A Phase I Pilot Study to Evaluate the Safety and Immunogenicity of the HIV-1 Vaccines MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) Given Alone or In Combination in HIV-1-Infected Adults Suppressed on Antiretroviral Therapy - The M&M Study
Phase: PHASE1
Conditions: HIV-1 Infection
Sponsor: University of North Carolina, Chapel Hill

STUDY PROTOCOL 
 
A Phase I Pilot Study to Evaluate the Safety and Immunogenicity of 
the HIV-1 Vaccines MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) 
Given Alone or In Combination in HIV-1-Infected Adults Suppressed 
on Antiretroviral Therapy - The M&M Study 
 
NCT number NCT03844386 
Document Date 02/19/2021 
 

IGHID 11810 – M&M Study 
Protocol Version 3.0 LOA #1 – 19 February 2021– DAIDS-ES ID 38563 
Page 1 of 2 
 
Letter of Amendment #1 
 
IGHID 11810 - A Phase I Pilot Study to Evaluate the Safety and Immunogenicity of the 
HIV-1 Vaccines MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) Given Alone or In 
Combination in HIV-1Infected Adults Suppressed on Antiretroviral Therapy – The 
M&M Study 
 
Protocol Version 3.0, dated 06 January 2021 
 
IND Number: IND 18368 
 
DAIDS‐ES ID 38563 
 
Date of Letter of Amendment (LOA) #1: February 19, 2021 
 
 Summary of Revisions and Rationale 
 
We would like to allow participants from the UNC IGHID 11627 study (UNC IRB 17-0468 Protocol 
version 1.0 dated 06-Feb-2017 and Protocol version 2.0 dated 15-Aug-2017) who received HIV-1 
Antigen Expanded Specific T Cell Therapy (HXTC) to participate in the M&M vaccine study, provided 
their last dose of HXTCs was greater than or equal to 12 months from M&M screening.  
 
Preliminary analysis and data from participants who received the dose 2 x 107/m2 indicate lack of 
immunogenicity and therefore, we feel this therapy has not increased or changed the nature of the existing 
HIV specific T-cell responses.  
 
 
Implementation  
This Letter of Amendment does not change the informed consent form. 
 
The plan is to incorporate the modifications included in this Letter of Amendment into the next full 
protocol amendment. Text noted below with a strikethrough represents deletion; text appearing below in 
bold represents an addition.  
 Protocol Changes  
 
1. Section 5.2 Exclusion Criteria (page 44)  
 
Item #11 
Use of any prior HIV vaccine (prophylactic and/or therapeutic) or HIV immunotherapy. 
Note: exceptions allowed for antibody therapies per PI review and approval. 
Note: exceptions allowed for IGHID 11627 (UNC IRB 17-0468; NCT 03212989) per PI 
review and approval provided there is greater than 12 months since receipt of study-provided 
treatment. 
 
 

IGHID 11810 – M&M Study 
Protocol Version 3.0 LOA #1 – 19 February 2021– DAIDS-ES ID 38563 
Page 2 of 2 
 
Letter of Amendment #1 
 
IGHID 11810 - A Phase I Pilot Study to Evaluate the Safety and Immunogenicity of the 
HIV-1 Vaccines MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) Given Alone or In 
Combination in HIV-1-Infected Adults Suppressed on Antiretroviral Therapy – The 
M&M Study 
 
Protocol Version 3.0, dated 06 January 2021 
 
IND Number: IND 18368 
 
DAIDS-ES ID 38563 
 
Date of Letter of Amendment (LOA) #1: February 19, 2021 
 
 
 
SIGNATURE PAGE 
 
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 (US) 
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 (e.g., US 
National Institutes of Health, Division of AIDS) and institutional policies. 
 
 
 
Protocol Principal Investigator:    
 
Print/Type 
 
Signed:  
Date:   
 
 
 
Title:   
 
 
 

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IGHID 11810 - A Phase I Pilot Study to Evaluate the Safety and 
Immunogenicity of the HIV-1 Vaccines MVA.tHIVconsv3 (M3) and 
MVA.tHIVconsv4 (M4) Given Alone or In Combination in HIV-1-
Infected Adults Suppressed on Antiretroviral Therapy – The M&M 
Study 
 
DAIDS ES-ID Protocol Number: 38563 
National Clinical Trial (NCT) Number: NCT03844386 
Grant Principal Investigator: Nilu Goonetilleke, PhD 
Protocol Principal Investigator: Cynthia Gay, MD, MPH 
IND Number: IND 18368 
Funded by:  National Institutes of Health (NIH) 
Division of AIDS (DAIDS) 
Version Number:  v3.0 
06 January 2021 
 
 
 

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IGHID 11810 - A Phase I Pilot Study to Evaluate the Safety and Immunogenicity of 
the HIV-1 Vaccines MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) Given Alone 
or In Combination in HIV-1-Infected Adults Suppressed on Antiretroviral Therapy – 
The M&M Study 
DAIDS ES-ID Protocol Number: 38563 
SIGNATURE PAGE 
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 (US) 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 (e.g., US National Institutes of Health, 
Division of AIDS) and institutional policies. 
 
 
Protocol Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
Signed: ___________________________________ Date: ____________________ 
 
Title: _____________________________________ 
 
 

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Table of Contents 
TABLE OF CONTENTS .................................................................................................. 3 
TABLE OF TABLES ........................................................................................................ 5 
TABLE OF FIGURES ...................................................................................................... 6 
STATEMENT OF COMPLIANCE ................................................................................ 7 
PROTOCOL TEAM ROSTER ....................................................................................... 8 
1 
PROTOCOL SUMMARY ...................................................................................... 10 
1.1 
Synopsis ................................................................................................................ 10 
1.2 
Schema ................................................................................................................. 13 
1.3 
Schedule of Events (SOE) ................................................................................... 13 
2 
INTRODUCTION.................................................................................................... 17 
2.1 
Study Rationale ................................................................................................... 17 
2.1.1 
HIV Infection and the Need for Alternative Therapies ............................. 17 
2.2 
Background .......................................................................................................... 17 
2.2.1 
MVA-Vectored Vaccines .............................................................................. 17 
2.2.2 
HIV Conserved Immunogens ....................................................................... 18 
2.2.3 
Pre-Clinical Experience with MVA-Vectored Vaccines Expressing 
HIV Immunogens .......................................................................................... 26 
2.2.4 
Clinical Experience with MVA-Vectored Vaccines in HIV Positive 
Populations .................................................................................................... 26 
2.3 
Risk/Benefit Assessment ..................................................................................... 27 
2.3.1 
Known Potential Risks .................................................................................. 27 
2.3.2 
Known Potential Benefits ............................................................................. 31 
2.3.3 
Assessment of Potential Risks and Benefits ................................................ 31 
3 
OBJECTIVES AND ENDPOINTS ........................................................................ 31 
4 
STUDY DESIGN ...................................................................................................... 35 
4.1 
Overall Design ..................................................................................................... 35 
4.2 
Scientific Rationale for Study Design ................................................................ 37 
4.3 
Justification for Dose .......................................................................................... 38 
4.4 
End of Study Definition ...................................................................................... 38 
5 
STUDY POPULATION .......................................................................................... 38 
5.1 
Inclusion Criteria ................................................................................................ 38 
5.2 
Exclusion Criteria ............................................................................................... 43 
5.3 
Screening .............................................................................................................. 47 
5.3.1 
Failures ........................................................................................................... 47 
5.3.2 
Re-screening................................................................................................... 47 
5.4 
Strategies for Recruitment and Retention ........................................................ 47 
5.4.1 
Recruitment ................................................................................................... 47 
5.4.2 
Co-enrollment Guidelines ............................................................................. 48 
6 
STUDY INTERVENTION ...................................................................................... 48 
6.1 
Study Intervention(s) Administration ............................................................... 48 
6.1.1 
Study Intervention Description .................................................................... 48 
6.1.2 
Dosing and Administration .......................................................................... 48 

