.
Disposition of Samples, Specimens and Data at Completion of the Protocol ............36
8.6.4.
Loss or Destruction of Samples, Specimens or Data ..................................................37
8.7.
Compensation .............................................................................................................37
8.8.
Safety Monitoring .......................................................................................................37
8.8.1.
Protocol Safety Review Team ....................................................................................37
9.
ADMINISTRATION AND LEGAL OBLIGATIONS ..............................................38
9.1.
Protocol Amendments and Termination .....................................................................38
9.2.
Study Documentation and Study Records Retention ..................................................38
9.3.
Data Collection, Data Sharing, and Protocol Monitoring ...........................................38

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9.3.1.
Data Collection ...........................................................................................................38
9.3.2.
Data Sharing Plan .......................................................................................................39
9.3.3.
Source Documents ......................................................................................................39
9.3.4.
Protocol Monitoring ....................................................................................................39
9.4.
Language .....................................................................................................................39
9.5.
Policy Regarding Research-Related Injuries ..............................................................39
10.
REFERENCES ...........................................................................................................40
APPENDIX I:
INFORMED CONSENT FORM ........................................................................44
APPENDIX II:
CONTACT INFORMATION ...........................................................................45
APPENDIX III:
SCHEDULE OF EVALUATIONS ..................................................................48
APPENDIX IV:
ASSESSMENT OF RELATIONSHIP TO VACCINE AND 
ADVERSE EVENT SEVERITY GRADING ............................................................50
 
LIST OF TABLES 
Table 1:  
VRC 317 Study Schema .............................................................................................14
Table 2:  
Probability of Observing Adverse Events ..................................................................27
 
 

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ABBREVIATIONS 
Abbreviation 
Term 
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase 
AoU
assessment of understanding
AST
aspartate aminotransferase
β-HCG 
human chorionic gonadotropin 
Cav
Cavity Filling Variant of RSV F protein 
CBC
complete blood count
CDC 
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
cGMP 
Current Good Manufacturing Practices 
CHIKV 
chikungunya virus
CI 
confidence interval
CMV
cytomegalovirus 
CRO 
contract research organization 
DENV
dengue virus
DNA
deoxyribonucleic acid
DS-Cav1 
Disulfide Bond, Cavity-Filling (Variant Molecule) 1 of RSV F 
protein
EDTA
ethylenediaminetetraacetate
ELISA 
enzyme-linked immunosorbent assay
ELISpot assay
enzyme-linked immunospot assay
F
fusion protein 
FDA
Food and Drug Administration 
G 
glycoprotein
GCP
Good Clinical Practices 
GLP
Good Laboratory Practices 
HIV 
human immunodeficiency virus
HLA 
human leukocyte antigen
HRPP
Human Research Protections Program
IB 
Investigator’s Brochure  
ICF 
informed consent form 
ICH
International Conference on Harmonisation
ICS 
intracellular cytokine staining
IM 
intramuscular
IND 
Investigational New Drug
IRB
Institutional Review Board
mAb
monoclonal antibody
mcg
microgram
MedDRA® 
Medical Dictionary for Regulatory Activities
mL
milliliter 
N 
nucleoprotein

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Abbreviation 
Term 
NHP
nonhuman primate
NIAID 
National Institute of Allergy and Infectious Diseases
NIH 
National Institutes of Health
NIH CC 
National Institutes of Health Clinical Center
NVITAL
NIAID Vaccine Immune T-Cell and Antibody Laboratory
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
PI
Principal Investigator
PSRT
Protocol Safety Review Team
RSV
Respiratory syncytial virus
SAE
serious adverse event
SARS
Severe acute respiratory syndrome 
SH 
small hydrophobic protein 
SST
serum separator tube
TCR
tissue cross reactivity
ULN 
upper limit of normal
UP 
unanticipated problem 
VE
vaccine efficacy
VIP
Vaccine Immunology Program
VITL
Vaccine Immunology Testing Laboratory
VLP
virus-like particle
VRC 
Vaccine Research Center
WBC
white blood cell
WHO
World Health Organization
 
 

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PRÉCIS 
Study Title: 
A Phase I Randomized, Open-Label Clinical Trial to Evaluate Dose, Safety, 
Tolerability and Immunogenicity of a Stabilized Prefusion RSV F Subunit Protein 
Vaccine, VRC-RSVRGP084-00-VP (DS-Cav1), Alone or with Alum Adjuvant 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-RSVRGP084-00-VP alone or with alum 
adjuvant in a 2-injection regimen.  The hypotheses are that the vaccine will be safe and 
tolerable for human administration, and will induce detectable immune response.  The 
primary objective is to evaluate the safety and tolerability of the investigational vaccine 
at 3 dose levels administered alone or with alum adjuvant as a homologous boost in 
healthy adults.  Secondary objectives relate to humoral and cellular immunogenicity of 
the investigational vaccine regimen. 
Product  
Description: 
VRC-RSVRGP084-00-VP (DS-Cav1) was developed by VRC, NIAID and is 
composed of the respiratory syncytial virus (RSV) fusion (F) glycoprotein ectodomain 
assembled as a trimer stabilized in its prefusion native conformation with a foldon 
trimerization domain at the C-terminus and 4 internal mutations designated DS-Cav1 
(4.1DHFR_RSVAF).  The sequence is based on the RSV A2 strain from subtype A.  
The product is provided at a concentration of 0.5 mg/mL in 3 mL glass vials filled to 
1.2 mL.  
Adjuvant is an aluminum hydroxide suspension (alum) provided in a sterile, pyrogen-
free suspension at a concentration of 5 mg/mL in 3 mL glass vials filled to 0.7 ± 0.10 
mL.  The alum dose is 500 mcg and will be field mixed.  
Subjects: 
Healthy adult subjects ages 18-50. 
Study Plan: 
Subject will be randomized into DS-Cav1 or DS-Cav1 plus alum in each dose during 
the study.  Dose continuation and dose escalation evaluations will occur to ensure the 
safety data support proceeding to the higher doses.  Subjects will be evaluated for 
safety and immune responses through blood and mucosal sample collection at specified 
timepoints throughout the study.  The study schema is below: 
VRC 317 Study Schema 
Group 
Subjects 
Dose 
Day 0 
Week 12[1] 
1 
15 
50 mcg 
DS-Cav1 
DS-Cav1 
2 
15 
DS-Cav1 + alum 
DS-Cav1 + alum 
3 
15 
150 mcg 
DS-Cav1 
DS-Cav1 
4 
15 
DS-Cav1 + alum 
DS-Cav1 + alum 
5 
15 
500 mcg 
DS-Cav1 
DS-Cav1 
6 
15 
DS-Cav1 + alum 
DS-Cav1 + alum 
Total 
90* 
All DS-Cav1 vaccinations are administered with needle and syringe 
into the deltoid muscle. *Up to 100 subjects may be enrolled if 
needed to evaluate safety or immunogenicity. 
[1] This dose is optional for the last 5 subjects enrolled in each group 
that receive the Day 0 injection and any additional subjects needed to 
evaluate safety or immunogenicity. 
Duration: 
The study schedule requires 13 clinic visits and a telephone contact after each injection.   

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1. 
INTRODUCTION  
Respiratory syncytial virus (RSV) causes upper and lower respiratory infections in children and 
adults of all ages, and leads to significant morbidity and mortality in pediatric, 
immunocompromised, and geriatric populations [1].  Worldwide, RSV is the leading cause of 
respiratory tract infections in children, infecting 50-70% of all children by age one and nearly all 
children by age two [2, 3].  About 2% of  all children will require hospitalization for RSV.  
Infants born prematurely or those with congenital heart disease  have a particularly high risk for 
severe disease, but more than half of hospitalized infants, have no identified risk factors.  The 
peak age of hospitalization is between 2 and 3 months of age, but more than half of all 
hospitalizations in children under 5 years of age occur after 6 months [4-7].   
Other risk factors include a family history or genetic predisposition to allergic inflammation and 
increase in IL-13 and IL-4 responses or a low level of maternally-transferred RSV-specific 
neutralizing activity [8].  Additionally, infants hospitalized for RSV are at greater risk for 
childhood wheezing and asthma.  Adults with compromised immune systems and those ages 65 
and older are also at increased risk of severe disease [9, 10].   
Nearly all humans contract RSV by the age of three and then repeatedly throughout their lifetime 
[11, 12].  The economic impact of RSV in the United States (US) alone exceeds $400 million per 
year [13, 14] and worldwide, annual RSV hospitalizations are estimated to number more than 3.4 
million [15]. 
Currently, there is no licensed RSV vaccine.  A single licensed antiviral therapy, Palivizumab 
(Synagis™), is currently available for prevention of RSV.  Palivizumab is an anti-RSV fusion 
protein-specific monoclonal antibody (mAb) used as passive prophylaxis to reduce the frequency 
of severe RSV disease in premature infants, but is only recommended for infants born at 28 
weeks of gestational age or less [16-20].  Target populations for an RSV vaccine include 
pregnant women, infants, young children, and the elderly.  It is anticipated that age-specific 
vaccine strategies will be needed to generate effective immunity across a range of age groups 
[21].  
Vaccines to prevent RSV mediated disease are both urgently needed and uniquely challenging.  
In the late 1960s, a formalin-inactivated RSV vaccine (FI-RSV) was associated with enhanced 
disease following subsequent RSV infection [22].  Among FI-RSV vaccine-immunized infant 
subjects (n=31), 80% required hospitalization following infection and two deaths were reported.  
This is compared to 5% requiring hospitalization following infection and no deaths among the 
parainfluenza vaccine-immunized control infants (n=40).  Severe RSV disease was found to be 
more frequent in vaccinees than in the same-age general population not enrolled in the vaccine 
study [23-25].  Because infants and small children are a primary target population for an 
effective RSV vaccine, the legacy from that trial represents a substantive obstacle for 
development of an RSV vaccine for antigen-naïve infants.   
Unique properties of RSV have provided challenges to the development of a successful vaccine. 
RSV encodes three envelope proteins, a small hydrophobic (SH) protein of unknown function, 
an attachment glycoprotein (G), and a fusion (F) protein.  Of these proteins, only the F protein is 
essential for infecting cells in vitro; although, in vivo, G protein expression provides an 
advantage for infection of human airway epithelia [26].  The G protein is more variable than any 
other RSV protein and a high proportion of G is secreted through an alternative translation 

