A Phase 1, Randomized, Open-label Clinical Trial to Evaluate the Safety and Immunogenicity of BG505 MD39.3, BG505 MD39.3 gp151, and BG505 MD39.3 gp151 CD4KO HIV Trimer mRNA Vaccines in Healthy, HIV-uninfected Adult Participants
Phase: PHASE1
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

PROTOCOL 
HVTN 302 
A phase 1, randomized, open-label clinical trial to 
evaluate the safety and immunogenicity of BG505 
MD39.3, BG505 MD39.3 gp151, and BG505 MD39.3 gp151 
CD4KO HIV trimer mRNA vaccines in healthy, HIV-
uninfected adult participants 
DAIDS DOCUMENT ID 38791 
IND 027679 HELD BY DAIDS 
CLINICAL TRIAL SPONSORED BY 
Division of AIDS (DAIDS) 
National Institute of Allergy and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
Department of Health and Human Services (DHHS) 
Bethesda, Maryland, USA 
STUDY PRODUCTS PROVIDED BY 
IAVI on behalf of Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD) 
New York, New York, USA 
July 7, 2023 
Final 
HVTN 302 
Version 3.0 

 
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Protocol Signature Page 
  
A phase 1, randomized, open-label clinical trial to evaluate the safety and 
immunogenicity of BG505 MD39.3, BG505 MD39.3 gp151, and BG505 MD39.3 
gp151 CD4KO HIV trimer mRNA vaccines in healthy, HIV-uninfected adult 
participants 
I will conduct the study in accordance with the provisions of this protocol and all 
applicable protocol-related documents. I agree to conduct this study in 
compliance with United States (U.S.) Health and Human Service regulations (45 
CFR 46); applicable U.S. Food and Drug Administration regulations; standards of 
the International Conference on Harmonization Guideline for Good Clinical 
Practice (E6); Institutional Review Board/Ethics Committee determinations; all 
applicable in-country, state, and local laws and regulations; and other applicable 
requirements (eg, U.S. National Institutes of Health, Division of AIDS) and 
institutional policies 
 
 
 
 
 
 
 
 
 
Investigator of Record Name (print) 
 
Investigator of Record Signature 
 
Date 
 
 
 
DAIDS Protocol Number: HVTN 302 
DAIDS Protocol Version: 3.0 
Protocol Date: July 7, 2023 
 
 
 
 
 

 
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Acronyms and abbreviations 
AE 
 
adverse event 
AESI 
 
Adverse events of special interest 
AoU 
 
assessment of understanding 
ALT 
 
alanine aminotransferase 
AUC 
 
area under the curve 
BAMA 
 
binding antibody multiplex assay 
BCR 
 
B cell receptor 
β-HCG 
 
beta human chorionic gonadotropin 
BMGF 
 
Bill & Melinda Gates Foundation 
bnAb 
 
broadly neutralizing antibody 
BP 
 
blood pressure 
CAB 
 
Community Advisory Board  
CBC 
 
complete blood count 
cGMP 
 
current Good Manufacturing Practice 
CHAVD  
Consortium for HIV/AIDS Vaccine Development 
CMV 
 
Cytomegalovirus 
CRPMC 
 
NIAID Clinical Research Products Management Center 
CRS 
 
clinical research site 
CSS 
 
clinical safety specialist 
DAIDS 
 
Division of AIDS 
EAE 
 
expedited adverse events 
EC 
 
ethics committee 
eDiary 
 
electronic diary 
EIA 
 
enzyme immunoassay 
ELISA 
 
enzyme-linked immunosorbent assay 
EMPEM  
electron microscopy-based polyclonal epitope mapping 
EUA 
 
emergency use authorized  
EUL 
 
emergency use listing 
FDA 
 
(US) Food and Drug Administration 
FNA 
 
Fine needle aspiration 
GINA 
 
Genetic Information Nondiscrimination Act  
GMP 
 
Good Manufacturing Practice 
GC 
 
germinal center 
GCP 
 
Good Clinical Practice 
HLA 
 
human leukocyte antigen 
IB 
 
Investigator’s Brochure 
IBC 
 
Institutional Biosafety Committee  

 
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ICS 
 
intracellular cytokine staining 
IM 
 
intramuscular 
IND 
 
investigational new drug (application) 
ISCOMIT  
immunostimulatory complex (ISCOM)-like nanoparticle 
comprised of self-assembled cholesterol, phospholipid, and 
Quillaja saponin made at Massachusetts Institute of 
Technology (MIT).  
IRB 
 
institutional review board 
LABA 
 
long-acting beta agonist 
LNP 
 
lipid nanoparticle 
MAAE 
 
medically attended adverse events 
mRNA 
 
Messenger ribonucleic acid 
nAb 
 
neutralizing antibody 
NHP 
 
non human primate 
NIAID 
 
National Institute of Allergy and Infectious Diseases  
NSAID 
 
non-steroidal anti-inflammatory drug 
PAB 
 
Pharmaceutical Affairs Branch 
PCR 
 
polymerase chain reaction 
PBMC 
 
peripheral blood mononuclear cells  
PEF 
 
peak expiratory flow 
PI 
 
principal investigator 
PrEP 
 
pre-exposure prophylaxis  
PSRT 
 
Protocol Safety Review Team 
RAB 
 
Regulatory Affairs Branch  
RE 
 
regulatory entity 
RSC 
 
Regulatory Support Center 
SAE 
 
serious adverse event 
SAP 
 
statistical analysis plan 
SDMC 
 
statistics and data management center 
SICF 
 
sample informed consent form 
SMB 
 
Safety Monitoring Board 
SPT 
 
Safety and Pharmacovigilance Team  
SSP 
 
Study Specific Procedures 
SUSAR 
 
suspected unexpected serious adverse reaction 
ULN 
 
upper limit of normal 
VISP 
 
vaccine-induced seropositivity 
VRC 
 
Vaccine Research Center 
WHO 
 
World Health Organization 

 
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Contents 
1 Executive summary ........................................................................................................8 
1.1 
Title ................................................................................................................8 
1.2 
Design .............................................................................................................8 
1.3 
Study products ................................................................................................8 
1.4 
Study population ............................................................................................9 
1.5 
Study plan and schema table ..........................................................................9 
1.6 
Duration per participant ...............................................................................10 
1.7 
Estimated total study duration ......................................................................10 
2 Introduction ..................................................................................................................11 
2.1 
Rationale for evaluation of BG505 MD39.3, BG505 MD39.3 gp151 and 
BG505 MD39.3 CD4KO gp151 ...................................................................13 
2.2 
Preclinical data .............................................................................................14 
2.3 
Rationale for Study Design ..........................................................................21 
2.4 
Rationale for Schedule .................................................................................22 
2.5 
Rationale for Dose of HIV Trimer mRNA/LNP ..........................................22 
2.6 
Rationale for Lymph Node Fine Needle Aspiration ....................................23 
2.7 
Rationale for Leukapheresis .........................................................................23 
2.8 
Risks and benefits .........................................................................................24 
2.9 
Assessment of immunogenicity endpoints ...................................................28 
3 Objectives and endpoints .............................................................................................29 
3.1 
Primary objectives and endpoints ................................................................29 
3.2 
Secondary objectives and endpoints ............................................................29 
3.3 
Exploratory objectives ..................................................................................30 
4 Laboratory strategy ......................................................................................................32 
5 Study design .................................................................................................................33 
5.1 
Study population ..........................................................................................33 
5.2 
Participant departure from vaccination schedule or withdrawal ..................38 
6 Statistical considerations ..............................................................................................43 
6.1 
Sample size justification and accrual ...........................................................43 
6.2 
Randomization .............................................................................................48 
6.3 
Statistical analyses ........................................................................................49 
7 Study vaccine preparation, storage, and administration ..............................................56 
7.1 
Vaccine Regimen .........................................................................................56 
7.2 
Study Product Formulation and Storage ......................................................57 
7.3 
Product Preparation ......................................................................................57 
7.4 
Study product labeling .................................................................................60 
7.5 
Study Vaccine Administration .....................................................................60 
7.6 
Acquisition of study products ......................................................................61 
7.7 
Study Vaccine Accountability ......................................................................61 
7.8 
Final Disposition of study product ...............................................................61 
8 Clinical procedures ......................................................................................................62 

 
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8.1 
Screening ......................................................................................................62 
8.2 
Definition of Study Day and Study Visit .....................................................62 
8.3 
Reactogenicity Assessments ........................................................................62 
8.4 
Cardiac symptom management ....................................................................63 
8.5 
Additional procedures for Part A participants ..............................................64 
8.6 
Extended follow-up for participants with unresolved study product-related 
urticaria-associated symptoms .....................................................................65 
8.7 
Visit procedures, schedule, windows and missed visits ...............................66 
8.8 
Monitoring for HIV infection .......................................................................66 
8.9 
Early termination visit ..................................................................................67 
9 Safety and adverse events ............................................................................................68 
9.1 
Adverse events .............................................................................................68 
9.2 
AESIs ...........................................................................................................69 
9.3 
Serious adverse events .................................................................................69 
9.4 
Safety monitoring .........................................................................................71 
9.5 
Total blood volume ......................................................................................71 
9.6 
Sentinel Safety Reviews ...............................................................................72 
9.7 
Safety pause and prompt PSRT AE review..................................................72 
9.8 
Study termination .........................................................................................74 
9.9 
Pregnancy .....................................................................................................75 
10 Protocol conduct and informed consent .......................................................................76 
10.1 Protocol conduct ...........................................................................................76 
10.2 Compliance with NIH guidelines for research involving products containing 
recombinant or synthetic nucleic acid molecules .........................................76 
10.3 Informed consent ..........................................................................................76 
11 Exploratory studies ......................................................................................................78 
11.1 Specimen storage and other use of specimens .............................................78 
12 Literature cited .............................................................................................................79 
Appendix A Schedule of procedures for participants undergoing LN FNA and/or 
leukapheresis ................................................................................................84 
Appendix B Schedule of procedures for participants undergoing neither LN FNA nor 
leukapheresis ................................................................................................86 
Appendix C Schedule of procedures for extended follow-up for participants with 
unresolved study product-related urticaria-associated symptoms ................88 
Appendix D Visit windows for main study ......................................................................89 
Appendix E Visit windows for follow-up of participants with unresolved study product-
related urticaria-associated symptoms .........................................................90 
Appendix F Sample informed consent form ....................................................................91 
Appendix G Sample Addendum Informed Consent Form for follow-up of participants 
with unresolved study product-related urticaria-associated symptoms ......115 
Appendix H Low risk guidelines for US ........................................................................119 

 
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Appendix I Approved birth control methods ................................................................122 
Appendix J Case definition for Myocarditis and pericarditis ........................................124 
Appendix K Protocol team ..............................................................................................132 
Appendix L Version history ...........................................................................................133 
 

 
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1 
Executive summary 
1.1 
Title  
A phase 1, randomized, open-label clinical trial to evaluate the safety and 
immunogenicity of BG505 MD39.3, BG505 MD39.3 gp151, and BG505 MD39.3 
gp151 CD4KO HIV trimer mRNA vaccines in healthy, HIV-uninfected adult 
participants. 
1.2 
Design 
This is an open-label, multicenter, randomized phase 1 study to evaluate the 
safety and immunogenicity of BG505 MD39.3, BG505 MD39.3 gp151, and 
BG505 MD39.3 gp151 CD4KO HIV trimer mRNA. These trimers are based on 
the BG505 MD39 native-like trimer reported in Steichen et al. Immunity 2016 
(1). The primary hypothesis is that the BG505 MD39.3 soluble and membrane-
bound trimer mRNA vaccines will be safe and well-tolerated among HIV-
uninfected individuals and will elicit autologous neutralizing antibodies. 
1.3 
Study products 
• BG505 MD39.3 mRNA (labeled as mRNA-1574v1-GP140) formulated in a 
lipid nanoparticle (soluble trimer): a prefusion-stabilized, cleavage-
independent, glycan-hole-masked soluble trimer. To be administered as 100 
mcg or 250 mcg intramuscularly. 
• BG505 MD39.3 gp151 mRNA (labeled as mRNA-1574v2-GP151) formulated 
in a lipid nanoparticle (membrane-bound trimer): a prefusion-stabilized, 
cleavage-independent, glycan-hole-masked trimer in a membrane-bound 
format including a transmembrane domain but lacking a C-terminal domain. 
To be administered as 100 mcg or 250 mcg intramuscularly. 
• BG505 MD39.3 gp151 CD4KO mRNA (labeled as mRNA-1574v3-CD4KO-
GP151) formulated in a lipid nanoparticle (membrane-bound trimer): a 
prefusion-stabilized, cleavage-independent, glycan-hole-masked trimer in a 
membrane-bound format including a transmembrane domain but lacking a C-
terminal domain with a point mutation in the CD4bs that reduces CD4 
binding. To be administered as 100 mcg or 250 mcg intramuscularly. 
• Diluent: Sodium Chloride Injection, USP, 0.9% is commercially sourced from 
Spectra Medical Devices, Inc. Sodium Chloride Injection, USP, 0.9% is a 
sterile, nonpyrogenic, isotonic solution of sodium chloride and water for 

 
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injection. Each mL contains sodium chloride 9 mg. It contains no bacteriostat, 
antimicrobial agent or added buffer. 
Note: In this protocol we will collectively refer to the study products as BG505 
MD39.3 mRNA vaccines or mRNA1574 vaccines for clarity and improved 
readability. 
1.4 
Study population 
Healthy adults aged 18 to 55 years, inclusive 
1.5 
Study plan and schema table 
Participants will receive BG505 MD39.3 mRNA, BG505 MD39.3 gp151 mRNA 
or BG505 MD39.3 gp151 CD4KO mRNA, at doses of 100 mcg or 250mcg, 
administered via intramuscular (IM) injections into the deltoid muscle. 
Participants will be evaluated for safety and immune responses through blood and 
lymph node fine-needle aspiration collection at specified timepoints throughout 
the study. The study schema is below: 
Table 1-1 Schema 
Study 
Arm 
N 
Dose 
(mcg) 
Month 0 
Month 2  
Month 6 
Part A 
 
 
 
 
 
Group 1 
18 
100 
BG505 MD39.3 
mRNA 
BG505 MD39.3 
mRNA 
BG505 MD39.3 
mRNA 
Group 2 
18 
100 
BG505 MD39.3 
gp151 mRNA 
BG505 MD39.3 
gp151 mRNA 
BG505 MD39.3 
gp151 mRNA 
Group 3 
18 
100 
BG505 MD39.3 
gp151 CD4KO 
mRNA 
BG505 MD39.3 
gp151 CD4KO 
mRNA 
BG505 MD39.3 
gp151 CD4KO 
mRNA 
Part B 
 
 
 
 
 
Group 4 
18 
250 
BG505 MD39.3 
mRNA 
BG505 MD39.3 
mRNA 
BG505 MD39.3 
mRNA 
Group 5 
18 
250 
BG505 MD39.3 
gp151 mRNA 
BG505 MD39.3 
gp151 mRNA 
BG505 MD39.3 
gp151 mRNA 
Group 6 
18 
250 
BG505 MD39.3 
gp151 CD4KO 
mRNA 
BG505 MD39.3 
gp151 CD4KO 
mRNA 
BG505 MD39.3 
gp151 CD4KO 
mRNA 
Total 
108 
 
 
 
 
A dose escalation plan will be implemented, whereby sentinel safety groups 
(n=12, approximately 4 for each of the three low-dose groups) in Part A would 

 
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be enrolled and evaluated for safety 2 weeks after the first vaccination. If safety 
criteria are met, then enrollment of the Part B sentinel safety groups (n=12, 
approximately 4 per group) and the remainder of the Part A participants would 
commence. Safety for the sentinel groups in Part B will be assessed after the first 
vaccination prior to full enrollment of Part B. In addition, standard safety 
evaluations will occur routinely throughout the trial.  
1.6 
Duration per participant 
Main study: Up to 12 months of scheduled visits.  
Extended follow-up: For the small group of participants with unresolved study 
product-related urticaria-associated symptoms (eg; wheal and flare lesions, 
pruritis, and/or erythematous lesions), up to an additional 48 months of 
scheduled contacts.  
1.7 
Estimated total study duration 
Main study: 22 months (includes enrollment, planned safety holds, and follow-
up). 
Extended follow-up for participants with unresolved study product-related 
urticaria-associated symptoms (eg; wheal and flare lesions, pruritis, and/or 
erythematous lesions): estimated total study duration would be up to 70 months 
(includes main study and extended follow-up). 
1.8 
Study sites  
HVTN Clinical Research Sites (HVTN CRSs) to be specified in the Site 
Announcement Memo. 
 

 
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2 
Introduction 
This first-in-human phase 1 clinical trial will evaluate whether messenger 
ribonucleic acid (mRNA)/lipid nanoparticle (LNP) delivery of soluble or 
membrane-bound HIV Env trimers is a promising platform for rapid and iterative 
HIV vaccine development. This platform is expected to be advantageous in terms 
of the speed and cost of deployment as well as the magnitude and quality of the 
human immune responses. The comparison of the immune responses elicited by 
the HIV Env trimers selected for this study will determine whether a modified 
membrane-bound trimer lacking CD4 affinity elicits improved antibody 
responses.  
Achieving a goal of developing a sequential vaccine regimen that induces 
sustained protective levels of HIV broadly neutralizing antibodies in humans will 
require expeditious iterative testing of multiple vaccine regimens in humans. 
However, the slow timeline and relatively high costs of Good Manufacturing 
Practice (GMP) protein manufacture present barriers to success. Modified 
mRNA delivered within LNPs is an emerging vaccine platform that offers the 
potential for GMP manufacture in a substantially shorter time and with lower 
costs compared to protein manufacture (2-5).  
The primary vaccine strategies investigated by the Scripps Consortium for 
HIV/AIDS Vaccine Development (CHAVD) include germline targeting and 
immuno-focusing using a sequence of HIV Env trimer immunogens, serving the 
general purposes of: (i) priming appropriate precursor B cells; (ii) "shepherding" 
or guiding affinity maturation toward broadly neutralizing antibody (bnAb) 
development; and (iii) "polishing" or optimizing the vaccine response in terms of 
neutralization breadth, potency, magnitude, and durability. This strategy will 
employ modified trimers to serve at the priming or shepherding stages followed 
by native-like trimers at the polishing stage. Therefore, identification of a rapid 
GMP delivery platform for trimers would expedite the process of evaluating 
human immune responses to HIV vaccines of sufficient strength and quality to 
enable iterative and measurable progress toward bnAb elicitation. 
Fully native trimers are anchored to a lipid membrane on the virus or an infected 
cell, but most vaccine discovery efforts utilize trimers in a soluble format owing 
to the difficulties associated with production and purification of membrane 
proteins. Trimer delivery by mRNA/LNPs allows for deployment of membrane-
bound trimer immunogens, which may be advantageous for trimer 
conformational sampling and glycosylation. This method also allows occluding 
the base of the trimer that, when exposed on soluble trimers, is immunodominant 
and elicits non-neutralizing and trimer-degrading antibodies.  
The Scripps CHAVD teams have achieved demonstrable successes using soluble 
trimer immunization to elicit bnAbs or partially mature bnAb in mouse models 
with restricted repertoires (1, 6, 7); to elicit protective autologous neutralizing 

 
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antibodies against BG505 SHIV in rhesus macaques (8, 9); and to improve 
trimer responses via slow-release (10) and Alum-targeting (11). However, 
significant challenges are associated with the soluble trimer format. In particular, 
the "base" of the trimer, the region that is occluded by the membrane on a viral-
associated trimer but exposed on soluble gp140, is highly immunogenic or 
immunodominant in mice, rabbits, and non-human primates (NHPs) (10, 12-14) 
and Andrew Ward’s lab at the Scripps Research Institute has recently shown that 
base-directed responses are likely associated with trimer degradation in vivo 
(unpublished data). Furthermore, in some cases, soluble trimers have been shown 
to have glycosylation profiles that are less native-like than corresponding 
membrane-bound trimers, potentially leading to differences in the elicitation of 
neutralizing responses (15). 
Experiments with trimer-nanoparticles in which the base of the trimer is fused to 
self-assembling proteins have found that trimer-nanoparticles can exhibit 
improved trafficking to follicular dendritic cell networks and increased 
concentration in germinal centers (16). Compared to soluble trimers, trimer-
nanoparticles can elicit stronger neutralizing responses to epitopes well-exposed 
on the nanoparticle (17). However, there remain significant challenges for this 
presentation format. In particular, autologous neutralizing and protective 
responses are not always improved by trimer presentation on a nanoparticle; the 
nanoparticle core and the trimer bottom both remain immunogenic, in some 
cases highly immunogenic(18); and trimer-degrading antibodies are still elicited. 
Elicitation of responses to the nanoparticle core and trimer base is likely due at 
least in part to particle disassembly in vivo. Thus, while trimer nanoparticles 
remain of significant interest, the platform requires additional technical 
improvement.  
An important additional uncertainty about trimer immunization in humans is 
whether trimer binding to host CD4 and the ensuing trimer conformational 
changes will negatively impact the magnitude and/or specificity of antibody 
responses. There is a substantial risk that the trimer-CD4 interaction will alter the 
human antibody response because the germinal center reaction where antibody 
maturation occurs involves dynamic interactions between CD4+ T cells and B 
cells in the presence of antigen. The risk of such an undesired response may be 
heightened for membrane-bound trimers that may interact with CD4+ T cells in a 
highly multivalent manner via presentation on microvesicles, or exosomes or cell 
surfaces. Therefore, evaluating a platform which reduces trimer-CD4 interactions 
is of interest.  
A transformative vaccine delivery platform is needed to provide a combination 
of speed and reduced cost with sufficiently strong and high-quality immunity. In 
collaboration with Moderna and partnership with IAVI and the Bill & Melinda 
Gates Foundation (BMGF), rabbit immune responses to BG505-based stabilized 
trimers delivered as mRNA/LNPs or protein plus an immunostimulatory 
complex (ISCOM)-like nanoparticle comprised of self-assembled cholesterol, 

 
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phospholipid, and Quillaja saponin made at Massachusetts Institute of 
Technology (MIT) called ISCOMIT (adjuvant) in both soluble trimer and 
ferritin-nanoparticle formats were evaluated. The ISCOMIT adjuvant is 
synthesized as described in Tokatlian et al Science 2019 (16). Membrane-bound 
trimer format via mRNA/LNP delivery was also assessed. As discussed below, 
the responses have been particularly favorable for the membrane-bound trimer 
format, in that: (i) autologous neutralizing responses have been at least as good 
as for purified trimer protein plus adjuvant; (ii) base-directed responses have 
been substantially reduced, according to enzyme-linked immunosorbent assay 
(ELISA) and electron microscopy-based polyclonal epitope mapping (EMPEM); 
and (iii) trimer-degrading responses have been reduced according to EMPEM.  
These findings, and the partnership with IAVI and BMGF, along with National 
Institute of Allergy and Infectious Diseases (NIAID), NIAID/Division of 
AIDS(DAIDS) and NIAID/Vaccine Research Center (VRC) leadership, have led 
to the proposed study.  
This study involving mRNA/LNP delivery of trimers could greatly accelerate 
progress toward development of an HIV vaccine, as the rapid timescale and 
reduced cost of GMP manufacture will enable a larger number of constructs and 
regimens to be tested in the clinic. Additionally, this approach would likely 
transform the field and cause most or many future HIV vaccine clinical studies to 
employ this or similar nucleic acid delivery strategies, at least for the process of 
iterative regimen optimization. Whether a final licensed vaccine to elicit durable 
bnAb responses would employ mRNA/LNPs or adjuvanted protein or another 
technology would remain to be determined.  
The proposed trial will also reveal whether or not HIV trimers for human 
immunization should be engineered to lack CD4 affinity. If knocking out CD4 
binding is found to be important for improving human responses, the field will 
likely adopt this strategy. The VRC is currently carrying out a Phase 1 study 
(NCT03783130) with an adjuvanted trimer that has 10-fold reduced affinity for 
CD4 (BG505 DS-SOSIP). However, the VRC molecule still retains high affinity 
with a KD of 10 nM (19), allowing for potentially avid interactions with cell 
surface CD4. In contrast, BG505 MD39.3 gp151 CD4KO HIV trimer mRNA has 
at least 1000-fold reduced avidity for CD4+ T cells (20). Evaluating responses 
generated by the BG505 MD39.3 gp151 CD4KO trimer and those induced by the 
DS-SOSIP trimer in a different study should provide guidance to the field on 
whether and to what degree trimer affinity for human CD4 should be suppressed. 
2.1 
Rationale for evaluation of BG505 MD39.3, BG505 MD39.3 gp151 and 
BG505 MD39.3 CD4KO gp151  
HVTN 302 will test mRNA/LNP as a platform for delivery of soluble and 
membrane-bound HIV trimers. The key advantages of mRNA/LNPs are the 
substantially reduced time and cost for GMP manufacture compared to purified 

 
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protein and the feasibility of delivering membrane-bound trimers. Key potential 
advantages of the following membrane-bound trimers are reduced elicitation of 
base-directed responses that are non-neutralizing and potentially trimer-
degrading; increased elicitation of responses to regions of the trimer other than 
the base; more native-like glycosylation (15) and more native-like 
conformational sampling due to the membrane anchor: 
1. A prefusion-stabilized, cleavage-independent, glycan-hole-masked soluble 
trimer (BG505 MD39.3). MD39 is an improved version of BG505 SOSIP 
with improved antigenicity, trimer yield, and thermal stability that has been 
engineered via structure-guided mammalian display directed evolution (1). 
MD39.3 includes the following changes to the original MD39: a linker 
("link14") across the gp120-gp41 cleavage site that has also been engineered 
by directed evolution (21), and mutations that previously described to 
introduce glycosylation sites in the well-known 241/289 glycan holes of 
BG505 (20). 
2. The matched trimer as in 1. but in a membrane-bound format including a 
transmembrane domain but lacking a C-terminal domain (BG505 MD39.3 
gp151) 
3. The same membrane-bound trimer as in 2. but with a point mutation in the 
CD4bs that was computationally designed and experimentally demonstrated 
to abrogate CD4 binding (BG505 MD39.3 CD4KO gp151) (20). 
This study will determine whether mRNA/LNP delivery of soluble or 
membrane-bound trimers is a promising platform for expeditious iterative 
vaccine development in terms of the speed and cost of deployment and the 
magnitude and quality of the human immune responses. This study will also 
disclose whether a modified membrane-bound trimer lacking CD4 affinity elicits 
improved antibody responses.  
2.2 
Preclinical data 
2.2.1 
Toxicity studies for BG505 MD39.3 HIV mRNA trimer vaccines 
A non-GLP study in Sprague Dawley rats was conducted to characterize the 
potential toxicity of the BG505 MD39.3, BG505 MD39.3 gp151 and BG505 
MD39.3 CD4KO gp151 trimer vaccines at IM dose levels of 30, 60, and 100 
mcg administered on Days 1, 22, and 43. Post-dose observations continued for 2 
weeks post the third dose. All injections were well tolerated and did not result in 
any animal deaths. Swelling at the injection site was noted in all animals, 
whereas transient pale skin resulted in a subset of animals due to lower blood 
counts. Other clinical pathology findings were consistent with an inflammatory 
and/or immune process. Overall, the results from the BG505 MD39.3, BG505 
MD39.3 gp151 and BG505 MD39.3 CD4KO gp151 trimer vaccines non-GLP 

 
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study demonstrate a similar, consistent, and acceptable toxicity profile 
supportive of this Phase 1 clinical trial.  
2.2.2 
Immunogenicity studies 
2.2.2.1 
In Rabbits 
BG505 MD39.3 was developed by introducing two glycosylation sites at 
positions 241 and 289 to BG505 MD39.2, a link14, cleavage-independent native-
like trimer. MD39.2 delivered as Moderna mRNA or purified soluble protein in 
multiple formats was tested in a large rabbit immunization study. Rabbits were 
immunized by the IM route at weeks 0, 8, and 24, with either 100 mcg 
mRNA/LNP or 30 mcg protein + 75U ISCOMIT. The different molecular 
structures of MD39.2 included: 
• 
Soluble trimer: MD39.2 (mRNA and protein) and MD39.2 with wild-type 
signal peptide leader sequence – MD39.2WTsp (mRNA)  
• 
MD39.2 ferritin nanoparticle (mRNA and protein)  
• 
Two types of membrane-bound trimers tested only as mRNA: membrane-
tethered trimer (MD39.2 PDGFR – MD39.2 fused via a long flexible 
linker to plasma derived growth factor receptor [PDGFR] transmembrane 
domain) and natively membrane-bound trimer (MD39.2 gp160-dCT).  
• 
BG505 SOSIP trimer (mRNA and protein), MD39 (soluble trimer protein 
with intact cleavage site), olio6 (a variant of MD39, protein only), and 
gp120 foldon (protein only) as controls (Figure 2-1).  
The hypothesis was that autologous neutralization responses generally provide a 
readout on the degree to which the trimer constructs maintain a native-like state 
in vivo. In this study, very little autologous neutralization was detected after two 
immunizations in any of the groups. However, after three immunizations, the 
Moderna mRNA-launched MD39.2 gp160-dCT membrane-bound trimer elicited 
autologous neutralizing antibodies as well or better than any other mRNA group 
(left side of Figure 2-1). 
 

 
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Figure 2-1 BG505-T332N autologous neutralization by purified serum IgG from week 26 
(post 3rd vaccination) from rabbit experiment #1 
Figure 2-1 also shows that the MD39.2 gp160-dCT mRNA construct performed 
approximately as well as any of the purified protein groups (right side of Figure 
2-1).Using a Kruskal-Wallis statistical test that corrects for multiple 
comparisons, the MD39.2 gp160-dCT group was not significantly different from 
any other mRNA or protein group except the MD39.2 ferritin (mRNA) and 
gp120 foldon (protein). The caveat with the data in Figure 2-1 is that the 
neutralization titers for both protein and mRNA groups are low compared to 
historical data for three administrations of BG505 SOSIP protein plus adjuvant 
in rabbits (22, 23). Assuming that an unknown factor reduced titers in all groups 
relatively equally, it seems fair to conclude that the membrane-bound trimer 
performed well against all other mRNA or protein groups. 
A smaller follow-up rabbit study was conducted to further evaluate mRNA 
trimer forms:  
• Soluble trimers (MD39.2 and MD39.3) 
• Membrane-bound (MD39.2 gp160-dCT) 
• Circularly-permuted soluble trimer CPG9 (20) that eliminates the cleavage 
site and affords a degree of glycan masking on the trimer base.  
In both experiments, rabbits were immunized by the IM route at weeks 0, 8, and 
24, with 100 mcg mRNA/LNP. 
Membrane-bound gp160-dCT MD39.2 and MD39.2 delivered via mRNA 
elicited autologous neutralizing IgG antibodies at titers similar to or greater than 
soluble trimer at both week 10 (post two vaccinations) and week 26 (post three 

 
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immunizations) (Figure 2-2). Also, the week 26 neutralization titers for MD39.3 
gp160-dCT in this experiment were within the range of BG505 autologous 
neutralization titers elicited by three administrations of stabilized BG505 soluble 
trimers in rabbits (22, 23) or NHPs (8, 9). 
 