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6.2 
Preparation/Handling/Storage/Accountability................................................. 50 
6.2.1 
Acquisition and accountability .................................................................... 50 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................ 50 
6.2.3 
Product Storage and Stability ...................................................................... 51 
Preparation ...................................................................................................................... 51 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................. 52 
6.4 
Study Intervention Compliance ......................................................................... 53 
6.5 
Concomitant Medications ................................................................................... 53 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .............................................................. 54 
7.1 
Discontinuation of Study Intervention .............................................................. 54 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................... 55 
7.3 
Lost to Follow-Up ................................................................................................ 57 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................. 57 
8.1 
Efficacy Assessments ........................................................................................... 57 
8.2 
Safety and Other Assessments ........................................................................... 61 
8.2.1 
Screening ........................................................................................................ 61 
8.2.2 
Participant Enrollment ................................................................................. 62 
8.2.3 
Leukapheresis ................................................................................................ 62 
8.2.4 
Randomization .............................................................................................. 63 
8.2.5 
Study Un-blinding ......................................................................................... 63 
8.2.6 
Unscheduled Visits ........................................................................................ 63 
8.2.7 
Vaccine or Placebo Administration Visit:................................................... 64 
8.2.8 
Post Vaccination/Injection Management: ................................................... 65 
8.2.9 
Post Vaccination Symptom Log ................................................................... 65 
8.2.10 
Solicited AE Assessments: ............................................................................ 66 
8.2.11 
Laboratory Evaluations ................................................................................ 67 
8.3 
Adverse Events and Serious Adverse Events ................................................... 70 
8.3.1 
Definition of Adverse Events (AE) .............................................................. 70 
Definition of Serious Adverse Events (SAE) ................................................................. 71 
8.3.2 
Classification of an Adverse Event .............................................................. 71 
8.3.3 
Time Period and Frequency for Event Assessment and Follow-Up ......... 73 
8.3.4 
Adverse Event Reporting ............................................................................. 75 
8.3.5 
Serious Adverse Event Reporting ................................................................ 79 
8.3.6 
Reporting Events to Participants ................................................................. 80 
8.3.7 
Events of Special Interest ............................................................................. 80 
8.3.8 
Reporting of Pregnancy ................................................................................ 81 
8.4 
New Safety Information ...................................................................................... 82 
8.4.1 
Definition of New Safety Information (NSI) ............................................... 82 
8.4.2 
NSI Reporting ................................................................................................ 82 
8.4.3 
Reporting NSI to Participants...................................................................... 83 
9 
STATISTICAL CONSIDERATIONS ................................................................... 83 
9.1 
Statistical Hypotheses ......................................................................................... 83 

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9.2 
Sample Size Determination ................................................................................ 83 
9.2.1 
Primary Sample Size Consideration............................................................ 83 
9.3 
Statistical Analyses .............................................................................................. 85 
9.3.1 
General Approach ......................................................................................... 85 
9.3.2 
Immunological and Virologic Analysis ....................................................... 85 
9.3.3 
Analysis of the Primary Endpoint(s) ........................................................... 86 
9.3.4 
Analysis of the Secondary Endpoint(s) ....................................................... 86 
9.3.5 
Immunological and Virologic Analysis ....................................................... 86 
9.3.6 
T cell Magnitude: .......................................................................................... 86 
9.3.7 
T cell Breadth: ............................................................................................... 87 
9.3.8 
Safety Analyses .............................................................................................. 88 
9.3.9 
Tabulation of Individual Participant Data ................................................. 89 
9.3.10 
Exploratory Analyses .................................................................................... 89 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 89 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................. 89 
10.1.1 
Informed Consent Process ............................................................................ 89 
10.1.2 
Study Discontinuation and Closure ............................................................. 90 
10.1.3 
Confidentiality and Privacy ......................................................................... 91 
10.1.4 
Future Use of Stored Specimens and Data ................................................. 92 
10.1.5 
Key Roles and Study Governance ............................................................... 92 
10.1.6 
Safety Oversight ............................................................................................ 93 
10.1.7 
Clinical Monitoring ....................................................................................... 94 
10.1.8 
Quality Assurance and Quality Control ..................................................... 95 
10.1.9 
Data Handling and Record Keeping ........................................................... 95 
10.1.10 
Protocol Deviations ....................................................................................... 96 
10.1.11 
Publication and Data Sharing Policy........................................................... 96 
10.1.12 
Conflict of Interest Policy ............................................................................. 97 
10.2 
Abbreviations ...................................................................................................... 97 
10.3 
Protocol Amendment History .......................................................................... 102 
11 REFERENCES ....................................................................................................... 103 
Table of Tables 
Table 1 
Clinical Testing of MVA.HIVconsv in HIV Seronegative and 
Seropositive Participants ........................................................................ 21 
Table 2 
Order of Mosaic Regions of tHIVconsv3 and tHIVconsv4 ................. 22 
Table 3 
Clinical Testing of MVAs in HIV Seropositive Individuals ................ 25 
Table 4 
Local Reactions ....................................................................................... 28 
Table 5 
Systemic Reactions .................................................................................. 28 
Table 6 
Randomized Assignment ........................................................................ 36 
Table 7 
Adequate Organ Function Values for Inclusion . Error! Bookmark not 
defined. 

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Table 8 
Arms in the Clinical Study ..................................................................... 49 
Table 9 
Medication Complete History or Timeframe ....................................... 58 
Table 10 
Local Reaction Solicited AE Assessments ............................................. 66 
Table 11 
Systemic Reaction Solicited AE Assessments ....................................... 67 
Table 12 
Blood Volumes Associated with Study Visits ....................................... 70 
Table 13 
Severity Grade for Parameters .............................................................. 71 
Table 14 
Distribution of Regions of HIV Epitopes Targeted by T-Cells in HIV-1 
Infected Participants Durably Suppressed with ART ......................... 87 
Table 15 
Key Roles ................................................................................................. 92 
Table of Figures 
Figure 1 
Six Regions in the HIV Proteome are Included in tHIVconsvX Vaccine 
Immunogen ............................................................................................ 202 
Figure 2 
Amino acid alignments of the Two Complementary Mosaics ............. 21 
Figure 3 
Generation of Markerless Recombinant MVA Vectors ...................... 23 
 
 

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STATEMENT OF COMPLIANCE 
The conduct of this clinical trial will be in accordance with International Conference on 
Harmonization Good Clinical Practice (ICH GCP) and the following:  
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The Institutional Review Board (IRB) will review and approve the protocol, informed 
consent form(s), recruitment materials, and all participant materials submitted.  Approval 
of both the protocol and the consent form must be obtained before any participant is 
enrolled.  Any amendment to the protocol will require review and approval by the IRB 
before the changes are implemented to the study.  In addition, all changes to the consent 
form will be IRB-approved; a determination will be made regarding whether a new consent 
needs to be obtained from participants who provided consent, using a previously approved 
consent form. 
 
 

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PROTOCOL TEAM ROSTER  
Grant Principal Investigator 
Nilukshi Goonetilleke, PhD  
Assistant Professor 
Dept. Microbiology & Immunology / 
Medicine 
University of North Carolina 
120 Mason Farm Road, CB# 7042 
2023 (Office 2017), Genetic Medicine 
Building 
Chapel Hill, NC 27599-7042 
Phone: (919) 962-3129 
Email: nilu_goonetilleke@med.unc.edu   
Protocol Principal Investigator  
Cynthia Gay, MD, MPH  
Associate Professor 
Medical Director UNC HIV Cure Center 
University of North Carolina 
Division of Infectious Disease  
130 Mason Farm Road,  
 
Bioinformatics Building, Suite 2112, CB# 
7030  
Chapel Hill, North Carolina 27599-7030 
Phone: (919) 843-2726 
Fax: (919) 966-8928 
Email: cynthia_gay@med.unc.edu    
 
Co-Investigator  
Joseph Eron, MD 
Professor of Medicine, School of Medicine  
Director, Clinical Core, UNC Center for 
AIDS Research 
University of North Carolina  
130 Mason Farm Road, 
Bioinformatics Building, Suite 2110, CB# 
7030  
Chapel Hill, North Carolina 27599-7030 
Phone: (919) 966-2536  
Fax: (919) 966-6714 
Email: joseph_eron@med.unc.edu    
Co-Investigator  
David Margolis, MD 
Professor of Medicine, Microbiology & 
Immunology, and Epidemiology 
University of North Carolina 
120 Mason Farm Road, 2016  
Genetic Medicine Building, CB# 7042 
Chapel Hill, NC 27599-7042 
Phone: (919) 966-6388 
Email: david_margolis@med.unc.edu  
Co-Investigator  
Nancie M. Archin, Ph.D. 
Research Assistant Professor 
University of North Carolina 
Division of Infectious Diseases 
120 Mason Farm Rd, CB# 7042 
Genetic Medicine Building, RM 2060 
Chapel Hill, NC, 27599-7042 
Phone: (919) 962-0180 
Email: nancie_archin@med.unc.edu 
 
Co-Investigator 
Tomáš Hanke, PhD 
Professor of Vaccine Immunology, 
Distinguished Professor 
University of Oxford, Nuffield Department 
of Medicine 
The Jenner Institute 
ORCRB Roosevelt Drive, Oxford OX3 
7DQ 
United Kingdom 
Phone: +44 1865 617630 
 Email: tomas.hanke@ndm.ox.ac.uk  
 
 

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Clinical Program Director  
JoAnn Kuruc, MSN, RN 
Clinical Program Director  
UNC HIV Cure Center 
University of North Carolina 
130 Mason Farm Road,  
 
Bioinformatics Building, Suite 2100, CB# 
7030  
Chapel Hill, North Carolina 27599-7030 
Phone: (919) 966-8533 
Fax: (919) 843-7625 
Email: joann_kuruc@med.unc.edu 
Statistician  
Ann Marie Weideman, MS 
University of North Carolina 
Center for AIDS Research 
Manager, CFAR Biostatistics Core 
3126 McGavran-Greenberg Hall 
Chapel Hill, NC 27599-7042 
Phone: (919) 966-8421 
Email: anndo1@live.unc.edu 
 