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initiation site, and acts as an immunomodulatory decoy for adaptive immune responses [27].  
Non-structural RSV gene products, NS1 and NS2, both interfere with innate immune responses 
through cooperative inhibition of interferon induction and effector functions [28, 29]. 
RSV lacks an optimal animal model.  Rodent models such as mice and cotton rats are only semi-
permissive for RSV infection, although they are useful for defining immune response patterns 
and rank-ordering candidate vaccines for neutralizing potency and protective capacity.  
Nonhuman primates (NHP) are useful for immunogenicity and challenge studies, but possess 
variable levels of susceptibility to infection and generally require large inocula intranasally and 
intratracheally to consistently establish infection.   
Substantive advances in understanding both RSV biology and immune system development and 
function have resulted in a number of RSV vaccine development approaches using a variety of 
platforms, many of which have advanced to clinical evaluation, including live-attenuated 
vaccines, chimeric virus vaccines and viral-vectored vaccines, usually expressing F, sometimes 
in combination with other viral genes [30-33].  However, none of these designs based on F have 
yet demonstrated vaccine efficacy in clinical trials, despite showing protection in animal models, 
emphasizing the need to use an antigen that induces immune responses relevant to human 
protection. 
Several trials with RSV subunit vaccines have been conducted in pre-immune children and 
adults.  A series of adjuvanted RSV F protein candidate vaccines administered alone or in 
combination with G and/or N (nucleoprotein) were deemed safe in seropositive subjects, but did 
not generate immune responses of sufficient breadth or potency to advance into antigen-naïve 
infants [34-38].  Another subunit vaccine composed of a fusion of a protein G fragment to the 
albumin-binding domain of streptococcal protein G elicited robust immune responses in 
seropositive humans, but subjects reported an unacceptable rate of erythema purpura [39, 40].  A 
version of RSV F protein in the post-fusion conformation formulated without adjuvant has 
advanced to Phase 2 trials.  Among 1600 subjects age 60 years or older, 44% effectiveness in 
preventing all RSV symptoms, 64% effectiveness in preventing lower respiratory tract 
symptoms, and a 4.8-fold increase in anti-F IgG response among vaccinees was observed [41]. 
1.1. 
Rationale for Evaluation of DS-Cav1 
Based on the reduction of severe disease by palivizumab, which is specific for the RSV F 
glycoprotein and studies of maternal cord serum, there is evidence that neutralizing activity in 
serum is a correlate of protection against RSV.  Palivizumab is recommended for prophylactic 
administration to high-risk neonates during their first winter season, at the height of RSV 
infection risk [42].  The RSV F protein, like multiple other Class I viral fusion proteins, 
undergoes a dramatic structural rearrangement as it mediates the membrane fusion process 
required for viral entry.  During this process, it transitions from a metastable prefusion to stable 
postfusion conformation.  By protein adsorption and competition studies, the prefusion 
conformation of RSV F (pre-F) has been demonstrated to elicit the majority of neutralizing 
activity in human serum [43, 44].  Knowledge of these key facts led the Vaccine Research Center 
(VRC) to pursue a structure-guided design approach to preserve neutralization-sensitive sites on 
pre-F surfaces and produce a stabilized pre-F subunit candidate vaccine.   
The co-crystal structure of the RSV F protein and the D25 mAb revealed a previously-
unidentified, prefusion-specific quaternary antigenic site, designated antigenic site zero (Ø) that 

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is abolished in the shift to the stable postfusion conformation.  Computational modelling studies 
undertaken on the basis of this crystal structure led to experiments that evaluated more than 100 
combinations of those sequence changes projected to stabilize F in the prefusion conformation.  
A variant comprising S155C, S290C, S190F, and V207L within the context of wild type F 
protein sequence, including native C-terminus, met criteria for expression of the F protein 
stabilized in the prefusion conformation.  The two cysteines (S155C, S290C) form a disulfide 
bond, the two bulky side chain mutations (S190F, V207L) occlude a hydrophobic cavity and 
promote hydrophobic packing interactions, and  together these changes enable expression of an 
unprecedented conformationally-stable F prefusion protein, DS-Cav1 (Di-Sulfide; Cavity, first 
variant) [45, 46].  The protein assumed a quaternary structure closely approximating the 
previously-solved D25-bound RSV F, bound prefusion-specific antibodies with nanomolar to 
subnanomolar affinities, and in both mouse and NHP vaccine studies, elicited neutralizing titers 
between 70- and 80-fold greater than those elicited by postfusion F.  The majority of antibodies 
induced by DS-Cav1 are specific for the unique surfaces on prefusion F and the rest target 
surfaces shared between pre-F and post-F conformations.  Because the large majority of RSV 
neutralizing antibodies in human sera recognize surfaces unique to pre-F, it is anticipated that 
boosting adults with DS-Cav1 will elicit a greater boost in neutralization activity than prior RSV 
candidate vaccines that have utilized F antigens in the postfusion conformation.  
Based on its safety, immunogenicity and efficacy profiles in preclinical studies [45], the 
candidate DS-Cav1 vaccine is being evaluated for the first time in healthy adults in this Phase 1 
clinical trial. Because preliminary data suggest immune responses after the first dose alone may 
provide valuable data regarding the duration of the vaccine-induced immune response, the last 5 
subjects enrolled into each group will have the option to receiving (or not receiving) the second 
vaccine dose. 
1.2. 
Rationale for Use of Aluminum–Based Adjuvant  
Adjuvants improve the immune response to many vaccines [47, 48].  The most common 
aluminum-based adjuvants includes aluminum hydroxide, aluminum phosphate, potassium 
aluminum sulfate, or mixed aluminum salts [49, 50].  Several phenomena contribute to the effect 
of aluminum hydroxide based adjuvants including: a ‘repository effect’ that occurs when the 
antigens aggregate on the adjuvant particle and are deposited to the immune cell for long 
duration to induce immune responses, a pro-phagocytic effect, and possibly the activation of the 
pro-inflammatory nucleotide like receptor protein 3 dependent pathways [50].  Aluminum-based 
adjuvants often improve humoral and innate responses and may lead to increased antibody titers, 
rapid induction of responses, reduction in size or frequency of doses, increased breadth of 
responses to overcome pathogen diversity, induction of long-lasting immune memory responses, 
and induction of response to overcome poor immune systems in elderly and young children [51-
54].  Based on over six decades of use, aluminum is broadly accepted to be safe, well-tolerated 
and effective [51, 52]. 
1.3. 
Previous Human Experience  
The only human experience with VRC-RSVRGP084-00-VP alone or with adjuvant is from the 
current trial that is ongoing.  As of August 08, 2019 a total of 95 subjects have enrolled and 
received one or two injections of a 50, 150, or 500 mcg DS-Cav1 vaccine, alone or with alum. 

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All dose escalation steps have been completed as per protocol; and no stopping or pausing rules 
have been met at any time during the study.Overall, all formulations of the DS-Cav1 vaccine 
have been well-tolerated and assessed as safe by the Protocol Safety Review Team (PSRT). 
Immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from 
antibodies targeting prefusion-specific surfaces of RSV F [55].  
Aluminum adjuvants have been used in vaccines for many decades with a demonstrated safety 
profile [56].  Aluminum is the most common adjuvant used in human vaccines licensed by the 
Food and Drug Administration (FDA) [57, 58].  Aluminum-containing vaccines have been 
associated with erythema, subcutaneous nodules, contact hypersensitivity, granulomatous 
inflammation [56, 59].  A specific limitation is neurotoxicity in patients with decreased renal 
function [57].  
Aluminum-based adjuvants promote strong humoral immune responses, and therefore, are 
incorporated in vaccines against diseases where neutralizing antibodies are required for 
protection such as diphtheria, tetanus and hepatitis B [54].  The licensed HPV VLP vaccines, 
Gardasil (Merck & Co, Inc.) and Cervarix (GlaxoSmithKline) have aluminum in the 
formulations at 0.5 mg of aluminum hydroxyphosphate sulphate per dose and 0.5 mg of 
aluminum hydroxide per dose, respectively [60].  
As per 21 Code of Federal Regulations (CFR) part 610.15, the amount of aluminum in biological 
products cannot exceed 0.85 mg/dose.  The amount of aluminum in vaccines currently licensed 
in the US ranges from 0.125-0.85 mg/dose [58].  Based on FDA regulations, experience with 
HPV VLP vaccines and VRC pre-clinical data, VRC plans to use 0.5 mg/dose of aluminum 
hydroxide adjuvant in this phase 1 study. 
1.4. 
Assessment of Immunogenicity 
Specimens to evaluate immunogenicity will be collected at baseline and at specified time points 
throughout the study.  The primary immunogenicity time points are 2 and/or 4 weeks after the 
first dose.  Measurements of RSV-specific humoral immune responses will be assessed by 
neutralization antibody assays.  ELISA and other exploratory assays to assess humoral and 
cellular immune responses may be performed with stored samples.  Human leukocyte antigen 
(HLA) type may be obtained from stored samples if needed to assess HLA-class restricted 
cellular responses.  Additional measurements of antibody, B cell and T cell responses may also 
be assessed from stored samples for timepoints throughout the study as exploratory evaluations. 
This includes tests using a number of high-throughput functional assays and high-throughput 
biophysical profiling tools to comprehensively profile the humoral immune response elicited by 
DS-Cav1 vaccination.  
The immunogenicity testing will be performed at the NIAID Vaccine Immunology Program 
(VIP) laboratory (formerly NVITAL and VITL), in research laboratories at the VRC, or by other 
approved scientific collaborators.  
2. 
STUDY PRODUCTS 
Study products are manufactured under current Good Manufacturing Practices (cGMP) by 
VRC/NIAID/NIH at the VRC Pilot Plant operated under contract by the Vaccine Clinical 