Figure 2-2 BG505-T332N autologous neutralization by purified IgG from week 10 and 26 
from rabbit experiment #2. All immunizations were mRNA/LNP except the group labelled CPG9 
(pt). 
One hypothetical benefit of employing membrane-bound trimer immunogens 
would be reducing non-neutralizing base-directed responses and a potential 
increase of responses to other epitopes on the trimer. To investigate this, ELISA 
analyses were carried out on the week 10 sera from rabbits in both experiments. 
The responses were characterized by the area under the curve (AUC) of the 
serum titration. Responses were measured against MD39 captured by PGT128 
Fab, a protocol in which MD39 has a native antigenic profile with good binding 
to bnAbs, including N332 bnAbs and reduced binding to non-nAbs directed to 
V3 or the CD4bs (not shown). By capturing MD39 with PGT128, the base of the 
trimer was well-exposed in the ELISA assay. All of the soluble trimer 
immunogens, whether protein or mRNA, elicited stronger responses to MD39 
than either of the membrane-bound gp160-dCT immunogens (Figure 2-3A). To 
determine the degree of binding to epitopes other than the base, responses to 
MD39 in the presence of a high concentration (20 mcg/mL) of a base-directed 
antibody, 19R (also known as 1E6), were measured. In that competition assay, 
there was no significant difference in the responses to membrane-bound trimers 
compared to soluble trimers (Figure 2-3B), indicating that membrane-bound 
trimers elicit comparable responses to the "top" of the trimer as soluble trimers. 
From these two assays, the fraction of the response to MD39 that was directed to 
the base (Figure 2-3C) was computed. By this measure, approximately 50% of 
the response to any of the soluble trimers was directed to the base, whereas the 
membrane-bound trimers elicited a near-zero anti-base response (blue arrows in 
Figure 2-3C). In conclusion, mRNA-delivered, membrane-bound trimers can 
elicit significantly reduced anti-base responses while eliciting similar levels of 
responses to other trimer epitopes. 

 
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Figure 2-3 ELISA analysis of serum antibody binding responses from week 10 (post two 
vaccinations) for rabbit experiments 1 and 2 combined. A: Response to MD39; B: 
Response to MD39 in presence of base-directed antibody 19R, to reveal responses to 
epitopes other than the base; C: Fraction of response to MD39 that is directed to the base. 
Immunogens were mRNA/LNP unless indicated otherwise. 
Summary of rabbit studies 
Overall, the mRNA-delivered, natively membrane-bound trimer performed as 
well as or better than other formats in head-to-head comparisons, based on (a) 
BG505 autologous neutralization (b) ELISA analyses (c) Electron microscopy 
(EM) mapping of polyclonal responses (data not shown), and (d) EM analysis of 
trimer degradation (data not shown). In rabbits, immunization 100 mcg of HIV 
Trimer mRNA/LNP was well tolerated with no observed morbidity or mortality 
and only elicited modest autologous neutralization titers. 
 
Improvement of cell surface expression 
The rabbit experiments were carried out with a gp160-dCT design that 
inadvertently included a known endocytosis motif (GYXXØ) at the C-terminus. 
The designs were modified to eliminate that motif, and the new construct is 
referred as a gp151 design. The new gp151 design exhibited approximately 8-
fold higher cell surface expression compared to the original gp160-dCT design, 
as measured by in vitro transfection and cytometry (A). The new gp151 MD39.3 
mRNA trimers also maintained a favorable antigenic profile (B) (compared to 
wild type [WT], there is reduced binding to non-neutralizing 4025 and B6 
antibodies while retention of binding to bnAbs). For the clinical trial, membrane-

 
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bound trimers are manufactured based on the new gp151 format, as higher cell 
surface expression combined with favorable antigenicity is expected to lead to 
stronger favorable immune responses.  
 
Figure 2-4 Cell surface expression and antigenic profile for membrane-bound BG505 
trimers as gp160-dCT or gp151 
2.2.2.2 
In non human primates (NHPs) 
Five groups of six rhesus macaques were immunized via IM injection bilaterally 
in each deltoid at weeks 0, 8 and 24 using BG505 MD39.3 constructs listed 
below.  
1. BG505 MD39.3 soluble trimer delivered by mRNA (100 mcg total dose) 
2. BG505 MD39.3 gp151 membrane-bound trimer delivered by mRNA (100 
mcg total dose) 
3. BG505 MD39.3 CD4KO gp151 membrane-bound trimer delivered by mRNA 
(100 mcg total dose) 
4. BG505 MD39.3 gp151 membrane-bound trimer delivered by mRNA (300 
mcg total dose) 
5. BG505 MD39.3 soluble trimer delivered with adjuvant (100 mcg protein + 
750 mcg SMNP adjuvant total dose) 
All five groups elicited similar levels of binding antibodies at assessed at weeks 
10 and 26 with the binding titers increasing for all groups following the third 
immunization at week 24 (Figure 2-5). 

 
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Figure 2-5 ELISA analysis of serum antibody binding responses from week 10 (post two 
immunizations) and week 26 (post three immunizations) in NHPs 
None of the animals receiving BG505 MD39.3 soluble trimer delivered by 
mRNA developed autologous neutralizing antibodies even after three 
immunizations (Figure 2-6, Grp1). Half of the animals receiving the 100 mcg 
dose of BG505 MD39.3 gp151 membrane-bound trimer delivered by mRNA 
developed detectable autologous neutralizing antibodies at week 10 which 
increased in potency at week 26 (Figure 2-6, Grp2). Two of six animals 
receiving the 100 mcg dose of BG505 MD39.3 gp151 CD4KO membrane-bound 
trimer delivered by mRNA developed autologous neutralizing antibodies at week 
26 (Figure 2-6, Grp3). Four out of the six animals in the group receiving the 300 
mcg dose of BG505 MD39.3 gp151 membrane-bound trimer delivered by 
mRNA developed detectable autologous neutralizing antibodies at week 26 
(Figure 2-6, Grp4). A similar response was seen in the BG505 MD39.3 soluble 
trimer delivered with adjuvant group Figure 2-6, Grp5). Overall, BG505 MD39.3 
gp151 membrane-bound trimers delivered by mRNA elicited similar antibody 
responses compare to soluble trimer protein + adjuvant.  
To date, most trimer immunogen design and characterization in the HIV vaccine 
field has been focused on soluble trimers. Although none of the NHP animals 
receiving BG505 MD39.3 soluble trimer by mRNA (Grp 1) developed 
autologous neutralizing antibodies in this study, it is known that studies in 
animal models do not reliably predict human responses. Therefore, to identify 
the best trimer platform for mRNA delivery in humans, it is essential to test the 
most common trimer design employed by the HIV vaccine field (soluble gp140) 
along with the membrane-bound trimers that have performed well in our pre-
clinical studies (as shown above) and that are analogous to the membrane-bound 
trimers in human SARS-CoV-2 mRNA vaccines.  
 

 
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Figure 2-6 BG505-T332N autologous serum neutralization in NHPs from weeks 10 and 26. 
Bars represent median ID50 among animals with detectable neutralization (ie, ID50 titer 
greater than 10). 
2.2.2.3 
In rats 
Rats administered mRNA-1574, mRNA-1574.2 or mRNA-1574.3 demonstrated 
dose-independent binding Ab titers to autologous trimer antigen on Day 56. 30, 
60 and 100 mcg doses of mRNA-1574, mRNA-1574.2 and mRNA-1574.3 
elicited serologic responses to autologous trimer antigen in rats by 56 days (2 
weeks post 3rd dose) and the magnitude of responses was independent of the 
dose. 
2.3 
Rationale for Study Design 
The study design, randomized, open-labelled, unblinded and without a placebo 
control, allows for rapid access of study samples by the laboratory investigators 
earlier than is typical for blinded, placebo-controlled trials; thereby facilitating 
expeditious iterative development between the laboratory, pre-clinical and 
clinical arenas. In particular, exploratory assays may begin on samples before the 
majority of the participants have reached primary timepoints and prior to 
completion of the primary immunogenicity assays. This semi-experimental 
medicine design is being utilized within the HVTN for a suite of trials testing a 
range of HIV vaccine formulations expected to contribute to the goal of 
eventually developing HIV vaccines with broad neutralizing capabilities. The 
BG505 MD39.3 HIV trimer vaccines in HVTN 302 are not on the development 
pathway toward licensure. The lessons learned from this trial will inform the 
formulation of future products that will aim toward eliciting increasingly broad 
neutralization immune responses. Immunogenicity assays do not require 
comparison between immune responses elicited by vaccine versus by placebo as 
baseline samples may serve as controls where needed. Additionally, safety 
assessments do not require placebo recipient comparisons. The unblinded safety 
reports reviewed weekly by the Protocol Safety Review Team (PSRT) during the 
vaccination phase will also facilitate safety monitoring between study arms and 
across dosing groups which would allow potentially for differential action to be 

 
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taken by study arm, as appropriate, if safety or tolerability concerns arose for a 
particular study arm. 
2.4 
Rationale for Schedule 
To match the schedule used in other comparable trials and pre-clinical studies, 
BG505 MD39.3 HIV Trimer mRNA vaccines will be administered at a dose of 
100 mcg or 250 mcg at Month 0, 2 and 6. Rabbit studies described above 
demonstrated that autologous neutralizing antibody responses were significantly 
increased following the third compared with the second vaccine administration 
timepoint. A similar experimental mRNA vaccine being evaluated for 
Cytomegalovirus (CMV), the Moderna mRNA CMV vaccine (mRNA-1647), is 
administered at Month 0, 2 and 6. Neutralizing antibody titers increased 
following the Month 2 vaccination, were further boosted after the Month 6 
vaccination and were then sustained for at least 12 months (24-26).  
2.5 
Rationale for Dose of HIV Trimer mRNA/LNP 
We propose to test both the 100 mcg dose and a higher dose of 250 mcg in order 
to find the maximum tolerable dose that gives strong human antibody responses 
and that can distinguish responses between the three different immunogens in the 
trial.  
The Moderna Phase 1 trial of the SARS-CoV-2 vaccine candidate mRNA-1273, 
a membrane-anchored glycoprotein trimer analogous to membrane-anchored 
trimers proposed here, administered vaccine at 25, 100 and 250 mcg doses at two 
timepoints. Binding antibody titers were greater with increasing dose levels, 
although pseudoneutralization antibody titers were generally similar between the 
100 and 250 mcg doses. Reactogenicity was generally of greater frequency and 
intensity at higher doses and following the second administration. Systemic 
solicited adverse events were more common after the second vaccination and 
21% of participants in the 250 mcg dose group reported one or more severe 
systemic adverse events after the second vaccination, however, no serious 
adverse events were reported and no stopping rules were met in the trial (4).  
Furthermore, the Moderna CMV vaccine (mRNA-1647) has been administered 
in doses up to 300 mcg, with multiple administrations per volunteer. In the Phase 
1 trial, at the 12 month interim analysis, there were no vaccine-related serious 
adverse events (SAEs) and safety and tolerability at the 300 mcg dose level was 
similar to that observed at the 180 mcg level (26). Reactogenicity tended to 
increase in frequency and intensity after the second dose compared to the first, 
but (for the 90 and 180 mcg doses) decreased or remained similar after the third 
dose relative to post second dose (25).  

 
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Finally, in the rabbit immunization studies with 100 mcg HIV trimer 
mRNA/LNPs, the autologous neutralization titers have been modest, suggesting 
that testing a higher dose of the BG505 MD39.3 HIV mRNA trimers is 
warranted in humans for eliciting neutralizing antibodies. Thus, in order to find 
the maximum safe dose for mRNA/LNP delivery of HIV Env trimers in humans, 
testing both 100 mcg and 250 mcg will be important. Tolerability at the 250 mcg 
dose level for these BG505 MD39.3 HIV mRNA trimer vaccines is not yet 
predictable given that reactogenicity of mRNA vaccines appears to be antigen-
dependent and this trial is a first-in-human assessment of these HIV antigens. 
The enrollment strategy utilizing safety sentinel cohorts for both of the 100 mcg 
and 250 mcg dose groups will facilitate careful safety monitoring by group 
following each administration. A non-GLP toxicity study was performed with 
three administrations of the mRNA1574 vaccines at 30, 60, and 100 mcg dose in 
rats. The toxicity report is included in the IB and supports the starting dose level 
of 100 mcg. 
For additional information, see the Investigator’s Brochure (IB). 
2.6 
Rationale for Lymph Node Fine Needle Aspiration 
A subset of participants (approximately 1/2 of each group at the 100 mcg dose 
level) will undergo fine-needle aspiration (FNA) of the axillary draining lymph 
node after each dose of BG505 MG39.3 mRNA vaccines to gain understanding on 
how the magnitude and kinetics of germinal center (GC) B and T-cell responses 
may differ between: a) soluble and membrane trimers and b) CD4KO and WT-
CD4bs membrane trimers. The analysis of these FNA/GC responses will be 
compared to FNA/GC responses in NHPs administered the same immunogens, 
thus allowing for greater understanding of how and whether NHP responses can 
be used to predict human responses. The FNA/GC responses here will also provide 
baseline data on human GC responses to trimer mRNA immunization that can be 
evaluated relative to future adjuvanted protein trimer immunization studies. This 
same subset will have samples collected for B-cell sorting and sequencing to 
obtain information on the B cell receptor (BCR) repertoires of the GC and memory 
B cells induced by these mRNA immunogens, in particular to look for differences 
in BCR repertoire responses between: a) soluble and membrane trimers and b) 
CD4KO and WT-CD4bs membrane trimers. 
2.7 
Rationale for Leukapheresis 
This protocol will employ leukapheresis also in approximately 1/2 of each group 
at the 100 mcg dose level to ensure adequate specimens for analysis of rare 
precursors. Leukapheresis will be performed after the second and third doses of 
BG505 MG39.3 mRNA vaccines have been administered. The rationale for 
performing leukapheresis two weeks post vaccination is based upon detailed 

 
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preclinical investigations into the kinetics of the germinal center response in 
rhesus macaques (10). 
Samples collected through leukapheresis after the second and third vaccine 
administration will be used for MHC Class II human leukocyte antigen (HLA) 
typing and CD4+ T-cell epitope mapping to understand the breadth and potency 
of CD4 epitopes in these trimers. These studies will a) provide insight into how 
soluble, membrane-bound, and membrane-bound-CD4KO trimers may differ in 
their induction of CD4+ T-cell responses and b) most importantly, assist design 
of future sequential immunization regimens that incorporate these trimers to 
ensure that T-helper epitopes that are cross-reactive over vaccine recipients and 
common MHC alleles are shared among different immunogens in the regimen. 
To assess the expansion of antigen specific precursor B cell populations and 
CD4+ T-cell repertoire large numbers of peripheral blood mononuclear cells 
(PBMCs) are required. There are approximately 1 million PBMCs per milliliter 
of blood and therefore peripheral blood sampling at volumes associated with 
typical blood donation (~500 mL) would not provide sufficient PBMC numbers. 
Leukapheresis can provide 6-10 billion PBMCs without depleting red blood cells 
or other blood components.  
2.8 
Risks and benefits 
2.8.1 
Potential risks  
While other mRNA vaccines have been evaluated in humans, this is the first 
study in humans of the MD39.3 mRNA HIV trimer vaccines. The nature of the 
antigen may affect the safety and tolerability profile of the vaccine. Therefore, 
most of the risks noted are based on risks of vaccines in general.  
On May 25, 2022, study enrollments and vaccinations were paused due to the 
occurrence of delayed urticarial rash with dermatographism in two participants 
(out of 106 participants enrolled at that point). The first event was reported by a 
42 year-old male participant with a history of seasonal allergies. The onset of the 
rash was 10 days after receiving dose 1 of BG505 MD39.3gp151 mRNA at 100 
mcg (Group 2). The rash was erythematous, pruritic, and diffuse, but without 
mucosal involvement or respiratory symptoms. Dermatographism was also 
observed. The event was assessed as related to the investigational product and 
assigned grade 2 in severity by the investigator. The participant was treated with 
oral and topical antihistamines. As of June 8, 2022 (approximately 6 weeks after 
onset), the event was improved but not resolved. The second event was reported 
by a 39 year-old male participant who developed diffuse pruritis and urticaria 
approximately 10-17 days after receiving dose 1 of BG505 MD39.3 mRNA at 
100 mcg (Group 1). This rash initially was attributed to an environmental 
exposure and improved with oral antihistamines with residual mild pruritus. On 
May 19, 2022, six days after the second dose of study vaccine, the participant 

 
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developed worsening diffuse pruritis with urticaria and dermatographism. No 
mucosal involvement or shortness of breath was reported. This participant later 
developed scrotal edema following recreational activity and presented to an 
emergency room where he was treated with intravenous and oral steroids and 
antihistamines. The event was assessed as related to the investigational product 
and assigned grade 2 in severity by the investigator. As of June 8, 2022, the 
event was improved but not resolved. Vaccinations were permanently 
discontinued for both of these participants. 
After extensive reviews and further follow up on these 2 events, the vaccination 
pause for enrolled participants was lifted on June 16, 2022 with participants 
being informed and re-consented. Subsequently, the protocol and protocol 
informed consent were amended and the enrollment pause was lifted on July 21, 
2022. Enrollment in the trial was completed on August 9, 2022.  
Update of urticaria events as of May 23, 2023: The 2 participants with urticaria 
events described above still have some symptoms, although they have improved 
over time with less symptom frequency and are using less medication. Since the 
initial report regarding these 2 participants, 5 additional participants developed 
mild or moderate hives after receiving their first or second study vaccinations. 
One participant developed hives about 10 hours after getting the vaccination 
which went away by the next day without treatment. Four participants developed 
hives 1-3 weeks after their study vaccination and have required medication to 
control outbreaks since then. Two participants received additional doses of study 
vaccine and did not experience a worsening of their initial symptoms. None of 
the reported reactions included symptoms of anaphylaxis, and all reactions were 
assessed as mild or moderate in severity.   
Overall, urticaria symptoms resolved for 3 of 7 participants and have improved 
over time with and without medication for the other 4 participants.   
Delayed-onset urticarial reactions (occurring >4 hours post-vaccination) have 
been observed following COVID-19 vaccination, both mRNA and other 
platforms, and differ distinctly from immediate-onset (<4 hours) Type I 
hypersensitivity reactions and are not associated with anaphylaxis (27-29). The 
timing of onset may vary from <1 day to 21 days post-vaccination and the time 
to resolution may vary from 24 hours to 6 weeks (27-30). Onset is more often 
reported following the first vaccination and may occur at later doses. It is 
common for subsequent vaccinations to be received without recurrence of 
urticarial reactions. Treatment is typically with H1-blocking antihistamines and 
may also include H2-blocking antihistamines; corticosteroids have also been 
used. The prevalence of symptomatic dermatographism in the general population 
is not well known, but is a fraction of those with simple dermatographism 
(prevalence 1.5-6% of the general population) (31, 32). Urticaria with 
dermatographism arising anew following receipt of COVID-19 mRNA vaccines 
has been reported rarely in the literature (32) yet has been observed by practicing 

 
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allergy/immunology specialists. Receipt of subsequent COVID-19 mRNA 
vaccinations was not contra-indicated for these cases, and refractory urticaria 
with dermatographism (persistent symptoms despite above standard doses of 
antihistamines) has been treated successfully with omalizumab (32). It is 
important to note, however, that causality of these events has not been 
established with respect to  vaccines, and a comparative analysis of these events 
occurring in the background over a similar timeframe has not been done. 
Frequent potential side effects resulting from other intramuscular (vaccines) and 
subcutaneous (local anesthetic prior to FNA) injections include stinging, 
discomfort, redness and/or swelling of skin, itching, or mild bruising at injection 
site. 
Side effects of varying frequency from other intramuscular vaccines include: 
headache, fever, chills, rash, aches and pains, nausea, dizziness and fatigue. If 
these occur, they will be monitored, but with other vaccines, these effects are 
generally short term, mild to moderate in severity, and usually do not require 
treatment. Less frequently, severe symptoms that temporarily prevent normal 
activities or require treatment may occur with some vaccines. Side effects from 
some vaccines may be more intense or more frequent following a subsequent 
administration of the vaccine. 
Rare risks with any injection procedure include infection at the site of injection. 
Signs of infection at the injection site include severe pain, erythema, induration, 
warmth or drainage. There are rare reports of anaphylaxis with many vaccines. 
There may be side effects from the study products which may be serious or life 
threatening that we do not know about yet. 
If antibodies elicited by the study vaccine result in a positive or indeterminate 
HIV test (ie, vaccine-induced seropositivity or VISP), this may have a negative 
impact on employment, health care, insurance, travel, and personal relationships. 
HIV polymerase chain reaction (PCR) will be used to exclude or confirm HIV 
infection.  
Blood drawing may cause pain, bruising, fainting, and, rarely, infection at the 
site where the blood is taken. Leukapheresis can also cause pain, bruising, and, 
rarely infection. Additional risks may depend on local leukapheresis procedures. 
Fainting can also occur, but occurs less frequently than with blood drawing. 
Fine needle aspiration of lymph nodes can uncommonly cause pain, bruising, 
and/or bleeding at the site where the needle is inserted. Similar to any procedure 
where a needle is inserted into the skin (such as vaccination, as described above), 
there is a rare risk of localized infection. The local anesthetic rarely can cause 
temporary arm numbness or weakness. 
Risks during Pregnancy: Because possible effects of the study vaccine on a fetus 
or nursing infant are unknown, persons assigned female sex at birth who have 

 
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reproductive potential will be tested for pregnancy at screening and prior to 
administration of each dose of study vaccine. Such persons will be asked to 
notify the site immediately if they suspect or learn they are pregnant during this 
study. In case of pregnancy, participants will continue to be followed for safety 
and the participant will not receive any additional vaccinations. The participant 
will be contacted about the outcome of a pregnancy that begins during the study.  
Other Risks: The medical tests performed as part of this research protocol may 
result in new diagnoses or abnormal values without clinical significance. 
Depending on the medical findings and consequences of being provided with the 
results of these tests, the study participant may view this as either a risk or a 
benefit. Any such information will be shared and discussed with the participant 
and, if requested by the participant, may be forwarded to the primary health care 
provider for further workup and management. 
Participants in this study risk experiencing discrimination or other personal 
problems that may result from study participation itself: these are known 
collectively as negative social impacts. The HVTN clinical research site (CRS) is 
obliged to provide advocacy for and assistance to participants regarding these 
negative social impacts associated with the vaccine trial. If HVTN CRS staff 
have questions regarding ways to assist a participant dealing with a negative 
social impact, a designated HVTN Core representative can be contacted. 
2.8.2 
Myocarditis and Pericarditis with mRNA COVID-19 vaccines  
In the general population, myocarditis is diagnosed in approximately 10 to 20 
individuals per 100,000 per year, occurs more commonly and at younger ages in 
persons assigned male sex at birth compared with those assigned female, and 
may be caused by various bacterial, viral and other infectious agents, toxins, 
drugs, allergens, and autoimmune conditions (33-35). Increased cases of 
myocarditis and pericarditis have been reported after mRNA COVID-19 
vaccination (Pfizer-BioNTech and Moderna), predominantly in adolescents and 
young adults 16 to 29 years of age assigned male sex at birth; however, cases 
have also been reported in older persons of both sexes (36). Onset was typically 
within several days after mRNA COVID-19 vaccination, and cases have 
occurred more often after the second dose than the first dose.  
In most of the reported cases, individuals who presented for medical care have 
responded well to medications (nonsteroidal anti-inflammatory agents, 
glucocorticoids, or intravenous immunoglobin) and rest with prompt 
improvement of symptoms, although some cases have been severe. Follow-up 
data is limited, and it is not yet known whether the risk of myocarditis or 
pericarditis remains increased following additional doses of the mRNA COVID-
19 vaccine. CDC and its partners are continuing to investigate these reports of 
myocarditis and pericarditis following mRNA COVID-19 vaccination. 

 
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While the pathophysiology of SARS-CoV-2 infection on the cardiovascular 
system and the association with myocarditis, pericarditis, myocardial infarction, 
thromboembolic disease has received intense scrutiny (33, 37, 38), the 
underlying pathophysiology linking COVID-19 mRNA vaccines to cardiac 
disease is not well understood (27). It is not known whether the risk of 
myocarditis or pericarditis is increased following other mRNA vaccines. Given 
this, study participants will be instructed to seek medical attention and to notify 
study site staff if symptoms of myocarditis and/or pericarditis occur following 
vaccination, and include chest pain, shortness of breath, palpitations [a fluttering 
sensation, fast heartbeat, pounding heart, or irregular heartbeat], or syncope.  
2.8.3 
Benefits 
Study participants will not receive direct health benefit from study participation. 
The public may benefit from knowledge gained in this study that may aid in the 
future development of an HIV vaccine. The investigational vaccines are not 
expected to provide protection from HIV infection. 
Participants may benefit from more frequent counseling, laboratory tests and 
physical exams while enrolled in the study. Participants may also experience 
positive social impacts as a benefit of study participation. When asked, 
participants from previous HVTN studies say that being in a study made them 
feel good about helping others, increased their knowledge about HIV, and 
improved their self-esteem. 
2.9 
Assessment of immunogenicity endpoints 
The primary immunogenicity endpoint assay will measure the occurrence and 
magnitude of serum antibody neutralization of pseudoviruses (BG505 MD39.3, 
BG505 MD39.3 gp151, and BG505 MD39.3 gp151 CD4KO) by the TZM-bl 
assay two weeks after the third vaccination. Occurrence and magnitude of serum 
IgG binding antibodies to BG505 trimer, and specific epitopes (base of trimer, 
V3, internal epitope) will be measured by ELISA and/or BAMA two weeks after 
the third vaccination. Response rate and magnitude of CD4+ T cell responses 
will be assessed by intracellular cytokine staining assays (ICS) two weeks after 
the last vaccination. 
Lymphocytes from an axillary lymph node obtained by FNA of the node will be 
examined for a germinal center activity and induction and maturation of 
germinal center B cells 3-6 weeks after vaccination.  
Additional assays may be performed on selected responders and at additional 
timepoints at the discretion of Protocol Team leadership based on its evaluation 
of primary results following the third vaccination (see Section 3.1).  

 
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3 
Objectives and endpoints 
3.1 
Primary objectives and endpoints 
Primary objective 1: 
To evaluate the safety and tolerability of BG505 MD39.3 trimer mRNA vaccines 
in healthy, HIV-uninfected adults 
Primary endpoint 1: 
Local and systemic reactogenicity signs and symptoms for a minimum of seven 
days following receipt of any study product. Laboratory measures of safety. All 
adverse events (AEs) for thirty days after receipt of study vaccination 
All serious adverse events (SAEs), medically attended adverse events (MAAEs), 
adverse events of special interest (AESIs), and AEs leading to early participant 
withdrawal or permanent discontinuation will be collected throughout the study 
Primary objective 2: 
To evaluate the ability of BG505 MD39.3 trimer mRNA vaccines to elicit 
autologous neutralizing antibodies and to compare responses between the 
membrane-bound vaccine regimen (BG505 MD39.3 gp151 mRNA) and the 
membrane-bound knockout (BG505 MD39.3 gp151 CD4KO mRNA) and between 
the membrane-bound vaccine regimen (BG505 MD39.3 gp151 mRNA) and the 
soluble trimer (BG505 MD39.3 mRNA) vaccine arms, within each dose level 
Primary endpoint 2: 
Occurrence, magnitude, and response rate of serum antibody neutralization of a 
vaccine-matched tier 2 HIV-1 strain as measured by the TZM-bl assay two 
weeks after the third vaccination 
3.2 
Secondary objectives and endpoints 
Secondary objective 1: 
To evaluate the ability of BG505 MD39.3 trimer mRNA vaccines to elicit 
humoral and cellular immune responses and to compare responses between the 
membrane-bound vaccine regimen (BG505 MD39.3 gp151 mRNA) and the 
membrane-bound knockout (BG505 MD39.3 gp151 CD4KO mRNA) and between 
the membrane-bound vaccine regimen (BG505 MD39.3 gp151 mRNA) and the 
soluble trimer (BG505 MD39.3 mRNA) vaccine arms, within each dose level and 
to compare responses between dose levels for each vaccine regimen 

 
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Secondary endpoints 1: 
• Occurrence, magnitude, and response rate of serum antibody neutralization of 
a vaccine-matched tier 2 HIV-1 strain as measured by the TZM-bl assay two 
weeks after the second vaccination 
• Occurrence, magnitude, and response rate of serum IgG binding antibodies to 
the BG505 trimer, and specific epitopes (base of trimer, V3, internal epitope) 
as measured by binding antibody multiplex assay (BAMA) two weeks after 
the second and third vaccination  
• Occurrence, magnitude, and response rate of CD4+ T-cell responses as 
assessed by intracellular cytokine staining assays (ICS) two weeks after the 
third vaccination 
Secondary objective 2: 
To evaluate the durability of humoral immune responses to BG505 MD39.3 
trimer mRNA vaccines and to compare durability between arms 
Secondary endpoints 2: 
• Occurrence, magnitude, and response rate of serum antibody neutralization of 
a vaccine-matched tier 2 HIV-1 strain, as measured by the TZM-bl assay six 
months after the third vaccination  
• Occurrence, magnitude, and response rate of serum IgG binding antibodies to 
the BG505 trimer, and specific epitopes (base of trimer, V3, internal epitope), 
as measured by BAMA six months after the third vaccination 
3.3 
Exploratory objectives 
Exploratory objective 1 
To determine whether higher doses of BG505 MD39.3 trimer mRNA vaccines 
induce stronger and/or more consistent humoral and/or cellular immune responses 
Exploratory objective 2 
To evaluate the epitope specificity of autologous (BG505/T332N) neutralization 
Exploratory objective 3 
To evaluate serum antibody specificities and elicitation of trimer degrading 
antibodies by electron microscopy-based polyclonal epitope mapping (EMPEM) 

 
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Exploratory objective 4 
To evaluate the magnitude and kinetics of BG505-specific GC B and T-cell 
responses  
Exploratory objective 5 
To evaluate BCR repertoires and sequences of the BG505-specific GC and 
memory B cells  
Exploratory objective 6 
To evaluate CD4+ T-cell mapping and HLA typing by BG505 MD39.3 trimer 
mRNA vaccines in a subset of participants 
Exploratory objective 7 
To evaluate the ability of the vaccine regimen to elicit HIV-1 specific 
heterologous tier 2 neutralizing antibodies 
Exploratory objective 8 
To characterize monoclonal antibodies derived from BCR sequences from 
BG505-specific B cells 
Exploratory objective 9 
To characterize antibody avidity and Fc-mediated antibody functions (eg, 
antibody-dependent cellular phagocytosis [ADCP] and antibody-dependent 
cellular cytotoxicity [ADCC]) 
Exploratory objective 10 
To evaluate binding antibody responses elicited by BG505 MD39.3 trimer 
mRNA vaccines as measured via ELISA  
Additional exploratory objectives 
To conduct analyses related to furthering the understanding of HIV, 
immunology, vaccines, and clinical trial conduct. To further evaluate 
immunogenicity of each vaccine regimen, additional immunogenicity assays 
may be performed in a subset of participants, including on samples from other 
timepoints, based on the HVTN Laboratory Assay Algorithm. 