Statistician  
Michael Hudgens, PhD 
Professor, Department of Biostatistics 
Director, Center for AIDS Research 
(CFAR) Biostatistics Core 
University of North Carolina 
Chapel Hill, NC 27599 
Phone: (919) 966-7253 
Email: mhudgens@bios.unc.edu  
DAIDS Medical Officer  
Lawrence Fox, MD, Ph.D.  
Captain, US Public Health Service  
Senior Medical Officer, HIV Research 
Branch  
Division of AIDS, NIAID, NIH, DHHS  
phone: 240-627-3069  
FAX:    240-627-3106 
Email: LFOX@niaid.nih.gov  
DAIDS Program Officer  
Steve Smiley, PhD 
Program Officer 
Therapeutics Research Program 
Division of AIDS, NIAID, NIH, DHHS 
5601 Fishers Lane, Room 9E59 
Bethesda, MD 20892-9830 
Phone: 240-627-3071  
Fax: 240-627-3106  
Email: stephen.smiley@niaid.nih.gov 
 
 
 

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1  PROTOCOL SUMMARY 
1.1 
Synopsis  
Title: 
IGHID 11810 - A Phase I Pilot Study to Evaluate the Safety and 
Immunogenicity of the HIV-1 Vaccines MVA.tHIVconsv3 
(M3) and MVA.tHIVconsv4 (M4) Given Alone or In 
Combination in HIV-1-Infected Adults Suppressed on 
Antiretroviral Therapy – The M&M Study 
Study Description: 
 
 
 
Hypotheses: 
This is a Phase 1, double blind, randomized, placebo-controlled, 
parallel design study to evaluate the safety and immunogenicity 
of MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) 
vaccines. 
Intramuscular (IM) vaccination with M3 or M4, given 
individually or together (M3+M4) in adult HIV-infected 
participants on suppressive combination antiretroviral therapy 
(ART) will be safe and increase HIV-1-specific T cell responses 
targeting conserved regions of HIV-1.  
The simultaneous administration of M3 with M4 (M3+M4) will 
result in a greater increase in the breadth of HIV-1-specific T 
cells targeting conserved regions of HIV-1 than individual 
administration of M3 or M4. 
Objectives: 
 
Primary Objective:   
Evaluate the safety of vaccination with M3 or M4 given 
individually or in combination (M3+M4) in HIV-1 infected 
participants on ART with plasma HIV-1 RNA <50 copies/mL. 
 
Secondary Objectives:  
Compare the within-participant relative change in magnitude of 
HIV-1-specific T cell responses following vaccination with 
either M3 or M4 or M3+M4 combined. 
Compare the between-arm change in breadth of HIV-1-specific 
T cell responses following vaccination with either M3 or M4 or 
M3+M4 combined. 
 
 

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Other Objectives:  
Compare the change in function and phenotype of HIV-1-
specific T cell responses in participants from pre-vaccination to 
post-vaccination with either M3 or M4 or M3+M4. 
Evaluate the kinetics of immunologic responses in participants 
pre- and post-vaccination with either M3 or M4 or M3+M4. 
Evaluate the kinetics of CD8+ T cell mediated HIV inhibition 
pre- and post-vaccination with either M3 or M4 or M3+M4. 
Explore cellular activation status of total CD4+ and CD8+ T cells 
pre- and post-vaccination with either M3 or M4 or M3+M4. 
Explore the impact of vaccination with either M3 or M4 or 
M3+M4 on low-level plasma viremia.  
Explore the impact of vaccination with either M3 or M4 or 
M3+M4 on cell-associated HIV RNA in CD4+ T cells. 
Explore the impact of vaccination with either M3 or M4 or 
M3+M4 on total HIV DNA in CD4+ T cells. 
Endpoints: 
Primary Endpoint: Safety 
Occurrence of at least one ≥ Grade 3 Adverse Event (AE) 
including signs/symptoms, lab toxicities, and/or clinical events, 
that is possibly, probably or definitely related to study treatment 
any time from the first day of treatment through 28 days 
following vaccination. 
Secondary Endpoint: Safety 
Occurrence of any ≥ Grade 1 AE including signs/symptoms, lab 
toxicities, and/or clinical events, that is possibly, probably, or 
definitely related to study treatment any time from the first day 
of treatment through Day 168 (Week 24) following vaccination. 
Safety data will include local and systemic signs and symptoms, 
laboratory measures of safety/toxicity, and all adverse and 
serious adverse events. Safety data will be routinely collected 
throughout the duration of the study.   

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NOTE: The occurrence of a Grade 3 elevated blood pressure 
during a study-related leukapheresis that resolves following 
completion of the procedure will not be included as a primary 
safety endpoint. 
Secondary Endpoints: Immunogenicity 
Relative change in magnitude of T cell responses to HIV-1 
conserved regions from pre-vaccination (Day 0) to post-
vaccination at Day 7 and Day 14. 
Change in breadth of T cell responses targeting HIV conserved 
regions from pre-vaccination (Day 0) to post-vaccination at Day 
28.  
Study Population: 
HIV-infected men and women ≥ 18 and ≤ 65 years of age with 
viral suppression on ART as measured on standard HIV RNA 
assays.  Eligible participants must have a CD4 cell count ≥ 350 
cells/mm3 at screening.  
Phase: 
Phase 1  
Description of 
Facilities Enrolling 
Participants: 
Single site - The University of North Carolina, Chapel Hill, 
North Carolina, USA. 
Description of 
Study Intervention: 
This is a double blind, randomized, placebo-controlled, parallel 
design, study in which 24 HIV-infected participants with durable 
viral suppression will be randomly assigned to receive 
vaccination with MVA.tHIVconsv3 (M3), MVA.tHIVconsv4 
(M4), M3+M4 combined, or placebo.  
Participants will be randomized 7:7:7:3 to one of four study 
arms, and receive study treatment or placebo at Day 0.  
Study Schema 
Arm 
N 
Day 
Treatment 
Dose (pfu) 
Route 
1 
7 
0 
M3 
2108 
IM 
2 
7 
0 
M4 
2108 
IM 
3 
7 
0 
M3+M4 
1108, each 
vaccine 
IM 

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4 
3 
0 
Placebo 
(saline) 
- 
IM 
M3 = MVA.tHIVconsv3 
M4 = MVA.tHIVconsv4 
pfu = plaque forming units 
IM = intramuscular  
Study Duration: 
The study will take approximately 2.5 years from the time the 
study opens to enrollment until completion of data analyses. 
Participant 
Duration: 
Each enrolled participant will complete the study in 
approximately 33.5 weeks (8.4 months).  
 
 
1.2 
Schema 
 
 
1.3 
Schedule of Events (SOE) 
PLEASE NOTE: This study combined Visits 2 and 3, eliminating one study visit from the 
Schedule of Events prior to Day 0. To avoid issues with data and protocol implementation 
related to renumbering all study visits, the numbering of the Day 0 through Day 168 Visits 
will remain unchanged (Visits 4 through 12). We eliminated the Visit 3 from the Schedule 
of Events.  
DAY 0 
RANDOMIZATION & VACCINATION 
Screen              Enroll                Baseline
DAY 2    DAY 7    DAY 14    DAY 28    DAY 56   DAY 70  Day 84  Day 168
Continues ART Therapy 
Continues ART Therapy 
Baseline Clinical and 
Research Labs 
Arm 1 
M3
n=7
Arm 2
M4
n=7
Arm 3
M3 + M4
n=7
Arm 4
Placebo
n=3
Safety Assessments 
Research Assay Collections 
Leukaphere
Leukapheresis
Optional Lymph Node
Optional 
Lymph Node

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Screening 
 
Enrollment   
 and Baseline 
 
Day 0 
 
Day 2 
Day 7 
 
Day 14 
 
Day 28 
 
Day 56 
Day 70           
Day 84 
Day 168 
Visit # 
1 
21 
 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Visit Windows in days  
Standard  
 
≤ 60 of 
Visit 1  
 
≤ 10 of 
Visit 2 
 
 
-/+2 
- /+7  
-/+ 7  
- 6/+7 
-/ +6 
-/+7 
Visit anchored to date of Day 0  
Day -60 
Estimated 
Day -10 
 
 
 
Day 7 
Day 12 - 
Day 16 
Day 21 - 
Day 35  
Day 49 - 
Day 63 
Day 64 - 
Day 77  
Day 78  - 
Day 90 
Day 161 - 
Day 175  
Clinical Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility and 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Locator Information 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PID assignment  
X 
 
 
 
 
 
 
 
 
 
 
 
SID assignment  
 
X 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
 
X 
 
 
 
 
 
 
 
 
Medical and Medication 
History 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Complete Physical Exam  
X 
 
 
 
 
 
 
X 
 
 
 
 
Targeted Physical 
Assessment 
 
 
 
X 
 
X 
X 
 
X 
X 
 
 
Vital Signs (VS) 2 
X 
X3 
 
X 
 
X 
X 
X 
X 
X 
 
 
Height (in cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
Calculate Body Mass Index 
(BMI) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG)  
X 
 