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Materials Program, Leidos Biomedical Research, Inc., Frederick, MD.  Specific manufacturing 
information is included on the product vial label and in the IB.  Quality Assurance lot release 
testing by the manufacturer and ongoing stability programs verify conformance to product 
specifications throughout use in clinical trials. 
2.1. 
VRC-RSVRGP084-00-VP 
VRC-RSVRGP084-00-VP (DS-Cav1) vaccine is a sterile, aqueous, buffered solution filled into 
single dose vials.  Details on VRC-RSVRGP084-00-VP composition and manufacturing are 
found in the IB.  
2.2. 
Aluminum Hydroxide Suspension - Adjuvant 
Aluminum Hydroxide Suspension (adjuvant) is a sterile, pyrogen-free, suspension filled into 
glass vials at a nominal fill volume of 0.7 mL ± 0.10 mL to allow withdrawal of 0.5 mL.  
Aluminum concentration is 5 ± 1 mg/mL.  Adjuvant is stored at 2-8°C, do not freeze. 
2.3. 
Preclinical Toxicology Studies of VRC-RSVRGP084-00-VP 
Details on preclinical studies conducted with VRC-RSVRGP084-00-VP along or with adjuvant 
can be found in the IB. 
3. 
STUDY OBJECTIVES  
3.1. 
Primary Objectives 
• To evaluate the safety and tolerability of DS-Cav1 alone or with adjuvant when 
administered IM at a dose of 50 mcg to healthy adults. 
• To evaluate the safety and tolerability of DS-Cav1 alone or with adjuvant when 
administered IM at a dose of 150 mcg to healthy adults. 
• To evaluate the safety and tolerability of DS-Cav1 alone or with adjuvant when 
administered IM at a dose of 500 mcg to healthy adults. 
3.2. 
Secondary Objectives 
• To evaluate the antibody response as measured by neutralization assay of DS-Cav1 
alone or with adjuvant at 2 and/or 4 weeks post first injection for each group. 
• To evaluate the antibody response as measured by neutralization assay of DS-Cav1 
alone or with adjuvant at 2 and/or 4 weeks post second injection for each group. 
3.3. 
Exploratory Objectives 
• To evaluate the frequency and magnitude of RSV-specific T cell, antibody and other 
immune responses at specified timepoints throughout the study. 
• To determine if measurable levels of RSV-specific neutralizing antibodies can be 
found in salivary and nasal secretions at specified timepoints throughout the study. 

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• To evaluate epitope-specific neutralization and monoclonal antibody binding (using 
the Octet System, (Bio-Layer Interferometry (BLI)) by competition assays at 
specified timepoints throughout the study. 
4. 
STUDY DESIGN AND CLINICAL PROCEDURES 
This is an open-label, dose-escalation study to examine the safety, tolerability and dose of the 
DS-Cav1 vaccine alone or with adjuvant in healthy adults.  A vaccine regimen of DS-Cav1 as a 
prime followed 12 weeks later with a DS-Cav1 boost will be compared to a vaccine regimen of 
an adjuvanted DS-Cav1 prime followed 12 weeks later with an adjuvanted DS-Cav1 boost for 
each dose level.  The last 5 subjects enrolled in each group will be offered the option not to 
receive the boost at Week 12, such that immunogenicity of a single vaccine dose can be 
evaluated. The hypotheses are that the vaccine will be safe and tolerable for human 
administration and will induce detectable immune responses.  The primary objective is to 
evaluate the safety and tolerability in healthy adults of the investigational vaccine alone and with 
adjuvant.  Secondary objectives are related to the immunogenicity of the vaccine alone and with 
adjuvant.  The study schema is shown in Table 1.  
Table 1:   
VRC 317 Study Schema 
VRC 317 Study Schema 
Group 
Subjects 
Dose 
Day 0 
Week 12[1] 
1 
15 
50 mcg 
DS-Cav1 
DS-Cav1 
2 
15 
DS-Cav1 + alum 
DS-Cav1 + alum 
3 
15 
150 mcg 
DS-Cav1 
DS-Cav1 
4 
15 
DS-Cav1 + alum 
DS-Cav1 + alum 
5 
15 
500 mcg 
DS-Cav1 
DS-Cav1 
6 
15 
DS-Cav1 + alum 
DS-Cav1 + alum 
Total 
90* 
All DS-Cav1 vaccinations are administered with needle and syringe 
into the deltoid muscle. *Up to 100 subjects may be enrolled if 
needed to evaluate safety or immunogenicity.  
[1] This dose is optional for the last 5 subjects enrolled in each group 
that receive the Day 0 injection and any additional subjects enrolled 
to evaluate safety or immunogenicity.
The study will be conducted at the VRC Vaccine Evaluation Clinic (VEC) in the NIH Clinical 
Center (NIH CC).  The visit schedule is shown in Appendix III.  The expected duration of time 
on study per subject is approximately 44 weeks. 

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4.1. 
Eligibility Criteria 
All inclusion and exclusion criteria must be met for eligibility. 
4.1.1. 
Inclusion Criteria 
A subject must meet all of the following criteria: 
1. 18 to 50 years of age. 
2. Willing and able to complete the informed consent process. 
3. Available for clinic visits through 44 weeks after enrollment. 
4. Able to provide proof of identity to the satisfaction of the study clinician completing the 
enrollment process. 
5. Willing to donate blood and mucosal samples to be stored and used for future research. 
6. In good general health without clinically significant medical history. 
7. Physical examination and laboratory results without clinically significant findings and a 
Body Mass Index (BMI) ≤40 within the 56 days prior to enrollment.  
Laboratory criteria within 56 days prior to enrollment: 
8. WBC and differential either within institutional normal range or accompanied by 
Principal Investigator (PI) or designee approval. 
9. Platelets = 125,000 – 500,000/mm3. 
10. Hemoglobin within institutional normal range. 
11. Creatinine ≤ 1.1 x ULN. 
12. ALT ≤1.25 x ULN. 
13. Negative for HIV infection by an FDA approved method of detection.  
Criteria applicable to women of childbearing potential: 
14. Negative result on a human chorionic gonadotropin pregnancy test on day of enrollment 
before receiving study product. 
15. Agree to use effective means of birth control from at least 21 days before enrollment 
through 4 weeks after the last injection. 
4.1.2. 
Exclusion Criteria 
A subject will be excluded if one or more of the following conditions apply: 
Criteria applicable to women of childbearing potential: 
1. Breast-feeding or planning to become pregnant through 4 weeks after the last injection. 
Subject has received any of the following: 
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. 

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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 allergen immunotherapy with antigen injections, unless on maintenance 
schedule. 
8. Current anti-TB prophylaxis or therapy. 
Subject has any of the following: 
9. Serious reactions to vaccines that preclude receipt of study injections as determined by 
the investigator. 
10. Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema. 
11. Asthma that is not well controlled. 
12. Diabetes mellitus (type I or II), with the exception of gestational diabetes. 
13. Thyroid disease that is not well controlled. 
14. Hypertension that is not well controlled. 
15. Evidence of autoimmune disease or immunodeficiency. 
16. Idiopathic urticaria within the past year. 
17. 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. 
18. Malignancy that is active or history of malignancy that is likely to recur during the study. 
19. 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. 
20. Asplenia, functional asplenia or any condition resulting in the absence or removal of the 
spleen. 
21. Psychiatric condition that precludes compliance with the protocol; past or present 
psychoses; or within 5 years prior to enrollment, a history of suicide plan or attempt. 
22. Any medical, psychiatric, or social condition that, in the judgment of the investigator, is a 
contraindication to protocol participation or impairs a subject’s ability to give informed 
consent. 
4.2. 
Clinical Procedures and Evaluations  
Evaluation of this investigational vaccine will include laboratory tests, medical history, physical 
assessment by clinicians and subject self-assessment.  The schedule of study visits is shown in 

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the Schedule of Evaluations (Appendix III).  Total blood volume drawn from each subject will 
not exceed 550 mL in any 8 week period. 
4.2.1. 
Screening 
Screening for this study will be completed through the VRC’s screening protocol, VRC 500 
(NIH 11-I-0164).  Subjects will be recruited through Institutional Review Board (IRB)-approved 
advertising.  Evaluations and sample collections for screening processes include a medical 
history review, physical exam, any laboratory tests needed to confirm eligibility, and pregnancy 
test for women of reproductive potential.  If screening evaluations suggest a concerning health 
condition, appropriate evaluations should be conducted based on clinical judgment.  Screening 
evaluations for specific eligibility criteria must be completed within the time interval specified 
prior to enrollment for the given parameter and may be repeated, as needed, to confirm 
eligibility.  Blood samples for research must be collected during screening; although generally 
collected in the 56 days prior to enrollment, a particular interval of time prior to enrollment for 
collection of these samples is not specified.   
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 screening 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 317 ICF.  Incorrect answers will 
be explained by the study clinician, and the VRC 317 ICF may be signed once the clinician is 
satisfied with the subject’s understanding of the study.  
4.2.2. 
Enrollment 
Day 0 is defined as the day of protocol enrollment and first study injection.  Protocol-specific 
eligibility is reviewed on Day 0 as part of the enrollment process, but eligibility evaluations 
conducted during a screening visit are routinely used for eligibility if the screening occurred 
within the specified window prior to the Day 0 visit.  However, if clinical assessment on Day 0 
suggests significant changes may have occurred since the screening visit, then evaluations done 
on Day 0 are used for eligibility.  Day 0 evaluations and medical history prior to the first 
injection are the baseline for subsequent safety assessments. 
4.2.3. 
Product Administration 
On each injection day (prior to injection), laboratory and research samples will be collected and 
subjects will be clinically evaluated.  A subject who arrives at the clinic with fever or evidence of 
an acute illness, which precludes administration of the vaccine, may be rescheduled within the 
allowed visit window.  Pregnancy test results for females of reproductive potential must be 
confirmed as negative within 24 hours before each injection.  
When choosing a site 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.  It is recommended, but not required, that the first 
injection be administered into the non-dominant arm.  It is preferred, but not required, to 
alternate arms for study injections.   