 
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4 
Laboratory strategy  
The primary goal of HVTN 302 is to determine whether the BG505 MD39.3 
HIV trimer mRNA vaccines can drive the induction of tier 2 serum neutralizing 
antibody responses. To this end, HVTN immunogenicity assays will be used to 
evaluate induction of autologous and heterologous neutralization as well as 
vaccine and epitope-specific binding antibodies. These data will also be used to 
identify and prioritize samples for in-depth immunogenicity analyses, including 
epitope-mapping of serum neutralizing antibody responses, and isolation and 
characterization of neutralizing monoclonal antibodies. Germinal center B cells 
and T cells will be evaluated in fine needle aspirates from lymph nodes to assess 
the impact of the different immunogen modalities and modifications (such as 
aberration of CD4 binding) in the trafficking and retention of antigen in the 
draining lymph nodes and degree of germinal center activity. The detailed 
laboratory strategy is described in the Central Assay Plan and will be updated as 
new reagents and techniques are incorporated into assay planning. This 
document will be available on the protocol webpage. Descriptions of the 
standard HVTN laboratory assays can be found online at 
https://www.hvtn.org/content/dam/hvtn/scientific-programs/hvtn-laboratory-
assay-descriptions.pdf.  
 
 

 
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5 
Study design 
This is a multicenter, randomized, open-label, Phase 1 study to evaluate the 
safety and immunogenicity of BG505 MD39.3, BG505 MD39.3 gp151, and 
BG505 MD39.3 gp151 CD4KO HIV trimer mRNA in healthy adults. The 
primary hypothesis is BG505 MD39.3 soluble and membrane-bound trimer 
mRNA vaccines will be safe and well-tolerated among HIV-uninfected 
individuals and will elicit autologous neutralizing antibodies. 
5.1 
Study population 
All inclusion and exclusion criteria must be met for eligibility. Screening 
procedures to determine eligibility must be performed within 56 days prior to 
enrollment.  
Investigators should always use good clinical judgment in considering a 
volunteer’s overall fitness for trial participation. Some volunteers may not be 
appropriate for enrollment even if they meet all inclusion/exclusion criteria. 
Medical, psychiatric, occupational, or other conditions may make evaluation of 
safety and/or immunogenicity difficult, and some volunteers may be poor 
candidates for retention. 
5.1.1 
Inclusion criteria 
1. Able and willing to complete the informed consent process, including an 
Assessment of Understanding: volunteer demonstrates understanding of this 
study; completes a questionnaire prior to first vaccination with verbal 
demonstration of understanding of all questionnaire items answered incorrectly. 
2. 18-55 years old, inclusive, on day of enrollment. 
3. Agrees to comply with planned study procedures and be available for clinic 
follow-up through the last clinic visit.  
4. Agrees not to enroll in another study of an investigational agent during 
participation in the trial. If a potential participant is already enrolled in another 
clinical trial, approvals from the other trial sponsor and the HVTN 302 PSRT are 
required prior to enrollment into HVTN 302. 
5. In good general health according to the clinical judgement of the site 
investigator. 
6. Physical examination and laboratory results without clinically significant 
findings that would interfere with assessment of safety or reactogenicity in the 
clinical judgement of the site investigator. 

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7.
Assessed as low risk for HIV acquisition per low risk guidelines (see Appendix 
H), agrees to discuss HIV infection risks, agrees to risk reduction counseling, and 
agrees to avoid behavior associated with high risk of HIV exposure through the 
final study visit. Low risk may include persons stably taking pre-exposure 
prophylaxis (PrEP) as prescribed for 6 months or longer.
8.
Hemoglobin
•
≥ 11.0 g/dL for volunteers who were assigned female sex at birth
•
≥ 13.0 g/dL for volunteers who were assigned male sex at birth and 
transgender males who have been on hormone therapy for more than 6 
consecutive months
•
≥ 12.0 g/dL for transgender females who have been on hormone therapy for 
more than 6 consecutive months
•
For transgender participants who have been on hormone therapy for less than 
6 consecutive months, determine hemoglobin eligibility based on the sex 
assigned at birth
9.
White blood cell (WBC) count > 3,500/mm3
10. Platelets ≥125,000 /mm3
11. Alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN) based on 
the institutional normal range
12. Serum creatinine ≤1.1 x ULN based on the institutional normal range
13. Negative results for HIV infection by an (US) Food and Drug Administration
(FDA)-approved enzyme immunoassay (EIA) or chemiluminescent microparticle 
immunoassay (CMIA).
14. Negative for anti-Hepatitis C antibodies (anti-HCV) or negative HCV nucleic 
acid test (NAT) if anti-HCV antibodies are detected.
15. Negative for Hepatitis B surface antigen.
16. For a volunteer capable of becoming pregnant:
•
Volunteers who were assigned female sex at birth and are of reproductive 
potential must agree to use effective means of birth control from at least 21 
days prior to enrollment through 3 months after their third vaccination 
timepoint (see Appendix I)

 
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• Has negative β-HCG (beta human chorionic gonadotropin) pregnancy test 
(urine or serum) at screening and prior to study product administration on day 
of enrollment. 
5.1.2 
Exclusion criteria 
1. Volunteer who is breast-feeding or pregnant. 
2. Hypertension that is not well controlled. If a person has been found to have 
elevated blood pressure or hypertension during screening or previously, exclude 
for blood pressure that is not well controlled. Well-controlled blood pressure is 
defined in this protocol as consistently < 140 mm Hg systolic and < 90 mm Hg 
diastolic, with or without medication, with only isolated, brief instances of higher 
readings, which must be ≤ 150 mm Hg systolic and ≤ 100 mm Hg diastolic. For 
these volunteers, blood pressure must be < 140 mm Hg systolic and < 90 mm Hg 
diastolic at enrollment. If a person has NOT been found to have elevated blood 
pressure or hypertension during screening or previously, exclude for systolic 
blood pressure ≥ 150 mm Hg at enrollment or diastolic blood pressure ≥ 100 mm 
Hg at enrollment. 
3. Diabetes mellitus type 1 or type 2. (Not exclusionary: type 2 cases controlled 
with diet alone or a history of isolated gestational diabetes). 
4. Previous or current recipient of an investigational HIV vaccine (previous placebo 
recipients are not excluded). 
5. Acutely ill or febrile (temperature ≥ 38.0°C/100.4°F) on the day of the first 
vaccination. Participants meeting this criterion may be rescheduled within the 
enrollment window period. Afebrile participants with minor illnesses can be 
enrolled at the discretion of the Investigator. 
6. Immunosuppressive medications received within 168 days before first 
vaccination (Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled 
corticosteroids; [3] topical corticosteroids for mild, uncomplicated dermatologic 
condition; or [4] a single course of oral/parenteral prednisone or equivalent at 
doses < 60 mg/day and length of therapy < 11 days with completion at least 30 
days prior to enrollment). 
7. Blood products or immunoglobulin within 16 weeks prior to enrollment; receipt 
of immunoglobulin within 16 weeks prior to enrollment requires PSRT approval. 
8. Receipt of any of the following: 
• Within 4 weeks prior to enrollment: 
 Any licensed live, attenuated vaccine  

 
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 Any mRNA-based SARS-CoV-2 vaccine with FDA licensure, FDA 
emergency use authorization (EUA), or World Health Organization 
(WHO) emergency use listing (EUL)  
• Within 2 weeks prior to enrollment: 
 Any licensed killed/subunit/inactivated vaccine 
 Any adenoviral-vectored or protein SARS-CoV-2 vaccine with FDA 
licensure, FDA EUA, or WHO EUL 
Receipt of any SARS-CoV-2 vaccination series should be completed 4 weeks 
prior to enrollment when possible; however, exceptions may be made by 
approval of the HVTN 302 PSRT. 
9. Initiation of antigen-based immunotherapy for allergies within the previous year 
(stable immunotherapy is not exclusionary); inclusion of participants who 
initiated immunotherapy within the previous year requires PSRT approval. 
10. Receipt of investigational research agents with a half-life of 7 or fewer days 
within 4 weeks prior to enrollment. If a potential participant has received 
investigational agents with a half-life greater than 7 days (or unknown half-life) 
within the past year, PSRT approval is required for enrollment. 
11. History of serious reaction (eg, hypersensitivity, anaphylaxis) to any vaccine or 
any component of the study vaccine. 
12. History of myocarditis and/or pericarditis. 
13. Hereditary angioedema, acquired angioedema, or idiopathic forms of 
angioedema. 
14. Idiopathic urticaria within the past year. 
15. Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or 
platelet disorder requiring special precautions). 
16. Seizure disorder; febrile seizures as a child or seizures secondary to alcohol 
withdrawal more than 5 years ago are not exclusionary.  
17. Asplenia or functional asplenia. 
18. Active duty and reserve US military personnel. 
19. Any other chronic or clinically significant condition that in the clinical 
judgement of the investigator would jeopardize the safety or rights of the study 
participant, including, but not limited to: clinically significant forms of drug or 
alcohol abuse, serious psychiatric disorders, or cancer that, in the clinical 

 
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judgement of the site investigator, has a potential for recurrence (excluding basal 
cell carcinoma). 
20. Asthma is excluded if the participant has ANY of the following: 
• Required either oral or parenteral corticosteroids for an exacerbation two or 
more times within the past year; OR 
• Needed emergency care, urgent care, hospitalization, or intubation for an 
acute asthma exacerbation within the past year (eg, would NOT exclude 
individuals with asthma who meet all other criteria but sought 
urgent/emergent care solely for asthma medication refills or co-existing 
conditions unrelated to asthma); OR 
• Uses a short-acting rescue inhaler more than 2 days/week for acute asthma 
symptoms (ie, not for preventive treatment prior to athletic activity); OR 
• Uses medium-to-high-dose inhaled corticosteroids (greater than 250 mcg 
fluticasone or therapeutic equivalent per day), whether in single-therapy or 
dual-therapy inhalers (ie, with a long-acting beta agonist [LABA]); OR 
• Uses more than one medication for maintenance therapy daily. Inclusion of 
anyone on a stable dose of more than one medication for maintenance 
therapy daily for greater than two years requires PSRT approval. 
21. A participant with a history of an immune-mediated disease, either active or 
remote. Not exclusionary: 1) remote history of Bell’s palsy (>2 years ago) not 
associated with other neurologic symptoms, 2) mild psoriasis that does not 
require ongoing systemic treatment. 
22. Immunodeficiency 
5.1.3 
Additional eligibility criteria for subset undergoing FNA and/or 
leukapheresis procedures 
1. Meeting local site requirements related to these procedures (eg, any specific 
hemoglobin level requirements by pheresis center)  
2. No concern by site investigator for difficulty with venous access based upon 
clinical history and physical examination. For example, history of IV drug abuse 
or substantial difficulty with previous blood draws. 
3. Willing to undergo lymph node FNA three times and/or leukapheresis twice per 
schedule of procedures. 
4. Participant may not be taking warfarin, oral antithrombin equivalents (including, 
but not limited to, apixiban, rivaroxiban, dabigatran), enoxaparin injections, or 

 
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other medications that would increase the risk of bleeding as assessed by the site 
investigator. 
5. No history of allergy to local anesthetic (eg, Novocaine, Lidocaine). 
6. No evidence of localized condition that would pose a contraindication to 
performance of axillary FNA of the draining lymph nodes ipsilateral to 
vaccination site as assessed by the site investigator. Note that FNA will only be 
performed following injections in the deltoid; in the event that the thigh is the 
injection site location, FNA will not be performed. 
5.2 
Participant departure from vaccination schedule or withdrawal  
5.2.1 
Delaying vaccinations for a participant 
Under certain circumstances, a participant’s scheduled vaccination will be 
delayed. The factors to be considered in such a decision include but are not 
limited to the following: 
• Intercurrent illness or pre-vaccination abnormal vital signs or clinical 
symptoms that may mask assessment of vaccine reaction 
• Treatment with systemic glucocorticoids (eg, prednisone or other 
glucocorticoid), immune targeting monoclonal antibodies or other 
immunomodulators (other than nonsteroidal anti-inflammatory drugs 
[NSAIDs]), with the exception that study injection may continue per 
principal investigator (PI) discretion if the next study injection occurs at least 
2 weeks following completion of glucocorticoid treatment; 
• Receipt of any live attenuated vaccines within 4 weeks prior to study vaccine 
administration 
• Receipt of any inactivated vaccines within 2 weeks prior to study vaccine 
administration with exception as below: 
• Timing of study vaccination with respect to SARS-CoV-2 vaccination:  
• After administration of SARS-CoV-2 vaccination, a minimum of 4 weeks 
is required before administration of study vaccine 
• Before administration of SARS-CoV-2 vaccine, a minimum of 4 weeks is 
recommended after administration of study vaccine  
• Timing of study vaccination with respect to monkeypox vaccination:  
 JYNNEOS vaccine:  

 
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 After administration of JYNNEOS vaccine, a minimum of 4 weeks is 
required before administration of study vaccine 
 Before administration of JYNNEOS vaccine, a minimum of 2 weeks 
is recommended after administration of study vaccine 
 ACAM2000 vaccine:  
 After administration of ACAM2000 vaccine, a minimum of 4 weeks is 
required before administration of study vaccine if vaccination scab is 
no longer present  
 If vaccination scab is still present at 4 weeks after receiving 
ACAM2000, delay study vaccination until the scab is no longer 
present 
 Before administration of ACAM2000 vaccine, a minimum of 4 weeks 
is recommended after administration of study vaccine 
Vaccinations should not be administered outside the visit window period 
specified in Appendix D and Appendix E without PSRT approval. 
Where not otherwise specified above, participants should be counseled to also 
avoid the above products in the interval between a study vaccination and 
completion of the 2-week postvaccination follow-up visit, whenever possible. 
However, the health and welfare of participants will be prioritized, so there is no 
need to delay any of the licensed or authorized vaccines or systemic 
glucocorticoids after the study vaccine, if necessary. 
5.2.2 
Discontinuation of study vaccine administration 
Under certain circumstances, an individual participant’s vaccinations will be 
permanently discontinued. Specific events that will result in stopping a 
participant’s vaccination schedule include: 
• SAE that is subsequently considered to be related to vaccination 
• Pregnancy (regardless of outcome) 
• HIV infection 
• Grade 3 AE assessed as related to study vaccine, with the following 
exceptions: 
o Grade 3 subjective reactogenicity and injection site reactions: 
injection site pain/tenderness and erythema/induration (grade 3 by 
size only), fatigue, generalized myalgia, generalized arthralgia, chills, 
headache, nausea (unless IV rehydration required) 

 
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o AEs reviewed by the PSRT and approved for vaccination 
continuation  
• Grade 4 AE assessed as related to study vaccine 
• Clinically significant type 1 hypersensitivity associated with study vaccine 
For ease of reference and review, the clinically significant type 1 
hypersensitivity definition, as per the Second National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network symposium 
criteria for anaphylaxis (39), is provided below:  
Anaphylaxis is highly likely when any one of the following criteria are 
fulfilled: 
1 
Acute onset of an illness (minutes to several hours) with involvement of the 
skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula)  
AND AT LEAST ONE OF THE FOLLOWING:  
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, 
stridor, reduced peak expiratory flow(PEF), hypoxemia)  
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (eg, hypotonia [collapse], syncope, incontinence)  
2 
Two or more of the following that occur rapidly after exposure to a likely 
allergen for that patient [participant] (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-
flush, swollen lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, 
stridor, reduced PEF, hypoxemia)  
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], 
syncope, incontinence)  
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, 
vomiting)  
3 
Reduced BP after exposure to known allergen for that patient [participant] 
(minutes to several hours). Adults: systolic BP of less than 90 mm Hg or greater 
than 30% decrease from that person’s baseline 

 
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• PI assessment that it is not in the best interest of the participant to continue 
receiving study vaccine. 
• Co-enrollment in a study with an investigational research agent (rare 
exceptions allowing for the continuation of vaccinations may be granted 
with the unanimous consent of the HVTN 302 PSRT) 
Participants discontinuing study vaccine for reasons other than HIV infection 
should be encouraged to participate in follow-up visits and procedures per the 
protocol. At the discretion of the CRS clinician and the PSRT (for composition 
of PSRT see Section 9.4), some clinic procedures and sample collections may be 
modified or discontinued. 
If a participant becomes HIV-infected during the course of the study, no 
additional study vaccine will be administered. Participants will be encouraged to 
continue until the final scheduled study visit. At post-infection follow-up visits, 
only samples for protocol-specified clinical labs (with the exception of HIV 
diagnostic testing) will be collected. In addition, some clinic procedures may be 
modified or discontinued. 
5.2.3 
Participant departure from vaccine schedule 
If a participant misses a scheduled vaccination, they are eligible for future 
vaccinations.  
5.2.4 
Discontinuation of study participation 
A participant may be discontinued from protocol participation for the following 
reasons: 
• Participant voluntarily withdraws; 
• CRS determines the participant is lost to follow-up; 
• The investigational new drug (IND) application Sponsor or regulatory 
authorities stop the study; or, 
• PI assessment that it is not in the best interest of the participant to continue 
participation in the study or that the participant’s compliance with the study 
is not sufficient. 
If a participant terminates participation in the study early for any reason, the site 
principal investigator should consider if the following assessments are 
appropriate: end-of-study HIV test, complete blood count (CBC) with 
differential, serum chemistry (alanine aminotransferase (ALT) and creatinine), 
physical examination, and if indicated, a pregnancy test (see Appendix A and 
Appendix B). For participants with HIV infection, please see Section 8.8. If the 

 
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site principal investigator has questions regarding a termination visit, they should 
consult with the PSRT.  

 
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6 
Statistical considerations 
6.1 
Sample size justification and accrual 
Recruitment will target enrolling 108 healthy, HIV-uninfected adult participants. 
108 healthy, HIV-uninfected adult participants will be enrolled into three 100 
mcg vaccine dose groups in Part A and into three 250 mcg vaccine dose groups 
in Part B (n=18 per group). The study will begin by enrolling a Part A sentinel 
safety cohort with 1:1:1 randomization into Groups 1-3 (of n=12) to be evaluated 
for safety two weeks after the first vaccination. Participants that are randomized 
but not enrolled will be replaced to ensure that at least 12 participants are 
enrolled before initiation of the planned enrollment pause. 
The PSRT will convene after the 12th participant in the Part A sentinel safety 
cohort has received their first vaccination and completed the 2 week post 
vaccination safety visit to determine if further participants should be enrolled. If 
safety criteria are met, enrollment will proceed with Part B sentinel group of 
n=12 with 1:1:1 randomization and the remainder of Part A (n=42) with 1:1:1 
randomization. Once the safety criteria for the Part B sentinel safety cohort have 
been met, the remaining Part B participants (n=42) will be enrolled with 1:1:1 
randomization. Figure 6-1 illustrates this plan. 
 
Figure 6-1 Schema of enrollment strategy 
Since enrollment is concurrent with receiving the first study vaccination, all 
participants will provide some safety data. However, for immunogenicity 
analyses, it is possible that data may be missing for various reasons, such as 
participants terminating from the study early, problems in shipping specimens, 
low cell viability of processed peripheral blood mononuclear cells (PBMCs), or 
high assay background. Immunogenicity data from 17 phase 1 and 2 phase 2a 
HVTN vaccine trials, which began enrolling after June 2005 (data as of 

 
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September 2014), indicate that 15% is a reasonable estimate for the rate of 
missing data at Month 6.5. For this reason, the sample size calculations in below 
account for 15% enrolled participants having missing data for the primary 
immunogenicity endpoints. 
6.1.1 
Power calculations for immunogenicity 
The immunogenicity sample size calculations allow for a 15% rate of missing 
immunogenicity data at Month 6.5. Of the n=18 enrolled per arm, we assume 
n=15 will be available for analysis. 
A primary objective is to evaluate the ability of the BG505 MD39.3 trimer 
mRNA vaccines to elicit autologous neutralizing antibodies. The primary 
endpoint will be the occurrence and magnitude of serum antibody neutralization 
of pseudoviruses (BG505 T332N) as measured by the TZM-bl assay two weeks 
after the third vaccination which will be compared between the membrane-bound 
vaccine regimen (BG505 MD39.3 gp151 mRNA) and the membrane-bound 
knockout (BG505 MD39.3 gp151 CD4KO mRNA) and between the membrane-
bound vaccine regimen (BG505 MD39.3 gp151 mRNA) and the soluble trimer 
(BG505 MD39.3 mRNA) vaccine arms, within each dose level. Secondary 
analyses will test for differences between dose levels. If no significant difference 
is seen between the 100mcg and 250mcg dose (eg, between Groups 1 and 4, 
between Groups 2 and 5 or between Groups 3 and 6), secondary analyses may 
aggregate over dose groups for comparisons between the vaccine regimens. For 
example, if no significant difference is seen between doses for the soluble trimer 
regimen in Groups 1 and 4 or between doses for the membrane-bound vaccine 
regimen in Groups 2 and 5, we may aggregate over the dose to compare 
responses of Groups 1 and 4 (n=30) to Groups 2 and 5 (n=30).  
The precision with which the true immune response rate can be estimated from 
the observed data depends on the true underlying response rate and the sample 
size. Two-sided 95% confidence intervals for the response rate based on 
observing a particular rate of responses in the vaccinees is shown in Table 6-1. 
Calculations are done using the score test method (29). 

 
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Table 6-1 Two-sided 95% confidence intervals for the true response rate based on 
observing a particular rate of responses in the vaccinees (n = 15, 30)  
No. of responses 
Observed response rate (%) 
95% Confidence interval 
4/15 
26.7 
(9.0, 51.9) 
7/15 
46.7 
(24.8, 69.9) 
11/15 
73.3 
(48.0, 89.1) 
12/15 
80.0 
(54.8, 93.0) 
8/30 
26.7 
(14.2, 44.4) 
15/30 
50.0 
(33.2, 66.8) 
22/30 
73.3 
(55.6, 85.8) 
24/30 
80.0 
(62.7, 90.5) 
As shown in Table 6-2, there is limited power for a formal comparison of 
immunogenicity response rates between vaccine arms of size n = 15. For either 
80% or 90% power, the sizes of differences that the trial is powered to detect are 
large. These calculations use a Fisher’s exact 2-sided test with a Type I error rate 
of 0.05. The trial is, however, adequately powered to detect group differences 
based on data from a study in rabbits led by Dr. William Schief. There is 90% 
power to detect an 11-fold difference in ID50 pseudovirus neutralization and a 
1.9-fold difference in serum binding responses between two dose groups or 
between two dose levels of n=15 evaluable samples each. For the comparisons of 
BG505 MD39.2 gp151 mRNA vs. BG505 MD39.3 mRNA (or vs. BG505 
MD39.3 gp151 CD4KO mRNA) that aggregate arms over the low and high dose 
levels, the trial has 90% power to detect a 5.2-fold difference in ID50 pseudovirus 
neutralization and a 1.6-fold difference in serum binding responses between two 
groups, aggregated over dose level (n=30 evaluable samples in each of the 
aggregated groups). These calculations use a two-sided t-test with a Type I error 
rate of 0.05 and estimated standard deviation of 0.85 for log10 ID50 values and of 
0.23 for ELISA AUC MD39 at day 182 (shown in Figure 6-2). The standard 
deviation estimates were based on the mean standard deviation across four groups 
of rabbits, with n=6 per group, given either soluble or membrane-bound MD39.3 
or MD39.2 vaccine at 2 weeks after 3rd vaccination.  
Table 6-2 Power for comparison of response rates between 2 arms (n1 = n2 = 15)  
True response rate 
Arm 1 (%) 
Minimum true response rate in Arm 2 in order to detect a 
difference 
80% power 
90% power 
10 
64 
71 
20 
76 
82 
30 
85 
90 
40 
92 
95 
50 
97 
99 
 

 
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Figure 6-2 Effect size necessary to detect a difference between groups for n=3 to 20 per group. 
Estimated standard deviation of log10 ID50 values from day 182 is 0.85 (left). Estimated standard 
deviation of ELISA AUC MD39 is 0.23 (right). The two figures are identical except for the y-axis scale 
which depends on the outcome-specific estimated standard deviation 
In addition, “generic” power calculations inform the power of the study to 
compare immune response magnitudes between arms. These presume a 
continuous immune response, transformed to a 1-standard deviation scale, and a 
mean shift in scaled immune response between arms. Table 6-3 shows the power 
for comparing immune responses between two arms at Month 6.5 (n = 15 per 
arm, n = 30 per group). Note that the study is powered to detect moderate 1.1-
standard deviation differences in immune responses between arms for n=15 per 
arm and to detect 0.8- standard deviation differences in immune responses 
between groups for n=30 per group. 
6.1.2 
Power calculations for safety 
The goal of the safety evaluation for this study is to identify safety concerns 
associated with vaccine administration. The ability of the study to detect SAEs 
can be expressed by the true event rate above which at least one SAE would likely 
be observed and the true event rate below which no events would likely be 
observed. Specifically, with n=4 in the sentinel safety group for a given arm, there 
is at least 90% chance of observing at least one safety event among those 4 if the 
true rate of such an event is 45% or more; and there is at least a 90% chance of 
observing no events among the 4 if the true rate is 2.5% or less. Safety 
calculations are evaluated using historical controls. As a reference, in HVTN 
vaccine trials conducted in the US from April 2008 through March 2018, about 
1% of participants who received placebos experienced an SAE. 
 

 
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Table 6-3 Power for comparing the magnitude of a generic immune response between arms. 
Immune responses are compared using 0.025-level one-sided Wilcoxon rank sum tests. 
Continuous immune responses are assumed to follow a normal distribution, transformed to a 1-
standard deviation scale, with a mean of zero in one arm and the same standard deviation in the 
two arms. To allow for missing immunogenicity data, analyses include 15 participants in each arm 
and 30 participants if aggregating over dose level in Part A and Part B. Power is based on 5000 
simulations. 
Mean difference between arms 
(in standard-deviation units) 
Power, n=15 per arm 
Power, n=30 per group 
(aggregating over dose) 
0.8 SD 
51% 
84% 
0.9 SD 
63% 
91% 
1.0 SD 
71% 
96% 
1.1 SD 
80% 
98% 
1.2 SD 
86% 
100% 
1.3 SD 
91% 
100% 
Binomial probabilities of observing 0, 1 or more events among the n=4 sentinel 
participants receiving each study vaccine are presented in Table 6-4 for a range of 
possible true adverse event rates. Probabilities are also provided for the total 
safety sentinel group for each dose group (n=12) as well as for each vaccine arm 
(n=18). These calculations provide a more complete picture of the sensitivity of 
this study design to identify potential safety problems with the vaccine. 
Table 6-4 Probability of observing 0 events, 1 or more events among arms of n=4, 12, 18 for 
different true event rates 
True event rate (%) 
arm size 
0 events 
1+ events 
10 
4 
0.66 
0.34 
20 
4 
0.41 
0.59 
30 
4 
0.24 
0.76 
10 
12 
0.28 
0.72 
20 
12 
0.07 
0.93 
30 
12 
0.01 
0.99 
10 
18 
0.15 
0.85 
20 
18 
0.02 
0.98 
30 
18 
0 
1 

 
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An alternative way of describing the statistical properties of the study design is in 
terms of the 95% confidence interval for the true rate of an adverse event based 
on the observed data. Table 6-5 shows the 2-sided 95% confidence intervals for 
the probability of an event based on a particular observed rate for each arm of the 
sentinel groups (n=4), for the sentinel group for each dose group (n=12), and for 
each vaccine arm (n=18). Calculations are done using the score test method for CI 
described in Agresti and Coull formula 2 (40). If none of the 4 participants 
receiving the study vaccine in one of the sentinel safety cohort arms experience a 
safety event, the 95% 2-sided upper confidence bound for the true rate of such 
events in the total vaccinated population is 49.0%. If none of the 54 participants 
receiving the vaccine regimen in Part A or B experience a safety event, the 95% 
2-sided upper confidence bound for the true rate of such events in the total 
vaccinated population at that dose level is 6.7%. 
Table 6-5 Two-sided 95% confidence intervals for the probability of observing a safety event 
based on observing a particular rate of safety endpoints in an arm of 4, 12, 18, 54 study 
participants 
Observed event rate 
95% Confidence interval (%) 
0/4 
[0 ; 49.0] 
1/4 
[4.6 ; 69.9] 
2/4 
[15.0 ; 85.0] 
0/12 
[0: 24.3] 
1/12 
[1.5: 35.4] 
2/12 
[4.7: 44.8] 
0/18 
[0: 17.6] 
1/18 
[1.0: 25.8] 
2/18 
[3.1: 32.8] 
0/54 
[0: 6.7] 
1/54 
[0.3: 9.8] 
2/54 
[1.0: 12.5] 
6.2 
Randomization 
Participants will first be randomized in a 1:1:1 ratio into the Part A sentinel safety 
cohort. If safety criteria are met, enrollment will proceed with Part B sentinel 
group of n=12 with 1:1:1 randomization and the remainder of Part A (n=42) with 
1:1:1 randomization, with some sites enrolling into the Part B sentinel cohort 
while other sites are enrolling the remainder of Part A. Once the safety criteria for 
the Part B sentinel safety cohort have been met, the remaining Part B participants 
(n=42) will be enrolled with 1:1:1 randomization.  
Randomization to Groups 1-3 will be stratified by willingness to consent to FNA 
and/or leukapheresis. A maximum of 27 participants in total that do NOT consent 
to either FNA and leukapheresis collection will be enrolled.  