 
 
 
 
 
 
 
 
 
 
Review ART and ART 
adherence  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted Reproductive 
History  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Update Medical History 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Update Concomitant 
medications 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess Signs and Symptoms 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess Adverse Events  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Screening 
 
Enrollment   
 and Baseline 
 
Day 0 
 
Day 2 
Day 7 
 
Day 14 
 
Day 28 
 
Day 56 
Day 70           
Day 84 
Day 168 
Study Treatment or Placebo 
 
 
 
X 
 
 
 
 
 
 
 
 
Post-vaccine/placebo 
assessment  
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Completion of Post-
vaccine/placebo Symptom 
Log by the participant 
 
 
 
 
X 
X 
 
 
 
 
 
 
Leukapheresis 
 
X--------------------X3 
 
 
 
X4 
 
 
 
 
Lymph Node Procedure 5,6 
 
X---------------------X 
 
X -------------- X 
 
 
 
 
Telephone Assessment 
 
 
X 
 
 
 
X 
X 
Clinical Laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
Screening chemistry 7 
X 
 
 
 
 
 
 
 
 
 
 
 
Safety chemistries8 
 
X 
 
 
 
X 
X 
X 
 
X 
 
 
Pregnancy test 9 
X 
 
 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy – POCT 10 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Coagulations Test 
(PT/INR/APTT)  
X 
 
 
 
 
 
 
 
 
 
 
 
HIV Ag/Ab test11 
X 
 
 
 
 
 
 
 
 
 
 
 
CD4+ T Cell Differential 
Panel  
X 
 
 
 
 
X 
X 
 
 
X 
 
 
HIV-1 RNA PCR 
X 
 
 
 
 
X 
 
 
 
X 
 
 
RPR 
X 
 
 
 
 
 
 
 
 
 
 
 
HBsAg & HCV Ab 12 
X 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
X 
 
 
Research  Laboratory 
Assays 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typing  
 
X 
 
 
 
 
 
 
 
 
 
 
Flow cytometry sample6 
 
X-------------------X 
 
X ------------------ X 
 
 
 
 

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Screening 
 
Enrollment   
 and Baseline 
 
Day 0 
 
Day 2 
Day 7 
 
Day 14 
 
Day 28 
 
Day 56 
Day 70           
Day 84 
Day 168 
Plasma and PBMC for 
Immunologic and Virologic 
Studies 13 
X 
X14, 15 
 
X 
 
X 
X 
X15, 16 
X 
X 
 
 
 
1. Visit 2 and all associated procedures (inclusive of leukapheresis) will occur within 60 days of Visit 1. 
If required for scheduling, the leukapheresis visit can occur separately from Visit 2 but within 60 days 
of Visit 1 and after the Enrollment/Baseline visit. If the leukapheresis is on a separate day, perform the 
safety labs, vital signs and BMI assessment at the leukapheresis visit and the Day 0 visit within 10 
days of the leukapheresis. 
2. Pulse (P), blood pressure (BP), respiratory rate (RR), temperature (T) (°C, oral) and weight (kg).   
3. Reference Section 8.2.3 
4. Reference Section 8.2.3 
5. Optional Lymph Node Procedure –consenting participants will complete 2 procedures: the first 
between Enrollment (Visit 2) and Day 0 and the second between Day 7 and Day 21.   
6. Draw blood sample (3 mL EDTA) on day of FNA procedure, unless procedure done on the same day 
as the leukapheresis or on a visit day where blood sample is already being collected for plasma & 
PBMCs for Immunology and Virologic Studies.  
7. Screening chemistries: sodium, chloride, potassium, CO2/bicarbonate, glucose, blood urea nitrogen 
(BUN), creatinine, calcium, phosphate, albumin, magnesium, LDH, total protein, total bilirubin, AST 
(SGOT), ALT (SGPT) and alkaline phosphatase 
8. Safety chemistries: sodium, chloride, potassium, CO2/bicarbonate, BUN, creatinine, calcium, 
magnesium, glucose, total bilirubin, AST (SGOT), ALT (SGPT) and alkaline phosphatase 
9. Serum pregnancy on all women at screening and on the day of vaccine/placebo only if pregnancy 
suspected. 
10. POCT at Day 0 on all women and at any post vaccine visit where pregnancy suspected in WOCBP 
only.  
11. Optional - HIV testing at screening only if documentation of HIV infection needed.  
12. Reactive Hepatitis C Antibody test reflex for Hepatitis C RNA; negative RNA test is acceptable for 
study participation. 
13. Collect research samples in ACD tubes.  
14. Collect separate research PBMCs samples at Enrollment (Visit 2).  
15. Leukapheresis product 
16. Draw 42.5 mL ACD for research assays at Day 28 if leukapheresis scheduled after Day 35.  
 
 
 

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2  INTRODUCTION 
2.1 
Study Rationale  
2.1.1 
HIV Infection and the Need for Alternative Therapies 
Multiple strategies to eradicate latent HIV are under investigation. The most advanced 
include latency reversing agents (LRA) that aim to drive infected cells out of latency. 
Several groups including ours have now demonstrated that LRAs can increase cell-
associated HIV RNA in participants, though no decrease in the overall size of the HIV 
reservoir has been observed (1,2). These clinical observations are consistent with in vitro 
studies that suggest latency reversal is not itself cytopathic and current LRAs reactivate 
only a fraction of all infected cells, most of which harbor virus that is not replication 
competent (1).   
Clearance of reactivated cells by CD8+ T cells has been demonstrated in in vitro studies (1, 
3). These observations are consistent with the extensively documented role of CD8+ T cells 
in the control of untreated HIV infection, as well as more recent studies suggesting CD8+ T 
cells contribute to control of HIV reactivation and/or virus rebound (4-6). 
Immunotherapeutic strategies to eliminate the need for ART by strengthening HIV-specific 
T-cell immune response have been attempted, although results have been largely 
disappointing (7-10). Only a small number of HIV vaccine trials have reported an impact 
of vaccines on the size of the latent reservoir; finding either no sustained impact (11, 12) 
or, at best, a small, transient decline in the frequency of replication-competent latent 
infection (13) and below the threshold of what our group identified as necessary to achieve 
significance (14).  
While further iterative testing of both LRAs and immunotherapies are needed, ultimately, 
it is likely that combination strategies that incorporate both latency reversal and T-cell 
mediated clearance will be needed to achieve HIV eradication (16).  To advance the field 
of HIV curative therapy, we propose to evaluate the safety and immunogenicity of MVA-
vectored vaccines expressing conserved regions of HIV. The proposed clinical trial will 
administer MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) vaccines either alone or 
in combination (M3+M4) in HIV-infected individuals durably suppressed with 
combination antiretroviral therapy (ART).  
2.2 
Background  
2.2.1 
MVA-Vectored Vaccines 
Modified vaccinia virus Ankara strain (MVA) is a highly attenuated derivative of vaccinia 
virus that is unable to replicate efficiently in humans due to a replication defect that occurs 
late in virion assembly (16).  MVA was administered to more than 120,000 people as a 

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safer alternative to the original smallpox vaccine. MVA in its unmodified form is licensed 
as a smallpox virus vaccine in Europe and Canada (Imvamune®/Imvanex®, Bavarian 
Nordic). Recombinant MVAs (rMVAs) have proven excellent vaccines that express high 
levels of the vaccine transgene product (immunogen) (16, 17). The MVA vector also 
provides potent adjuvant capacity for the induction and/or boosting of T-cell responses 
against the passenger immunogen. Comparable to the unmodified form, rMVA vaccines 
also have extensive and excellent safety profiles in clinical studies, including in HIV-
infected (viremic, aviremic) individuals (18-23), infants, (23, 24) and advanced cancer 
patients (25). 
rMVAs have reproducibly increased T-cell responses whether used alone in pre-immune 
individuals (26) or as a boosting vaccination following priming with recombinant protein, 
attenuated viruses, DNA and mycobacterial vaccines. rMVAs have been safely delivered 
by either intramuscular (IM) or intradermal (ID) delivery. Both routes elicit comparable T-
cell responses in the blood, though IM delivery may elicit more potent mucosal T cell 
responses (27). MVA doses of 1-2x108 pfu have been both well tolerated and 
immunogenic (28-30).  
2.2.2 
HIV Conserved Immunogens  
Rationale for HIV conserved-region T-cell vaccines: The first HIV vaccines, including 
rMVAs, expressed full-length, clade consensus proteins and were tested both in HIV 
seronegative (31) and HIV positive participants (32). However, T-cell responses elicited by 
vaccination with full-length HIV immunogens often disproportionately target regions of 
HIV that are highly variable (32-34) with two implications. Firstly, T cell responses 
elicited against the more variable or ‘high entropy’ regions of the HIV proteome are less 
likely to afford broad coverage of participants’ latent reservoir (35). Secondly, CD8+ T cell 
responses that target variable or ‘high entropy’ HIV epitopes are more susceptible to rapid 
virus escape that can occur within weeks of infection (36). These virus escape variants are 
incorporated into the HIV reservoir (37).  By contrast, CD8+ T cells targeting more 
conserved or low entropy regions of HIV escape significantly more slowly with escape 
sometimes taking years (38). This suggests that on balance, the ‘pre-existing’ viral escape 
mutants in the replication competent viral reservoir exist at higher frequency in variable 
regions in HIV. Conserved region immunogen designs therefore afford broader population 
coverage and help limit the negative impact of pre-existing virus escape in the HIV 
reservoir.  
MVA.HIVconsv: HIVconsv is the first HIV conserved-region T cell immunogen designed 
by Dr Hanke.  HIVconsv comprises 14 conserved regions of the HIV-1 proteome (39). 
Each segment is a consensus sequence from one of the four major HIV-1 clades A, B, C, 
and D, which alternate to ensure equal clade coverage (39). MVA.HIVconsv has been 
tested or is in testing in eight trials in both HIV seronegative and seropositive individuals, 
mostly given IM (1-3 immunizations) at a dose of 2x108 pfu (Table 1).  In most studies, 