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All injections will be administered IM into upper arm deltoid muscle by needle and syringe.  For 
groups receiving adjuvant, the adjuvant will be field mixed by the site pharmacist prior to 
administration.  
4.2.4. 
Post-Injection Follow-Up and Diary Card 
Post-Injection Follow-Up:  Following each study injection, subjects will be observed for a 
minimum of 60 minutes.  Vital signs (temperature, blood pressure and pulse) will be taken at 
least 60 minutes post-injection.  The injection site will be inspected for evidence of local 
reaction.  In keeping with the institution’s 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. 
Study clinicians must inform subjects to contact the clinic at any time after each study injection 
if the subject has any concerning signs or symptoms.  Follow-up on subject well-being will be 
performed by telephone on the first or second day following all injections and by clinic visits as 
shown in the Schedule of Evaluations (Appendix III). 
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.  Other clinical concerns may prompt a study visit based on clinical 
judgment.  
Oral and nasal mucosal samples will be collected at specified study visits according to the 
Schedule of Evaluations in Appendix III.  A small ophthalmic sponge designed for clinical use 
will be used to collect oral mucosal samples.  Flocked swabs will be used to collect the nasal 
mucosal samples.  These samples are for research purposes only and are not used for evaluating 
subject health.  
Diary Card:  Subjects will be given a “Diary Card” to use as a memory aid, on which to 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 also 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, the paper diary card will be used as a source document.  When neither a paper nor 
electronic diary is available from the subject, the 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, and pain/tenderness 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.   
4.2.5. 
Follow-Up through End of Study 
Study follow-up will continue via clinical visits through 44 weeks after the first study injection.  
The visit schedule is based on intervals of time after each study injection administration.  Any 
subject who receives at least one study injection (including those subjects who elect not to 

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receive the optional second dose) will be expected to continue with follow-up for safety and 
immunogenicity through study Week 44 as per Schedule of Evaluations (Appendix III). 
Throughout the study, any subject who is suspected of having an upper respiratory infection 
based on the presence of rhinorrhea in conjunction with at least one additional sign and/or 
symptom should be evaluated by nasal flock swab for PCR diagnostic purposes.   
The schedule of visits, allowable windows for completing the visits, and evaluations performed 
at each visit are shown in the Schedule of Evaluations in Appendix III.  After Day 0, deviations 
from the visit windows in completing study visits are discouraged and will be recorded as 
protocol deviations, but are permitted at the discretion of the PI. 
4.2.6. 
Concomitant Medications  
Only routine prescription medications at the time of enrollment are recorded in the study 
database.  Subsequently, concomitant medications are only updated or recorded in the study 
database if there is an occurrence of an adverse event (AE) that requires expedited reporting or if 
the subject develops a new chronic condition that requires ongoing medical management. 
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, the concomitant medication changes throughout the study will be 
recorded in the subject’s chart as needed for general medical records, but will not be recorded in 
the study database. 
4.3. 
Dose Continuation and Dose Escalation Plans 
Dose groups will be enrolled sequentially, with no more than one subject per day for the first 2 
study injections of the study.  Dose continuation and escalation will occur after subjects have 
completed the first injection and following interim safety data reviews. Approval to proceed will 
be obtained from the Protocol Safety Review Team (PSRT).  
• The dose continuation review (for 50 mcg) will occur when at least 5 subjects who 
received 50 mcg in either Group 1 or Group 2 have completed post-injection follow-
up through completion of the 7 day diary card.  If assessed as safe to continue, 
enrollment of additional subjects in Group 1 and Group 2 may proceed. 
• The first dose escalation review (50 mcg to 150 mcg) will occur when at least 10 
subjects who received 50 mcg in either Group 1 or Group 2 have completed post-
injection follow-up through at least the “Study Week 2” visit.  If assessed as safe, 
enrollment of additional subjects may proceed until at least 10 subjects have enrolled 
in each Group 1 and Group 2.  After that, enrollments may begin in Group 3 and 
Group 4.  
• The second dose escalation review (150 mcg to 500 mcg) will occur when at least 10 
subjects who received 150 mcg in either Group 3 or Group 4 have completed post 
injection follow-up through at least the “Study Week 2” visit.  If assessed as safe, 
enrollment of additional subjects may proceed until at least 10 subjects have enrolled 
in each Group 3 and Group 4.  After that enrollments may begin in Group 5 and 
Group 6. 

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• The final dose continuation review (for 500 mcg) will occur when at least 10 subjects 
who received 500 mcg in either Group 5 or Group 6 have completed post injection 
follow-up through at least the “Study Week 2” visit.  If assessed as safe, enrollment 
of additional subjects may proceed until at least 10 subjects have enrolled in each 
Group 5 and Group 6. 
• The second injection for all groups may occur once the first dose of that dose level 
has been assessed as safe at the “Study Week 2” visit. 
If the first study injection is not completed or there are discontinuations from the study before 
there are sufficient data to conduct the dose escalation review for a group, then extra subjects 
may be enrolled into that group in order to have the requisite data on at least 10 subjects.  
Additionally, AEs assessed as related to the study product at the time of a dose escalation review 
may be judged by the PSRT to warrant adding additional subjects at a given dose level. 
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 4.4) 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. 
4.4. 
Criteria for Discontinuing Subject Participation   
Decisions to discontinue study injections or protocol participation for a subject will be made by 
the PI.  
4.4.1. 
Discontinuation from Study Injections 
A subject may be discontinued from study injections for the following reasons:  
• Pregnancy; 
• Grade 3 AE assessed as related to study product (except that self-limited Grade 3 
solicited reactogenicity does not require discontinuation of injections); 
• Grade 4 AE assessed as related to study product; 
• Immediate hypersensitivity reaction associated with study product; 
• Intercurrent illness that is not expected to resolve before the next scheduled injection; 
• 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 injection may continue per PI discretion if 
the next one occurs at least 2 weeks following completion of glucocorticoid 
treatment; or, 
• The PI assesses that it is not in the best interest of the subject to continue receiving 
study product.   

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4.4.2. 
Discontinuation from Protocol Participation 
A subject may be discontinued from protocol participation for the following reasons:  
• Subject voluntarily withdraws; 
• The IND Sponsor or regulatory authorities stop the study; or, 
• The PI assesses that it is 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.  
4.5. 
Criteria for Pausing and Resuming the Study  
4.5.1. 
Criteria for Pausing the Study  
The PI and PSRT will closely monitor and analyze study data as they become available and will 
make determinations regarding the presence and severity of AEs.  Enrollments and 
administration of study product will be paused by the PI, and the IND Sponsor will be promptly 
notified, according to the following criteria: 
• One (or more) subject experiences a Serious Adverse Event (SAE) assessed as related 
to study product. 
• Two (or more) subjects experience the same Grade 3 or higher unsolicited AE assessed 
as related to the study product. 
4.5.2. 
Plan for Review of Pauses and Resuming Rules 
The IND Sponsor with participation by the PSRT, will conduct the review and make the decision 
to resume, amend or close the study.  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. 
Enrollments and study product administration would resume only if review of the AEs that 
caused the pause result in a recommendation to permit further study injections and enrollments.  
When indicated, safety data reports and changes in study status will be submitted to relevant 
regulatory authorities including the IRB in accordance with Section 5.3 and institutional policy.  
5. 
SAFETY AND ADVERSE EVENTS 
5.1. 
Adverse Events 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (e.g., abnormal physical exam or laboratory finding), symptom, or 
disease temporally associated with the use of study treatment, whether or not considered related 
to the study treatment.   
AEs will be graded according to the Table for Grading Severity of AEs (Appendix IV).  The 
following guidelines will be used to determine if an AE should be recorded in the database: 
• Solicited AEs (i.e. reactogenicity parameters) will be recorded in the study database for 7 
days after each study injection without the collection of product attribution assessments.  

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Clinicians will follow and collect resolution information for any reactogenicity symptoms 
that are not resolved within 7 days. 
• Unsolicited AEs will be recorded in the study database from the date of receipt of each 
study injection through the visit scheduled at 28 days after each injection with the 
collection of product attribution assessments.  At other time periods between injections 
and when greater than 28 days after the last injection, only SAEs (as detailed in 
Section 5.2) and new chronic medical conditions will be recorded as an AE through the 
last study visit.   
5.2. 
Serious Adverse Events 
5.2.1. 
Serious Adverse Event Definition 
The term “serious adverse event” (SAE) as defined in 21 Code of Federal Regulations (CFR) 
312.32 as follows: “an adverse event or suspected adverse reaction is considered "serious" if, in 
the view of either the investigator or 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 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 represented an immediate risk of death to 
the subject.  An event that hypothetically may cause death if it occurs in a more severe form is 
not considered life-threatening.  Similarly, a hospital admission for an elective procedure is not 
considered a SAE.  
5.2.2. 
Reporting Serious Adverse Events to the IND Sponsor  
AEs that meet SAE Reporting Requirements must be reported by the clinical site and submitted 
on an expedited basis to the IND Sponsor, according to sponsor guidelines as follows:  
• results in death; 
• is life-threatening; 
• results in persistent or significant disability/incapacity; 
• requires unplanned inpatient hospitalization or prolongation of existing 
hospitalization; 
• is a congenital anomaly/birth defect in the offspring of a study subject; or, 
• is an important medical event that may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed above. 

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Additionally, any event, regardless of severity, which in the judgment of a PI represents a SAE, 
may be reported on an expedited basis. 
An investigator will communicate an initial SAE report within 24 hours of site awareness of 
occurrence to the IND Sponsor by email to the VRC Protocol Operations Office (Appendix II).  
A written report by the investigator should be submitted to the IND Sponsor within 3 working 
days.  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.  
5.2.3. 
IND Sponsor Reporting to the FDA 
It is the responsibility of the IND Sponsor to make the determination of which SAEs are “serious 
and unexpected suspected adverse reactions” (SUSARs) as defined in 21 CFR 312.32. 
• Suspected adverse reaction means any AE for which there is a reasonable possibility 
that the drug 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.  All IND Safety Reports will 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. 
5.3. 
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, and 
• New information that might affect the willingness of subjects to enroll or continue 
participation in the study. 
5.3.1. 
Unanticipated Problem 
An unanticipated problem (UP) is defined as any incident, experience, or outcome that meets all 
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 

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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. 
5.3.2. 
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, hether 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. 
5.3.3. 
Protocol Deviation 
A protocol deviation is defined as any change, divergence, or departure from the IRB-approved 
research protocol and is 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.  