 
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A participant’s randomization assignment will be computer generated and 
provided to the HVTN CRS pharmacist through a web-based randomization 
system. At each institution, the pharmacist with primary responsibility for 
dispensing study products is charged with maintaining security of the treatment 
assignments (except in emergency situations as specified in the HVTN Manual of 
Operations [MOP]). 
6.3 
Statistical analyses 
This section describes the final study analysis, unblinded as to treatment arm 
assignment. All data from enrolled participants will be analyzed regardless of how 
many vaccinations they received. In the rare instance that a participant receives 
the wrong treatment at a specific vaccination time, the Statistical Analysis Plan 
(SAP) will address how to analyze the participant’s safety and immunogenicity 
data. Analyses are modified intent-to-treat in that individuals who are randomized 
but not enrolled do not contribute data and hence are excluded. Because of 
blinding and the brief length of time between randomization and enrollment—
typically no more than 4 working days—very few such individuals are expected. 
Analyses for primary endpoints will be performed using SAS and R. All other 
descriptive and inferential statistical analyses will be performed using SAS, 
StatXact, or R statistical software. 
For the primary and secondary immunogenicity analysis comparisons, the 
following groups may be pooled: groups 1 and 4, groups 2 and 5, groups 3 and 6. 
Unpooled group comparisons will also be considered. 
No formal multiple comparison adjustments will be employed for multiple safety 
endpoints, multiple primary immunogenicity endpoints, or secondary endpoints. 
However, multiplicity adjustments will be made for certain immunogenicity 
assays, as discussed below, when the assay endpoint is viewed as a collection of 
hypotheses (eg, testing multiple peptide pools to determine a positive response). 
6.3.1 
Analysis variables 
The analysis variables consist of baseline participant characteristics, safety, and 
immunogenicity for primary- and secondary-objective analyses. 
6.3.2 
Baseline comparability 
Treatment arms will be compared for baseline participant characteristics using 
descriptive statistics. 

 
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6.3.3 
Safety/tolerability Analyses 
Since enrollment is concurrent with receiving the first vaccination, all participants 
will have received at least 1 vaccination and therefore will provide some safety 
data. 
6.3.3.1 
Reactogenicity  
The number and percentage of participants experiencing each type of 
reactogenicity sign or symptom will be tabulated by severity and treatment arm 
and the percentages displayed graphically by arm. For a given sign or symptom, 
each participant’s reactogenicity will be counted once under the maximum 
severity for all injection visits. In addition, to the individual types of events, the 
maximum severity of local pain or tenderness, induration or erythema, and of 
systemic symptoms will be calculated. Kruskal-Wallis tests will be used to test for 
differences in severity between arms. 
6.3.3.2 
Adverse events (AEs) and serious adverse events (SAEs) 
Adverse events (AEs) will be summarized using Medical Dictionary for 
Regulatory Activities (MedDRA) System Organ Class and preferred terms. 
Tables will show by treatment arm the number and percentage of participants 
experiencing an AE within a System Organ Class or within preferred term 
category by severity or by relationship to study product. For the calculations in 
these tables, a participant with multiple AEs within a category will be counted 
once under the maximum severity or the strongest recorded causal relationship to 
study product. Formal statistical testing comparing arms is not planned since 
interpretation of the magnitude of differences must rely heavily upon clinical 
judgment. 
A listing of SAEs reported to the DAIDS Regulatory Support Center (RSC) 
Safety Office will provide details of the events including severity, relationship to 
study product, time between onset and last vaccination, and number of 
vaccinations received.  
6.3.3.3 
Local laboratory values  
Box plots of local laboratory values will be generated for baseline values and for 
values measured during the course of the study by treatment arm and visit. Each 
box plot will show the first quartile, the median, and the third quartile. Outliers 
(values outside the box plot) will also be plotted. If appropriate, horizontal lines 
representing boundaries for abnormal values will be plotted. 
For each local laboratory measure, summary statistics will be presented by 
treatment arm and timepoint, as well as changes from baseline for postenrollment 
values. In addition, the number (percentage) of participants with local laboratory 
values recorded as meeting Grade 1 AE criteria or above as specified in the 

 
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Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Corrected Version 2.1 – July 2017, will be tabulated by 
treatment arm for each postvaccination timepoint. Reportable clinical laboratory 
abnormalities without an associated clinical diagnosis will also be included in the 
tabulation of AEs described above. 
6.3.3.4 
Reasons for vaccination discontinuation and early study termination 
The number and percentage of participants who discontinue vaccination and who 
terminate the study early will be tabulated by reason and treatment arm. 
6.3.4 
Immunogenicity analyses 
6.3.4.1 
General approach 
For the statistical analysis of immunogenicity endpoints, data from enrolled 
participants will be used according to the initial randomization assignment 
regardless of how many injections they received. Additional analyses may be 
performed, limited to participants who received all scheduled injections per 
protocol. Assay results that are unreliable are excluded; results from specimens 
collected outside of the visit window, or from HIV-infected participants post-
infection, may be excluded. Since the exact date of HIV infection is unknown, 
any assay data from blood draws 4 weeks prior to an infected participant’s last 
seronegative sample and thereafter may be excluded. If an HIV-infected 
participant does not have a seronegative sample postenrollment, then all data from 
that participant may be excluded from the analysis. 
Discrete categorical assay endpoints (eg, response rates) will be analyzed by 
tabulating the frequency of positive response for each assay by antigen and 
treatment arm at each timepoint for which an assessment is performed. Crude 
response rates will be presented with their corresponding 95% confidence interval 
estimates calculated using the score test method (40). Barnard or Fisher’s exact 
tests, as specified in the SAP, will be used to compare the response rates of any 2 
vaccine arms, with a significant difference declared if the 2-sided p-value is ≤ 
0.05. In general Barnard’s is preferred since under most circumstances it is more 
powerful than Fisher’s exact test (41). 
For quantitative assay data (eg, percentage of positive cells from ICS assay), 
graphical and tabular summaries of the distributions by antigen, treatment arm, 
and timepoint will be made. For all primary and secondary immunogenicity 
endpoints, box plots and plots of estimated reverse cumulative distribution curves 
will be used for graphical display of all of the study arms. Typically, the results 
will be shown for each vaccine arm.  
The difference between arms at a specific timepoint will be tested with a 
nonparametric Wilcoxon rank sum test if the data are not normally distributed and 
with a 2-sample t-test if the data appear to be normally distributed. The primary 

 
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analysis consists of 4 individual tests comparing the membrane-bound vaccine 
regimen (BG505 MD39.3 gp151 mRNA) to the membrane-bound knockout 
(BG505 MD39.3 gp151 CD4KO mRNA) and to the soluble trimer (BG505 
MD39.3 mRNA) vaccine arms within each dose level, unless prespecified. That is, 
we compare Groups 2 vs 1, Groups 2 vs 3, Groups 5 vs 4, and Groups 5 vs 6. 
Secondary analyses will compare responses between dose levels for each regimen. If 
no differences are seen between dose levels for a given vaccine regimen, subsequent 
comparisons of that vaccine regimen may be based on the aggregated arms (eg, 
pooling over dose). If rank-based tests are used, then the tests will be inverted to 
construct Hodges-Lehmann point estimates and 2-sided (1-0.05/15) × 100% CIs 
about the differences in location centers of the 3-15 pair-wise comparisons of 
vaccine arms. If actual-value tests are used then the Dunnett’s procedure will be 
used to construct simultaneous confidence intervals about the pairs of mean 
differences for the many-to-one comparisons (42) when multiple vaccine arms are 
each compared with one common control arm. When all pair-wise comparisons 
between the multiple vaccine arms are of interest, the Tukey procedure (43) will 
be used. If only specific comparisons between pairs of the multiple vaccine arms 
are of interest, the Holm-Bonferroni procedure will be used. An appropriate data 
transformation (eg, log10 transformation) may be applied to better satisfy 
assumptions of symmetry and homoscedasticity (constant variance). Significance 
of the differences between pairs will be evaluated using two procedures, first 
based on whether the simultaneous 95% CIs exclude zero and secondly based on 
whether the nominal (unadjusted) 95% CIs exclude zero. 
Some immunologic assays have underlying continuous or count-type readout that 
are dichotomized into responder/nonresponder categories (eg, BAMA, TZM-BL). 
If treatment arm differences for these assays are best summarized by a mixture 
model, then either Lachenbruch’s test statistic (44) or an alternative two-part test 
(45) (as defined in the SAP) will be used to evaluate the composite null 
hypothesis of equal response rates in the 2 arms and equal response distributions.  
Based upon previous HVTN trials, missing 15% of immunogenicity results for a 
specific assay is common due to study participants terminating from the study 
early, problems in shipping specimens, or low cell viability of processed 
peripheral blood mononuclear cells (PBMCs). To achieve unbiased statistical 
estimation and inferences with standard methods applied in a complete-case 
manner (only including participants with observed data in the analysis), missing 
data need to be missing completely at random (MCAR). Following the most 
commonly used definition, MCAR assumes that the probability of an observation 
being missing does not depend on any participant characteristics (observed or 
unobserved data [ie, the observed data are just a random sample of all the 
potential data]). When missing data are minimal (specifically if no more than 20% 
of participants are missing any values), then standard complete-case methods will 
be used, because violations of the MCAR assumption will have little impact on 
the estimates and hypothesis tests. 

 
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If a substantial amount of immunogenicity data are missing for an endpoint (at 
least 1 value missing from more than 20% of participants), then using the methods 
that require the MCAR assumption may give misleading results. In this situation, 
analyses of the immunogenicity endpoints at a specific timepoint will be 
performed with methods such as targeted minimum loss-based estimation 
(TMLE), parametric generalized linear models fit by maximum likelihood, 
augmented inverse probability weighting (AIPW) methods or multiple imputation 
methods. TMLE and AIPW are typically preferred because they are doubly 
robust, providing consistent estimation and appropriate inferences if either the 
outcome regression or the probability of observing the response value are 
modeled correctly, under the assumption that the missing data are missing at 
random (MAR). MAR assumes that the probability of an observation being 
missing only depends upon the observed responses and upon observed covariates, 
but not upon any unobserved data. TMLE methods will typically be implemented 
with the drtmle R package (46) available at CRAN, and will entail specification of 
a library of learners for the outcome regression and for the probability of 
observing the response value. When data are not missing at random, sensitivity 
analyses may be performed as an exploratory analysis. For assessing repeated 
immunogenicity measurement, linear mixed effects models will be used. If the 
immunological outcomes are left- and/or right- censored, then the linear mixed 
effects models of Hughes (47) will be used, because they accommodate the 
censoring. In addition, secondary analyses of repeated immunogenicity 
measurements may be done using weighted GEE (48) methods, which are valid 
under MAR. All of the models described above in this paragraph will include as 
covariates all available baseline predictors of the missing outcomes. 
Some “resource-intensive” immunogenicity endpoints are only measured in 
subset of participants, eg, fine needle lymph node aspirates and leukapheresis will 
be performed only on participants consenting to these optional procedures, and 
immunogenicity endpoints based on these samples will only exist for those 
participants. For such endpoints, exploratory analyses will be conducted to assess 
the correlation of participant characteristics measured in (nearly) all participants 
with the resource-intensive endpoints. For example, if the same assay is 
performed on blood and fine needle lymph node aspirate samples, then a 
scatterplot and Spearman rank correlation coefficient (r) will be used to assess the 
correlation of responses. If at least moderate correlations exist (eg, r ≥ 0.3), then 
TMLE is the preferred method estimate the mean of the resource-intensive 
endpoint for each group and to compare means between groups. Another potential 
method to apply is the semiparametric locally efficient analysis method of 
Rotnitzky and Robins (49) as described in Gilbert, Sato et al. for application to 
vaccine studies (50). 
6.3.4.2 
Multivariate display of immunogenicity endpoints 
Data visualization techniques may be used to explore the relationship among 
immunogenicity readouts. The set of readouts may be based on one of the primary 
endpoints (eg, TZM-BL), on the set of primary endpoints, or on immunogenicity 

 
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endpoints that also include secondary or exploratory endpoints. To understand the 
relationship between pairs of readouts, scatter plots may be used when the number 
of readouts is small or for a larger number of readouts, a heatmap showing the 
degree of correlation between any two pairs. Principal component analysis (PCA) 
and associated ‘biplots’ of the scores and loadings are particularly useful to 
understand associations between readouts, especially when readouts are correlated 
(51). PCA is a method to reduce the dimensionality of the number of readouts to a 
smaller set of values (principal components) that are normalized linear 
combinations of the readouts in such a way that the first principal component 
accounts for the most variability in the data and subsequent components, while 
maximizing variability, are uncorrelated with each other. A ‘biplot’ displays the 
first and second principal component scores and principal component loadings. 
The x-axis is the value from the first principal component and the y-axis is the 
second principal component, where each axis label includes the percentage of 
variation in the total set of readouts captured by the principal component. The top 
axis is the first principal component loadings and the right axis is the second 
principal component loadings. An arrow is drawn for each immunogenicity 
readout (eg, Env-specific CD4+ T cell polyfunctionality score, Env-specific 
CD8+ T cell total magnitude) from the origin to the point defined by its first two 
principal component loadings. The length of the arrow represents the amount of 
total variation of the set of readouts captured by the given readout. The direction 
of an arrow conveys the extent to which the variation of a readout is in the 
direction of the first or second principal component. The angle between two 
arrows conveys information about the correlation of the two readouts, with a zero-
degree angle denoting perfect correlation and a 90 degree angle denoting no 
correlation. Each arrow on the biplot is labeled by the immunogenicity readout it 
represents. A biplot is annotated with key meta-information such as the treatment 
arm (most common application) or a demographic category. Depending on the 
application, K-means clustering and hierarchical clustering may also be applied 
for multivariate graphical display of immunogenicity readouts. 
The occurrence and magnitude of serum antibody neutralization of pseudoviruses 
(BG505 MD39.3, BG505 MD39.3 gp151, and BG505 MD39.3 gp151 CD4KO) 
measured by the TZM-bl assay, the occurrence and magnitude of serum IgG 
binding antibodies to BG505 trimer, and specific epitopes (base of trimer, V3, 
internal epitope) measured by ELISA and/or BAMA, and the response rate and 
magnitude of CD4+ T‑cell responses measured by intracellular cytokine staining 
assays (ICS) will be summarized using descriptive statistics. Data will be 
tabulated and graphically displayed by visit number and by number of doses 
received. 
Discrete categorical assay endpoints (eg, response rates) will be analyzed by 
tabulating the frequency of positive response. Crude response rates will be 
presented with their corresponding 95% confidence interval estimated based on 
the score test method (40). Barnard’s exact tests may be employed to compare the 
response rates of immune responses between groups. 

 
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Quantitative assay endpoints will be summarized by time point. Nonparametric 
paired comparisons will be performed using Wilcoxon signed-rank tests, and the 
Wilcoxon rank sum test will be used to compare independent samples. More 
details of the analyses of each assay will be provided in the statistical analyses 
plan (SAP). 
6.3.4.3 
Analysis of CD4+ and CD8+ T-cell responses as measured by the ICS 
assay 
The analysis of CD4+ and CD8+ T-cell response rates as measured by the ICS 
assay will be evaluated and compared as described under the general approach. 
For each T-cell subset, the positivity call for each peptide pool will include a 
multiple comparison adjustment for the number of peptide pools used in the 
assay. In general, the Mixture Models for Single-cell Assays (MIMOSA) 
statistical framework (52) and/or the Fisher’s exact test-based positivity criteria 
will be used. Details of the positivity criteria will be discussed in the SAP. The 
magnitude of marginal response will be analyzed as described for quantitative 
data in the general approach section. For each T-cell subset, graphs will be used to 
display the background-subtracted magnitudes for each participant by protein, 
treatment arm and timepoint. When 3 or more cytokines are being measured by 
the ICS assay, the polyfunctionality of ICS responses may also be analyzed as an 
exploratory endpoint. Besides descriptive plots of the magnitude of polyfunctional 
responses, the COMPASS (Combinatorial Polyfunctionality analysis of Antigen-
Specific T-cell Subsets) statistical framework (53) may also be used to perform 
joint modelling of multiple T-cell subsets of different cytokine combinations. For 
example, the functionality score (FS) and the polyfunctionality score (PFS) may 
be used to summarize the multi-parameter ICS responses. 

 
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7 
Study vaccine preparation, storage, and 
administration 
7.1 
Vaccine Regimen 
The schedule of vaccination is shown in Section 1 and additional information is 
given below. 
Group 1  
100 mcg of BG505 MD39.3 mRNA (labeled as mRNA-1574v1-GP140) to be 
administered as 0.5 mL doses intramuscularly (IM) at months 0, 2, and 6 
Group 2 
100 mcg of BG505 MD39.3 gp151 mRNA (labeled as mRNA-1574v2-GP151) to 
be administered as 0.5 mL doses intramuscularly (IM) at months 0, 2, and 6 
Group 3 
100 mcg of BG505 MD39.3 gp151 CD4KO mRNA (labeled as mRNA-1574v3-
CD4KO-GP151) to be administered as 0.5 mL doses intramuscularly (IM) at 
months 0, 2, and 6 
Group 4  
250 mcg of BG505 MD39.3 mRNA (labeled as mRNA-1574v1-GP140) to be 
administered as 0.5 mL doses intramuscularly (IM) at months 0, 2, and 6 
Group 5 
250 mcg of BG505 MD39.3 gp151 mRNA (labeled as mRNA-1574v2-GP151) to 
be administered as 0.5 mL doses intramuscularly (IM) at months 0, 2, and 6 
Group 6 
250 mcg of BG505 MD39.3 gp151 CD4KO mRNA (labeled as mRNA-1574v3-
CD4KO-GP151) to be administered as 0.5 mL doses intramuscularly (IM) at 
months 0, 2, and 6 

 
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7.2 
Study Product Formulation and Storage 
7.2.1 
BG505 MD39.3 mRNA (labeled as mRNA-1574v1-GP140 Injection) is 
formulated in a lipid nanoparticle (soluble trimer).  
The visual appearance of the formulated product is a white to off-white dispersion 
which may contain visible, white or translucent product-related particulates. The 
drug product is supplied as a frozen liquid in a 2 mL borosilicate glass vial. Each 
vial contains 0.6 mL of mRNA-1574v1-GP140 at a concentration of 0.5 mg/mL 
and is stored at -60°C to -90°C.  
7.2.2 
 BG505 MD39.3 gp151 mRNA (labeled as mRNA-1574v2-GP151 
Injection) formulated in a lipid nanoparticle (membrane-bound 
trimer).  
The visual appearance of the formulated product is a white to off-white dispersion 
which may contain visible, white or translucent product-related particulates. The 
drug product is supplied as a frozen liquid in a 2 mL borosilicate glass vial. Each 
vial contains 0.6 mL of mRNA-1574v2-GP151 at a concentration of 0.5 mg/mL 
and is stored at -60°C to -90°C. 
7.2.3 
BG505 MD39.3 gp151 CD4KO mRNA (labeled as mRNA-1574v3-
CD4KO-GP151 Injection) formulated in a lipid nanoparticle 
(membrane-bound trimer)  
The visual appearance of the formulated product is a white to off-white dispersion 
which may contain visible, white or translucent product-related particulates. The 
drug product is supplied as a frozen liquid in a 2 mL borosilicate glass vial. Each 
vial contains 0.6 mL of mRNA-1574v3-CD4KO-GP151 at a concentration of 0.5 
mg/mL and is stored at -60°C to -90°C. 
7.2.4 
Diluent (Sodium Chloride Injection, USP, 0.9%) 
Sodium Chloride Injection, USP, 0.9% is supplied only in single dose ampules (5 
mL and 10 mL Glass Ampules). The diluent is stored at controlled room 
temperature 15-30°C, avoid freezing. 
7.3 
Product Preparation 
There are 6 mRNA 1574 vaccine Dose Preparation and Administration 
Worksheets in total, two for each of the three vaccines for the 100 mcg and 250 
mcg doses. These worksheets, as well as detailed instructions with respect to their 
use, can be found in the HVTN 302 Study Specific Procedures (SSP).  
Below are general guidelines for the product preparation.  

 
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• Two vials of vaccine are required to prepare each dose since the maximum 
extractable volume is 0.3-0.4mL. 
• Pharmacists must follow appropriate aseptic technique and sterile preparation 
procedures/guidance as outlined in USP <797> [medium risk], utilizing a 
pharmacy biosafety cabinet/isolator or better. Local regulations and site 
institutional policies and procedures for use of personal protective equipment, 
such as gloves, gowns, masks, and safety glasses, must be followed. 
Pharmacists should follow the requirements of their country, their institution, 
and their pharmacy regulatory authority regarding these procedures.  
• Any unused portion of study product will not be used for another participant. 
(Exception note: If two participants are scheduled for the 100 mcg dose of the 
same vaccine on the same day, both doses may be prepared from the mixing 
vial) Empty vials, unused portion of entered vials, or unused prepared study 
product should be discarded in a biohazard container and disposed of in 
accordance with institutional or pharmacy policy. 
7.3.1 
Preparation of the 100 mcg doses of mRNA-1574 vaccines 
• Remove two vials of the appropriate mRNA-1574 vaccine from the -60°C to -
90°C freezer and allow to thaw at room temperature for a maximum of 30 
minutes. 
• Once thawed the product must be diluted within 30 mins using 0.9% sodium 
chloride for injection, USP.  
• Clean the neck of the ampule of 0.9% sodium chloride for injection, USP with 
an alcohol swab. Grasp the head of the ampule with the alcohol swab and snap 
the neck open. Dispose of the ampule head and swab in an approved sharps 
collector.  
• Using a filter needle (eg, Becton Dickinson Catalog no. 305211) and 3 mL 
syringe withdraw 0.9 mL of 0.9% sodium chloride for injection, USP from the 
ampule. Passively recap the filter needle and remove the filter needle and 
dispose the filter needle in an approved sharps collector.  
• Attach a 21G x1 ½ inch or 22G x1 ½ inch needle to the syringe and inject the 
0.9 mL of 0.9% sodium chloride for injection, USP into a 2 mL sterile empty 
mixing vial. 
• Using a 21G x1 ½ inch or 22G x1 ½ inch needle and 1 mL syringe withdraw 
as much of the contents as possible of one of the mRNA-1574 vaccine vials 
and inject into the second mRNA-1574 vaccine vial. 

 
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• Gently invert vial number 2 of the mRNA-1574 vaccine 20 times until the 
components are mixed. Do not mix vigorously, sonicate, shake or vortex. 
• Using a new 1 mL syringe and new 21G x1 ½ inch or 22G x1 ½ inch needle 
withdraw 0.6 mL of mRNA -1574 vaccine and inject into the mixing vial 
containing the 0.9% sodium chloride for injection, USP. Gently invert the 
mixing vial 20 times. The mixing vial now contains 1.5 mL of a 200 mcg/mL 
vaccine.  
• Using a new 1 mL syringe and a new 21G x1 ½ inch or 22G x1 ½ inch needle 
withdraw slightly more than 0.5 mL into the dosing syringe. Invert the syringe 
and vial and remove any air bubble from the dosing syringe. Adjust the 
volume of solution to 0.5 mL for a dose of 100 mcg and withdraw the needle 
from the vial. 
• Draw back the plunger until air is just visible in the tip of the syringe and 
remove the needle from the dosing syringe. 
• Add either a luer lock cap or an administration needle (22G to 25 G 1 to1 ½ 
inch) for IM injection as agreed upon by pharmacy and clinic. Label the 
syringe and assign expiration time of 8 hours after syringe has been filled. It is 
recommended that the dose is administered immediately after syringe 
preparation. However, a maximum of 8 hours is allowed for holding dosing 
solution in dosing syringes prior to completion of administration 
• If two participants are scheduled for the 100 mcg dose of the same vaccine on 
the same day, both doses may be prepared from the mixing vial.  
7.3.2 
Preparation of the 250 mcg doses of mRNA-1574 vaccine  
• Remove two vials of the appropriate mRNA-1574 vaccine from the -60°C to 
-90°C freezer and allow to thaw at room temperature for a maximum of 30 
minutes. 
• Using a 21G x1 ½ inch or 22G x1 ½ inch needle and 1 mL syringe withdraw 
as much of the contents as possible of one of the mRNA-1574 vaccine vials 
and inject into the second mRNA-1574 vaccine vial. Gently invert vial 
number 2 of the mRNA-1574 vaccine 20 times until the components are 
mixed. Do not mix vigorously, sonicate, shake or vortex. 
• Using a new 1 mL syringe and a new 21G x1 ½ inch or 22G x1 ½ inch 
needle withdraw slightly more than 0.5 mL into the dosing syringe. Invert the 
syringe and vial and remove any air bubble from the dosing syringe. Adjust 
the volume of solution to 0.5 mL for a dose of 250 mcg and withdraw the 
needle from the vial.  

 
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• Draw back the plunger until air is just visible in the tip of the syringe and 
remove the needle from the dosing syringe. 
• Add either a luer lock cap or an administration needle (22G to 25 G 1 to1 ½ 
inch) for IM injection as agreed upon between pharmacy and clinic.  
• Label the syringe and assign expiration time of 8 hours after syringe has been 
filled. It is recommended that the dose is administered immediately after 
syringe preparation. However, a maximum of 8 hours is allowed for holding 
dosing solution in dosing syringes prior to completion of administration. 
7.4 
Study product labeling  
Label the study product as follows: 
• Participant identifier(s)  
• Study Product 
• Dose 100 mcg OR Dose 250 mcg (depending on group randomization) 
• Final volume (0.5 mL)  
• Route (IM)  
• Beyond use date and time  
• Any additional information required by jurisdiction 
7.5 
Study Vaccine Administration 
Study product will be administered as one 0.5 mL injection intramuscularly into 
the deltoid muscle by needle and syringe. 
If the injection cannot be administered in either deltoid muscle, the injection 
should be administered in separate alternate body site (eg, lateral thigh). The 
appropriate study staff should document this clearly. Under this circumstance, 
this is NOT a protocol violation. 
When preparing a dose in a syringe and administering the dose, consideration 
should be given to the volume of solution in the needle before and after the dose 
is administered. Particularly if the needle used to withdraw the product is 
replaced prior to vaccine administration, consideration should be given to 
conserving the full dose of product. The pharmacy and clinic staff members are 
encouraged to work together to administer the dose specified in the protocol. 

 
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7.6 
Acquisition of study products 
BG505 MD39.3 mRNA (labeled as mRNA-1574v1-GP140), BG505 MD39.3 
gp151 mRNA (labeled as mRNA-1574v2-GP151) and BG505 MD39.3 gp151 
CD4KO mRNA (labeled as mRNA-1574v3-CD4KO-GP151) were current Good 
Manufacturing Practice cGMP manufactured by – Moderna, Cambridge MA and 
will be provided by IAVI (New York, NY, USA). IAVI will also provide 0.9% 
sodium chloride for injection, USP. These products will be available through the 
CRPMC. 
The following items must be procured locally and will not be available through 
the NIAID Clinical Research Products Management Center (CRPMC): 2 mL 
sterile empty mixing vials, 1 mL syringes, 3 mL syringes, 21G x1 ½ inch needles 
or 22G x1 ½ inch dose preparation needles, filter needles, 21G x1 ½ inch to 25G 
x1 ½ inch administration needles, sterile luer lock syringe caps.  
Once an HVTN CRS is protocol registered, the pharmacist can obtain study 
products from the NIAID CRPMC by following the ordering procedures given in 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks 
(https://www.niaid.nih.gov/research/daids-clinical-research-pharmacy-and-
study-products-management). 
7.7 
Study Vaccine Accountability 
The HVTN CRS pharmacist is required to maintain complete records of all study 
products. The pharmacist of record is responsible for maintaining randomization 
codes and randomization confirmation notices for each participant in a secure 
manner.  
7.8 
Final Disposition of study product 
For US clinical research sites, all unused study products must be returned to the 
CRPMC after the study is completed or terminated unless otherwise instructed 
by the study sponsor. For non-US clinical research sites, all unused study 
products must be destroyed after the study is completed or terminated unless 
otherwise instructed by the study sponsor. The procedures are included in the 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. 