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MVA.HIVconsv was given as a boosting vaccination following a vaccination with a 
simian adenovirus (ChAd63.HIVconsv) also expressing, HIVconsv. However, in HIV-
CORE 001, MVA.HIVconsv was given three times by IM alone. For all studies, 
MVA.HIVconsv was manufactured by IDT Biologika, Germany.  
Across all studies, safety data indicate MVA.HIVconsv vaccination was well tolerated and 
safe (Investigator Brochure [IB], MVA.tHIVconsv3 2.0, IB, MVA.tHIVconsv4 version 
2.0). Both adverse event (AE) profiles and the frequency of reactions were similar to those 
observed in HIV seronegative individuals. The few SAEs reported were not attributed to 
vaccination, AEs associated with MVA boosting were mostly mild or moderate and there 
were no reported interactions with ART.  
Both MVA.HIVconsv and other rMVA expressing HIV immunogens increased pre-
existing HIV-specific T-cell responses in HIV-1 infected, ART-treated study participants 
(26, 40). In both ex vivo ELISpot, and multi-parameter flow cytometry assays, HIV-
specific T-cell responses peaked 1-2 weeks after rMVA vaccination (41). MVA.HIVconsv 
vaccination also increased HIV inhibitory capacity of CD8+ T cells with CD8+ T cells post-
vaccination exerting in vitro control of replication of four major HIV clades A, B, C, and D 
(41-43). MVA.HIVconsv delivered as part of combination latency-reversal (romidepsin) 
and vaccination strategy produced a signal of viremic control during a monitored ART 
pause in 36% of vaccine recipients (44) (Table 1) .   
Table 1 
Clinical Testing of MVA.HIVconsv in HIV Seronegative and 
Seropositive Participants 
Study  
HIV 
status 
N= 
Route 
Dose 
(pfu) 
No. doses 
Treatment 
related 
SAE  
HIV-CORE 001 (41) 
+ 
19 
IM 
5x107/ 
2x108 
3 
0 
HIV-CORE 002 (46)1 
- 
23 
IM 
2x108 
1 
0 
BCN011,2 
+ 
24 
IM 
2x108 
1 
0 
HIV-CORE 0041,3 
- 
60 
IM 
2x108 
1 
0 
HIV-CORE 0031,4 
- 
31 
IM 
2x108 
1 
0 
PEACHI 0041,5 
_ 
32 
IM 
2x108 
1 
0 
BCN01ROMI1,6 
+ 
15 
IM 
2x108 
2 
0 
RIVER1,7 
+ 
30 
IM 
2x108 
1 
0 
1 Heterologous vaccination with simian adenovirus 
or DNA 
3 ClinicalTrials.gov NCT02099994 
 
2 ClinicalTrials.gov NCT01712425 
4 ClinicalTrials.gov NCT02425241; combination 
vaccination with simian adenovirus or DNA and 
SAP 
5 ClinicalTrials.gov NCT02362217 
7 ClinicalTrials.gov NCT02336074 
6 ClinicalTrials.gov NCT02616874 
 

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Motivation for design of second generation immunogen: The regions of HIV included 
in the first generation immunogen HIVconsv were identified on the basis of sequence 
conservation only. Immunogencity of these regions was not considered. To improve 
population-level vaccine immunogenicity, second generation HIV immunogens were 
designed to maximize the inclusion of HIV sequences that spanned regions of HIV that are 
both conserved and protective (i.e. enriched in participants with lower HIV plasma virus 
loads). The protective T cell epitopes included in the second generation immunogens had 
been previously identified in studies of treatment-naive patient cohorts on four continents, 
including North America (46). Figure 1 identifies the six regions of HIV included in the 
second generation conserved immunogens, collectively called, tHIVconsvX (47). 
 
Six regions (ordered 1-6, highlighted with HXB2 alignment)  
Figure 1 
Six Regions in the HIV Proteome are Included in tHIVconsvX Vaccine 
Immunogen 
Rationale for mosaic immunogen design: Even in the most conserved regions of the HIV 
proteome, some sequence variability exists. In silico approaches were used to generate two 
mosaic immunogens, Mosaic 1 and Mosaic 2, which together provide greater coverage of 
global HIV sequence variability (Figure 2). Both Mosaic-1 and Mosaic-2 are 872 amino 
acids long. They differ in 84 amino acids or 9.6% of amino acids. Protein alignment using 
the SerialCloner 2-6-1 software scores the two proteins as 96.44% similar (Figure 2) (48). 
Mosaic-1 and -2 are complementary sequences and equivalent in their coverage of HIV 
sequence variability.  

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(Mosaic-1 red, Mosaic-2 blue) comprised of six conserved regions of HIV-1. Each region is identified by the 
protein from which it is derived and its position relative to the HIV HXB2 reference strain 
Figure 2 
Amino acid alignments of the Two Complementary Mosaics  
The vaccine immunogen tHIVconsv3 (immunogen of M3) is comprised of Mosaic-1 
regions; however, the order of the six regions differs from the native proteins (Table 2). 
tHIVconsv4 (immunogen of M4) is comprised of Mosaic-2 regions and again, the order of 
the six regions differs (Table 2). The aim of scrambling the order of HIV regions is to 
minimize induction of T-cell responses to the junctional sequences and maximize 
induction of T cell responses against the common HIV regions. This will be relevant for 
possible future trials where M3 and M4 vectors may be combined with other recombinant 
vaccine vectors such as simian adenoviruses. 

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Table 2 
Order of Mosaic Regions of tHIVconsv3 and tHIVconsv4 
Insert 
Immunogen 
Region Order1 
tHIVconsvX 
tHIVconsv3 
Mosaic-1 
3-6-2-5-1-4 
tHIVconsv4 
Mosaic-2 
4-1-5-2-6-3 
1Numbers correspond to the number shown in Figure 1and the region number (protein-X) listed as part of the 
sequence identifier for each region in Figure 2. 
The human tissue plasminogen activator sequence (tPA-LS, Genbank sequence ID: 
AAA61213.1,) has been incorporated as a leader sequence to enhance expression of the 
tHIVconsvX immunogens (49-51). Recombinant MVA vaccines containing tPA-LS have 
been tested without report of serious adverse events (28, 30, 52). 
Construction of the M3 and M4 vaccines: The parental non-replicating MVA originates 
directly from Professor Anton Mayr, passage 575 dated 14 December, 1983 (53) and was 
modified to contain red fluorescent protein (RFP)(54) (Figure 3). The tHIVconsv3 and 
tHIVconsv4 genes were first cloned into transfer plasmid p856MVA containing the green 
fluorescent protein (GFP) gene under control of the modified H5 promoter (p856MVA-
GFP-TD-mH5). Recombinant MVAs were made as follows. SPF chicken embryo 
fibroblast (CEF) cells were infected with parental MVA.RED at a multiplicity of infection 
(MOI) of 1 and transfected with p856MVA-GFP-TD-mH5.tHIVconsv3 or p856MVA-
GFP-TD-mH5.tHIVconsv4. The cell lysate from this recombination was harvested and 
used to infect CEF. RFP and GFP double positive cells were MoFlo single-cell sorted into 
96-well plates and these were used to culture recombinant virus following addition of fresh 
CEF. Multiple passages gives rise to spontaneous intramolecular recombination between 
homology regions resulting in one of two possible products: antigen insertion (containing 
vaccine immunogen) or parental revertant (Figure 3). Those wells containing suitably 
infected (RFP-) cells were harvested and screened by PCR to confirm identity and test 
purity. Plaque picking was performed until the culture was free of parental virus, as 
determined by PCR.  