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• 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.   
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. 
5.3.4. 
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. 
5.3.5. 
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.  
5.3.6. 
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. 
5.3.7. 
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; 

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• 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.. 
5.3.8. 
Annual Reporting to the NIAID IRB 
The following will be reported to the 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. 
6. 
STATISTICAL CONSIDERATIONS AND SAMPLE ANALYSIS 
6.1. 
Overview 
This is a dose-escalation study to evaluate the safety and immunogenicity of a 2-dose regimen 
with the DS-Cav1 vaccine given alone or with adjuvant. As available, the effect of a 1-dose 
regimen will also be evaluated in up to 5 subjects in each group who will be offered the option to 
receive only a single administration of the study product.   The primary objectives relate to safety 
and tolerability; the secondary and exploratory objectives relate to immunogenicity and 
durability of immune responses.  
6.2. 
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 product 
administration and safety evaluated by clinical visits through the study duration. 
The following parameters will be assessed: 
• Local reactogenicity signs and symptoms  
• Systemic reactogenicity signs and symptoms  
• Laboratory measures of safety  
• Adverse events  
• Serious adverse events  
• New chronic medical conditions  

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6.2.2. 
Secondary Endpoints: Immunogenicity 
The principal immunogenicity endpoints are antigen-specific antibody responses as evaluated by 
neutralization assays.  The primary timepoints for immunogenicity evaluation are 2 and/or 4 
weeks after the first injection for each group.  Immunogenicity after the second injection will 
also be evaluated when applicable.   
6.2.3. 
Exploratory Endpoints 
ELISA, neutralization assay, and T cell assays performed with research samples collected at 
study timepoints as well as other immunogenicity assays throughout the study may be completed 
as exploratory evaluations. 
6.3. 
Sample Size and Accrual 
The study design is to have 90 healthy adult subjects divided equally among 6 groups.   
6.3.1. 
Power Calculations for Evaluation of 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.   
Table 2 describes the probability of observing 0 and 2 or more adverse events among 10, 15, 30, 
and 90 subjects, based on a range of true underlying probabilities. For example, if an adverse 
event of interest has a true incidence rate of 1%, there is an 86% chance that we won’t see any 
events in a group of 15 participants.  However, if this same 1% incidence applies to all 90 
participants in the study, there is a 60% (100-40%) chance of observing at least one occurrence 
and a 23% chance of observing 2 or more. 
 
Table 2:   
Probability of Observing Adverse Events 
 
Probability 
of Adverse 
Event 
Prob. 
0/10 
Prob. 
2+/10 
Prob. 
0/15 
Prob. 
2+/15 
Prob. 
0/30 
Prob. 
2+/30 
Prob. 
0/90 
Prob. 
2+/90 
0.01 
0.90 
<0.01 
0.86 
0.01 
0.74 
0.04 
0.40 
0.23 
0.05 
0.60 
0.09 
0.46 
0.17 
0.21 
0.45 
0.01 
0.94 
0.10 
0.35 
0.26 
0.21 
0.45 
0.04 
0.82 
<0.01 
>0.99 
If we do not observe any AEs in a group of 10 (for example, at the dose escalation review), the 
upper 95% confidence interval for the true incidence rate at that dose is 31%; that is, we can be 
reasonably confident that the true rate is no more than 31%. If we do not observe any of a 
specific type of adverse events in a specific arm (n=15), the upper bound of a 95% confidence 
interval for the true incidence is 21.8%. Similarly, if we do not observe any of a specific type of 

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adverse events in a pair of arms (such as 1 & 2; n=30), the upper bound of a 95% confidence 
interval for the true incidence is 12%. 
6.3.2. 
Power Calculations for Evaluation of Immunogenicity 
Although immunogenicity is a secondary endpoint, it is of sufficient interest that we briefly 
present the power to detect a difference between immune responses before and after the first 
dose, and between two dose cohorts.  Based on previous research[44], we expect the ELISA and 
neutralization results to be approximately normally distributed on the log10 scale, with standard 
deviation approximately 0.2-0.5 log10.  Using the conservative value of 0.5log10 for the true 
standard deviation, we will have good power (90% or better) to detect a difference in the 
magnitude of the immune response of approximately .45 log10 with 15 per group. With 30 per 
group, we will be able to detect a difference in the average magnitude of approximately 0.3 log10.  
6.4. 
Statistical Analysis  
Since enrollment is concurrent with receiving the first study vaccination, the expectation is that 
all participants will receive at least one vaccination and therefore will provide some safety data.  
All statistical analyses will be performed using statistical software R.  No formal multiple 
comparison adjustments will be employed for safety endpoints or immunogenicity endpoints.  
6.4.1. 
Baseline Demographics 
Baseline characteristics including demographics and laboratory measurements will be 
summarized using descriptive statistics. 
6.4.2. 
Safety Analysis 
Reactogenicity:  The number and percentage of subjects experiencing each type of 
reactogenicity sign or symptom will be tabulated by severity.  For a given sign or symptom, each 
subject’s reactogenicity will be counted once under the maximum severity for all assessments. 
Adverse Events:  AEs will be coded into Medical Dictionary for Regulatory Activities 
(MedDRA) preferred terms.  The number and percentage of subjects experiencing each specific 
AE will be tabulated by severity and relationship to study product.  For the calculations in these 
tables, each subject’s AE will be counted once under the maximum severity or strongest 
recorded causal relationship to treatment. 
A complete listing of AEs for each subject will provide details including severity, relationship to 
treatment, onset, duration and outcome. 
Safety Laboratory Values:  Boxplots of local laboratory values will be generated for baseline 
values and for values measured during the course of the study.  Each boxplot 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. 
6.4.3. 
Analysis of Immune Responses 
The primary immunogenicity time points are 2 and/or 4 weeks after the first dose, although 
immunogenicity data at other time points will be examined as well.  The magnitude of the 

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responses will be compared within subjects (before and after first dose; before and after second 
dose) and between subjects (between dose cohorts and between those who receive Alum and 
those who do not).  The primary comparisons at 2 and/or 4 weeks post first dose will be 
compared using Wilcoxon Rank Sum tests, but regression models will also be explored that 
model post-dose immune response as a function of pre-dose immune response, dose, Alum 
(yes/no), and possibly demographic variables such as age and gender.  Immunogenicity will be 
analyzed for a variety of cohorts defined based on vaccination status, and specified in the 
Statistical Analysis Plan (SAP).  At minimum these may include ITT, PP, and mITT cohorts.  
6.4.4. 
Missing Data 
Missing responses will be assumed to be missing completely at random.  Analyses will include 
all samples available at each study time point. 
6.4.5. 
Interim Analyses 
An interim analysis of immunogenicity data may be performed when at least 10 subjects from 
Groups 1-4 reach 4 weeks post first dose.  Reports will be provided to the PI and other key VRC 
investigators for the purpose of informing future trial-related decisions in a timely manner and 
may be published as preliminary data.  Results should in no way influence the conduct of the 
trial in terms of early termination or later safety or immunogenicity endpoint assessments. 
6.4.6. 
Randomization of Treatment Assignments  
At the start of the study, subjects will be randomized 1:1 to Groups 1 and 2.  If the criteria for the 
first Dose Escalation are met, procedures for the interim safety review are completed, and there 
are at least 10 people enrolled in each of Groups 1 and 2, subjects will be randomized 1:1 in 
Groups 3 and 4.  If the criteria for the second Dose Escalation are met, procedures for the interim 
safety review are completed, and there are at least 10 people enrolled in each of Groups 3 and 4, 
subjects will be randomized 1:1 in Groups 5 and 6.  Once all groups have at least 10 subjects per 
group, or if the dose escalation criteria are not met, subjects will be randomized in equal 
proportions to all groups that are open.  
The subject and the study clinicians will be informed of the subject’s group assignment upon 
completing the enrollment in the database.
To decrease the potential for participant dropouts during the period between randomization and 
initial vaccination, randomization will occur on Day 0 after the study consent is signed and 
eligibility is confirmed.  If subjects accrued to a study group do not complete the number of 
injections and/or a follow-up duration specified, then additional subjects may be accrued in that 
group.  
7. 
PHARMACY PROCEDURES 
7.1. 
Study Products 
The study products are prepared under cGMP by the VRC Pilot Plant and must meet lot release 
specifications prior to clinical use.  This study includes one investigational vaccine, one 
adjuvant, and one diluent as follows: 

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• VRC-RSVRGP084-00-VP (DS-Cav1) drug product is a sterile, aqueous, buffered 
solution filled under aseptic conditions into single dose vials at a concentration of 500 
mcg/mL.  The formulation buffer is comprised of 20mM Histidine (buffer), 100mM 
Potassium Chloride (isotonic acid), 100mM Arginine HCl (stabilizer) and 2.5% 
weight per volume Sucrose (stabilizer) at pH 6.5.  The drug product is aseptically 
filled at a volume of 1.2 ± 0.10 mL in a 3 mL glass vial.  Vials contain a clear to 
slightly hazy sterile solution; some small white translucent particles may be visible. 
• Aluminum Hydroxide Suspension, alum, adjuvant is composed of Alhydrogel® 2% 
(Brenntag Biosector, Frederikssund Denmark) diluted with water for injection to a 
concentration of 5 mg/mL.  Adjuvant is aseptically filled at a volume of 0.7 ± 0.1 mL. 
• VRC-PBSPLA043-00-VP, diluent, is comprised of Phosphate Buffered Saline (PBS) 
aseptically filled into single dose vials at a volume of 1.2 ± 0.10 mL. 
7.2. 
Study Product Presentation and Storage 
7.2.1. 
Labels 
At the time of study product delivery to the pharmacy, study products labels will have specific 
product information (e.g., lot number, fill volume, storage temperature).  Labels will contain an 
Investigational Use Statement (“Limited by Federal Law to Investigational Use”) and 
manufacturer information. 
7.2.2. 
Storage 
VRC-RSVRGP084-00-VP:  DS-Cav1 vaccine vials will be shipped within the recommended 
temperature range using appropriate shipping configurations, to the study pharmacist or 
designee.  Vials of vaccine should be stored until use at -35°C to -15oC in a qualified, 
continuously monitored, non-frost-free freezer until use.  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.   
Vials, intended for single use only, do not contain preservative and should not be refrozen after 
thaw.  Vaccine vials are removed from the freezer and equilibrated to room temperature prior to 
product administration.  
Aluminum Hydroxide Suspension:  Vials of alum are stored until use at 2oC to 8oC in a qualified, 
continuously monitored refrigerator.  Do not freeze.  Vials of adjuvant are intended for single use 
only. 
 VRC-PBSPLA043-00-VP:  Vials of PBS are stored until use between -45°C to -10°C in a 
qualified, continuously monitored, non-frost-free freezer.  Vials of diluent are intended for single 
use only and should not be refrozen after thawing. 
7.2.2.1. 
Deviations in Temperatures   
Temperature excursions that are outside of the specified ranges will be reported per pharmacy 
guidelines.  If deviations in storage temperature occur from the normal allowance, the site 
pharmacist or designee must report the storage temperature excursion promptly to the PI and 
IND Sponsor and product must be quarantined in a separate area.  The excursion must be 