 
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8 
Clinical procedures 
8.1 
Screening 
Screening for eligibility will be performed after informed consent has been 
obtained and properly documented before enrollment. Screening evaluations and 
sample collection include medical history review, physical exam, and any 
clinical laboratory tests as detailed in the Schedule of procedures (Appendix A 
and Appendix B ) needed to confirm eligibility. Persons assigned female sex at 
birth who are of reproductive potential will be given a pregnancy test. Additional 
assessments of health may be conducted at screening based on clinical judgment.  
An Assessment of Understanding (AoU) will be completed prior to enrollment. 
Records will be kept documenting the reason that screened participants did not 
enroll. 
8.2 
Definition of Study Day and Study Visit  
Study Day 1 is defined as the day of the first vaccination. A study visit may be 
conducted remotely, such as via phone, text message, email, or other electronic 
means, in lieu of, or in combination with, in-person visits. As long as they are 
completed within the visit window (see Appendix D and Appendix E), 
procedures for a study visit can be completed over multiple days. 
8.3 
Reactogenicity Assessments 
Pre-Vaccine Administration: Medical history and evaluations including vital 
signs and planned injection site evaluation are performed prior to each vaccine 
administration. 
Post-Vaccine Administration Follow-Up in Clinic: Following each vaccine 
administration, participants will be observed for a minimum of 30 minutes 
(between 30-60 minutes will be acceptable) post-injection, vital signs (at a 
minimum temperature and heart rate are assessed; other vital signs [blood 
pressure and respiratory rate] are assessed as clinically indicated) will be 
assessed, the injection site will be inspected for evidence of local reaction, and 
any evidence of systemic symptoms will be assessed.  
Post-Clinic Follow-Up: Participants are asked to record symptoms on a daily 
basis using an electronic participant diary. Signs and symptoms considered to 
represent reactogenicity from the vaccine include systemic events of increased 
body temperature, fatigue, generalized myalgia, generalized arthralgia, headache, 
chills, nausea, and local events at the injection site including pain/tenderness, 
induration and erythema. Participant diaries will be reviewed by a clinician and 

 
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reconciled for accuracy and completeness. No attribution assessment will be 
performed for systemic reactogenicity events reported in the participant diary 
without additional evaluation of the participant by clinician. 
Participants will be given a thermometer for oral temperature measurement, a 
ruler, and provided access to the electronic study diary (eDiary). The information 
collected by eDiary might include personal health information, contact 
information, and information about app usage. The eDiary does not collect 
personal information about participant activities over time or from other websites 
or online services. It also does not allow third parties to collect that information.  
Participants will be encouraged to use the preferred electronic diary but will have 
the option to use a paper diary. The paper diary, if used, will be transcribed into 
the study database and stored in the participant file for monitoring purposes. The 
participant will use the diary to record daily their highest temperature as well as 
local and systemic signs and symptoms for 7 full days following each study 
vaccination. Participants will be provided training on diary completion, proper 
thermometer usage, and the use of the measuring device to measure any injection 
site induration and/or erythema.  
Remote or in-person contact between the participant and the site staff should take 
place at least once on the third- or fourth-day following vaccination. The 
reactogenicity assessment period is seven days following vaccine administration. 
Clinicians will follow and collect resolution information for any reactogenicity 
signs and symptoms that have not resolved within 7 days. 
Any postvaccination reaction grade 2 or higher will be assessed by a clinician 
within 48 hours after onset, unless the reaction is improving and/or has 
completely resolved. Additionally, other clinical concerns may prompt a study 
visit based on the judgment of a study clinician. 
8.4 
Cardiac symptom management 
Participants will be instructed to observe for any cardiac symptoms (chest pain, 
shortness of breath, feeling of an abnormal heartbeat [fluttering sensation, fast 
heartbeat, heart pounding, or irregularity], or syncope that occur within days to 
weeks following each vaccination, and to seek medical attention and notify study 
site staff if any of these symptoms occur. Site staff will request medical records 
for any cardiac workup that has occurred. Any events of myocarditis and/or 
pericarditis occurring during this trial will be reported as AESIs (see Section 
9.2); and are subject to study pause rules (see Section 9.7). Serum samples stored 
at baseline or post-vaccination study visits could be retrospectively assayed for 
additional safety labs if indicated on a case-by-case basis. 

 
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8.5 
Additional procedures for Part A participants 
Approximately half of the participants in Part A (groups 1-3) will undergo lymph 
node FNA and half will have leukapheresis performed. These procedures require 
that participants meet additional eligibility criteria (see Sections 5.1.3, 8.5.1 and 
8.5.2). The participants willing to undergo these procedures may choose to have 
only lymph node FNA, only leukapheresis, or both procedures. Other 
participants in Part A may choose to have neither procedure performed. 
8.5.1 
Lymph node FNA 
Tissue sampling of an axillary lymph node ipsilateral to the deltoid injection site 
will be carried out percutaneously by FNA. Lymph node FNA will not be 
performed if the injection is given in the thigh. This procedure will be performed 
in accordance with the standard practices of the participating provider and/or 
facility. The procedure involves tissue retrieval with a needle via a small skin 
incision under sonographic guidance. Approximately 2-4 passes will be made to 
retrieve cytologic material. 
Post-procedural safety assessments will be performed in accordance with the 
standard practices of the participating provider and/or facility. The participant 
will be advised to contact the study site if they experience severe pain, fever 
(post-procedural body temperature ≥ 38.0°C or 100.4°F) or other evidence of 
infection (inflammation and/or pus) at the aspiration site, or arm numbness or 
weakness. 
Eligibility for lymph node FNA: 
• Participant may not be taking warfarin, oral antithrombin equivalents 
(including, but not limited to, apixiban, rivaroxiban, dabigatran), 
enoxaparin injections, or other medications that would increase the risk 
of bleeding as assessed by the clinician performing the procedure. 
• The vaccine injection was given in the deltoid and there is no evidence of 
localized infection directly superior to the axillary aspiration site 
• No other contraindication to procedure as assessed by the clinician 
performing the procedure 
• Participants who can become pregnant must have a negative pregnancy 
test within 48 hours prior to the procedure. 
8.5.2 
Leukapheresis 
Collection of PBMC via leukapheresis will be performed in accordance with the 
standard practices of the participating apheresis center. Ideally, in this procedure, 
approximately 1.5 liters of blood will be processed over about 1 hour using 

 
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peripheral veins for venous access. The blood will be anti-coagulated in 
accordance with standard practice of the apheresis center.  
Post-procedural safety assessments will be performed in accordance with the 
standard practices of the participating apheresis center. Additionally, the 
participant will be advised to contact the study site if they experience any 
adverse events following the procedure. 
Eligibility for leukapheresis: 
• Prior to leukapheresis, participant must meet all apheresis center 
requirements for this procedure. 
• Participants who can become pregnant must have a negative pregnancy 
test within 48 hours prior to the procedure. 
8.6 
Extended follow-up for participants with unresolved study product-
related urticaria-associated symptoms 
Participants with unresolved study product-related urticaria-associated symptoms 
(eg; wheal and flare lesions, pruritis, and/or erythematous lesions) at Visit 15 
(month 12) will be asked to have follow-up remote contacts (eg, via phone) with 
CRS staff until all associated signs and symptoms resolve, or for up to an 
additional 48 months (4 years) after the month 12 visit, whichever time is shorter 
(see HVTN 302 SSP for detail). In addition, participants will come into the clinic 
for serum collections for banking at the following times (See Appendix C): 
• Visit 102 
• At clinic visit(s) scheduled in response to a urticaria-associated symptom. 
This can be multiple visits for a single flare or during recurrent visits for 
multiple flares.  
• Participant’s exit visit  
A sample addendum informed consent form is provided in Appendix G. 
Participants who consent for this extended follow-up period will follow the 
schedule of visits and evaluations shown in Appendix C.  
CRS staff will record the following: 
• Updates on dermatological AEs deemed related to study product;  
• New or updates to current concomitant medications;  
• A brief urticaria-related symptom questionnaire;  

 
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• New SAEs, regardless of attribution to study product;  
• New dermatological AEs, regardless of attribution to study product; and 
• Targeted physical exam findings (if a physical exam is conducted).  
Resolution of symptoms that would allow for termination of extended follow-up 
are defined as the following:  
• For participants not taking antihistamines prior to enrollment (aka 
baseline): absence of study product-related urticaria-associated symptoms 
(eg; wheal and flare lesions, pruritis, and/or erythematous lesions) while 
off antihistamines for at least 8 weeks. The HVTN 302 PSRT will be 
consulted prior to terminating a participant from study follow-up.  
• For participants taking antihistamines for pre-existing allergic conditions 
prior to enrollment (aka baseline): back-to-baseline dosage of 
antihistamines, with lack of wheal and flare lesions and/or pruritic, 
erythematous lesions for at least 8 weeks. The HVTN 302 PSRT will be 
consulted prior to terminating a participant from study follow-up.  
8.7 
Visit procedures, schedule, windows and missed visits 
The schedule of visits and evaluations performed at each visit are shown in 
Appendix A (for participants undergoing LN FNA and/or leukapheresis) and 
Appendix B (for participants undergoing neither LN FNA nor leukapheresis) and 
Appendix C (for participants in extended follow-up). Visit windows are shown in 
Appendix D and Appendix E. The procedures for documenting missed visits and 
out-of-window visits are described in the HVTN 302 SSP. If the missed visit is 
one that required safety assessments or local safety labs, HVTN CRS staff 
should attempt to bring the participant in for an interim visit as soon as possible. 
8.8 
Monitoring for HIV infection 
Study participants will be tested for HIV infection periodically throughout the 
study as indicated in the schedules included in Appendix A and Appendix B. The 
Laboratory Program (or approved diagnostic laboratory) will follow the HVTN 
HIV testing algorithm (see HVTN Laboratory Center MOP) which is able to 
distinguish vaccine-induced antibody responses from actual HIV infections. 
Participants will be promptly informed and counseled if they become HIV-
infected during the study and referred for treatment (see Section 5.2.2). 
Study participants will receive regularly scheduled counseling regarding 
avoidance of HIV infection in accordance with the most recent Centers for 
Disease Control and Prevention HIV counseling guidelines. 

 
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Although the study vaccine will not cause HIV infection, it may induce 
antibodies detectable by standard HIV infection screening techniques. This is 
referred to as vaccine induced seropositivity (VISP). The following steps will be 
taken to protect participants from adverse consequences associated with VISP: 
• Participants will be counseled to avoid HIV antibody testing outside of the 
HVTN CRS during study participation. 
• Participants can receive HIV diagnostic testing from the CRS following 
their last scheduled visit until they are told they do not have VISP. 
• Participants with VISP will be offered poststudy HIV diagnostic testing 
(per the HVTN poststudy HIV testing algorithm) periodically free of 
charge as medically/socially indicated (approximately every 6 months) 
unless or until HIV antibody testing is no longer standard in clinical 
settings. 
• Unless they request that their names be removed, the names of all 
participants in HVTN studies are entered into a secure VISP registry in 
order to verify that an individual received an HIV vaccine (and therefore 
has the potential for VISP) and to qualify former participants for post-
study HIV testing to distinguish between VISP and HIV infection. 
Information in the VISP registry is not used for research.  
8.9 
Early termination visit 
If a participant terminates participation in the study early for any reason, the site 
principal investigator should consider if the following assessments are 
appropriate: end-of-study HIV test, CBC with differential, serum chemistry 
(ALT and creatinine), physical examination, social impact assessment, and if 
indicated, a pregnancy test (see Appendix A and Appendix B). If the site 
principal investigator has questions regarding a termination visit, they should 
consult with the PSRT. 
For participants with HIV infection, please see Section 5.2.2. If the site principal 
investigator has questions regarding a termination visit, they should consult with 
the PSRT.  
Early termination to extended follow-up consider all study procedures and 
sample collection in Appendix C. 

 
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9 
Safety and adverse events 
9.1 
Adverse events 
Unsolicited AEs will be collected over a period of 30 days after each 
vaccination. All collected AEs are captured in the clinical database on the 
appropriate CRF. Clinic staff should evaluate every AE to determine if (1) the 
AE meets the requirements for expedited reporting (see Section 9.3.1), (2) if the 
AE meets the criteria for a safety pause/prompt AE review (see Section 9.7), (3) 
if the AE meets the criteria for an MAAE, and (4) if the AE is an adverse event 
of special interest (AESI). Reportable AESIs will be myocarditis and pericarditis.  
In addition, a limited set of AEs will be collected and reported through the end of 
the main study. 
• SAEs/expedited adverse events (EAEs) 
• MAAEs (defined as any adverse events leading to an unscheduled visit to a 
healthcare professional) 
• AEs leading to early participant withdrawal or early discontinuation of study 
vaccine(s) administration.  
• Adverse Events of Special Interest (AESIs): 
• myocarditis 
• pericarditis  
• Participants in the Extended Follow-up (see Section 8.6) will have this subset 
of AEs collected and reported through the end of their study participation: 
• New dermatologic AEs (indicate if an MAAE)  
• SAEs 
Adverse events (AEs) will be graded according to the Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected 
Version 2.1 – July 2017 (https://rsc.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables), with the following exceptions:  
• Unintentional Weight Loss is required to be reported as an AE only if it is 
considered to be potentially deleterious to the participant’s health (see 
HVTN 302 SSP); 

 
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• Creatinine is required to be reported as an AE only if it is gradable per the 
increase from local lab ULN parameter. Do not grade elevated creatinine 
based on the change from the baseline parameter. 
• Do not grade creatinine clearance or eGFR based on the change from the 
baseline parameter. Do not grade on the basis of eGFR if there is clinical 
concern for kidney injury.  
• Injection Site Erythema or Redness and Injection Site Induration or 
Swelling will not consider surface area and interference with usual social 
and functional activities such that: 
o Grade 1 is: 2.5 to < 5 cm in diameter; 
o Grade 2 is: ≥ 5 to < 10 cm in diameter; 
o Grade 3 is: ≥ 10 cm in diameter OR ulceration OR secondary 
infection OR phlebitis OR sterile abscess OR drainage; 
o Grade 4 is: Potentially life-threatening consequences (eg, abscess, 
exfoliative dermatitis, necrosis involving dermis or deeper tissue); 
9.2 
AESIs 
Any possible, probable, or confirmed/definitive case of myocarditis and/or 
pericarditis, should be reported as an AESI whether diagnosed from a local 
clinical evaluation or if meeting the CDC or Brighton Collaboration case 
definitions. The event should also be reported as an SAE if it meets seriousness 
criteria (Section 9.3). The CDC and Brighton Collaboration case definitions are 
provided in Appendix J, as guidance. 
9.3 
Serious adverse events 
The term “Serious Adverse Event” (SAE) is defined in 21 CFR 312.32 as follows: 
“An adverse event or suspected adverse reaction is considered serious if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 
• death,  
• a life-threatening adverse event,  
• inpatient hospitalization or prolongation of existing hospitalization,  

 
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• a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions,  
• 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 adverse event that at occurrence represents an 
immediate risk of death to the subject. Similarly, a hospital admission for an 
elective procedure is not considered an SAE.  
9.3.1 
Expedited reporting of adverse events to DAIDS 
Requirements, definitions and methods for expedited reporting of AEs are 
outlined in Version 2.0 (January 2010) of the Manual for Expedited Reporting of 
Adverse Events to DAIDS (DAIDS EAE Manual), which is available on the RSC 
website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-
reporting-adverse-events-daids. 
The internet based DAIDS Adverse Experience Reporting System (DAERS) must 
be used for EAE reporting to DAIDS. In the event of system outages or technical 
difficulties, expedited AE reports may be submitted via the DAIDS EAE Form. 
This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. 
For questions about DAERS, please contact CRMSsupport@niaid.nih.gov or 
from within the DAERS application itself. 
For questions about EAE reporting, please contact the DAIDS RSC Safety Office 
at (DAIDSRSCSafetyOffice@tech-res.com). 
The SAE Reporting Category will be used throughout the study. After completion 
of the study the suspected unexpected serious adverse reaction (SUSAR) 
reporting category will be used if clinical staff becomes aware of an event on a 
passive basis. 
The study products for which expedited reporting are required are: mRNA-
1574v1-gp140, mRNA-1574v2-gp151, mRNA-1574v3-CD4KO. There is no 
placebo product administered in this protocol. The NIAID/DAIDS will report all 

 
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unexpected SAEs related to the study products observed in this clinical trial to the 
FDA in accordance with 21 CFR 312.32 (IND Safety Reports). 
In addition to the expedited Reporting Category identified above, other AEs that 
must be reported in an expedited manner are: myocarditis and/or pericarditis 
(AESIs). 
9.4 
Safety monitoring 
9.4.1 
Protocol Safety Review Team (PSRT) 
The PSRT comprises the Study Chairs, participating CRS PI(s), HVTN Protocol 
Team Leader, DAIDS Medical Officer, HVTN Clinical Safety Specialist (CSS), 
and other Study Clinicians. The Protocol Team clinic coordinator, clinical data 
manager, vaccine developer representative, clinical trial manager, and others may 
also be included in HVTN 302 PSRT meetings. The PSRT will review study 
safety information on a weekly basis through two weeks after the last participant 
receives the final study injection. Because participants can be enrolled in the 
study with a Grade 1 ALT value (up to <2.5 x ULN), the PSRT will monitor all 
gradable ALT abnormalities reported as adverse events. Less frequent safety 
reviews will be conducted at the discretion of the PSRT.  
9.4.2 
HVTN Safety Monitoring Board (SMB) 
The safety monitoring board (SMB) is a multidisciplinary group consisting of 
biostatisticians, clinicians, and experts in HIV vaccine research that, collectively, 
has experience in the conduct and monitoring of vaccine trials. Members of the 
SMB are not directly affiliated with the protocols under review. 
The SMB reviews safety data (including cumulative reactogenicity events, AEs, 
laboratory safety data, and individual SAE reports) approximately every 4 
months. The SMB conducts additional special reviews at the request of the HVTN 
302 PSRT. 
Study sites will receive SMB summary minutes and are responsible for 
forwarding them to their institutional review board (IRB)/ethics committee (EC) 
and any applicable Regulatory Entity (RE). 
9.5 
Total blood volume 
Required blood volumes per visit are shown in Appendix A, Appendix B, and 
Appendix C. Not shown is any additional blood volume that would be required if 
a safety lab needs to be repeated, or if a serum pregnancy test needs to be 
performed. The additional blood volume would likely be minimal. The total blood 
volume drawn for each participant will not exceed 500 mL in any 56-day (8-

 
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week) period as per American Red Cross guidelines for blood donation 
(https://www.redcrossblood.org/donate-blood/how-to-donate/eligibility-
requirements.html). 
The preferred laboratory specimen tube types for research samples are shown in 
Appendix A, Appendix B, and Appendix C. Alternate tube types may be used 
under certain circumstances (eg, ACD tube shortages) upon approval of the 
HVTN Laboratory Center. Refer to the HVTN 302 Specimen Collection SSP for 
more information. 
9.6 
Sentinel Safety Reviews  
Enrollment will start with Groups 1-3 simultaneously until a total of 12 
participants, approximately 4 participants in each group (Part A sentinel safety 
cohort) have been enrolled. Enrollment will then pause. The PSRT will review 
cumulative safety information recorded through the safety visit scheduled two 
weeks post first vaccination and will determine whether it is safe to proceed with 
enrolling the participants in Groups 4-6 and the rest of Groups 1-3.  
Enrollment will then start again for the first 12 participants in Groups 4-6 (Part B 
sentinel safety cohort) and the rest of Part A (Groups 1-3) in parallel. Once the 
Part B sentinel safety cohort (Groups 4-6) has been fully enrolled, enrollment in 
Groups 4-6 will then pause while the remainder of Part A (Groups 1-3) continues 
enrollment. The PSRT will review cumulative safety information recorded for 
Groups 4-6 (Part B sentinel safety cohort) through the safety visit scheduled two 
weeks post first vaccination and will determine whether it is safe to proceed with 
enrolling the remainder of participants in Groups 4-6 (see also Section 6.1). As 
PSRT safety reviews are performed weekly during the vaccination phase (Section 
9.4.1), this review will also automatically include cumulative safety data from 
Part A participants available at this time.  
This enrollment and safety review strategy allows for a single enrollment pause 
whilst maintaining separate randomization schemas for Part A and Part B 
participants. Additionally, this strategy allows for intervention of enrollment and 
vaccination plans for the higher dose group if safety concerns are identified in 
either Part A participants or the sentinel safety cohort of Part B.  
9.7 
Safety pause and prompt PSRT AE review 
The PSRT (see Section 9.4) will closely monitor participant safety. The trial 
overall, or by a particular dose level or group can be paused at any time for any 
reason by the PSRT. When a safety pause is implemented, enrollment and all 
vaccinations within the dose level(s), group(s) or overall trial that was placed on 
pause will be held until further notice. The AEs that will lead to a safety pause or 
prompt HVTN 302 PSRT AE review are summarized in Table 9-1. Vaccinations 

 
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may be suspended for safety concerns other than those described in the table, or 
before pause rules are met, if, in the judgment of the HVTN 302 PSRT, 
participant safety may be threatened. The enrollment strategy described above 
may allow for a safety pause for Part B participants alone if appropriate. Criteria 
for an individual participant’s departure from the schedule of vaccinations are 
listed in Section 5.2.3. 
Table 9-1 Pause Rules Table 
Event and 
relationship to study 
vaccine 
Severity 
Grade 
HVTN Site Actions 
HVTN Core action 
SAE, related 
5 or 4 
Phone 24/7 Safety Phone 
immediately 
Email 
vtn.clin.safety.spec@hvtn.org 
Submit CRFs immediately 
Immediate pause 
AESIa, related or 
unrelated 
Any grade Phone 24/7 Safety Phone 
immediately 
Email 
vtn.clin.safety.spec@hvtn.org 
Submit CRFs immediately 
Immediate pause 
SAE, related 
3, 2, or 1 
Email clinical safety specialist 
Submit CRFs immediately 
Prompt PSRT AE 
review to consider a 
pause  
AE, related 
(see Grade 3 
exceptions) 
4 or 3 
Email clinical safety specialist 
Submit CRFs immediately 
Prompt PSRT AE 
review to consider a 
pause 
a Adverse Events considered AESIs for the protocol are myocarditis and 
pericarditis. 
Exceptions to the related Grade 3 AEs (for Grade 3 subjective reactogenicity 
events and local reactions):  
• injection site pain/tenderness and erythema/induration (grade 3 by size 
only)  
• fatigue  
• generalized myalgia 
• generalized arthralgia  
• chills 
• headache 

 
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• nausea (unless IV rehydration required)  
Unrelated Participant Death: Sites will call the CSS office phone upon learning 
of any unrelated participant deaths. The site will also email the CSS and 
immediately submit CRFs. The PSRT will then be immediately notified. 
If you need to contact the CSS, refer to phone numbers and email addresses found 
on the Protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn302). 
9.7.1 
Plan for review of pause rules  
For all safety pauses, HVTN Core notifies the HVTN 302 PSRT, HVTN 
Regulatory Affairs, DAIDS Pharmaceutical Affairs Branch (PAB), DAIDS 
Regulatory Affairs Branch (RAB), DAIDS Safety and Pharmacovigilance Team 
(SPT), and participating HVTN CRSs. When an immediate safety pause is 
triggered, HVTN Core notifies the SMB. 
Once a trial is paused, the HVTN 302 PSRT reviews safety data and decides 
whether the pause can be lifted or permanent discontinuation of vaccination is 
appropriate, consulting the SMB if necessary. HVTN Core notifies the 
participating HVTN CRSs, HVTN Regulatory Affairs, DAIDS PAB, DAIDS 
RAB, and DAIDS SPT of the decision regarding resumption or discontinuation of 
study vaccinations. Based on the HVTN 302 PSRT assessment, DAIDS RAB 
notifies the FDA as needed. 
If an immediate HVTN 302 PSRT notification or prompt HVTN 302 PSRT AE 
review is triggered, HVTN Core notifies the HVTN 302 PSRT as soon as possible 
during working hours (local time)—or, if the information was received during off 
hours, by the morning of the next workday. If a prompt HVTN 302 PSRT AE 
review cannot be completed within 72 hours of notification (excluding weekends 
and US federal holidays), an automatic safety pause occurs. 
The HVTN requires that each CRS submit to its IRB/EC and any applicable RE 
protocol-related safety information (such as IND safety reports, notification of 
vaccine holds due to the pause rules, unanticipated problems involving risks to 
participants or others, and notification of other unplanned safety pauses). CRSs 
must also follow all applicable RE reporting requirements. 
9.8 
Study termination 
This study may be terminated early by the determination of the HVTN 302 PSRT, 
the NIH, the United States Department of Health and Human Services Office for 
Human Research Protections (OHRP), the FDA, or study product developers. In 
addition, the conduct of this study at an individual HVTN CRS may be terminated 
by the determination of the IRB/EC and any applicable RE. 

 
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9.9 
Pregnancy 
If a participant becomes pregnant during the course of the study, no more 
injections of study product will be given, but remaining visits and study 
procedures should be completed unless medically contraindicated or applicable 
regulations require termination from the study. During follow-up of persons who 
are confirmed pregnant, pregnancy testing is not required, unless clinically 
indicated. If the participant terminates from the study prior to the pregnancy 
outcome, the site should make every effort to keep in touch with the participant in 
order to ascertain the pregnancy outcome. Pregnancies and pregnancy outcomes 
will be reported as described in the HVTN 302 SSP section on Pregnancy 
Management and Reporting. If the participant is no longer pregnant, refer to 
Section 5.2.2. 

 
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10 
Protocol conduct and informed consent 
10.1 
Protocol conduct 
This research study will be conducted in compliance with the protocol, Good 
Clinical Practice (GCP) (ICH E6 (R2)), HVTN and DAIDS policies and 
procedures as specified in the HVTN Manual of Operations and DAIDS Clinical 
Research Policies and Standard Procedures Documents, and all applicable 
regulatory requirements. These policies and procedures include protocol 
monitoring (on-site and remote) and compliance. DAIDS and HVTN policies and 
procedures are available for review by any IRB/EC/RE upon request. Any 
policies or procedures that vary from DAIDS and HVTN standards or require 
additional instructions (eg, instructions for randomization specific to this study) 
will be described in the HVTN 302 SSP. Regarding protocol registration, sites 
should follow procedures outlined in the current version of the DAIDS Protocol 
Registration Manual.  
HVTN scientists and operational staff are committed to substantive community 
input into the planning, conduct, and follow-up of its research, ensuring that 
locally appropriate cultural and linguistic needs of study populations are met. 
Community Advisory Boards (CAB) are required by DAIDS and supported at all 
HVTN research sites to ensure community input in accordance with Good 
Participatory Practices (GPP) and all local and national guidelines. 
10.2 
Compliance with NIH guidelines for research involving products 
containing recombinant or synthetic nucleic acid molecules 
Because this study is evaluating products containing recombinant or synthetic 
nucleic acid molecules, it must comply with regulations set forth in the NIH’s 
Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid 
Molecules (April 2019). Information about the study must be submitted to the 
Institutional Biosafety Committee (IBC) for each CRS. Investigators at each CRS 
are responsible for obtaining IBC approval per NIH guideline section IV-B7-a-(1). 
IBC review and approval must be documented by the investigator and submitted 
as part of DAIDS’s initial protocol registration for this trial before participants are 
enrolled at the CRS. If this protocol is amended, investigators should follow the 
requirements of their respective IBC. 
10.3 
Informed consent 
The sample informed consent form (SICF) in Appendix F describes the 
investigational vaccine and all aspects involved in study participation. 
Documentation of appropriate informed consent must be in place prior to 
conducting study procedures with participants. Periodic assessment of 

 
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participants’ continued understanding of key study concepts and informed consent 
must also be documented. Study sites are strongly encouraged to have their local 
CABs review their site-specific consent forms. This review should include, but 
should not be limited to, issues of cultural competence, local language 
considerations, and the level of understandability. 
If any new information is learned that might affect the participants’ decisions to 
stay in the trial, this information will be shared with them. If necessary, 
participants will be asked to sign revised informed consent forms. 
An HVTN CRS may employ recruitment efforts prior to the participant 
consenting. For example, some HVTN CRSs use a telephone script to prescreen 
people before they come to the clinic for a full screening visit. Participants must 
sign a screening or protocol-specific consent before any procedures are performed 
to determine eligibility. HVTN CRSs must submit recruitment and prescreening 
materials to their IRB/EC and any applicable RE for human subjects protection 
review and approval. 
10.3.1 
Screening Consent Form 
Without a general screening consent, screening for a specific study cannot take 
place until the site receives protocol registration from the DAIDS RSC Protocol 
Registration Office. 
Some HVTN CRSs have approval from their IRB/EC and any applicable RE to 
use a general screening consent form that allows screening for an unspecified HIV 
vaccine trial. In this way, HVTN CRS staff can continually screen potential 
participants and, when needed, proceed quickly to obtain protocol-specific 
enrollment consent. Sites conducting general screening or prescreening approved 
by their IRB/EC and any applicable RE may use the results from this screening to 
determine eligibility for this protocol, provided the tests are conducted within the 
time periods specified in the eligibility criteria. 

 
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11 
Exploratory studies 
Samples may be used for other testing and research related to furthering the 
understanding of HIV immunology or vaccines. In addition, cryopreserved 
samples may be used to perform additional assays to support standardization and 
validation of existing or newly developed methods.  
Only genetic testing that is in accord with the language in the sample informed 
consent form (Appendix F and Appendix G) may be performed on samples.  
11.1 
Specimen storage and other use of specimens 
The HVTN stores specimens from all study participants indefinitely, unless a 
participant requests that specimens be destroyed or if destruction or a time limit 
for storage is required by IRB/EC, or RE. 
Other use of specimens is defined as studies not covered by the protocol or the 
informed consent form for the main study (see Appendix F). 
This research may relate to HIV, vaccines, the immune system, and other 
diseases. This could include genetic testing and, potentially, genome-wide studies. 
This research is done only to the extent authorized in each study site’s informed 
consent form, or as otherwise authorized under applicable law. Other research on 
specimens (“other use”) will occur only after review and approval by the HVTN, 
the IRB/EC of the researcher requesting the specimens, and the IRBs/ECs/REs of 
the CRSs if required. 
As part of consenting for the study, participants document their initial decision to 
allow or not allow their specimens to be used in other research, and they may 
change their decision at any time. The participant’s initial decision about other 
use of their specimens, and any later change to that decision, is recorded by their 
CRS in a Web-based tool that documents their current decisions for other use of 
their specimens. The HVTN will only allow other research to be done on 
specimens from participants who allow such use. 
CRSs must notify HVTN Regulatory Affairs if institutional or local governmental 
requirements pose a conflict with or impose restrictions on specimen storage or 
other use of specimens. 