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Red- and Green fluorescent protein expression is used to detect parental (RFP+) and intermediate 
(GRP+RFP+) recombinant MVAs. The markerless MVA containing the vaccine immunogen/ antigen is 
purified following serial passage in CEFs and identity and purity confirmed by PCR. HR=homology region. 
Black arrows indicate primer location. Schematic from Pavot et al (54) 
Figure 3 
Generation of Markerless Recombinant MVA Vectors  
 

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Table 3 
Clinical Testing of MVAs in HIV Seropositive Individuals 
Study 
MVA 
Indication 
N=  
Route 
Dose 
(pfu) 
# 
doses 
Treatment 
related 
SAE 
Summary of Treatment-related SAEs 
BCN02-ROMI1 
MVA.HIVconsv 
HIV 
15 
IM 
2108 
2 
0 
None 
River2 
MVA.HIVconsv 
HIV 
30 
IM 
2108 
 
0 
None 
BCN013 
MVA.HIVconsv 
HIV 
24 
IM 
2108 
1 
0 
None 
HIV-CORE 001 
(41) 
MVA.HIVconsv 
 
11 
IM 
2.2-
5108 
2 
0 
None 
GV-TH-01 (55)  
MVA62B 
HIV 
9 
IM 
1108 
2 
0 
None 
RisVac 03 (21) 
MVA-B 
HIV 
14 
 
1108 
3-4 
0 
None 
C-030-485 (19) 
MVA85A 
TB 
257 
 
 
 
0 
None 
TB011 (56) 
MVA85A 
TB 
12 
IM 
5107 
 
0 
None 
Greenough (57) 
MVA.envgag 
MVA.tatrevnef-
RT 
HIV 
20 
IM 
5107 
2 
2 
Classified possibly but probably not related 
to vaccination. 
Multiple cutaneous bullous lesions, none at 
immunization sites (developed from a 
papular lesion at time of immunization) 
Grade 4 CPK elevation (unexplained CPK 
elevations occurred prior to study 
participation) 
Dorrell (58)  
MVA. HIVA 
HIV 
16 
ID 
5107 
2 
0 
None 
Cosma (59) 
MVA. HIVnef 
HIV 
10 
SC 
5108 
3 
0 
None 
Harrer (60) 
MVA. HIVnef 
HIV 
50 
IM 
1 or 
5108 
3 
0 
None 
TOTAL 
 
 
126 
 
 
2 
 
1 ClinicalTrials.gov NCT02616874 
2 ClinicalTrials.gov NCT02336074 
3 ClinicalTrials.gov NCT01712425 
4ClinicalTrials.gov NCT00189930 

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2.2.3 Pre-Clinical Experience with MVA-Vectored Vaccines Expressing HIV 
Immunogens 
Toxicity: A formal animal toxicity study of M3 and M4 has not been performed. We 
consider the more informative safety profile is the extensive clinical experience with 
similar MVA vectors. These studies, in part summarized in Table 1 and Table 3, have 
consistently shown MVA vaccination is safe and well tolerated at the dose and IM route 
proposed in this trial, and in both HIV positive and seronegative men and women.  
A pre-clinical GLP toxicology study of MVA.HIVconsv (UNO 0011) assessed the 
systemic toxic potential of 2 x 107 pfu/dose of MVA.HIVconsv administered IM to groups 
of 10 male and 10 female BALB/c mice on days 1, 15 and 29. Vaccinations were not 
associated with any systemic toxicological changes.  
Pre-clinical immunogenicity. In pre-clinical studies in BALB/c mice, the second 
generation core immunogens M3+M4 together showed equivalent immunogenicity to the 
first generation MVA.HIVconsv. A single M3 immunization induced an average response 
of almost 4000 SFU/106 splenocytes. HIV-specific T-cell responses were detected against 
6 of 10 peptide pools containing overlapping peptides spanning the tHIVconsvX 
immunogen, indicating breadth of T cell responses. When tested in a combination prime-
boost regimen with recombinant simian adenoviruses also expressing tHIVconsvX 
immunogens, no T-cell responses were detected against junctional sequences in BALB/c 
and C57BL mouse strains (47). 
2.2.4 
Clinical Experience with MVA-Vectored Vaccines in HIV Positive 
Populations  
Recombinant MVAs expressing both HIV and non-HIV immunogens (TB) have been 
tested in 12 studies in the proposed study population of HIV-infected durably ART 
suppressed participants, in part summarized in Error! Reference source not found..  
MVA.HIVA. The HIVA immunogen was also designed at the University of Oxford, and 
comprises a consensus clade A gag p24/p17 and a string of clade A-derived CTL epitopes 
(61). MVA.HIVA has been given to both HIV seronegative and positive individuals. In 
HIV-uninfected volunteers, MVA.HIVA was shown to be safe in > 400 healthy HIV-
uninfected volunteers across different trials (62). Vaccinations were administered ID, IM 
and subcutaneous (SC) routes at doses ranging from 5 x 107- 2.5 x 108 pfu (63). No SAEs 
attributed to the vaccine were observed (reviewed in (62)). 
The safety and tolerability of MVAs expressing HIV and non-HIV antigens has also been 
demonstrated in HIV-1-infected individuals (Error! Reference source not found.). 
Among 16 HIV-1-infected persons receiving ART for at least 12 months with a CD4 count 
>300 cells/µl and plasma viral load <50 copies/ml who received two ID injections of 

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MVA.HIVA (5 x 107 pfu) four weeks apart, there were no SAEs in 192 person months of 
follow-up (58, 64). MVA.HIVA was also safely administered to 20-week-old infants born 
to HIV-uninfected and HIV-infected mothers in Kenya (24). 
MVA.tHIVconsv. In the HIV-CORE 001 study of MVA.HIVconsv only (Error! 
Reference source not found.) in which HIV-1-infected participants on ART were 
randomized to receive 3 doses of MVA.HIVconsv (5x107 pfu or 2x108 pfu) or placebo, 
there were no treatment-related SAEs or SUSARs. In this study, injection site 
reactions/AEs were the most commonly observed local AE and all were graded as mild or 
moderate. Systemic AEs observed were all mild or moderate, with malaise the most 
commonly reported in 7 of 15 vaccinated participants (IB, MVA.tHIVconsv3 version 2.0; 
IB, MVA.tHIVconsv4 version 2.0).   
MVA expressing HIVconsv has been given to 213 participants (269 doses) ranging from 
5.5x107 pfu to 2.2x108 PFU all given IM. The participant groups included HIV-1-
seropositive adults, including recently infected individuals with early virus suppression 
after initiation of ART. There have been no SAEs considered to be possibly or likely 
related to MVA.tHIVconsv. In sum, clinical trial data with MVA.HIVconsv administered 
by IM injection with 2x108 pfu indicates the vaccine is safe and well-tolerated 
(MVA.HIVconsv Investigator’s Brochure Version 7.0, October 10, 2017, Table 1). The 
majority of observed AEs (approximately 90%) were mild or moderate in severity and 
resolved in 24-48 hours following vaccination, with Grade 3 events reported in less than 
5% of vaccinees.  
Based on these collective data, we consider the risked associated with M3, M4 or M3+M4 
vaccination to be minimal. 
2.3 
Risk/Benefit Assessment   
2.3.1 
Known Potential Risks  
Risks of M3 and M4 vaccines 
Based on safety data from studies with earlier generations of the MVA.HIVconsv vaccines 
and other MVA-vectored vaccines, adverse reactions (AEs) to M3 and M4 vaccine are 
anticipated to involve transient Grade 1 and 2 local reactions such as pain or erythema at 
the injection site in addition to headache, malaise, and fever (IB, MVA.tHIVconsv3 
version 2.0; IB, MVA.tHIVconsv4 version 2.0). There have been no SAEs or SUSARs in 
several studies of MVA.HIVconsv administered in combination with other vaccines (IB, 
MVA.tHIVconsv3 version 2.0; IB, MVA.tHIVconsv4 version 2.0). 
Clinical trial data with MVA.HIVconsv administered by IM injection with 2x108 pfu 
indicates that the following AEs may occur in some participants: injection site tenderness, 
erythema, swelling, pruritus, induration, myalgia, headaches, dizziness, fatigue, fever, 

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malaise, nausea, chills, vomiting, flu-like symptoms, diarrhea, sweating, anorexia, 
abdominal pain, and/or syncope. 
Standard local (Error! Reference source not found.) and systemic reactions (Table 5) can 
occur, with most appearing within the first 24 hours and usually subsiding within 48 – 72 
hours.  
Table 4 
Local Reactions 
Injection site erythema (redness) 
Injection site pruritus (itching) 
Injection site tenderness  
Injection site swelling 
Warmth at injection site 
Skin discoloration 
Injection site pain  
Skin damage (vesiculation or ulceration) 
Induration (hardening or formation of a crust or scab) 
Table 5 
Systemic Reactions 
Vomiting 
Fatigue (extreme tiredness)  
Malaise  
Headache 
Flu like symptoms  
Temperature (fever >37.7°C or 99.9°F) 
Sweating 
Chills  
Diarrhea 
Abdominal pain 
Dizziness 
Myalgia (muscle pain) 
Anorexia 
Nausea 
Syncope 
 
The expectation is that these AEs will be primarily mild in severity; however, occasional 
moderate or severe AEs (local pain, headache, malaise, diarrhea, myalgia) have occurred in 
other vaccine studies with MVA.HIVconsv.   
Due to lack of experience in humans, there is no information available about the 
relationship of AEs to the administration of M3 or M4 vaccines. 
A potential concern regarding the safety of live attenuated viral vaccines is the possibility 
of pathogenesis, caused by viral mutation and replication. Any potential risk in this respect 
arising from the administration of M3 or M4 is thought to be very small, due to the 
avirulence and restricted replication of the parental virus MVA and the recombinant 
vaccine viruses MVA.tHIVcons3 and MVA.tHIVcons4 in human cells. 