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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 or designee if continued clinical use of the product is acceptable.  
7.3. 
Preparation of Study Products for Administration 
Refer to the group assignment for the study subject.  The pharmacy will label the syringe before 
delivery to the clinic with the subject identifier, the date, and the time allowance for 
administration.   
The following general instructions apply to all vaccine dose preparations (alone and with 
adjuvant) for injection. 
• Preparation will be done by a Pharmacist or designee in a clean preparation unit with 
limited access;  
• Prepare all doses under sterile conditions; 
• Thaw the vial(s) containing VRC-RSVRGP084-00-VP and VRC-PBSPLA043-00-VP 
at ambient temperature (15ºC to 25ºC); 
• The vaccine (alone and with adjuvant) is stable in the vial and syringe for 8 hours 
refrigerated or at room temperature following removal from recommended storage 
conditions; 
• Administer within 8 hours following removal of vaccine from freezer; 
• Keep the prepared syringe at room temperature and out of direct sunlight; 
• Inversion of a prepared vial or syringe is defined as a gentle, complete 180 degree 
rotation of the container. 
7.3.1. 
Preparation of VRC-RSVRGP084-00-VP (non-adjuvanted) 
• For 500 mcg dose: withdraw 1.0 mL (500 mcg) into a syringe for administration. 
• For 150 mcg dose: 
− Transfer 0.45 mL (225 mcg) of vaccine into a new sterile vial using a syringe, 
− Transfer 1.05 mL of PBS diluent into the same vial.  (Total preparation volume = 
1.5 mL), 
− Invert vial 5x to mix, 
− Withdraw 1.0 mL (150 mcg) into a new syringe for administration. 
• For 50 mcg dose:   
− Transfer 0.15 mL (75 mcg) of vaccine into a new sterile vial using a syringe, 
− Transfer 1.35 mL of PBS diluent into the same vial (Total preparation volume = 
1.5 mL), 
− Invert vial 5x to mix, 
− Withdraw 1.0 mL (50 mcg) into a new syringe for administration. 

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7.3.2. 
Preparation of VRC-RSVRGP084-00-VP with Adjuvant 
Vials of alum and diluent will be provided for field mixing.   
• For 500 mcg dose with adjuvant: 
− Add 0.12 mL of adjuvant directly to a new vial of VRC-RSVRGP084-00-VP (1.2 
mL vaccine; total preparation volume = 1.32 mL), 
− Invert vial 5x to mix, incubate at ambient temperature (15ºC to 25ºC) for 15 
minutes, 
− Withdraw 1.1 mL into a new syringe for administration,  
− Invert syringe 5x to mix, 
− If not administered immediately, invert syringe 5x to mix immediately prior to 
administration. 
• For 150 mcg dose with adjuvant: 
− Transfer 0.45 mL (225 mcg) of vaccine into a new sterile vial using a syringe, 
−  Transfer 0.15 mL of adjuvant into the same vial, 
− Invert vial 5x to mix, incubate at ambient temperature (15ºC  - 25ºC) for 15 
minutes, 
− Transfer 0.9 mL of PBS diluent into the same vial, invert 5x to mix. (Total 
preparation volume = 1.5 mL), 
− Withdraw 1.0 mL (150 mcg) into a new syringe for administration, 
− Invert syringe 5x to mix, 
− If not administered immediately, invert syringe 5x to mix immediately prior to 
administration. 
• For 50 mcg dose with adjuvant: 
− Transfer 0.15 mL (75 mcg) of vaccine into a new sterile vial using a syringe, 
− Transfer 0.15 mL of adjuvant into the same vial, 
− Invert vial 5x to mix, incubate at ambient temperature (15ºC to 25ºC) for 15 
minutes, 
− Transfer 1.2 mL of PBS diluent into the same vial, invert 5X to mix.  (Total 
preparation volume = 1.5 mL), 
− Withdraw 1.0 mL (50 mcg) into a new syringe for administration, 
− Invert syringe 5x to mix, 
− If not administered immediately, invert 5x to mix immediately prior to 
administration.  

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7.4. 
Study Product Administration 
Injections must be administered within the time allowance on the syringe label using standard 
needle and syringe injection technique.  The study product will be administered IM into the 
deltoid muscle by needle and syringe. 
The plan for injection administration is to use standard injection techniques as follows: 
• Group 1:  Administer one injection of 1.0 mL of the 50 mcg/mL preparation for each 
50 mcg non-adjuvanted dose; 
• Group 2:  Administer one injection of 1.0 mL of the 50 mcg/mL field mixed with 
alum for each 50 mcg dose; 
• Group 3:  Administer one injection of 1.0 mL of the 150 mcg/mL preparation for each 
150 mcg non-adjuvanted dose; 
• Group 4:  Administer one injection of 1.0 mL of the 150 mcg/mL field mixed with 
alum for each adjuvanted 150 mcg dose; 
• Group 5:  Administer one injection of 1.0 mL of the 500 mcg/mL preparation for each 
non-adjuvanted 500 mcg dose;   
• Group 6:  Administer one injection of 1.1 mL of the 500 mcg/mL field mixed with 
alum for each adjuvanted 500 mcg dose.  
7.5. 
Study Product Accountability 
7.5.1. 
Documentation 
The study pharmacist or designee will be responsible for maintaining an accurate record of the 
codes, inventory, and an accountability record of vaccine supplies for this study. Electronic 
documentation as well as paper copies will be used. 
7.5.2. 
Disposition 
The empty vials and the unused portion of a vial will be discarded in a biohazard containment 
bag and incinerated or autoclaved following the injection.  Any unopened vials that remain at the 
end of the study will be discarded 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. 
8. 
HUMAN SUBJECTS PROTECTION 
This research will be conducted in compliance with the protocol, Good Clinical Practices (GCP) 
guidance, and all applicable regulatory requirements. 
8.1. 
Institutional Review Board 
A copy of the protocol, proposed ICF, and any proposed advertising material will be submitted 
to the IRB for review and approval.  

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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 deviations from the 
protocol and AEs. 
The PI will be responsible for obtaining annual IRB approval/renewal throughout the duration of 
the study.   
8.2. 
Subject Recruitment and Enrollment 
All study activities will be carried out at the NIH CC.  Study subjects will be recruited through 
on-site and off-site advertising done for the screening protocol, VRC 500 (11-I-0164).  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 this study is designed for 
product evaluation 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 Site Employees 
NIH employees and members of their immediate families may participate in this protocol.  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 subject’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 
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.  Study staff will be trained on obtaining potentially sensitive 
and private information from co-workers or subordinates. 
8.3. 
Informed Consent 
The study ICF (provided as a separate document) describes the investigational products, the 
purpose, methods, anticipated benefits, and potential risks of the study.  Before a subject’s 
participation in the study, it is the investigator’s responsibility to ensure that written informed 
consent is obtained from the subject. 
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 will be provided to the subject.   

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8.4. 
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 of this study.  All records will be kept confidential to the extent 
provided by federal, state and local law.  Medical records will be made available for review 
when required by authorized agencies and regulatory authorities only under the guidelines set by 
the U.S. Federal Privacy Act and by relevant country-specific regulatory authorities.  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 that only the 
study team can link to the subject.  The requirement to maintain subject confidentiality is 
included in the ICF. 
8.5. 
Risks and Benefits 
8.5.1. 
Risks 
Risk of the DS-Cav1 vaccine:  This is the first study in humans of the investigational DS-Cav1 
vaccine.  The risks noted are based on risks of vaccines in general.   
Potential side effects resulting from intramuscular 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 
injection, 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 
usually do not require treatment.   
There may be side effects from the study products, which may be serious or life threatening, that 
we do not yet know about. 
Risks of Aluminum Hydroxide Suspension:  Aluminum is the most common adjuvant used in 
human vaccines licensed by the FDA [57] used in billions of individuals over decades of clinical 
use [51].  Side effects are generally limited to minor local reactions at the injection site [51].  
Other more severe local reactions like erythema, subcutaneous nodules, contact hypersensitivity 
and granulomatous inflammation may occur [58].   
Risks of Mucosa Sample Collection:  Collection of samples by swabs and wicks rubbed over 
the mucosal surfaces may cause momentary discomfort and, in some cases, minor bleeding.   
Risks of Blood Drawing:  Blood drawing may cause pain, bruising, fainting, and, rarely, 
infection at the site where the blood is taken. 
Risks during Pregnancy:  We do not know the possible effects of the study vaccine on the fetus 
or nursing infant.  Therefore, women and adolescents of reproductive potential will be tested for 
pregnancy prior to administration of each dose of study product.  Women will be asked to notify 
the site immediately if they suspect or learn they are pregnant during this study.  In case of 
pregnancy, subjects will continue to be followed for safety.  The subject will be contacted about 
the outcome of a pregnancy that begins during the study. 

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Other Risks:  It is possible that the standard medical tests performed as part of this research 
protocol will result in new diagnoses.  Depending on 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, may be forwarded to the 
subject’s primary health care provider for further workup and management.  
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 this study that may aid in the development of an RSV vaccine.  The 
investigational vaccine is not expected to provide protection from RSV infection.  
8.6. 
Plan for Use and Storage of Biological Samples 
To be eligible for this protocol, subjects must be willing to allow stored specimens to be used in 
the future for studying infectious diseases, immune function, vaccine responses, and other 
medical conditions.  If tests show evidence of any acute or chronic condition, subjects will be 
informed of the results and advised to seek appropriate medical care for the condition.  In 
general, testing performed at a research laboratory is not for diagnostic purposes and results will 
not be available to the study site or study subject. 
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 was 
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. 
8.6.2. 
Storage and Tracking of Blood Samples and Other Specimens 
All of the stored research samples are labeled by a code that only the site can link to the subject.  
Samples are stored at secure facilities with limited access including VIP laboratory (formerly  
NVITAL, Gaithersburg, MD,) and VRC Laboratories, (Building 40, Bethesda, MD) or other 
approved CRO facilities.  Data will be kept in password-protected computers.  Only investigators 
or 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.  Regulatory approval through the proper human subjects protection agency will be 
sought prior to any sharing of samples that constitutes human subjects research.  The research 
use of stored, unlinked or unidentified samples may be exempt from the need for IRB review and 
approval.  When appropriate, exemption may be obtained through the proper regulatory 
procedures. 