 
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Appendix A 
Schedule of procedures for participants undergoing LN FNA and/or leukapheresis 
Visit Number 
01 
02 
03 
04 
0516 
06 
07 
08 
0916 
10 
11 
12 
1316 
14 
15 
Study Month 
 
0 
0.25 
0.5 
1.5 
2 
2.25 
2.5 
3 
6 
6.25 
6.5 
7 
8 
12 
Study Week 
 
0 
1 
2 
6 
8 
9 
10 
12 
24 
25 
26 
28 
32 
52 
Study Day 
-56 to 1 
1 
8 
15 
43 
57 
64 
71 
85 
169 
176 
183 
197 
225 
365 
Procedure 
Screen1 
Vac 1 
 
 
 
Vac 2 
 
 
 
Vac 3 
 
 
 
 
 
Study procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Understanding 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history2 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam3 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Contraception status assessment4 
 
√ 
√ 
 
 
 
√ 
 
 
 
√ 
 
 
 
√ 
 
Risk reduction counseling5 
 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
√ 
Concomitant medications6 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Adverse Events (AEs) 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
MAAEs/AESIs/SAEs 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Vaccination7 
 
 
√ 
 
 
 
√ 
 
 
 
√ 
 
 
 
 
 
Reactogenicity assessment8 
 
 
√ 
 
 
 
√ 
 
 
 
√ 
 
 
 
 
 
Social impact assessment 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Social impact questionnaire 
 
 
 
 
 
 
√ 
 
 
 
√ 
 
 
 
 
√ 
Clinical labs 
Tube 
Vol (mL) 
Pregnancy test (urine or serum) 9, 10 
 
√ 
√ 
 
 
√15 
√ 
 
√17 
√15 
√ 
 
√17 
√15 
√ 
 
HBsAg/anti-HCV10 
SST 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV screening test 10,11 
SST 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Differential10 
EDTA 
5 
 
5 
 
 
 
5 
 
 
 
5 
 
 
5 
 
ALT/Creatinine10 
SST 
5 
 
5 
 
 
 
5 
 
 
 
5 
 
 
 
 
Storage for additional safety labs12 
SST 
 
y 
5 
y 
 
 
5 
y 
 
 
5 
y 
 
 
 
HIV diagnostic test 
EDTA 
 
 
 
 
 
 
 
10 
 
10 
 
 
 
10 
20 
Research samples13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC for assays and storage 
ACD 
 
42.5 
 
42.5 
 
85 
 
144.514 
 
85 
 
20414 
 
 
255 
Serum for assays and storage 
SST 
 
25.5 
 
25.5 
25.5 
25.5 
 
25.5 
25.5 
25.5 
 
25.5 
25.5 
25.5 
25.5 
Lymph Node Fine Needle Aspirate15 
 
 
 
 
 
√15 
 
 
 
√15 
 
 
 
√15 
 
 
Leukapheresis17 
 
 
 
 
 
 
 
 
√17 
 
 
 
√17 
 
 
 
Daily volume maximum (mL)18  
20 
68 
15 
68 
25.5 
110.5 
15 
180 
25.5 
120.5 
15 
229.5 
25.5 
40.5 
300.5 
56-day total volume maximum (mL)18  
20 
88 
103 
171 
196.
5 
307 
234 
399 
356.5 
120.5 
135.
5 
365 
390.
5 
431 
300.5 

HVTN 302 Version 3.0 / July 7, 2023 
HVTN302_v3.0_Final_07JUL23 / Page 85 of 137 
Green shading = Vaccination Visit; Blue shading = LN FNA visits, which are only applicable to participants undergoing LN FNA 
1 Screening evaluations at Visit 01 are performed no more than 56 days before Day 1.  
2 Medical history: A complete medical history is performed during screening. At enrollment and at subsequent visits, an interim medical history may be performed. 
3 A complete physical exam is performed at screening and last clinic visit, to include height, weight, vital signs, and clinical assessments of head, ears, eyes, nose, and throat; 
neck, lymph nodes; heart; chest; abdomen; extremities; neurological function; and skin. At other visits, a targeted physical exam will be performed as needed, based on 
participant report or indications of illness. 
4 Contraception status assessment is required only for participants who were assigned female sex at birth and are capable of becoming pregnant. 
5 Risk reduction counseling per CRS Standard Operating Procedures. 
6 Concomitant medications, including prescription and non-prescription drugs, vitamins, topical products, alternative/complementary medicines, recreational drugs, 
vaccinations, and allergy shots are recorded during screening, at enrolment, and at each subsequent clinic visit. 
7 Vaccination (in clinic assessments): At least 30 minutes after each vaccination and prior to clinic discharge, participants will have vital signs taken, the injection site will be 
assessed, and systemic symptoms will be assessed.  
8 Reactogenicity: Clinic staff will follow new or unresolved reactogenicity symptoms present at day 7 until resolution. 
9 Pregnancy test: For participants assigned female sex at birth. Pregnancy test may be performed on urine or blood specimens. Persons who are NOT capable of becoming 
pregnant due to total hysterectomy or bilateral oophorectomy (verified by medical records), or menopause (no menses for ≥ 1 year) are not required to undergo pregnancy 
testing. Persons who are confirmed pregnant, pregnancy testing is not required, unless clinically indicated. 
10 Local labs may assign appropriate alternative tube types for locally performed tests. 
11 HIV screening test: see Section 5.1.1. 
12 For additional assays to be performed if clinically indicated (See Section 8.4) 
13 Research samples: Blood draw volumes for each tube type shown.  
14 PBMC for assays and storage: To be collected only from participants who will not undergo leukapheresis. 
15 Lymph node fine needle aspirate: Will only be collected from participants who agreed to provide this sample type and who have met lymph node FNA eligibility criteria (see 
Section 8.5.1). A pregnancy test must be performed and confirmed negative within 48 hours prior to lymph node FNA (see also: footnote 9). For participants who decide not to 
continue providing Lymph Node FNA samples, procedures shown in Appendix B should be followed. 
16 Visits 5, 9 and 13 are required only for participants undergoing lymph node FNA. 
17 Leukapheresis: Will only be collected from participants who agreed to provide this sample type and who have met leukapheresis eligibility criteria (see Section 8.5.2). A 
pregnancy test must be performed and confirmed negative within 48 hours prior to leukapheresis (see also: footnote 9). For participants who decide not to continue providing 
leukapheresis samples, procedures shown in in Appendix B should be followed. 
18 Daily and 56-day total blood draw volumes will be lower for participants who are providing leukapheresis samples. 
y=SST blood collected for assays and serum storage will also cover specimen needs for storage for additional safety labs; no separate blood draw is needed.  

HVTN 302 Version 3.0 / July 7, 2023 
HVTN302_v3.0_Final_07JUL23 / Page 86 of 137 
Appendix B 
Schedule of procedures for participants undergoing neither LN FNA nor 
leukapheresis 
Visit Number 
01 
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
15 
Study Month 
 
0 
0.25 
0.5 
1.5 
2 
2.25 
2.5 
3 
6 
6.25 
6.5 
7 
8 
12 
Study Week 
 
0 
1 
2 
6 
8 
9 
10 
12 
24 
25 
26 
28 
32 
52 
Study Day 
-56 to 1 
1 
8 
15 
43 
57 
64 
71 
85 
169 
176 
183 
197 
225 
365 
Procedure 
Screen1 
Vac 1 
 
 
 
Vac 2 
 
 
 
Vac 3 
 
 
 
 
 
Study procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Understanding 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history2 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam3 
 
√ 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
√ 
Contraception status assessment4 
 
√ 
√ 
 
 
 
√ 
 
 
 
√ 
 
 
 
√ 
 
Risk reduction counseling5 
 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
√ 
Concomitant medications6 
 
√ 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
√ 
Adverse Events (AEs) 
 
 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
√ 
MAAEs/AESIs/SAEs 
 
 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
√ 
Vaccination7 
 
 
√ 
 
 
 
√ 
 
 
 
√ 
 
 
 
 
 
Reactogenicity assessment8 
 
 
√ 
 
 
 
√ 
 
 
 
√ 
 
 
 
 
 
Social impact assessment 
 
 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
√ 
Social impact questionnaire 
 
 
 
 
 
 
√ 
 
 
 
√ 
 
 
 
 
√ 
Clinical labs 
Tube 
Vol (mL) 
Pregnancy test (urine or serum) 9, 10 
 
√ 
√ 
 
 
 
√ 
 
 
 
√ 
 
 
 
√ 
 
HBsAg/anti-HCV10 
SST 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV screening test 10,11 
SST 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Differential10 
EDTA 
5 
 
5 
 
 
 
5 
 
 
 
5 
 
 
5 
 
ALT/Creatinine10 
SST 
5 
 
5 
 
 
 
5 
 
 
 
5 
 
 
 
 
Storage for additional safety labs12 
SST 
 
y 
5 
y 
 
 
5 
y 
 
 
5 
y 
 
 
 
HIV diagnostic test 
EDTA 
 
 
 
 
 
 
 
10 
 
10 
 
 
 
10 
20 
Research samples13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC for assays and storage 
ACD 
 
42.5 
 
42.5 
 
85 
 
144.5 
 
85 
 
204 
 
 
255 
Serum for assays and storage 
SST 
 
25.5 
 
25.5 
 
25.5 
 
25.5 
 
25.5 
 
25.5 
 
25.5 
25.5 
Daily volume total (mL)  
20 
68 
15 
68 
 
110.5 
15 
180 
 
120.5 
15 
229.
5 
 
40.5 
300.5 
56-day total volume (mL)  
20 
88 
103 
171 
 
281.5 
208.5 
373.5 
 
120.5 
135.5 
365 
 
405.5 
300.5 
Green shading = Vaccination Visit; Gray shading = FNA visits, which are not applicable to this subgroup 

HVTN 302 Version 3.0 / July 7, 2023 
HVTN302_v3.0_Final_07JUL23 / Page 87 of 137 
1 Screening evaluations at Visit 01 are performed no more than 56 days before Day 1.  
2 Medical history: A complete medical history is performed during screening. At enrollment and at subsequent visits, an interim medical history may be 
performed. 
3 A complete physical exam is performed at screening and last clinic visit, to include height, weight, vital signs, and clinical assessments of head, ears, eyes, nose, 
and throat; neck, lymph nodes; heart; chest; abdomen; extremities; neurological function; and skin. At other visits, a targeted physical exam will be performed 
as needed, based on participant report or indications of illness. 
4 Contraception status assessment is required only for participants who were assigned female sex at birth and are capable of becoming pregnant. 
5 Risk reduction counseling per CRS Standard Operating Procedures. 
6 Concomitant medications, including prescription and non-prescription drugs, vitamins, topical products, alternative/complementary medicines, recreational 
drugs, vaccinations, and allergy shots are recorded during screening, at enrolment, and at each subsequent clinic visit. 
7 Vaccination (in clinic assessments): At least 30 minutes after each vaccination and prior to clinic discharge, participants will have vital signs taken, the injection 
site will be assessed, and systemic symptoms will be assessed.  
8 Reactogenicity: Clinic staff will follow new or unresolved reactogenicity symptoms present at day 7 until resolution. 
9 Pregnancy test: For participants assigned female sex at birth. Pregnancy test may be performed on urine or blood specimens. Persons who are NOT capable of 
becoming pregnant due to total hysterectomy or bilateral oophorectomy (verified by medical records), or menopause (no menses for ≥ 1 year) are not required 
to undergo pregnancy testing. Persons who are confirmed pregnant, pregnancy testing is not required, unless clinically indicated. 
10 Local labs may assign appropriate alternative tube types for locally performed tests. 
11 HIV screening test: see Section 5.1.1. 
12 For additional assays to be performed if clinically indicated (See Section 8.4) 
13 Research samples: Blood draw volumes for each tube type shown.  
y=SST blood collected for assays and serum storage will also cover specimen needs for storage for additional safety labs; no separate blood draw is needed.  
 
 
 

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Appendix C 
Schedule of procedures for extended follow-up for participants with unresolved 
study product-related urticaria-associated symptoms 
 
Visit Number 
101 
102 
103 
104 
105 
106 
107 
108 
Urticaria-Associated 
Symptom Visit4 
Study Month 
15 
18 
21 
24 
30 
36 
48 
60 
 
Study Week 
65 
78 
91 
104 
130 
156 
208 
260 
 
Study Day 
456 
547 
638 
729 
911 
1093 
1457 
1821 
 
Study procedures 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
√ 
 
 
 
 
 
 
 
 
Urticaria-related symptom questionnaire  
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Medical history1 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Concomitant medications2 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Dermatological Adverse Events (AEs)  
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
SAEs 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Targeted Physical exam (if clinically 
indicated)3 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Research samples 
 
 
 
 
 
 
 
 
 
 
Serum for storage and assays4 
SST 
0 
17 
As clinically indicated and at the 
participant's exit visit4 
17 
17 
Daily volume total (mL)  
0 
17 
0 
0 
0 
0 
0 
17 
17 
56-day total volume (mL)  
0 
17 
0 
0 
0 
0 
0 
17 
 
1 Medical history: Based on the responses on urticaria-related symptom questionnaire, an interim medical history may be performed and documented in the participant’s chart. 
2 Concomitant medications, including review of prescription and non-prescription drugs, vitamins, topical products, alternative/complementary medicines, recreational drugs, 
vaccinations, and allergy shots are updated and any new information is recorded at each contact. 
3 Site may ask the participant to come in for a targeted (abbreviated) physical exam if during the remote visit, the participant reports anything that may require further evaluation. See 
Section 8.6. 
4See Section 8.6. Participants in extended follow will have clinic visits to collect 17 mls serum for banking at Visit 102, their exit visit, and at any clinic visit(s) scheduled to further 
evaluate urticaria-associated symptoms. 
 
 

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Appendix D 
Visit windows for main study 
Visit Number 
Visit Type 
Lower 
Allowable 
Window  
(-) 
Lower 
Target 
Window  
(-) 
Target 
Day1 
Upper 
Target 
Window 
(+) 
Upper 
Allowable 
Window  
(+) 
01.0 
Screening 
-56 
- 
 
- 
Up to Day 
1 
02.0 
Enrollment/Vaccination 1 
- 
- 
1 
- 
- 
03.0 
1 week post-vaccination 1 
 
-3 
8 
+2 
 
04.0 
2 weeks post-vaccination 1 
 
-4 
15 
+4 
+7 
05.0**  
6 weeks post-vaccination 1 
FNA 
-7 
-4 
43 
+4 
+7 
06.0 
Vaccination 2 
-7 
-4 
57 
+4 
+7 
07.0 
1 week post-vaccination 2 
 
-3 
64 
+2 
 
 
08 
2 weeks post-vaccination 2 
- 
-4 
71 
+4 
+7 
Leukapheresis 
 
-4 
71 
+1 
+4 
09.0** 
4 weeks post-vaccination 2 
FNA 
-7 
-4 
85 
+4 
+7 
10.0 
Vaccination 3 
-21 
-14 
169 
+14 
+21 
11.0 
1 week post-vaccination 3 
 
-3 
176 
+2 
 
 
12.0 
2 weeks post-vaccination 3 
Primary Immunogenicity 
 
-4 
183 
+4 
+7 
Leukapheresis 
 
-4 
183 
+1 
+4 
13.0** 
4 weeks post-vaccination 3 
FNA 
-7 
-4 
197 
+4 
+7 
14.0 
8 weeks post-vaccination 3 
 
-14 
-7 
225 
+7 
+14 
15.0 
Final Visit 
-28 
-14 
365 
+14 
+28 
Green shading = Vaccination Visit; Blue shading = FNA visit 
* All target dates are relative to Day 1, with the exception of the post-vaccination visits (visits 3.0-5.0, 
7.0-9.0, and 11.0-14.0) which are relative to the vaccination immediately preceding the visit. 
** Visits 5.0, 9.0, and 13.0 are only required for participants who are providing lymph node FNA 
collections. 
 

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HVTN302_v3.0_Final_07JUL23 / Page 90 of 137 
Appendix E 
Visit windows for follow-up of participants with 
unresolved study product-related urticaria-associated 
symptoms 
 
Visit Number 
Visit Type 
Lower 
Allowable 
Window  
(-) 
Lower 
Target 
Window  
(-) 
Target Day* 
Upper 
Target 
Window  
(+) 
Upper 
Allowable 
Window  
(+) 
101 
Initial contact 
-42 
-28 
456 
+28 
  +42 
102 
1.5-year contact 
-42 
-28 
547 
+28 
+42 
103 
1.75-year contact 
-42 
-28 
638 
+28 
+42 
104 
2-year contact 
-42 
-28 
729 
+28 
+42 
105  
2.5-year contact 
-84 
-56 
911 
+56 
+84 
106 
3-year contact 
-84 
-56 
1093 
+56 
+84 
107 
4-year contact 
-84 
-56 
1457 
+56 
+84 
108 
Final 5-year contact 
-84 
-56 
1821 
+56 
+84 
* All Target Days are relative to Day 1 of the main study (enrollment date); informed consent for follow-up can be 
collected any time prior and up to Visit 101 
 

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Appendix F 
Sample informed consent form 
Sponsor / Study Title: 
 
National Institutes of Health / “A phase 1, randomized, 
open-label clinical trial to evaluate the safety and 
immunogenicity of BG505 MD39.3, BG505 MD39.3 gp151, 
and BG505 MD39.3 gp151 CD4KO HIV trimer mRNA 
vaccines in healthy, HIV-uninfected adult participants” 
 
Protocol Number: 
 
HVTN 302 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
Thank you for your interest in our research study. Please read this consent form or ask 
someone to read it to you. If you decide to join the study, we will ask you to sign or 
make your mark on this form. We will offer you a copy to keep. We will ask you 
questions to see if we have explained everything clearly. You can also ask us 
questions about the study. 
Research is not the same as treatment or medical care. The purpose of a research 
study is to answer scientific questions. 
Key information 
• 
This is the first study in which the study vaccines will be given to people. 
• Being in this research study is voluntary. Whether you join or not is your choice. 
• You are being asked to take part in this study because you are age 18-55, HIV 
negative and healthy. 
• 
The purpose of this study is to see how a person’s immune system responds to the 3 
experimental vaccines (referred to as study vaccines throughout this form).  
• 
The study will also see if the study vaccines are safe to give to people and do not make 
people too uncomfortable. 
• You will be in this study for up to 12 months of clinic visits. 
• Procedures will include blood draws and injections of study vaccines.  
 You may be asked if we can collect white blood cells from your 
blood and cells from your lymph nodes. White blood cells will be 
collected by a procedure called leukapheresis. Lymph node cells 
will be collected by a doctor using a very thin needle guided by 

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HVTN302_v3.0_Final_07JUL23 / Page 92 of 137 
ultrasound. We will tell you more about these procedures later in 
this consent form. 
• There are risks from participating:  
 Because these study vaccines have not been given to people before, we do 
not know what all of the risks may be. Common side effects from all 
vaccines include headache, fever, chills, rash, aches and pains, nausea, 
dizziness, and fatigue (feeling tired). 
 Taking blood and giving injections can cause bruising, pain, fainting, 
soreness, redness, swelling, itching, a sore and bleeding.  
 Collection of white blood cells (leukapheresis) and collecting cells from 
your lymph node can cause pain, bruising, and rarely an infection. 
 We will tell you more information about risks later in this consent form. 
• We do not expect the study vaccines to benefit you in any way.  
About the study 
The HIV Vaccine Trials Network (HVTN) and the study site are doing this study to 
test 3 human immunodeficiency virus (HIV) vaccines. HIV is the virus that causes 
acquired immunodeficiency syndrome (AIDS). 
Up to 108 people will take part in this study. The researcher in charge of this study at 
this clinic is called the study doctor. The US National Institutes of Health (NIH) is 
paying for the study. 
 We are doing this study to answer several critical questions. 
• Are the study vaccines safe to give to people? 
• Are people able to take the study vaccines without becoming too 
uncomfortable? 
• How do people’s immune systems respond to the study vaccines? (Your 
immune system protects you from infections and disease.)  
 The study vaccines cannot give you HIV. 
The study vaccines are not made from HIV. It is impossible for the study vaccines to 
give you HIV. Also, they cannot cause you to give HIV to someone else. 
We do not know if the study vaccines will decrease, increase, or not change your risk 
of getting HIV if you are exposed to the virus.  

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 These study vaccines are experimental. 
We are testing three experimental vaccines: BG505 MD39.3 mRNA, BG505 MD39.3 
gp151 mRNA, and BG505 MD39.3 gp151 CD4KO mRNA. Experimental means they 
have not been approved by the U.S. Food and Drug Administration (FDA).  
Together, they are called the either BG505 MD39.3 mRNA or mRNA1574 vaccines. 
From here on, we will call the vaccines the study vaccines. If you join the study, you 
will only be given 1 of the 3 study vaccines. These study vaccines were developed by 
researchers at Scripps Research, and are provided for the study by IAVI. 
Each of these 3 study vaccines is made using messenger ribonucleic acid (mRNA) 
technology developed by Moderna, Inc. mRNA is a piece of genetic code carried into 
your body by the vaccine as a message with instructions in the same way that the 
mRNA vaccines against COVID instruct the body’s cells to make the SARS-CoV-2 
spike protein. Instead of showing your immune system actual pieces of HIV, the 
study vaccines carry instructions that show human muscle cells how to make small 
pieces that look like parts of HIV.  
When people get a vaccine injection in the muscle of their arm, the cells in that 
muscle will get the instructions and start to make the different types of HIV pieces 
described below, and to display these pieces on the muscle cell’s surface. The 
immune system will be able to see these HIV pieces and learn how to recognize them. 
Researchers hope that the immune system will respond by making antibodies and T-
cells that could fight HIV if a person is ever exposed to the real virus in the future.  
The mRNA instructions do their work in the part of the muscle cell called the 
cytoplasm. The mRNA does not get into the nucleus of the cells, which is where 
human DNA is located. The mRNA cannot interact with your DNA. The mRNA 
instructions only remain in the body for a couple of days before they break down 
naturally. 
 
As shown in the picture, HIV has protein spikes on its surface. These spikes are made 
from 3 pieces, known as a trimer. The trimer has an outer end that it uses to bind onto 
human cells, and a “stalk” that connects to the inner part of the virus. This “stalk” 
extends through the outer membrane layer of the virus. Each of the 3 study vaccines 
is made slightly differently to see how the immune system will respond to these 
different structures. 

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HVTN302_v3.0_Final_07JUL23 / Page 94 of 137 
• BG505 MD39.3 mRNA has the code for just the outermost part of the trimer. 
• BG505 MD39.3 gp151 mRNA has the codes for the outermost part of the trimer, 
part of the “stalk,” and a bit of the membrane layer. 
• BG505 MD39.3 gp151 CD4KO mRNA also has the codes for the outermost part 
of the trimer, part of the “stalk,” and a bit of the membrane layer, but a piece of 
the trimer called the CD4 binding site has been removed.  
The study vaccines have not been given to people before. Studies in rats and rabbits 
showed that animals that got the vaccines had symptoms similar to the general risks 
of other vaccines described below. Even if something looks like it is safe or works in 
animals, it may not be true for people. 
General risks of vaccines: 
All vaccines can cause headache, fever, chills, rash, aches and pains, nausea, 
dizziness, and feeling tired. Vaccines can also cause redness, swelling or itching 
where you got the injection. Most side effects do not interfere with daily activities or 
make a person visit the doctor. With mRNA vaccines for other diseases, people may 
experience more of these side effects after getting the second dose of the vaccine. 
Rarely, a vaccine can cause an allergic reaction, including a rash, hives, or trouble 
breathing. Allergic reactions can be life-threatening. Tell us if you ever had a bad 
reaction to an injection or vaccine. 
Risks of the study vaccines: 
• Hives: We previously told you about 2 participants that had developed itchy hives 
within 1-3 weeks after their first vaccinations. As of November 2022, these 2 
participants still have some symptoms, although they have improved over time. 
They are using less medication and have less frequent symptoms.  
Since then, we have seen 5 more participants develop hives after getting the first 
or second injection of a study vaccine (out of 108 participants enrolled total). 
These reactions have been mild or moderate. Of these 5 new people, 4 began to 
experience hives 1-3 weeks after their study vaccination and have required 
medication to control outbreaks since then. The fifth person developed hives 
about 10 hours after getting the vaccination which went away by the next day 
without medication.  
All 7 participants have been able to continue with their daily activities even 
though most of them needed to use antihistamine medications like Zyrtec. As of 
November 8, 2022, all but one of the participants’ symptoms have lasted at least 5 
weeks, and the reactions have resolved or are resolving with use of medications.   
Enrollment in the trial is now complete, but participants continue to receive study 
vaccinations. Of the 7 participants who reported these reactions, two have 

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HVTN302_v3.0_Final_07JUL23 / Page 95 of 137 
received additional doses of study vaccine and have not had a worsening of their 
initial symptoms. 
Many people get hives in reaction to foods, creams or lotions or medicines such 
as ibuprofen. We don’t have enough information to know why some study 
participants got hives after getting a study vaccine, but we will let you know if we 
learn anything new that might change your mind about participating in this study. 
• Myocarditis and pericarditis: Myocarditis (inflammation of the heart muscle) 
and pericarditis (inflammation of the lining around the heart) have occurred very 
rarely in some people who got mRNA vaccines against COVID-19. As discussed 
above, the vaccines in this study also use mRNA technology. Reports have been 
more common in young adults who were assigned male sex at birth than in older 
people. In most of these people, symptoms began within a few days after the 
second dose of the vaccine. Almost all people have responded well to medications 
and rest, and their symptoms improved quickly. The chance of having this 
inflammation occur is very low. It is not known whether the risk of myocarditis or 
pericarditis is increased following mRNA vaccines for other diseases. 
You should seek medical attention right away and inform your site staff if you 
have any of the following symptoms after getting the study vaccines: 
• 
Chest pain 
• 
Shortness of breath 
• 
Fainting 
• 
Having a fast-beating, fluttering, or pounding heart. 
There may be other side effects from these study vaccines that we don’t know about. 
We will tell you if we learn about new side effects that could affect your willingness 
to stay in the study. 
Joining the study 
 It is up to you whether or not to join the study. 
Take your time. Talk to people you trust. If you decide not to join this study or if you 
leave after you have joined, that will not affect your other care at this clinic and the 
benefits or rights you would normally have. 
You cannot be in this study while you are in another study where you get a study 
product. If you do not join this study, you may be able to join another study. 
During the study, you should not donate blood or tissue. 
Site: Remove item 5 if you use a separate screening consent that covers these 
procedures. 

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 If you want to join the study, we will screen you to see if you are eligible. 
Screening involves a physical exam, HIV test, and health history. A physical exam 
may include, but is not limited to: 
• Checking your weight, temperature, and blood pressure 
• Looking in your mouth and throat 
• Listening to your heart and lungs 
• Feeling your abdomen (stomach and liver) 
• Asking about any vaccines you have gotten recently. 
We will also do blood tests. These tell us about the health of your kidneys and liver 
and whether or not you have Hepatitis B or C. The study doctor may be required by 
law to report the result of these tests to the local health authority.  
We will ask you about medicines you are taking, including HIV pre-exposure 
prophylaxis (PrEP). We will ask you about behaviors that might put you at risk for 
getting HIV. If you were assigned female sex at birth, we will test you for pregnancy. 
We will review the test results with you. They may show you are not eligible for the 
study, even if you want to participate.  
Site: adapt the following section per the care available at your site 
 If we find that you have a health problem during screening or during the study, 
we will tell you about the care that we can give here at no cost. 
For the care that we cannot give, we will help you get care elsewhere. For health 
problems unrelated to the study, we will not pay for care. 
 If you were assigned female sex at birth and could become pregnant, you must 
use birth control to join this study. 
Site: If you want to include Appendix I, Approved birth control methods (for sample 
informed consent form), in this consent form, paste it below and delete paragraph 
below. 
You should not become pregnant during the study because we do not know how the 
study vaccine could affect a developing baby. For this reason, you must agree to use 
effective birth control from 21 days before your first injection until 3 months after the 
time of your third study injection (9 months total). We will talk to you about effective 
birth control methods. They are listed on a handout that we will give to you. 

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Being in the study 
If you join the study, here is what will happen: 
 You will come to the clinic for scheduled visits about 12-15 times over 12 
months. 
Site: Insert number of visits and range of visit lengths. (There is site-specific variation 
in screening protocols and in the number of possible follow-up visits between 
protocol-mandated visits.) 
Visits can last from [#] to [#] hours. 
You may have to come for more visits if you have a lab or health issue.  
We may contact you after the study ends (for example, to tell you about the study 
results). We may also contact you about other studies you may want to join. 
 We will give you compensation for each study visit you complete. 
«Compensation» 
You will be paid up to a total of $xx.xx if you complete this study. You will be paid 
for the visits you complete according to the following schedule: 
c. $xx.xx for Visits xxx.  
d. $xx.xx for Visits xxx.  
e. $xx.xx for Visits xxx.  
This amount is to cover the costs of [Site: Insert text]. You will receive ___________ 
[“following each completed visit”, “monthly”, “quarterly”, “at the end of your 
participation in the research study”, “following each completed visit or at the end of 
your participation in the research study, whichever you prefer”]. 
There is also additional compensation for participants in Groups 1-3 who have the 
optional study procedures. We will tell you more about these optional study 
procedures in Section 12 below.  
You will receive $xx.xx each time you have leukapheresis. This amount is to cover the 
costs of [Site: Insert text]. You will be paid ___________ [“following each completed 
visit”, “monthly”, “quarterly”, “at the end of your participation in the research 
study”, “following each completed visit or at the end of your participation in the 
research study, whichever you prefer”]. 
You will receive $xx.xx each time you have a lymph node cell collection. This amount 
is to cover the costs of [Site: Insert text]. You will be paid ___________ [“following 
each completed visit”, “monthly”, “quarterly”, “at the end of your participation in 

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the research study”, “following each completed visit or at the end of your 
participation in the research study, whichever you prefer”]. 
Payments you receive for being in the study may be taxable. We may need to ask you 
for your Social Security number for tax reasons. 
Costs 
You do not have to pay anything to be in this study. The study vaccine and all study 
procedures will be provided at no cost to you. 
 We will give you the study vaccines on a schedule. 
You will be in one of the 6 study groups shown in the table below. You will get 3 
injections of one of the study vaccines into the muscle of your upper arm during the 
study according to the schedule shown below. You have an equal chance of getting 
any of the 3 study vaccines. Whether you are enrolled in a lower dose group or higher 
dose group will depend on when you join the study. 
Because this is the first time the study vaccines are being given to people, the study 
has planned pauses when safety information will be reviewed to decide if it is safe to 
continue the study. The first pause will be after the first 4 participants in Groups 1-3 
have their first injection. If the safety review of these participants shows it is safe to 
continue, then enrollment will resume for the rest of the participants in the lower dose 
groups. At the same time, enrollment will start for the first 4 participants in Groups 4-
6. There will be another pause for a review of the safety information after they 
receive their first injection. If the review shows it is safe to continue, then enrollment 
will resume for the rest of the participants in the higher dose groups.  
 