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Animal reproduction studies have not been performed and human data on use during 
pregnancy are not available. Therefore, the vaccine should not be administered to pregnant 
women or women with the intention to become pregnant. 
As with any other vaccine, Guillain-Barré Syndrome (GBS) or immune-mediated reactions 
may occur that can lead to organ damage. These problems, however, are very rare events 
and have never occurred with recombinant MVA-vectored vaccines to date. 
Risk of Syncope 
Syncope (fainting) can occur before or following any vaccination as a stress response to 
the needle injection. 
Risks of Blood Drawing  
Blood drawing may cause pain and bruising and may infrequently cause a feeling of 
lightheadedness or fainting. Rarely, it may cause infection at the site where the blood was 
drawn. Problems from use of an intravenous (IV) for blood drawing are generally mild and 
may include pain, bruising, minor swelling or bleeding at the IV site, and rarely, infection, 
vein, or blood clot (phlebitis). We minimize risk by using sterile technique and universal 
precautions. 
Overdose 
Overdose of M3 and M4 is not addressed given all doses will be provided and 
administered by licensed study staff only and as prepared by the manufacturing facilities. 
Risks Associated with Leukapheresis  
These include common side effects similar to blood drawing. However, more serious side 
effects could occur such as flushing, infection due to contaminated equipment, and damage 
to red blood cells. These serious side effects occur in less than 1 in 10,000 procedures. No 
such serious adverse events have occurred in our prior studies, in now more the 400 cell 
collections from HIV+ donors at UNC.   
The following are the most common: 
• Pain or bruising at the site of needle sticks, 
• Phlebitis - Formation of a blood clot at the blood draw site, 
• Citrate toxicity (10%), 
• Oral paresthesia (tingling around the mouth),  
• Paresthesia (tingling/cramping in hands, fingertips, and feet), 
• Stiffness in the arms due to the immobilization during donation, 
• Fatigue or tiredness, and 

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• Temporary fluctuations in blood pressure or heart rate. 
Less common: 
• Infiltration – the needle dislodges and comes out of the vein causing the fluid to go into 
the tissue,  
• Muscle aches or cramps, 
• Chills,  
• Fever, 
• Nausea or vomiting, 
• Lightheadedness or headache, and 
 
• Vasovagal reaction resulting in decrease in blood pressure and heart rate. 
Rare: 
• Seizures or fainting, 
• Transient weight gain, ankle swelling, or increased urination for 24 hours due to fluid 
retention, 
• Infection due to contamination of equipment, 
• Skin rashes, flushing, or other allergic responses, 
• Damage to or loss of red blood cells due to machine malfunction, and  
• Remote possibility of air entering the vein and causing chest pains, shortness of breath 
or shock or death. 
Risks Associated with Lymph Node Biopsy Procedure 
• Serious complications after fine needle aspirations (FNA) or lymph node biopsies are 
rare.  
• Minor bleeding under the skin at the biopsy site can occur. This can result in a tender, 
swollen area called a hematoma. 
• Infection at the biopsy site is rare because of the use of sterile techniques and 
equipment. 
• Common Local Reactions 
o Swelling, 
o Soreness, and 
o Pain - typically treated with acetaminophen (Tylenol). 
Unknown Risks  
New therapies can lead to unexpected, incidental finding that could have a potential effect 
on the participant’s health. Upon confirmation of a potential health or reproductive effect, 
the study team will notify participants impacted by the new information and will advise 

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proper medical follow-up when indicated. If findings require more immediate medical 
attention, the study PI in conjunction with the study coordinators will assist participants in 
getting an appropriate care appointment.  
2.3.2 
Known Potential Benefits  
 
The addition of the M3, M4, or combined M3+M4 to a person’s ART regimen and the 
donation of one’s blood cells to this research study provides no direct medical benefits to 
participants. However, participation contributes to ongoing HIV research, potentially 
resulting in new treatments for HIV infection.   
2.3.3 
Assessment of Potential Risks and Benefits  
Given that many HIV-1-infected patients on effective ART have persistent low-level 
viremia that can be detected by ultrasensitive research assays and exhibit impaired HIV-1 
specific immune responses, interventions with the potential to improve HIV-specific T-cell 
responses and limit viremia should be tested. Therapies that improve clearance of 
persistently HIV-1-infected cells will likely be a necessary component of any HIV 
remission or eradication strategy. Based on the data outlined above, there is sufficient 
expectation that the proposed treatment interventions will be safe and well tolerated. 
Although participants in this early phase study will receive no direct benefit for their 
participation in this study, there remains a strong desire among HIV-infected individuals, 
and the HIV community at-large, to pursue HIV preventative and therapeutic vaccine 
strategies. The potential adverse effects, stigmatization, and financial costs encountered by 
HIV-infected persons receiving life-long antiretroviral therapy along with the potential 
harm of persistent immune activation/inflammation are strong reasons to pursue HIV 
vaccine research. In short, an HIV cure or sustained remission in the absence of ART 
remain desirable goals that would have substantial benefits for many individuals if 
achieved. An effective HIV vaccine represents a key strategy for both HIV prevention and 
cure. 
3 OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Primary 
 
 
Evaluate the safety of 
vaccination with M3 or M4 
or M3+M4 in HIV-1 
infected participants on ART 
with plasma HIV-1 RNA 
<50 copies/mL.  
Safety 
Occurrence of at least one ≥ 
Grade 3 Adverse Event (AE) 
including signs/symptoms, lab 
toxicities, and/or clinical 
events, that is possibly or 
The study will use 
standard safety grades 
used in HIV clinical 
trials. If exceeded, it is 
currently felt that such 
risks would be 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
 
definitely related to study 
treatment any time from the 
first day of treatment through 
28 days following vaccination. 
Safety data will include local 
and systemic signs and 
symptoms, laboratory measures 
of safety/toxicity, and all 
adverse and serious adverse 
events. Safety data will be 
routinely collected throughout 
the duration of the study.   
 
NOTE: The occurrence of a 
Grade 3 elevated blood 
pressure during a study-related 
leukapheresis that resolves 
following completion of the 
procedure will not be included 
as a primary safety endpoint. 
unacceptable in a 
research study of this 
nature. 
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Secondary 
 
 
 
Evaluate the safety of 
vaccination with M3 or M4 
or M3+M4 in HIV-1 infected 
participants on ART with 
plasma HIV-1 RNA <50 
copies/mL.  
 
Occurrence of any ≥ Grade 1 
AE including signs/symptoms, 
lab toxicities, and/or clinical 
events, that is possibly, 
probably, or definitely related 
to study treatment any time 
from the first day of treatment 
through Day 168 (Week 24) 
following vaccination. 
 
Compare the within-
participant relative change in 
magnitude of HIV-1-specific 
T cell responses in 
participants following 
vaccination with either M3 
or M4 or M3+M4. 
Relative changes in magnitude 
of T cell responses to HIV-1 
conserved regions measured 
by ex vivo IFN- ELISpot 
from pre-vaccination on Day 0 
to post-vaccination on Day 7 
and 14.  
Previous studies 
indicate that the rMVA 
-induced T cell 
response, typically 
measured by ex vivo 
IFN- ELISpot, peaks 
between day 7-14 days 
following vaccination.  
Compare the between-arm 
change in breadth of HIV-1-
specific T cell responses in 
participants from pre-
vaccination to post-
vaccination with M3 or M4 
or M3+M4. 
Change in breadth of T cell 
responses targeting HIV 
conserved regions from pre-
vaccination (Day 0) to post-
vaccination at Day 28. 
We hypothesize that the 
greater sequence 
coverage conferred by 
M3+M4 vaccination 
will breadth of HIV-
specific T cells that will 
remain detectable over 
time.   
Tertiary/Exploratory 
 
 
1. Compare the change in 
function and phenotype of 
HIV-1-specific T cell 
responses in participants 
from pre- to post-
vaccination with either M3 
or M4 or M3+M4. 
1. Relative change in 
magnitude and phenotype 
of HIV-1-specific CD8+ T 
cell populations, including 
tetramer reactivity, from 
pre-vaccination (Day 0) to 
Tertiary endpoints 1-3 
will explore how MVA 
vaccination impacts T 
cell function and 
phenotype and whether 
this manifests as 
increased in vitro 

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post-vaccination at Day 7 
and 14 by flow cytometry. 
clearance of HIV-
infected CD4+ T cells.  
2. Evaluate the kinetics of 
immunologic responses in 
participants’ pre- and post- 
vaccination with either M3 
or M4 or M3+M4. 
2. Describe the magnitude and 
phenotype of HIV-1-
specific CD8+ T cell 
populations at multiple pre- 
and post-vaccination time 
points by flow cytometry. 
3. Evaluate the kinetics of 
CD8+ T cell mediated HIV 
inhibition in participants 
pre- and post-vaccination 
with either M3 or M4 or 
M3+M4. 
 