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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 the IRB and the IND 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. 
8.7. 
Compensation 
Compensation for time and inconvenience of study participation will be provided to subjects in 
accordance with the standards for compensation of the Clinical Research Volunteer Program.  
The compensation per visit will be $275 for injection visits and $175 for visits that include a 
blood draw only.  Any visit that includes mucosal sample collection will be compensated an 
additional $50. Compensation for any clinic visit that does not include a blood draw or mucosal 
sample collection will be $75 and compensation for completion of electronic diary card will be 
$25.  The total compensation for the subject is based on the number of study clinic visits and 
injections completed.  The approximate total compensation is $2600, depending on the study 
visits and injections completed. 
Subjects will receive compensation about 2 weeks after each completed visit by direct deposit.  
Compensation may need to be reported to the Internal Revenue Service (IRS) as taxable income.   
8.8. 
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.  Study clinicians will conduct a daily safety 
review of any new clinical data.  The PSRT includes designated team members (PI, Associate 
Investigators, Study Coordinators, Protocol Specialist, and other study clinicians).  The PSRT 
will review the summary study safety data reports on a weekly basis through 4 weeks after the 
last subject receives the final study injection in order to be certain that the vaccine has an 
acceptable safety profile, and will continue to monitor the study safety data reports on at least a 
monthly basis through completion of the study.   

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9. 
ADMINISTRATION AND LEGAL OBLIGATIONS 
9.1. 
Protocol Amendments and Termination 
Protocol amendments must be made only with the prior approval of the IND Sponsor.  
Agreement from the investigator must be obtained for all protocol and ICF amendments.  All 
amendments will also be submitted to the IRB for approval.   
The VRC, NIAID, NIH, FDA and other regulatory authorities reserve the right to terminate the 
study.  The PI will notify the IRB of the study termination in writing and provide documentation 
to the IND Sponsor. 
9.2. 
Study Documentation and Study Records Retention 
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, radiographs, and correspondence.  Long-term storage of source 
documents may be in the form of electronic files.   
The investigator and staff are responsible for maintaining a comprehensive and centralized filing 
system of all essential study-related documentation, suitable for inspection at any time by 
representatives from the IND Sponsor, VRC, NIAID, NIH, IRB, FDA, and/or applicable 
regulatory authorities.  Elements include: 
• Subject files containing completed ICF and supporting copies of source documentation, 
and,  
• Study files containing the protocol with all amendments, the IB, and copies of all 
correspondence with the IRB. 
In addition, all original source documentation must be maintained and readily available. 
All essential documentation should 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 two 
years after marketing approval or refusal (21 CFR 312.62).  No study document should be 
destroyed without prior written agreement between the IND Sponsor and the PI. Should the 
investigator wish to assign the study records to another party or move them to another location, 
VRC must be notified in writing of the new responsible person and/or the new location. 
9.3. 
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.  Extracted data without subject identifiers will be sent to the protocol 
statistician for statistical analysis as needed.   

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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 and 
no later than 1 year after 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, paper diary cards, laboratory reports, pharmacy records and other research records 
maintained for the clinical trial. 
9.3.4. 
Protocol Monitoring 
The IND Sponsor or their authorized representatives are responsible for ensuring integrity of 
study data and compliance with the protocol.  The PI will allow the study monitors, the 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 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. 
9.4. 
Language 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are readily understood.  
9.5. 
Policy Regarding Research-Related Injuries 
The study site will provide immediate medical care for any injury resulting from participation in 
this research.  In general, VRC, the NIH, the NIH CC, and the U.S. Government will not provide 
long-term medical care or financial compensation for research-related injuries. 
 
 

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10. 
REFERENCES 
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2. 
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3. 
Graham, B.S., Pathogenesis of respiratory syncytial virus vaccine-augmented pathology. 
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Nair, H., et al., Global burden of acute lower respiratory infections due to respiratory 
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CDC. Respiratory Syncytial Virus Infection (RSV); Trends and Surveillance. 2015; 
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Hall, C.B., et al., The burden of respiratory syncytial virus infection in young children. N 
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Hall, C.B., Respiratory syncytial virus in young children. Lancet, 2010. 375(9725): p. 
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Miyairi, I. and J.P. DeVincenzo, Human genetic factors and respiratory syncytial virus 
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Falsey, A.R., et al., Respiratory syncytial virus infection in elderly and high-risk adults. 
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Papadopoulos, N.G., et al., Does respiratory syncytial virus subtype influences the 
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Bourgeois, F.T., et al., Relative impact of influenza and respiratory syncytial virus in 
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Paramore, L.C., et al., Economic impact of respiratory syncytial virus-related illness in 
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WHO. Immunization, Vaccines and Biologicals: RSV. [webpage]  [cited 2015 October 
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palivizumab and update on the use of RSV-IGIV. American Academy of Pediatrics 
Committee on Infectious Diseases and Committee of Fetus and Newborn. Pediatrics, 
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17. 
Martorell, L., et al., Somatic instability of the myotonic dystrophy (CTG)n repeat during 
human fetal development. Hum Mol Genet, 1997. 6(6): p. 877-80. 
18. 
Johnson, S., et al., A direct comparison of the activities of two humanized respiratory 
syncytial virus monoclonal antibodies: MEDI-493 and RSHZl9. J Infect Dis, 1999. 
180(1): p. 35-40. 

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19. 
Subramanian, K.N., et al., Safety, tolerance and pharmacokinetics of a humanized 
monoclonal antibody to respiratory syncytial virus in premature infants and infants with 
bronchopulmonary dysplasia. MEDI-493 Study Group. Pediatr Infect Dis J, 1998. 17(2): 
p. 110-5. 
20. 
Meissner, H.C., et al., Immunoprophylaxis with palivizumab, a humanized respiratory 
syncytial virus monoclonal antibody, for prevention of respiratory syncytial virus 
infection in high risk infants: a consensus opinion. Pediatr Infect Dis J, 1999. 18(3): p. 
223-31. 
21. 
Ruckwardt, T.J., K.M. Morabito, and B.S. Graham, Determinants of early life immune 
responses to RSV infection. Curr Opin Virol, 2016. 16: p. 151-7. 
22. 
Kim, H.W., et al., Respiratory syncytial virus disease in infants despite prior 
administration of antigenic inactivated vaccine. Am J Epidemiol, 1969. 89(4): p. 422-34. 
23. 
Kapikian, A.Z., et al., An epidemiologic study of altered clinical reactivity to respiratory 
syncytial (RS) virus infection in children previously vaccinated with an inactivated RS 
virus vaccine. Am J Epidemiol, 1969. 89(4): p. 405-21. 
24. 
Fulginiti, V.A., et al., Respiratory virus immunization. I. A field trial of two inactivated 
respiratory virus vaccines; an aqueous trivalent parainfluenza virus vaccine and an 
alum-precipitated respiratory syncytial virus vaccine. Am J Epidemiol, 1969. 89(4): p. 
435-48. 
25. 
Chanock, R.M., et al., Influence of immunological factors in respiratory syncytial virus 
disease. Arch Environ Health, 1970. 21(3): p. 347-55. 
26. 
Levine, S., R. Klaiber-Franco, and P.R. Paradiso, Demonstration that glycoprotein G is 
the attachment protein of respiratory syncytial virus. J Gen Virol, 1987. 68 ( Pt 9): p. 
2521-4. 
27. 
Bukreyev, A., L. Yang, and P.L. Collins, The secreted G protein of human respiratory 
syncytial virus antagonizes antibody-mediated restriction of replication involving 
macrophages and complement. J Virol, 2012. 86(19): p. 10880-4. 
28. 
Lo, M.S., R.M. Brazas, and M.J. Holtzman, Respiratory syncytial virus nonstructural 
proteins NS1 and NS2 mediate inhibition of Stat2 expression and alpha/beta interferon 
responsiveness. J Virol, 2005. 79(14): p. 9315-9. 
29. 
Spann, K.M., K.C. Tran, and P.L. Collins, Effects of nonstructural proteins NS1 and NS2 
of human respiratory syncytial virus on interferon regulatory factor 3, NF-kappaB, and 
proinflammatory cytokines. J Virol, 2005. 79(9): p. 5353-62. 
30. 
Wright, P.F., et al., Evaluation of a live, cold-passaged, temperature-sensitive, 
respiratory syncytial virus vaccine candidate in infancy. J Infect Dis, 2000. 182(5): p. 
1331-42. 
31. 
Karron, R.A., et al., Identification of a recombinant live attenuated respiratory syncytial 
virus vaccine candidate that is highly attenuated in infants. J Infect Dis, 2005. 191(7): p. 
1093-104. 
32. 
Bernstein, D.I., et al., Phase 1 study of the safety and immunogenicity of a live, 
attenuated respiratory syncytial virus and parainfluenza virus type 3 vaccine in 
seronegative children. Pediatr Infect Dis J, 2012. 31(2): p. 109-14. 
33. 
Malkin, E., et al., Safety and immunogenicity of a live attenuated RSV vaccine in healthy 
RSV-seronegative children 5 to 24 months of age. PLoS One, 2013. 8(10): p. e77104. 