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Group 
Number of 
participants 
Injection schedule  
At enrollment 
At 2 months 
At 6 months 
1 
18 
lower dose of BG505 
MD39.3 mRNA 
lower dose of BG505 
MD39.3 mRNA  
lower dose of BG505 
MD39.3 mRNA 
2 
18 
lower dose of BG505 
MD39.3 gp151 mRNA 
lower dose of BG505 
MD39.3 gp151 mRNA 
lower dose of BG505 
MD39.3 gp151 mRNA 
3 
18 
lower dose of BG505 
MD39.3 gp151 CD4KO 
mRNA 
lower dose of BG505 
MD39.3 gp151 CD4KO 
mRNA  
lower dose of BG505 
MD39.3 gp151 CD4KO 
mRNA 
4 
18 
higher dose of BG505 
MD39.3 mRNA 
higher dose of BG505 
MD39.3 mRNA 
higher dose of BG505 
MD39.3 mRNA 
5 
18 
higher dose of BG505 
MD39.3 gp151 mRNA 
higher dose of BG505 
MD39.3 gp151 mRNA 
higher dose of BG505 
MD39.3 gp151 mRNA 
6 
18 
higher dose of BG505 
MD39.3 gp151 CD4KO 
mRNA 
higher dose of BG505 
MD39.3 gp151 CD4KO 
mRNA 
higher dose of BG505 
MD39.3 gp151 CD4KO 
mRNA 
You will have to wait in the clinic for about 30-60 minutes after getting injections to 
see if there are any problems. Then for that night and for 7 more days, you will use a 
secure online symptom log or a paper log to keep track of how you are feeling. If you 
are unable or unwilling to use the online symptom log, please talk with us about the 
option to use a paper log. Within 4 days after each injection visit, we will contact you 
to ask how you are doing. Contact the clinic staff if you have any issues or concerns 
after getting an injection. 
As part of this research, you may need to use a phone or web app or an electronic 
study diary (eDiary). While using these, information about you may be collected and 
shared with the researchers or people outside of the study who have been approved by 
the researchers. This data might include personal health information, your contact 
information, and information about your use of the app such as the amount of time 
you spend on each screen. The eDiary does not collect personal information about 
your activities over time or from other websites or online services. It also does not 
allow third parties to collect that information. A complete description of the data 
collection and sharing can be found in the Privacy Policy associated with the app. If 
you would like to read these documents, the study doctor can tell you how to access 
this information.  
The Privacy Policy may include statements that limit your rights if you are harmed by 
using the app in this study. You do not release the study doctor, sponsor, this 
institution, or the research staff for responsibilities from mistakes. You also do not 
waive any of your rights as a research participant. 

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 In addition to giving you the study vaccines, we will do the procedures shown in 
the following table. 
 
 
Time after first injection visit 
Procedure 
Screening 
visit(s) 
First 
injection 
visit  
1 week 
2 weeks 
1½ months 
2 months 
2 ¼ months 
2½ months 
3 months  
6 months  
6 ¼ months 
6½ months 
7 months 
8 months 
12 months 
Injection 
 
√ 
 
 
 
√ 
 
 
 
√ 
 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
Brief physical 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Blood drawn 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Lymph node cell 
collection* 
 
 
 
 
√ 
 
 
 
√ 
 
 
 
√ 
 
 
Leukapheresis* 
 
 
 
 
 
 
 
√ 
 
 
 
√ 
 
 
 
Pregnancy test** 
√ 
√ 
 
 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
HIV testing  
√ 
 
 
 
 
 
 
√ 
 
√ 
 
 
 
√ 
√ 
Risk reduction 
counseling 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
√ 
Interview/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Notes: 
Grey shading: These additional visits are only for participants who provide lymph node cell samples. 
* Leukapheresis and lymph node cell collection will be done if you agree to these optional procedures and are eligible 
(Groups 1-3 only).  
** For persons who were assigned female sex at birth and who are capable of becoming pregnant. A negative 
pregnancy test is required within 48 hours before lymph node cell collection and leukapheresis. Persons who have 
had a hysterectomy (removal of the uterus) or removal of both ovaries (verified by medical records), do not have to 
have pregnancy tests.  
We will review test results with you at your next visit, or sooner if necessary. We will 
tell you about any results that are important to your health. 
When we take blood, the amount will depend on the lab tests we need to do. It will be 
some amount between 15 mL and 325 mL (a little more than 1 tablespoon to a little 
more than 1 cup) depending on the visit. Your body will make new blood to replace 
the blood we take out. To compare, people who donate blood in the US can give a 
total of about 500 mL (about 2 cups) in an 8-week period. 
Site: Of the following optional procedures for participants in Groups 1-3, include 
only those available to your participants and edit the information as needed to reflect 
how they will be done at the site/procedure facility. 
 Optional samples: if you are willing and eligible, there are 2 optional procedures 
to collect more samples. 
We would like to collect these samples from about half of the participants in Groups 
1-3. If you agree, we will collect one or two other samples to test your immune 
responses. Immune responses to vaccines involve cells in blood and in lymph nodes 
near the injection site. We would like to collect samples from these parts of the body 
to learn more about how the immune system responds to the study vaccines. We hope 
to see if we can detect any rare cells that respond to the study vaccines, and whether 

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these ways of making vaccines can stimulate the right kinds of cell responses. This 
information will guide the ways that vaccines are designed in the future.  
Both types of samples will not be collected by every clinic participating in the study. 
Some of the sample collections will be done at other locations instead of this study 
clinic.  
At the end of this form, we will ask if you agree to one or both of these sampling 
procedures. You can agree now and change your mind later. Even if you agree to give 
these samples, you may not be eligible to do so but you will remain in the study. You 
can decide not to give any of these samples and still be in the study.  
Site: Sites must obtain copies of the informed consent form and any other educational 
materials that are available from the facilities where leukapheresis and FNA will be 
performed, so that they can be reviewed with potential participants during the study 
informed consent process 
Leukapheresis procedure: 
This procedure collects larger amounts of white blood cells than we could get in an 
ordinary blood sample. Blood is made up of red cells that carry oxygen, white cells 
that fight infection, platelets that help form clots, and plasma, which is the fluid left 
over when all the cells are removed. During leukapheresis, the white blood cells are 
removed, and the rest of the blood is put back into the body. To get the number of 
white blood cells we need for this research, this procedure should take about an hour.  
The leukapheresis procedure will be done at a separate facility. Your eligibility to 
have this procedure will be decided by the study staff at our clinic and at the facility 
before you have the procedure. There will be another consent form for you to review 
and sign at the facility. It will provide additional details about the procedure and any 
risks involved. 
For the procedure, a clinician will insert a sterile needle into a vein in each of your 
arms. The needles are attached to tubes. Your blood will go out of your body through 
one tube and into a machine that separates the blood and takes out the white blood 
cells. After the white blood cells are taken out, the rest of the blood will go back into 
your body through the tube going into your other arm. Sometimes the fluid lost 
during the procedure is replaced by a sterile salt water solution, or a solution 
containing a protein called albumin. This protein is normally found in human blood. 
An anticoagulant may be added to your blood during the procedure. Anticoagulants 
prevent blood from clotting. 
It is normal to feel tired for up to 24 hours after having leukapheresis.  
The leukapheresis procedure will be done about 2 weeks after your 2nd injection visit 
and again about 2 weeks after your 3rd injection visit.  
Risks of leukapheresis 

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Generally, the risks of leukapheresis include pain, bruising, possibly fainting, and 
rarely, infection. Rarely, albumin can cause an allergic reaction. If the leukapheresis 
procedure has to be stopped, it could result in the loss of up to 1 cup of blood. Your 
body makes new blood within 2 weeks.  
If you notice any symptoms during leukapheresis, please let the nurse know 
immediately. Usually the symptoms can be reversed quickly by adding fluid or by 
slowing down the procedure. If there are any problems, the staff will use the 
appropriate medical procedures to treat you.  
Lymph node cell collection procedure: 
The formal name for this procedure is a “Fine Needle Aspiration”. This procedure 
collects cells from lymph nodes. Lymph nodes are one of the key places where 
immune responses develop, and they are located in several places on the human body. 
In this procedure, a doctor will use a very thin needle guided by ultrasound to collect 
cells from a lymph node on your arm or in your arm pit. This procedure allows 
researchers to understand the early immune responses that develop, before they can 
be seen in a blood sample. 
The lymph node cell collection procedure will be done at a separate facility three 
times as shown in the shaded columns in the table above. Your eligibility to have this 
procedure will be decided by the staff at our clinic during screening, and again at the 
facility before you have the procedure. There will be another consent form for you to 
review, sign, and date at the facility. It will provide additional details about the 
procedure and any risks involved. The procedure usually takes about [#] hour(s).  
Lymph node cell collection will happen about 6 weeks after your first injection visit 
and about 4 weeks after your second and third injection visits. In addition to having 
the procedure at a separate facility, you will also come to the study clinic at these 3 
times to provide a blood sample and to answer study questionnaires.  
To do the procedure, a clinician will find the appropriate lymph node by applying a 
cold gel to your skin and then pressing a hand-held ultrasound device against your 
skin. This device produces images of your lymph node that the clinician can watch on 
a computer monitor. If necessary, a small area near the lymph node may be shaved. 
Once the node is found, a cleaning solution will be applied to the skin in that area. 
The area will be numbed by an injection of a local anesthetic, such as lidocaine, 
which is like the numbing medicine used by dentists. The doctor will insert a very 
thin needle and use the images from the ultrasound to guide it into the lymph node. 
The needle may be moved up and down to collect cells from the lymph node. Fluid 
may also be collected through the needle into a syringe or bottle. Each cell collection 
lasts about 10-15 seconds. It usually takes about 4 separate cell collections to get 
enough cells. 
After the procedure is done, the area will be cleaned with warm water. A band-aid 
will be used to cover the site where the needle was inserted. 
Risks of lymph node cell collection: 

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The main risks of this procedure include pain, bruising, bleeding and infection where 
the needle is inserted. The cleaning solution or shaving the area may cause skin 
irritation. Injecting the local anesthetic may sting or burn for a little while until the 
numbing takes effect. The local anesthetic can rarely cause temporary arm numbness 
or weakness. Examining the lymph node area may be uncomfortable. 
If discomfort, problems, or side effects happen during or after lymph node cell 
collection, the staff will use the appropriate medical procedures to treat you. 
 We will counsel you about protecting yourself from HIV. 
We will ask you questions about your HIV risk factors such as sexual behavior, 
alcohol, and drug use. We will talk with you about ways to keep your risk of getting 
HIV low. 
These vaccines are experimental and are not expected to protect you from getting 
HIV during this study. 
 The HVTN will test your samples to see how your body, including your immune 
system, responds to the study vaccine. 
We will send your samples (without your name or other identifying information) to 
labs approved by the HVTN for this study. In rare cases, some of your samples may 
be sent to labs in other countries for research related to this study. 
Researchers may also do genetic testing on your samples. Your genes are passed to 
you from your birth parents. They affect how you look and how your body works. 
This genetic testing will involve only some of your genes, not all of your genes (your 
genome). It will involve genes related to the immune system and HIV. 
If you get HIV, the researchers may look at all of the genes of the virus found in your 
samples. The researchers will use this information to learn more about HIV and how 
the virus is impacted by the study vaccine. 
In some cases, researchers may take cells from your samples and grow more of them 
over time, so that they can continue to contribute to this study. 
These tests done on your samples are for research purposes, not to check your health. 
The labs will not give the results to you or this clinic because their tests are not 
approved for use in making health care decisions. These labs are only approved to do 
research tests.  
 When your samples are no longer needed for this study, the HVTN will continue 
to store them. When samples are no longer needed for this study, the HVTN 
wants to use them in other studies and share them with other researchers.  
The HVTN calls these samples “extra samples”. The HVTN will only allow your 
extra samples to be used in other studies if you agree to this. You will mark your 
decision at the end of this form. If you have any questions, please ask. 

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Do I have to agree? No. You are free to say yes or no, or to change your mind after 
you sign this form. At your request, the HVTN will destroy all extra samples that it 
has. Your decision will not affect your being in this study or have any negative 
consequences here. 
Where are the samples stored? Extra samples are stored in a secure central place 
called a repository. Your samples will be stored in the HVTN repository in the United 
States. 
How long will the samples be stored? There is no limit on how long your extra 
samples will be stored.  
Will I be paid for the use of my samples? No. Also, a researcher may make a new 
scientific discovery or product based on the use of your samples. If this happens, 
there is no plan to share any money with you. The researcher is not likely to ever 
know who you are. 
Will I benefit from allowing my samples to be used in other studies? Probably not. 
Results from these other studies are not given to you, this clinic, or your doctor. They 
are not part of your medical record. The studies are only being done for research 
purposes. 
Will the HVTN sell my samples and information? No, but the HVTN may share your 
samples with HVTN or other researchers. Once the HVTN shares your samples and 
information, it may not be able to get them back. 
How do other researchers get my samples and information? When a researcher wants 
to use your samples and information, their research plan must be approved by the 
HVTN. Also, the researcher’s institutional review board (IRB) or ethics committee 
(EC) will review their plan. IRBs/ECs protect the rights and well-being of people in 
research. If the research plan is approved, the HVTN will send your samples to the 
researcher’s location. 
What information is shared with HVTN or other researchers? The samples and 
information will be labeled with a code number. The key to the code will stay at this 
clinic. It will not be shared with the HVTN, other researchers, or with anyone else 
who does not need to know your name. Your name will not be part of the 
information. However, some information that the HVTN shares may be personal, 
such as your race, ethnicity, sex, health information from the study, and HIV status. 
The HVTN may share information about the study product you received and how 
your body responded to the study product. 
What kind of studies might be done with my extra samples and information? The 
studies will be related to HIV, vaccines, the immune system and other diseases. 
Researchers may also do genetic testing on your samples. 
In some cases, researchers may take cells from your samples and grow more of them 
over time, so that they can continue to do research with them. 

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If you agree, your samples could also be used for genome-wide studies. In these 
studies, researchers will look at all of your genes (your genome). The researchers 
compare the genomes of many people, looking for common patterns of genes that 
could help them understand diseases. The researchers may put the information from 
the genome-wide studies into a protected database so that other researchers can access 
it, but your name and other personal information will not be included. Usually, no one 
would be able to look at your genome and link it to you as a person. However, if 
another database exists that also has information on your genome and your name, 
someone might be able to compare the databases and identify you. If others found 
out, it could lead to discrimination or other problems. The risk of this is very small. 
There may be other unknown risks. 
Who will have access to my information in studies using my extra samples? 
People who may see your information are: 
• Researchers who use your extra samples and information for other research 
• Government agencies that fund or monitor the research using your extra samples 
and information 
• The researcher’s Institutional Review Board or Ethics Committee 
• Any regulatory agency that reviews clinical trials 
• The people who work with the researcher 
All of these people will do their best to protect your information. The results of any 
new studies that use your extra samples and information may be published. No 
publication will use your name or identify you personally. 
16. We will do our best to protect your private information. 
All of your samples and most of your study records will be labeled with a code 
number. Samples and study records are kept in secure locations. When you provide 
information in the online symptom log after the injection visits, that information only 
has your code number. Your data goes directly from the online symptom log into 
your study record. 
Site: Any change to the following boxed text requires approval from HVTN 
Regulatory Affairs. You can remove the box around the text.  

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We do need to share your name with the HVTN in case you need proof in the future 
that you participated in an HIV vaccine study. The HVTN will keep your name in a 
secure file with these items:  
• The name of your study 
• Your age or date of birth 
• Your study ID number 
• What study vaccines(s) you received 
No HIV test results are kept in this file. The HVTN will not share any information 
that could identify you without your agreement. The HVTN will remove your name 
from the file if you do not want it there. 
Clinic staff can see your study records. Your records may also be reviewed by groups 
that watch over this study to see that we are protecting your rights, keeping you safe, 
and following the study plan. These groups include: 
• The US National Institutes of Health and its study monitors, 
• The US Food and Drug Administration, 
• Any regulatory agency that reviews clinical trials, 
• Advarra IRB 
• Moderna, Inc., Scripps Research, IAVI, and people who work for them, 
• The HVTN and people who work for them, 
• The HVTN Safety Monitoring Board, and 
• The US Office for Human Research Protections. 
All reviewers will keep your records private. 
We cannot guarantee absolute privacy. If you have a medical condition that we are 
required to report by law, then some of your information may be shared. At this 
clinic, we have to report the following information:  
Site: Include any public health or legal reporting requirements. Bulleted examples 
should include all appropriate cases (reportable communicable disease, risk of harm 
to self or others, etc.) If your site does not have public health or legal reporting 
requirements, you may delete the last sentence in the paragraph above, along with 
the bullets below. 

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• [Item 1] 
• [Item 2] 
• [Item 3] 
To help protect your privacy, we have a Certificate of Confidentiality from the US 
government. With the certificate, we do not have to release information about you to 
someone who is not connected to the study, such as the courts or police. The 
Certificate of Confidentiality does not prevent our clinic from reporting certain 
medical conditions as required by law (see above). However, we cannot withhold 
information from the US government because it funds this research. You can still give 
information about yourself and your study participation to others. If you want your 
research information released to an insurer, medical care provider, or any other 
person not connected with the research, you must provide consent to allow the 
researchers to release it. 
The results of this study may be published. No publication will use your name or 
identify you personally. 
We may share information from the study with other researchers. We will not share 
your name or information that can identify you. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will not include information that can identify 
you. The website may include a summary of the study results. You can search this 
Web site at any time. 
17. We may stop your injections even if you want to stay in the study and even if you 
were scheduled for more injections. 
We will stop your injections if you become pregnant. We will encourage you to stay 
in the study, but it will be your choice. If you leave the study while you are pregnant, 
we will contact you after your due date to ask some questions about your pregnancy 
and delivery. 
We will stop your injections if you get HIV. We will also take fewer samples, and we 
will help you get care and support. We will encourage you to stay in the study for up 
to 12 months if you choose. We will counsel you about having HIV and about telling 
your partner(s). We will not provide or pay for your HIV care.  
We will stop your injections if you enroll in a different research study where you get 
another study product. 
18. We may take you out of the study at any time.  
We may take you out of the study if: 
• you do not follow instructions, 

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• we think that staying in the study might harm you, or 
• the study is stopped for any reason. 
Other Risks 
19. There are other risks to being in this study. 
In addition to the risks of the study vaccine and the procedures that were described 
above, this section describes the other risks we know about. There may be other risks, 
even serious ones. We will tell you if we learn anything new that may affect your 
decision to stay in the study. 
Risks of abnormal laboratory results  
Minor changes in laboratory test results occasionally happen. This means that the test 
results can show something to be abnormal when it is not. If this happens, we will ask 
you to come back to the clinic to be retested. This may cause you to worry, and it may 
be inconvenient to come back to the clinic. If retesting confirms something to be 
abnormal, we will provide care or help you get the care you need. 
Risks of routine medical procedures: 
Routine medical procedures such as taking blood and giving injections can cause 
bruising, pain, fainting, soreness, redness, stinging, swelling, itching, a sore, bleeding, 
and rarely infection where you got the injection. Taking blood can cause a low blood 
cell count (anemia), making you feel tired. 
Personal problems/discrimination/testing HIV antibody positive: 
Some people report personal problems or discrimination because they joined an HIV 
vaccine study. Family or friends may worry, get upset, or assume that you have HIV. 
Rarely, someone has lost a job because the study took too much time away from 
work, or because their employer thought they had HIV. 
Most vaccines cause the body to make antibodies to prevent infection. Your body 
may make antibodies to HIV because you received an HIV study vaccine. Those 
antibodies could cause you to test positive on some types of HIV tests, even if you do 
not have HIV. This is called vaccine-induced seropositivity (VISP). VISP means that 
after you get the study vaccine, a routine HIV test done outside this clinic is likely say 
you have HIV, even if you don’t. For this reason, you should get HIV tests only at 
this clinic. Our tests can tell the difference between true HIV infection and a positive 
result caused by the study vaccine. If you have VISP, we can arrange free HIV testing 
for as long as you need it.  
It is unlikely, but you could test antibody negative at the end of the study and then test 
positive sometime later, even though you don’t have HIV.  

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Site: Modify the following paragraph if applicable. If someone believes you have 
HIV, you could face discrimination and other problems. In some countries, you could 
be denied medical or dental care, employment, insurance, a visa, or entry into the 
military. If you have VISP, you will not be able to donate blood or organs. Your 
family and friends may treat you differently. We will give you a brochure that tells 
you more about VISP, and how you can avoid some of these problems. 
If you become pregnant during or after the study and have VISP, the antibodies might 
be passed to your baby. We know that this happens with some other vaccines. The 
antibodies are not a danger to the baby, and they go away, usually in about 6 months. 
You should tell the delivery staff if you have VISP. However, you may still be tested 
for HIV using the antibody test when you deliver your baby. If your test is positive, 
your baby may be started on antiretroviral treatment when it is not needed. If this 
happens, we can arrange for you and the baby to have tests that can distinguish true 
HIV infection from VISP. If you or the baby continue to have VISP, we can arrange 
this testing for free for as long as it is needed. 
Embarrassment/anxiety: 
You may feel embarrassed when we ask questions about HIV risks, such as sex and 
using drugs. Also, waiting for HIV test results could make you feel anxious. You 
could feel worried if test results show that you have HIV. If you feel embarrassed or 
anxious, please tell us and we will try to help you. 
Risks of disclosure of your personal information: 
Although the risk is very low, it is possible that someone may see your personal 
information who should not. If that happens, you could face discrimination, stress, 
and embarrassment. We can tell you more about how we will protect your personal 
information. 
Risks of genetic testing: 
It is possible that genetic tests could show you may be at risk for certain diseases. If 
others found out, it could lead to discrimination or other problems. However, genetic 
test results are not part of your study record, so it is almost impossible for anyone to 
connect them to you personally. 
Even if your genetic information somehow gets linked to your name, a federal law 
called the Genetic Information Nondiscrimination Act (GINA) helps protect you. 
GINA keeps health insurance companies and employers from seeing results of 
genetic testing when deciding about giving you health insurance or offering you 
work. GINA does not help or protect you against discrimination by companies that 
sell life, disability, or long-term care insurance. 
This law generally will protect you in the following ways: 

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• Health insurance companies and group health plans may not request your 
genetic information that the sponsor will get from this research. 
• Health insurance companies and group health plans may not use your 
genetic information when making decisions regarding your eligibility or 
premiums. 
• Employers with 15 or more employees may not use your genetic 
information that the sponsor will get from this research when making a 
decision to hire, promote, or fire you or when setting the terms of your 
employment. 
All health insurance companies and group health plans and all employers with 15 or 
more people must follow this law. 
Unknown risks: 
We do not know if the study vaccine will increase, decrease, or not change your risk 
of getting HIV if exposed. If you get HIV, we do not know how the study vaccine 
might affect your HIV infection or how long it takes to develop AIDS. 
We do not know if getting this study vaccine will affect how you respond to any 
future approved HIV vaccine. Currently, no HIV vaccine has been approved for use. 
We do not know how the study vaccine will affect a pregnant participant or a 
developing baby. 
Benefits 
20. The study vaccination will not benefit you. 
We do not expect the study vaccine to benefit you in any way. However, being in the 
study might still help you in some ways. The counseling that you get as part of the 
study may help you avoid getting HIV. The lab tests and physical exams might detect 
health problems you don’t yet know about. 
When asked, most study participants say that participating in a study made them feel 
good about helping others, increased their knowledge about HIV, and improved their 
self- esteem. 
This study may help in the search for a vaccine to prevent HIV. However, if the study 
vaccine later becomes approved for sale, there are no plans to share any money with 
you. 

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Your rights and responsibilities 
21. If you join the study, you have rights and responsibilities. 
We list these in the Bill of Rights and Responsibilities (BRR) for HIV Research. We 
will give you a copy of it. 
Leaving the study 
22. Tell us if you decide to leave the study. 
You are free to leave the study at any time and for any reason. This will not affect 
your care at this clinic and your legal rights. 
Previously collected information about you will remain in the study records and will 
be included in the analysis of results. Your information cannot be removed from the 
study records. 
We will ask you to come to the clinic one last time for a physical exam. We may also 
ask to take some blood samples and ask you to answer some questions. If you were 
assigned female sex at birth, we may test you for pregnancy. Whether you come for 
this last visit is up to you. 
Injuries 
23. If you get sick or injured during the study, contact us immediately. 
Your health is important to us. We will tell you about care that we can give here. For 
care that we cannot provide, we will explain how we will help you get care 
elsewhere. 
If you become sick or injured in this study, the HVTN has a process to decide if this 
is related to the study vaccine and/or procedures. If it is, we call it a study-related 
injury. There are funds to pay for treatment of study-related injuries if certain 
conditions are met. 
The study product provider has agreed to pay medical costs for study-related injuries 
that are determined to be caused by the study product. If provider funds are not 
enough, or if the injury is determined to be caused by study procedures, the HVTN 
has limited funds to pay medical costs that it determines are reasonable. If the injury 
is not study related, then you and/or your health insurance will be responsible for 
treatment costs. 
Some injuries are not physical. For example, you might be harmed emotionally by 
being in an HIV vaccine study. Or you might lose wages because you cannot go to 
work. However, there are no funds to pay for these kinds of injuries, even if they are 
study related. 

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You may disagree with the decision about whether your injury is study related. If you 
wish, the HVTN will ask independent experts to review the decision. You always 
have the right to use the court system if you are not satisfied. 
Questions  
24. Whom to contact about this study 
During the study, if you experience any medical problems, suffer a research-related 
injury, or have questions, concerns or complaints about the study, please contact the 
study at the telephone number listed on the first page of this consent document. If you 
seek emergency care, or hospitalization is required, alert the treating physician that 
you are participating in this research study.  
An institutional review board (IRB) is an independent committee established to help 
protect the rights of research participants. If you have any questions about your rights 
as a research participant, and/or concerns or complaints regarding this research study, 
contact: 
 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
or call toll free:    877-992-4724 
• 
or by email:          adviser@advarra.com 
Please reference the following number when contacting the Study Subject Adviser: Pro00056475. 
Your permissions and signature  
25. In Section 12 of this form, we told you about 2 other optional sample collection 
procedures. Please write your initials or make your mark in the boxes next to the 
procedure(s) that you agree to have done, or leave them blank if you do not want 
to provide these extra samples. You can change your mind after signing this 
form. There will also be an additional consent form to sign at the time the 
procedure is done. 
Site: Include boxes below only for the procedures available to your participants in 
Groups 1-3. 
 

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I agree to leukapheresis.  
 
 
 
I agree to lymph node cell collection. 
26. In Section 15 of this form, we told you about possible other uses of your extra 
samples and information, outside this study. Please choose only one of the 
options below and write your initials or make your mark in the box next to it. 
Whatever you choose, the HVTN keeps track of your decision about how your 
samples and information can be used. You can change your mind after signing 
this form. 
 
 
I allow my extra samples and information to be used for other studies related to HIV, 
vaccines, the immune system, and other diseases. This may include genetic testing and 
keeping my cells growing over time.  
OR 
 
 
I agree to the option above and also to allow my extra samples and information to be 
used in genome wide studies. 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes not 
allowing genetic testing, growing more of my cells, or genome wide studies.  
 
 
27. If you agree to join this study, you will need to sign or make your mark below. 
Before you sign or make your mark on this consent form, make sure of the 
following: 
• You have read this consent form, or someone has read it to you. 
• You feel that you understand what the study is about and what will happen to you 
if you join. You understand what the possible risks and benefits are. 
• You have had your questions answered and know that you can ask more. 
• You agree to join this study. 
You will not be giving up any of your rights by signing this consent form. 

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Participant’s name (print) 
 
Participant’s signature or mark 
 
Date 
 
Time 
 
 
 
 
 
 
 
Clinic staff conducting consent 
discussion (print) 
 
Clinic staff signature 
 
Date 
 
Time 
For participants who are unable to read or write, a witness should complete the 
signature block below: 
 
 
 
 
 
 
 
Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
*Witness is impartial and was present for the entire discussion of this consent form. 
 
 
 

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Appendix G 
Sample Addendum Informed Consent Form for 
follow-up of participants with unresolved study product-
related urticaria-associated symptoms 
 
Sponsor / Study Title: 
 
National Institutes of Health / “A phase 1, 
randomized, open-label clinical trial to evaluate the 
safety and immunogenicity of BG505 MD39.3, 
BG505 MD39.3 gp151, and BG505 MD39.3 gp151 
CD4KO HIV trimer mRNA vaccines in healthy, HIV-
uninfected adult participants” 
Protocol Number: 
 
HVTN 302 
Principal 
Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
You are a participant in HVTN 302, a research study that tests an experimental 
vaccine against HIV. Thank you for your participation.  
We have new information to share with you. Previously we told you about 7 different 
participants (out of 108 participants enrolled) that developed itchy hives and other 
related skin symptoms after getting their first or second vaccination. You are 1 of the 
participants who continue to have these symptoms. In order to continue to monitor 
your health, we are asking you to continue in the study for up to 4 years for additional 
follow-up.  
Please read this consent form or ask someone to read it to you. If you decide to join 
the follow-up part of the study, we will ask you to sign or make your mark on this 
form. We will offer you a copy to keep. We will ask you questions to see if we have 
explained everything clearly. You can also ask us questions about the study.  
  Information about the follow-up part of the study 
We are extending the study to continue to monitor the health of a small number of 
participants (including you) who continue to have hives/itchy rashes. You will be 
followed until the symptoms go away completely, or for up to 4 years from now, 
whichever time period is shortest.  

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We are doing this follow-up to see whether these symptoms go away over time and 
how they affect your quality of life. Most of the extra study visits will be done 
remotely, such as by phone. You will be asked to come in for at least two clinic visits. 
If the study staff feel that it is needed, you will be asked to come to the clinic for an 
additional in-person visits. 
 What happens now? 
We will contact you every 3 months during the coming year, twice a year for the 
second year, and once a year during the third and fourth years. If your symptoms go 
away sooner, you will have less contacts and your participation can end. You will 
come into the clinic to provide a blood sample at the 6 month visit, at any clinic visit 
scheduled to evaluate your symptoms (if needed), and your last visit. The blood 
samples you provide may allow us to see any changes in your immune system over 
time. The amount of blood collected at any one visit will be about 17 mL (a little 
more than a tablespoon). The table below shows the schedule of the visits and 
procedures. 
 