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34. 
Gonzalez, I.M., et al., Evaluation of the live attenuated cpts 248/404 RSV vaccine in 
combination with a subunit RSV vaccine (PFP-2) in healthy young and older adults. 
Vaccine, 2000. 18(17): p. 1763-72. 
35. 
Piedra, P.A., et al., Immunogenicity of a new purified fusion protein vaccine to 
respiratory syncytial virus: a multi-center trial in children with cystic fibrosis. Vaccine, 
2003. 21(19-20): p. 2448-60. 
36. 
Falsey, A.R., et al., Comparison of the safety and immunogenicity of 2 respiratory 
syncytial virus (rsv) vaccines--nonadjuvanted vaccine or vaccine adjuvanted with alum--
given concomitantly with influenza vaccine to high-risk elderly individuals. J Infect Dis, 
2008. 198(9): p. 1317-26. 
37. 
Munoz, F.M., P.A. Piedra, and W.P. Glezen, Safety and immunogenicity of respiratory 
syncytial virus purified fusion protein-2 vaccine in pregnant women. Vaccine, 2003. 
21(24): p. 3465-7. 
38. 
Swanson, K.A., et al., Structural basis for immunization with postfusion respiratory 
syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers. 
Proc Natl Acad Sci U S A, 2011. 108(23): p. 9619-24. 
39. 
Durbin, A.P. and R.A. Karron, Progress in the development of respiratory syncytial virus 
and parainfluenza virus vaccines. Clin Infect Dis, 2003. 37(12): p. 1668-77. 
40. 
Hurwitz, J.L., Respiratory syncytial virus vaccine development. Expert Rev Vaccines, 
2011. 10(10): p. 1415-33. 
41. 
Novavax. Novavax Announces Positive Top-Line Data from Phase 2 RSV F-Protein 
Vaccine Clinical Trial in Older Adults. 2015; Press Release]. Available from: 
http://ir.novavax.com/phoenix.zhtml?c=71178&p=irol-newsArticle&ID=2078538. 
42. 
Blanken, M.O., et al., Respiratory syncytial virus and recurrent wheeze in healthy 
preterm infants. N Engl J Med, 2013. 368(19): p. 1791-9. 
43. 
Magro, M., et al., Neutralizing antibodies against the preactive form of respiratory 
syncytial virus fusion protein offer unique possibilities for clinical intervention. Proc Natl 
Acad Sci U S A, 2012. 109(8): p. 3089-94. 
44. 
Ngwuta, J.O., et al., Prefusion F-specific antibodies determine the magnitude of RSV 
neutralizing activity in human sera. Sci Transl Med, 2015. 7(309): p. 309ra162. 
45. 
McLellan, J.S., et al., Structure-based design of a fusion glycoprotein vaccine for 
respiratory syncytial virus. Science, 2013. 342(6158): p. 592-8. 
46. 
Graham, B.S., K. Modjarrad, and J.S. McLellan, Novel antigens for RSV vaccines. Curr 
Opin Immunol, 2015. 35: p. 30-8. 
47. 
Brewer, J.M., (How) do aluminium adjuvants work? Immunol Lett, 2006. 102(1): p. 10-5. 
48. 
Kuroda, E., C. Coban, and K.J. Ishii, Particulate adjuvant and innate immunity: past 
achievements, present findings, and future prospects. Int Rev Immunol, 2013. 32(2): p. 
209-20. 
49. 
FDA. Common Ingredients in U.S. Licensed Vaccines. 2014; Available from: 
http://www.fda.gov/biologicsbloodvaccines/safetyavailability/vaccinesafety/ucm187810.
htm. 
50. 
He, P., Y. Zou, and Z. Hu, Advances in aluminum hydroxide-based adjuvant research 
and its mechanism. Hum Vaccin Immunother, 2015. 11(2): p. 477-88. 
51. 
Brito, L.A., P. Malyala, and D.T. O'Hagan, Vaccine adjuvant formulations: a 
pharmaceutical perspective. Semin Immunol, 2013. 25(2): p. 130-45. 

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52. 
Brito, L.A. and D.T. O'Hagan, Designing and building the next generation of improved 
vaccine adjuvants. J Control Release, 2014. 190: p. 563-79. 
53. 
Schijns, V.E. and E.C. Lavelle, Trends in vaccine adjuvants. Expert Rev Vaccines, 2011. 
10(4): p. 539-50. 
54. 
Oleszycka, E. and E.C. Lavelle, Immunomodulatory properties of the vaccine adjuvant 
alum. Curr Opin Immunol, 2014. 28: p. 1-5. 
55. 
Crank, M.C., et al., A proof of concept for structure-based vaccine design targeting RSV 
in humans. Science, 2019. 365(6452): p. 505-509. 
56. 
Clements, C.J. and E. Griffiths, The global impact of vaccines containing aluminium 
adjuvants. Vaccine, 2002. 20 Suppl 3: p. S24-33. 
57. 
Petrovsky, N. and J.C. Aguilar, Vaccine adjuvants: current state and future trends. 
Immunol Cell Biol, 2004. 82(5): p. 488-96. 
58. 
Baylor, N.W., W. Egan, and P. Richman, Aluminum salts in vaccines--US perspective. 
Vaccine, 2002. 20 Suppl 3: p. S18-23. 
59. 
Gupta, R.K., et al., Adjuvant properties of aluminum and calcium compounds. Pharm 
Biotechnol, 1995. 6: p. 229-48. 
60. 
Roldao, A., et al., Virus-like particles in vaccine development. Expert Rev Vaccines, 
2010. 9(10): p. 1149-76. 

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APPENDIX I:INFORMED CONSENT FORM
The ICF has been removed from the protocol and is (instead) provided as a separate document. 

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APPENDIX II:
CONTACT INFORMATION

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APPENDIX III:
SCHEDULE OF EVALUATIONS

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SCHEDULE OF EVALUATIONS FOR VRC 317 
Visit Number 
 
01 
02 
02A 
02B 
02C 
03 
04 
05 
06 
06A 
06C 
07 
08 
09 
10 
11 
Week of Study 
 
-8 to 0 
W0 
W1 
W1 
W1 
W2 
W4 
W8 
W12 
W13 
W13 
W14 
W16 
W24 
W36 
W44 
Day of Study 
 
-56 to 0 
D05 
D1 
D3 
D7 
D14 
D28 
D56 
D84 
D85 
91 
D98 
D112 D168 D252 D308 
Clinical Evaluations 
Tube 
 Screen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VRC 500 Screening Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VRC 317 AoU and Consent 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
1Targeted Physical  
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
2Vital Signs 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Preg. Prevention Counseling  
 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
Pregnancy Test 
 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
3Study Injection 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Begin Diary Card 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Phone Contact (or clinic visit) 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
4HLA typing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 
 
 
CBC differential, platelets 
EDTA 
3 
3 
 
 
3 
 
3 
 
3 
 
3 
 
3 
 
 
 
Creatinine and ALT 
GLT 
4 
4 
 
 
4 
 
4 
 
4 
 
4 
 
4 
 
 
 
HIV antibody 
SST 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Samples  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum  
SST 
16 
64 
 
 
16 
40 
40 
16 
40 
 
16 
40 
40 
40 
40 
40 
PBMC and plasma  
EDTA 
40 
60 
 
20 
60 
60 
40 
20 
40 
 
60 
60 
40 
40 
40 
40 
Oral secretions 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Nasal secretions 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Daily Volume (mL) 
 
67 
131 
- 
20 
83 
100 
87 
36 
87 
- 
83 
100 
87 
100 
80 
80 
Cumulative Volume (mL) 
 
67 
198 
198 
218 
301 
401 
488 
524 
611 
611 
694 
794 
881 
981 
1061 1141 
1 Targeted physical exam is performed as needed, based on subject report or indications of illness. 
2 Complete post injection evaluations (temperature, BP, pulse, respiration) at least 60 minutes after each injection 
3 The second injection is optional for the last 5 subjects enrolled in each group that receive the first injection. Subjects who receive only one injection will be expected to continue 
with follow-up through study Week 44. 
4 HLA type blood sample is collected only once at any timepoint and is shown at Visit 09 for convenience. If HLA type is already in the medical record, do not repeat. HLA type 
may also be obtained from a frozen sample. 
5 Day 0=day of enrollment and first injection. Day 0 evaluations and medical history prior to first injection are the baseline for subsequent safety assessments. If clinical 
assessment on Day 0 suggests changes since screening, then physical exam & laboratory tests done on Day 0 are used for eligibility and are baseline for safety 
assessments. 
Visit windows: Visits 02A, 06A (+1 day); Visit 02B (±1 day); Visit 02C, 06C (-2 days); Visit 03, 04, 05, 07, 08 (±3 days); Visit 06 (±7 days); and Visit 09, 10, 11 (±7 
days).  Schedule Visits 02A-06 relative to Visit 02, Visits 06A-11 relative to Visit 06.

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APPENDIX IV:
ASSESSMENT OF RELATIONSHIP TO VACCINE AND
ADVERSE EVENT SEVERITY GRADING
 

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Assessment of Causality Relationship of an Adverse Event to Study Vaccine:  
The relationship between an adverse event (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 product are related in time, and a 
direct association can be demonstrated. 
• Probably Related. The AE and administration of study product are reasonably related in 
time, and the AE is more likely explained by study product than other causes.  
• Possibly Related. The AE and administration of study product are reasonably related in 
time, but the AE can be explained equally well by causes other than study product. 
• Not Related. There is not a reasonable possibility that the AE is related to the study 
product.  
For purposes of preparing data reports in which AE attributions are limited to “Related” or “Not 
Related”, in this protocol, the “Definitely, Probably and Possibly” attributions  will be  mapped 
to the “Related” category.  The definitions that apply when these two categories alone are used 
are as follows: 
• Related – There is a reasonable possibility that the AE may be related to the study 
product. 
• Not Related – There is not a reasonable possibility that the AE is related to the study 
product. 
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. 
• Any 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 decrease.  Increases in hemoglobin are AEs only for values above the 
upper limit of normal and are graded by the systemic illness clinical criteria. 
• Severity grading definition for Grade 4 local reaction to injectable product 
(Erythema/Redness and Induration/Swelling) included added text “requiring medical 
attention”. 
• 1 X ULN was removed from the definition for PT increase. 
 
 

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When not otherwise specified in the table, 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 (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. 
 
 

Product: VRC-RSVRGP084-00-VP 
 
Protocol VRC 317, Version 7.0 
 August 23, 2019  
 
Page 53 of 56 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials 
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  
1Erythema/Redness   
2.5 – 5 cm  
5.1 – 10 cm  
> 10 cm  
Necrosis or  
exfoliative dermatitis 
requiring medical 
attention  
2 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  
 
3 Vital Signs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
4 Fever (°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  
Tachycardia - beats per  
minute  
101 – 115  
116 – 130  
> 130  
Hospitalization for  
arrhythmia  
5 Bradycardia - 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. Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
3. Subject should be at rest for all vital sign measurements.  
4. Oral temperature; no recent hot or cold beverages or smoking.  
5. 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. 

 

Product: VRC-RSVRGP084-00-VP 
 
Protocol VRC 317, Version 7.0 
 August 23, 2019  
 
Page 54 of 56 
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  
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  
 
Systemic Illness 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
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  
 
B. Tables for Laboratory Abnormalities  
The laboratory values provided in the tables below serve as guidelines and are dependent upon 
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  

Product: VRC-RSVRGP084-00-VP 
 
Protocol VRC 317, Version 7.0 
 August 23, 2019  
 
Page 55 of 56 
Serum* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
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***  
1.6 – 3.0 x ULN  
3.1 –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  
3.1 – 10 x ULN  
> 10 x ULN  
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-RSVRGP084-00-VP 
 
Protocol VRC 317, Version 7.0 
 August 23, 2019  
 
Page 56 of 56 
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  
1.41 – 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. 
 


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