 
 Follow-up study schedule  
 
Procedure 
 
3 months 
6 months 
9 months 
1 year 
1½ years 
2 years 
3 years  
4 years  
Clinic visit 
due to 
symptoms 
Medical history 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Brief physical exam* 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Interview/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Blood collection*** 
 
√ 
 
 
 
 
 
√** 
√ 
*Only if an in-person clinic visit is needed.  
** Your last blood collection may happen before the 4-year visit if your symptoms go away sooner.  
*** In addition to the 6-month and 4-year blood collections, blood samples will also be collected at any clinic     
      visit scheduled due to having symptoms.  
During these visits, we will: 
• Ask questions about your health, including medications you may be taking; 
• Ask questions about your quality of life and current health in relation to your 
hives and other symptoms; 
• Do a physical exam if an in-person clinic visit is needed. 
• Collect a blood sample  
 

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 Some things from the main study remain the same. 
Some information described in the original consent form that you signed remains the 
same, such as: 
• The potential risks and benefits of study participation that are not related to the 
study products; 
• Your rights and responsibilities as a study participant; 
• How your samples will be used; 
• How we will protect your private information and who can access your study 
records; 
• Reasons we might end your participation in the study; 
• What will happen if you get sick or injured during the study. 
As before, there is no cost to you for participating in the study. We will give you 
[Site: Insert compensation] for each study visit you complete. 
In the original consent form, you chose whether the HVTN could use your extra 
samples and information in other studies. The HVTN will continue to honor your 
choice. You can change your mind if you want to at any time. Your decision will not 
affect your being in this study or have any negative consequences. 
In the original consent form, we told you about the requirement to use contraception. 
Since enough time has passed since your last study injection, use of contraception is 
no longer required for the purpose of this study.  
 You can continue or leave the follow-up study at any time.  
You are still free to leave the study at any time and for any reason. If you want to 
leave, please tell us. If you choose to leave, your other care at this clinic and the 
benefits or rights you would normally have will not be affected. 
  Study Contacts 
During this follow-up part of the study, if you have any medical problems, have a 
research-related injury, or have questions, concerns, or complaints about the study, 
please contact the study staff at the telephone number listed on the first page of this 
consent form. If you seek emergency medical care or if hospitalization is required, 
alert the doctor treating you that you are participating in this research study.  
An institutional review board (IRB) is an independent committee that helps protect 
the rights of research participants. If you have any questions about your rights as a 
research participant, and/or concerns or complaints about this research study, contact: 

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• By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• or call toll free: 877-992-4724 
• or by email: adviser@advarra.com 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00056475. 
  If you agree to join this follow-up part of the study, you will need to sign or 
make your mark below. Before you do, make sure of the following: 
• You have read this consent form, or someone has read it to you. 
• You feel that you understand what this new part of the study is about and what will 
happen to you if you join. You understand what the possible risks and benefits are. 
• You have had your questions answered and know that you can ask more. 
• You agree to join this study. 
You will not be giving up any of your rights by signing this consent form. 
 
 
 
 
 
 
 
Participant’s name (print) 
 
Participant’s signature or mark 
 
Date 
 
Time 
 
 
 
 
 
 
 
Clinic staff conducting consent 
discussion (print) 
 
Clinic staff signature 
 
Date 
 
Time 
For participants who are unable to read or write, a witness should complete the 
signature block below: 
 
 
 
 
 
 
 
Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
*Witness is impartial and was present for the entire discussion of this consent form. 
 
 

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Appendix H 
Low risk guidelines for US  
The following are intended as guidelines for the investigator to help identify potential vaccine trial 
participants at “low risk” for HIV infection. These guidelines are based on behaviors within the last 6-12 
months prior to enrollment; however, it may be appropriate to consider a person’s behavior over a longer 
period of time than specified to assess the person’s likelihood of maintaining low risk behavior. Some 
volunteers may not be appropriate for enrollment even if they meet these guidelines. These guidelines 
should be supplemented and interpreted with local epidemiologic information about HIV prevalence in 
your area and community networks. The investigator may review the risk level of any volunteer with the 
site PI and/or the Protocol Safety Review Team. 
 
A volunteer may be appropriate for inclusion if he/she/they meets these guidelines: 
A. 
For US volunteers NOT on stable Pre-exposure prophylaxis (PrEP) 
1. SEXUAL BEHAVIORS 
In the last 12 months did not: 
A. Have oral, vaginal or anal intercourse with an HIV-infected partner, or a partner who uses 
injection drugs  
B. Give or receive money, drugs, gifts or services in exchange for oral, vaginal or anal sex 
AND 
 
In the last 6 months has abstained from penile/anal or penile/vaginal intercourse, OR 
 
In the last 6 months had 4 or fewer partners of the opposite birth sex for vaginal and/or anal 
intercourse, OR 
 
Is an MSM (person born male with partner(s) born male) who, in the last 12 months: 
• Had 2 or fewer MSM partners for anal intercourse and had no unprotected anal 
sex with MSM, OR 
•  Had unprotected anal intercourse with only 1 MSM partner, within a 
monogamous relationship lasting at least 12 months (during which neither partner 
had any other partners). If the monogamous relationship ended, the volunteer may 
then have had protected anal intercourse with 1 other MSM partner (total 2 or 
fewer partners in the last 12 months), OR  
Is a transgender person, regardless of the point on the transition spectrum, having sex 
with men (born male) and/or other transgender persons, who in the last 12 months: 
• Had 2 or fewer partners for anal or vaginal intercourse, and had no unprotected 
anal or vaginal sex, OR  
• Had unprotected anal or vaginal intercourse sex with 1 partner only within a 
monogamous relationship lasting at least 12 months (during which neither partner 
had any other partners). If the monogamous relationship ended, may then have 

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had protected anal or vaginal sex with 1 other partner (total 2 or fewer partners in 
the last 12 months). 
AND 
Uses or intends to use condoms in situations which may include penile/anal or 
penile/vaginal intercourse with new partners of unknown HIV status, occasional 
partners, 
partners outside a primary relationship, and/or partners known to have other partners. 
 
2. NON-SEXUAL BEHAVIORS 
In the last 12 months did not: 
• Inject drugs or other substances without a prescription 
• Use cocaine, methamphetamine, or excessive alcohol, which in the investigator’s 
judgment, rendered the participant at greater than low risk for acquiring HIV 
infection. 
The investigator’s judgment should consider local epidemiologic information about HIV 
prevalence in the area and community networks. 
 
A volunteer is NOT appropriate for inclusion if he/she: 
 
Acquired an STI (ie, new infection) in the last 12 months: 
 
• Syphilis  
• Gonorrhea  
• Non-gonococcal urethritis  
• Herpes Simplex Virus type 2 (HSV2)  
• Chlamydia  
• Pelvic inflammatory disease (PID)  
• Trichomonas  
• Mucopurulent cervicitis  
• Epididymitis  
• Proctitis  
• Lymphogranuloma venereum  
• Chancroid  
• Hepatitis B 
B. 
For US volunteers on Pre-exposure prophylaxis (PrEP) 
1. PrEP ASSESSMENT 
• 
Reports equal to or greater than six months of protective PrEP use 
• 
Commits to maintaining protective PrEP use throughout trial 

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• 
Participant reports equal to or greater than 70% when asked the following:  
“Thinking about the past 4 weeks, what percent of the time were you able to take all your PrEP 
medications?” 
2. SEXUAL BEHAVIORS 
Persons stably taking PrEP as described above for 6 months or longer are considered low risk of 
HIV infection, regardless of any sexual behavior that might otherwise be associated with high 
risk of HIV exposure. 
 
3. NON-SEXUAL BEHAVIORS 
In the last 12 months did not: 
• Inject drugs or other substances without a prescription 
• Use cocaine, methamphetamine, or excessive alcohol, which in the investigator’s 
judgment, rendered the participant at greater than low risk for acquiring HIV 
infection. 
The investigator’s judgment should consider local epidemiologic information about HIV 
prevalence in the area and community networks. 
 

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Appendix I 
Approved birth control methods 
Site: Any change to the following boxed text requires approval from HVTN Regulatory 
Affairs at vtn.core.reg@hvtn.org. You can remove the box around the text. 
You should not become pregnant during the study because we do not know how the 
study vaccine could affect the developing baby. 
You must agree to use effective birth control from 21 days before your first injection 
until 3 months after your last study injection.  
Effective birth control means using any of the following methods every time you 
have sex: 
• Birth control drugs that prevent pregnancy—given by pills, shots, patches, vaginal 
rings, or inserts under the skin; 
• Male or female condoms, with or without a cream or gel that kills sperm; 
• Diaphragm or cervical cap with a cream or gel that kills sperm; 
• Intrauterine device (IUD); or 
• Any other contraceptive method approved by the researchers. 
You do not have to use birth control if: 
• You are only having sex with a partner or partners who have had a vasectomy. 
(We will ask you some questions to confirm that the vasectomy was successful.); 
• You have reached menopause, with no menstrual periods for one year; 
• You have had a hysterectomy (your uterus removed); 
• You have had your ovaries removed; 
• You have a tubal ligation (your “tubes tied”) or confirmed successful placement 
of a product that blocks the fallopian tubes; 
• You are having sex only with a partner(s) assigned female sex at birth; 
• You only have oral sex; or, 
• You are sexually abstinent (no sex at all). 

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Remember: If you are having sex, male and female condoms are the only birth 
control methods that also provide protection against HIV and other sexually 
transmitted infections. 
If you join the study, we will test you for pregnancy at some visits, including before 
each study injection. 

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Appendix J 
Case definition for Myocarditis and pericarditis 
I. Brighton collaboration myocarditis case definition, by level of 
certainty – Level 1 (definitive), 2 (probable), and 3 (possible) 
(https://brightoncollaboration.us/myocarditis-case-definition-update/)  
 
 
 
OR
Troponin T
Troponin I
AND
OR
New focal or difuse left or right ventricular function abnormalities (eg. decreased 
ejection fraction)
Segmental wall motion abnormalities
Global systolic or diastolic function depression/abnormality 
Ventricular dilation 
Wall thickness change 
Intracavitary thrombi
Abnormal Cardiac Magnetic Resonance Study (at least 1 of the findings below)
Abnormal Echocardiogram (at least 1 of the findings below)
Abnormal Imaging study
Late gadolinium enhancement on T1 weighted study with an increased 
enhancement ratio between myocardial and skeletal muscle typically involving at 
least one non-ischemic regional distribution with recovery (myocyte injury).
Myocarditis_Level of Certainty - 1 (Definitive Case)
Histopathologic examination of myocardial tissue (autopsy or endomyocardial biopsy) showed 
myocardial inflammation
Edema on T2 weighted study, typically patchy in nature
Elevated myocardial biomarkers (at least 1 of the findings below)

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Myocarditis_Level of Certainty - 2 (Probable Case)
Cardiac Symptoms (at least 1 finding below)
Acute chest pain or pressure
Palpitations
Dyspnea after exercise, at rest, or lying down
Diaphoresis
Sudden death
OR
Non-Specific Symptoms (at least 2 findings below)
Fatigue
Abdominal pain
Dizziness/syncope
Edema
Cough
OR
Infants and young children (at least 2 findings below)
Irritability
Vomiting
Poor feeding
Tachypnea
Lethargy
AND
Troponin T 
Troponin I
CK Myocardial band
OR
New focal or difuse left or right ventricular function abnormalities (eg. decreased 
ejection fraction)
Segmental wall motion abnormalities
Global systolic or diastolic function depression/abnormality 
Ventricular dilation 
Wall thickness change 
Intracavitary thrombi
OR
Paroxysmal or sustained atrial or ventricular arrhythmias (premature atrial or 
ventricular beats, and/or supraventricular or ventricular tachycardia, 
interventricular conduction delay, abnormal Q waves, low voltages)
AV nodal conduction delays or intraventricular conduction defects (atrioventricular 
block (grade I-III), new bundle branch block)
Continuous ambulatory electrocardiographic monitoring that detects frequent 
atrial or ventricular ectopy  
AND
No alternative diagnosis for symptoms 
Clinical Symptoms
Testing supporting diagnosis (Biomarkers, ECHO, and EKG)
Echocardiogram (ECHO) abnormalities (at least 1 of the findings below)
Electrocardiogram (EKG) abnormalities that are new and/or normalize on recovery(at least 
1 of the findings below)
Elevated myocardial biomarkers (at least 1 of the findings below)

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Cardiac symptoms (at least 1 finding below)
Acute chest pain or pressure
Palpitations
Dyspnea after exercise, at rest, or lying down
Diaphoresis
Sudden death
OR
Non-Specific Symptoms (at least 2 findings below)
Fatigue
Abdominal pain
Dizziness/syncope
Edema
Cough
OR
Infants/Young children (at least 2 findings below)
Irritability
Vomiting
Poor feeding
Tachypnea
Lethargy
AND
Biomarkers supporting evidence of inflammation  (at least 1 finding below)
Elevated CRP
Elevated ESR
Elevated D-Dimer
AND
ST-segment or T-wave abnormalities (elevation or inversion)
PACs and PVCs 
AND
No alternative diagnosis for symptoms
Non-Specific Electrocardiogram (EKG) Abnormalities that are new and/or normalize on 
recovery (at least 1 finding below)
Myocarditis_Level of Certainty - 3 (Possible Case)
Clinical Symptoms

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II. Brighton collaboration pericarditis case, by level of certainty – 
Level 1 (definitive), 2 (probable), and 3 (possible) 
(https://brightoncollaboration.us/myocarditis-case-definition-update/) 
 
 
OR
OR
Diffuse concave-upward ST-segment elevation
ST-segment depression in aVR
PR-depression throughout the leads without reciprocal ST-segment changes
OR
Pericarditis_Level of Certainty - 1 (Definitive Case)
Histopathologic examination of pericardial tissue (autopsy or pericardial biopsy) showed pericardial inflammation
Evidence of abnormal fluid collection or pericardial inflammation by imaging (Echo, MR, cMR, CT)
Electrocardiogram (EKG) Abnormalities that are new and/or normalize on recovery (must have all findings)
Abnormal testing need at least 2 of 3 of the following:
Physical examination findings: at least 1 finding
Pericardial friction rub
Distant heart sounds (infant/children)
Pulsus paradoxus

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Clinical Cardiac Symptoms (at least 1 finding below)
Acute chest pain or pressure
Palpitations
Dyspnea after exercise, at rest, or lying down
Diaphoresis
Sudden death
OR
Infants/Children (at least 2 findings below)
Irritability
Vomiting
Poor feeding
Sweating
AND
OR
OR
Diffuse concave-upward ST-segment elevation
ST-segment depression in aVR
PR-depression throughout the leads without reciprocal ST-segment changes
AND
No alternative diagnosis for symptoms (e.g. MI, PE, mediastinitis, etc)
Electrocardiogram (EKG) Abnormalities that are new and/or normalize on recovery (at least 1 finding below)
Evidence of abnormal fluid collection or pericardial inflammation by imaging (Echo, MR, cMR, CT)
Pulsus paradoxus
Pericarditis_Level of Certainty - 2 (Probable Case)
Clinical Symptoms
Physical examination findings: (at least 1 findings)
Pericardial friction rub

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Clinical Cardiac symptoms (at least 1 finding below)
New onset cardiac chest pain or pressure
Palpitations
Dyspnea after exercise, at rest, or lying down
AND
Non-Specific Symptoms (at least 1 finding below)
Cough
Weakness
Gastrointestinal - nausea, vomiting diarrhea
Shoulder/upper back pain
Cyanosis
Low grade intermittent fever
Altered Mental Status
Edema
Fatigue
OR
Infants/Children (at least 2 findings below)
Irritability
Vomiting
Poor feeding
Back Pain
Tachypnea
Lethargy
AND
OR
Non-specific changes that are new and/or normalize in recovery
AND
No alternative diagnosis for symptoms (e.g. MI, PE, mediastinitis, etc)
Abnormal chest radiograph showing enlarged heart
Abnormal testing
Electrocardiogram (EKG) abnormalities
Pericarditis_Level of Certainty - 3 (Possible Case)
Clinical Symptoms

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III. CDC working case definition of myocarditis and pericarditis and 
myopericarditis (54) 
Condition 
Definition 
Acute 
myocarditis 
Probable case 
Confirmed case 
Presence of ≥1 new or worsening of the 
following clinical symptoms:* 
Presence of ≥1 new or worsening of the 
following clinical symptoms:* 
     • chest pain, pressure, or discomfort 
     • chest pain, pressure, or discomfort 
     • dyspnea, shortness of breath, or pain 
with breathing 
     • dyspnea, shortness of breath, or pain with 
breathing 
     • palpitations 
     • palpitations 
     • syncope 
     • syncope 
 
OR, infants and children aged <12 years 
might instead have ≥2 of the following 
symptoms: 
OR, infants and children aged <12 years might 
instead have ≥2 of the following symptoms: 
 
     • irritability 
     • irritability 
 
     • vomiting 
     • vomiting 
 
     • poor feeding 
     • poor feeding 
 
     • tachypnea 
     • tachypnea 
 
     • lethargy 
     • lethargy 
 
AND 
AND 
 
≥1 new finding of 
≥1 new finding of 
 
     • troponin level above upper limit of 
normal (any type of troponin) 
     • Histopathologic confirmation of 
myocarditis† 
 
     • abnormal electrocardiogram (ECG or 
EKG) or rhythm monitoring findings 
consistent with myocarditis§ 
 
     • abnormal cardiac function or wall 
motion abnormalities on echocardiogram 
     • cMRI findings consistent with 
myocarditis¶ in the presence of troponin level 
above upper limit of normal (any type of 
troponin) 
 
     • cMRI findings consistent with 
myocarditis¶ 
 
AND 
AND 
 
     • No other identifiable cause of the 
symptoms and findings 
     • No other identifiable cause of the 
symptoms and findings 
Acute 
pericarditis** 
Presence of ≥2 new or worsening of the following clinical features: 
     • acute chest pain†† 
     • pericardial rub on exam 
     • new ST-elevation or PR-depression on EKG 

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Condition 
Definition 
     • new or worsening pericardial effusion on echocardiogram or MRI 
 
Myopericarditis 
 
This term may be used for patients who meet criteria for both myocarditis and pericarditis. 
Abbreviations: AV = atrioventricular; cMRI = cardiac magnetic resonance imaging; 
ECG or EKG = electrocardiogram. 
 * Persons who lack the listed symptoms but who meet other criteria may be 
classified as subclinical myocarditis (probable or confirmed). 
 † Using the Dallas criteria (Aretz HT, Billingham ME, Edwards WD, et al. 
Myocarditis. A histopathologic definition and classification. Am J Cardiovasc Pathol 
1987; 1:3–14). Autopsy cases may be classified as confirmed clinical myocarditis on 
the basis of meeting histopathologic criteria if no other identifiable cause. 
 § To meet the ECG or rhythm monitoring criterion, a probable case must include at 
least one of 1) ST-segment or T-wave abnormalities; 2) Paroxysmal or sustained 
atrial, supraventricular, or ventricular arrhythmias; or 3) AV nodal conduction delays 
or intraventricular conduction defects. 
 ¶ Using either the original or the revised Lake Louise criteria. 
https://www.sciencedirect.com/science/article/pii/S0735109718388430?via%3Dihube
xternal icon 
 ** https://academic.oup.com/eurheartj/article/36/42/2921/2293375external icon 
 †† Typically described as pain made worse by lying down, deep inspiration, or 
cough, and relieved by sitting up or leaning forward, although other types of chest 
pain might occur. 

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Appendix K 
Protocol team 
Protocol leadership 
Chair 
Jesse Clark 
University of California, 
Los Angeles 
310-825-3543 
jlclark@mednet.ucla.edu 
Statistician 
Zoe Moodie 
HVTN SDMC, Fred Hutch 
206-667-7077 
zoe@fredhutch.org 
Co-chair 
Sharon Riddler 
University of Pittsburgh 
412-383-1675 
riddler@pitt.edu 
DAIDS Medical 
Officer 
Mary Allen 
DAIDS, NIAID 
240-627-3036 
mallen@niaid.nih.gov 
Protocol Team leader 
& Core medical monitor 
Briana Furch 
HVTN LOC, Fred Hutch 
206-667-6607 
bfurch2@fredhutch.org 
Laboratory lead 
Georgia Tomaras 
HVTN Laboratory Center 
919-681-5598 
gdt@duke.edu 
Other contributors to the original protocol 
Core medical monitor 
 
Nicole Grunenberg 
HVTN LOC, Fred Hutch 
Clinical safety specialist 
Maija Anderson 
HVTN LOC, Fred Hutch 
Study product developer 
representative 
William Schief 
Scripps Research 
Clinical trials manager 
Shelly Ramirez 
HVTN LOC, Fred Hutch 
Study product provider 
representative 
Antu Dey 
IAVI, New York 
Clinical data managers 
Brian Ingersoll 
Eva Hom 
HVTN SDMC, Fred Hutch 
Laboratory center 
representatives 
Lisa Sanders 
Jen Hanke 
HVTN Laboratory Center, Fred 
Hutch 
SDMC Associate director 
of operations 
Jessica Andriesen 
HVTN SDMC, Fred Hutch 
Regulatory affairs associate 
Megan Brandon 
HVTN LOC, Fred Hutch 
SDMC Associate director 
of lab science 
April Randhawa 
HVTN SDMC, Fred Hutch 
Clinic coordinator 
Stacey Edick 
University of Pittsburgh 
DAIDS Product Lead 
Michael Eller 
DAIDS, NIAID 
Community Advisory Board 
(CAB) member 
Rick Church 
New York City CAB 
Protocol development 
managers 
Kajari Mondal 
Daciana Margineantu 
HVTN LOC, Fred Hutch 
DAIDS protocol pharmacist 
Shawn Chiambah 
DAIDS, NIAID 
301-761-7336 
 
Community engagement 
unit representative 
Gail Broder  
HVTN LOC, Fred Hutch 
Statistical research associate 
Helen Lu 
HVTN SDMC, Fred Hutch 
Community 
educator/recruiter 
Christopher Blades 
University of California, Los 
Angeles 
Technical editor 
Anders McConachie 
CoVPN LOC, Fred Hutch 
 
 

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Appendix L 
Version history 
The Protocol Team may modify the original version of the protocol. Modifications are 
made to HVTN protocols via clarification memos, letters of amendment, or full protocol 
amendments. 
The version history of, and modifications to, Protocol HVTN 302 are described below. 
Protocol history and modifications 
Date: July 7, 2023 
Protocol version: Version 3.0 
Protocol modification: Full Protocol Amendment 2 
Item 1 
Revised in Section 1.6, Duration per participant; Section 2.8.1, Potential risks; 
Section 8.6, Extended follow-up for participants with unresolved study product-
related urticaria-associated symptoms; Section 8.9, Early termination visit; 
Section 9.5, Total blood volume; Appendix C, Schedule of procedures for 
extended follow-up for participants with unresolved study product-realted 
urticaria-associated symptoms; Appendix G, Sample Addendum Informed 
Consent Form for follow-up of participants with unresolved study product-
realted urticaria-associated symptoms: Language related to adding serum 
collection for participants in extended follow-up 
Item 2 
Updated in Appendix K, Protocol Team: name and contact information for 
DAIDS Medical Officer and DAIDS protocol pharmacist 
Item 3 
Updated Title page; and Appendix L, Version History: date, version number 
and contents of this amendment 
Item 4 
Updated per Protocol Version 2.0, Clarification Memo 1, dated January 12, 
2022 
Item 5 
Updated per Protocol Version 2.0, Letter of Amendment 1, dated March, 29, 
2022 
Item 6 
Updated per Protocol Version 2.0, Letter of Amendment 2, dated May 6, 2022 
Item 7 
Updated per Protocol Version 2.0, Letter of Amendment 3, dated June 27, 2022 
Item 8 
Updated per Protocol Version 2.0, Clarification Memo 2, dated August 16, 
2022 
Item 9 
Updated per Protocol Version 2.0, Clarification Memo 3, dated September 16, 
2022 
Item 10 Updated per Protocol Version 2.0, Letter of Amendment 4, dated November 18, 
2022 
Item 11 Updated per Protocol Version 2.0, Letter of Amendment 5, dated March 16, 
2023 
Item 12 Minor editorial and formating changes have been made throughout the protocol 

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Date: March 16, 2023 
Protocol version: Version 2.0 
Protocol modification: Letter of Amendment 5 
Item 1 
Updated in Section 1.6, Duration per participant; Section 1.7, Estimated 
total study duration; new Section 8.6, Extended follow-up for 
participants with unresolved study product-related urticaria-associated 
symptoms; Section 9.1, Adverse events; new Appendix C, Schedule of 
procedures for following up participants with unresolved study product-
related urticaria-associated symptoms; Appendix D, Visit windows for 
the main study; new Appendix E, Visit windows for follow-up of 
participants with unresolved study product-related urticaria-associated 
symptoms and Appendix G, Sample Addendum Informed Consent Form 
for follow-up of participants with unresolved study product-related 
urticaria-associated symptoms: language related to following up 
participants with unresolved study product-related urticaria-associated 
symptoms 
Item 2 
Updated in Appendix K; Protocol team: Name and contact information 
for protocol team Leader and Core medical monitor 
Item 3 
Updated throughout the protocol: Section numbering and cross 
references 
Date: November 18, 2022 
Protocol version: Version 2.0 
Protocol modification: Letter of Amendment 4 
Item 1 
Added in Section 2.8.1, Potential risks and Appendix D, Sample informed 
consent form: updated information related to observed skin reactions 
Item 2 
Updated in Appendix H, Protocol team: Name and contact information for 
Community Advisory Board (CAB) member 
Date: September 16, 2022 
Protocol version: Version 2.0 
Protocol modification: Clarification Memo 3 
 
Date: August 16, 2022 
Protocol version: Version 2.0 
Protocol modification: Clarification Memo 2 
Item 1 
Added in Section 9.5, Total blood volume: alternate laboratory specimen tube 
types allowed for research samples upon HVTN laboratory center approval 
Item 1 
Updated in Section 5.2.1, Delaying vaccinations for a participant: 
considerations for timing of receipt of SARS-CoV-2 vaccines and monkeypox 
vaccines 

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Date: June 27, 2022 
Protocol version: Version 2.0 
Protocol modification: Letter of Amendment 3 
Item 1 Updated in Section 2.8.1, Potential risks; Section 12, Literature cited; 
and Appendix D, Sample informed consent form: information due to new 
observed skin reactions 
Item 2 Updated in Appendix D, Sample informed consent form: language 
related to payment for study related injury in section 23 
Item 3 Corrected in Section 6.1.1, Power calculations for immunogenicity and 
Section 6.3, Statistical analysis: language related to statistical analysis 
plan 
Date: May 6, 2022 
Protocol version: Version 2.0 
Protocol modification: Letter of Amendment 2 
Item 1 Updated in Appendix A, Schedule of procedures for participants 
undergoing LN FNA and/or leukapheresis and Appendix B, Schedule of 
procedures for participants undergoing neither LN FNA nor 
leukapheresis: collection of PBMCs during vaccination 2 and 
vaccination 3 visits 
Item 2 Updated in Appendix A, Schedule of procedures for participants 
undergoing LN FNA and/or leukapheresis and Appendix B, Schedule of 
procedures for participants undergoing neither LN FNA nor 
leukapheresis: footnote #9 related to the pregnancy testing 
Item 3 Deleted in Appendix A, Schedule of procedures for participants 
undergoing LN FNA and/or leukapheresis and Appendix B, Schedule of 
procedures for participants undergoing neither LN FNA nor 
leukapheresis: row and footnote specifying plasma harvest 
Item 4 Clarified in Section 8.3, Reactogenicity Assessments: details regarding 
vital signs collection 
Date: March 29, 2022 
Protocol version: Version 2.0 
Protocol modification: Letter of Amendment 1 
Item 1 Added in Section 5.1.1, Inclusion criteria: Language related to 
participants enrolled in other clinical trials 
Item 2 Revised in Section 5.1.2, Exclusion criteria and Acronyms and 
abbreviations: Language related to participants who have received 
SARS-CoV-2 vaccination before enrollment 
Item 3 Revised in Appendix E, Low risk guidelines for US and Section 5.1.1, 
Inclusion criteria: Language to remove the requirement for PSRT 
consultation 

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Item 4 Added in Section 5.2.1, Delaying vaccinations for a participant: 
Language to describe guidance for scheduling licensed vaccinations 
Item 5 Revised in Section 7.3, Product preparation: Language to specify details 
about vaccine Dose Preparation and Administration Worksheets 
Item 6 Clarified in Section 1.5, Study Plan and schema table and Section 9.6, 
Sentinel Safety Reviews: Number of participants in sentinel safety groups 
Item 7 Corrected in Section 4, Laboratory Strategy: URL for the description of 
the standard HVTN laboratory assays 
Item 8 Updated in Appendix H, Protocol team: Name and contact information 
for Laboratory lead 
Date: January 12, 2022 
Protocol version: Version 2.0 
Protocol modification: Clarification Memo 1 
 
Item 1 Updated in Section 7.3, Product Preparation: needle size for product 
administration 
Item 2 Updated in Section 9.4.1, Protocol Safety Review Team (PSRT): 
abnormal ALT monitoring and reporting process 
Item 3 Updated in Appendix A, Schedule of procedures for participants 
undergoing LN FNA and/or leukapheresis and Appendix B, Schedule of 
procedures for participants undergoing neither LN FNA nor 
leukapheresis: blood storage volume for additional safety labs 
Item 4 Corrected in Appendix D, Sample informed consent form: formatting 
error affecting sections 14 and 15 
Date: September 30, 2021 
Protocol version: Version 2.0 
Protocol modification: Full Protocol Amendment 1 
Item 1 
Added in Section 2.8.2, Myocarditis and Pericarditis with mRNA COVID-19 
vaccines, Section 3.1, Objectives and endpoints, Section 5.1.2, Exclusion 
criteria, Section 8.4, Cardiac symptom management, Section 9.1, Adverse 
events, Section 9.2, AESIs, Section 9.3.1, Expedited reporting of adverse events 
to DAIDS, Section 9.7, Safety pause and prompt PSRT AE review, Appendices 
A through D and Appendix G: Information on myocarditis and pericarditis 
following COVID-19 mRNA vaccines and risk mitigation and management 
approaches in response to the comments received from the FDA dated 17 
August 2021. 
Item 2 
Added in Section 2.2.2.2, In non human primates (NHPs): Rationale for 
evaluating BG505 MD39.3 mRNA vaccine in response to the comment 
received from FDA dated September 10, 2021 

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Item 3 
Added in Section 8.8, Early termination visit, Appendix A, Schedule of 
procedures for participants undergoing LN FNA and/or leukapheresis, 
Appendix B, Schedule of procedures for participants undergoing neither LN 
FNA nor leukapheresis and Appendix D, Sample informed consent form: Social 
impact assessment and Social impact assessment questionnaire 
Item 4 
Added in Section 8.3, Reactogenicity Assessment and Appendix D, Sample 
informed consent form: Additional information regarding electronic diary and 
paper diary 
Item 5 
Revised Appendix D, Sample informed consent form: to include changes 
requested upon Central IRB review of Protocol Version 1. 
Item 6 
Updated Acronyms and abbreviations 
Item 7 
Updated in Title page, Table of contents, Appendix 12, Literature cited, and 
Appendix I, Version history: date, version number and contents of this 
amendment 
Item 8 
Minor editorial and formatting changes have been made throughout the 
protocol 
Date: July 8, 2021 
Protocol version:1.0  
Protocol modification: Not applicable 
Original protocol