3. Relative change in HIV p24 
levels in CD4+ T cells at 
multiple pre- and post-
vaccination time points by 
virus inhibition assay.  
 
4. Explore cellular activation 
status of total CD4+ and 
CD8+ T cells pre- and 
post-vaccination with 
either M3 or M4 or 
M3+M4. 
4. Describe the cellular 
activation status of CD4+ 
and CD8+ T cell subsets at 
multiple pre- and post-
vaccination time points by 
flow cytometry. 
Exploratory endpoint 4 
examines whether MVA 
vaccination induces 
general activation of T 
cell subsets. This will 
inform the timing of 
treatments in future 
combination studies 
with other 
immunotherapies or 
LRAs. 
5. Explore the impact of 
vaccination with either M3 
or M4 or M3+M4 on low-
level plasma viremia.  
5. The proportion of 
participants in whom HIV-1 
plasma RNA decreases 
from pre-vaccination 
(geometric mean of Day -60 
and 0) to post-vaccination 
(geometric mean of Day 56 
and 70) as measured by 
single copy assay. 
Exploratory endpoints 
5– 7 examines whether 
MVA vaccination has 
an in vivo effect on 
persistent HIV 
infection. 
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Tertiary/Exploratory  
 
 
6. Explore the impact of 
vaccination with either M3 
or M4 or M3+M4 on cell-
associated HIV RNA in 
CD4+ T cells. 
6.  The proportion of 
participants in whom cell-
associated RNA in total 
CD4+ T cells decreases 
post-vaccination (geometric 
mean of Day 28 and Day 
56) compared to pre-
vaccination (geometric 
mean of Day -45 and Day 
30.) 
Exploratory endpoints 
5– 7 examine whether 
MVA vaccination has 
an in vivo effect on 
persistent HIV 
infection. 
7. Explore the impact of 
vaccination with either M3 
or M4 or M3+M4 on total 
viral DNA in CD4+ T cell.  
7. Proportion of participants in 
whom total HIV DNA in 
total CD4+ T cells decreases 
post-vaccination (geometric 
mean of Day 28 and Day 56) 
compared to pre-vaccination 
(geometric mean of Day -45 
and Day 30.) 
4 STUDY DESIGN  
4.1 
Overall Design 
This is a Phase 1, single site, pilot study to evaluate the safety and immunogenicity of the 
M3 and M4 vaccines administered alone or in combination in HIV-infected participants 
suppressed on ART. 
This is a double blind, randomized, placebo-controlled, parallel design study to evaluate 
the safety and immunogenicity of viral-vector, MVA, expressing immunogens, 
tHIVconsv3 (M3) and tHIVconsv4 (M4), derived from conserved yet immunogenic 
regions of HIV-1. The participant population is HIV-1 infected adults suppressed on ART 
with plasma HIV-1 RNA <50 copies/mL. 
We hypothesize that the administration of M3 or M4 or M3+M4 together will be safe in 
HIV-1-infected participants suppressed on ART.  We hypothesize that the simultaneous 
administration of M3 with M4 (M3+M4) will result in both an increase in total magnitude 

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of HIV-1-specific T cell responses and increase the breadth of T cells targeting conserved 
regions of HIV-1 compared with either M3 or M4 vaccination alone. 
We will administer vaccine and placebo doses to all participants as an IM injection in the 
deltoid muscle of the non-dominant arm, unless a participant requests vaccination in their 
dominant arm. Participants continue their baseline ART regimen throughout the study. 
Randomized assignment 7:7:7:3 occurs at Day 0 to one of four arms as provided in Table 
6.  
Table 6 
Randomized Assignment 
Arm 
N 
Day 
Treatment 
Dose (pfu) 
Route 
1 
7 
0 
M3 
2108 
IM 
2 
7 
0 
M4 
2108 
IM 
3 
7 
0 
M3+M4 
1108, each vaccine 
IM 
4 
3 
0 
Placebo/saline 
- 
IM 
M3 = MVA.tHIVconsv3  
M4 = MVA.tHIVconsv4  
pfu = plaque forming units 
IM = intramuscular   
The primary safety outcome is the occurrence of at least one ≥ Grade 3 Adverse Event 
(AE) including signs/symptoms, lab toxicities, and/or clinical events that are possibly, 
probably, or definitely related to study treatment through 28 days following vaccination. 
The primary safety analysis will be blinded through Day 28 after the last dose of 
vaccine/placebo and the second leukapheresis is completed by the last participant. 
Screening, Enrollment, and Leukapheresis. The participant reviews and signs the 
informed consent (ICF). Participants meeting eligibility requirements enroll and undergo 
one leukapheresis procedure between Day -60 and Day 0. The leukapheresis procedure 
collects white blood cells allowing for completion of detailed immunologic and virologic 
assays with minimal blood loss. Participants have the option to consent to a lymph node 
FNA; participants choosing this option will complete the pre-vaccine FNA between Day -
60 and Day 0 and a post-vaccine FNA between Day 7 and Day 21. The post-vaccine FNA 
should be collected even if the pre-vaccine collection attempt is unsuccessful. 
Randomization, Study Treatment, Follow-up Assessment, and Leukapheresis. 
Randomization occurs at Day 0 when a randomization identification number (RID) will be 
assigned. All participants receive a vaccine or placebo dose as an IM injection. Post 

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vaccination safety assessments occur via clinical evaluations, and lab testing/evaluations. 
The study will collect research assays at designated visits.   
At Day 28, all participants will undergo their 2nd leukapheresis. This procedure can be 
completed between Day 21 through Day 35. The leukapheresis product will be used for 
immunologic and virologic research assays post vaccine/placebo. Participants will be 
followed for immunogenicity assessments through Day 70 and safety assessments through 
Day 168 (Week 24) following the administration of vaccine/placebo at Day 0.   
Note: The post-vaccine leukapheresis must be done as close to Day 28 as possible. There 
may be a rare situation where the completion of the procedure in the 2-week visit window 
will not be possible. As soon as the study coordinator becomes aware of this scenario, they 
should notify the study PI (or designee) to schedule the procedure outside the study 
window, preferably earlier (between Days 14 and 28). If the procedure can only be done 
after Day 35, participants should complete the Day 28 visit with collection of a 42.5 mL 
ACD sample at that visit.  
4.2 
Scientific Rationale for Study Design 
As detailed above, MVA-vectored vaccines have excellent safety profiles in clinical 
studies, including in HIV-infected individuals and infants (39, 40, 47, 60-62). MVA 
vectored vaccines have also been equally immunogenic in men and women (34, 48, 63, 
64). The dosing, route of immunization and scheduling for this study have all been 
previously tested using very similar vaccines and all parameters have been well tolerated.  
Accordingly, in our target population for HIV curative strategies of HIV-1 infected, 
durably suppressed male or female participants, this is a low risk study. The potential 
benefit provided in the induction of HIV-specific CD8+ T cell responses has been 
associated with increased HIV control and may increase participants’ anti-HIV immunity.  
Individuals who were chronically infected prior to ART treatment will be prioritized for 
enrollment. Results from this study will inform the next study combining the ChAdOx 
vaccine, a novel vaccine incorporating a recombinant, attenuated, replication-defective 
Chimpadenovirus vector, with the MVA vaccine strategy determined to be the most 
immunogenic and safe in this study. The key hypothesis is that M3 and M4 vaccination 
will shift T cell dominance away from variable epitopes to immunogenic, but more 
conserved epitopes that are less subject to escape. Therefore, for this first proof-of-
principle study we are seeking chronically HIV-infected participants who harbor a 
detectable and complex reservoir containing escape viruses. 
We established inclusion criterion of > 2 years of durable suppression for two reasons. 
Firstly, one of our endpoint virologic measures is change in total HIV DNA. Total HIV 
DNA levels do not stabilize until a year following ART (65). Secondly, HIV infection 
produces progressive immune dysregulation including effects on T cell proliferative 

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capacity and oligofunctionality. ART suppression over years, helps restore some, though 
not all, immune dysfunction (66). 
4.3 
Justification for Dose 
Route of Immunization: Intramuscular injection 
MVA vaccines have been given successfully using both IM and ID injections. MVA has 
proven to be safe and tolerated when delivered as an IM injection (61-64). In a study of 
MVA expressing influenza antigens delivered as an IM injection (n=8), fewer local 
adverse events were observed than with ID injection (n=12) (65). Systemic adverse events 
(AEs) were similar for both IM and ID injection (65).  
Total Dosing: 2 x 108 pfu  
Multiple studies were conducted that used the 2 X 108 pfu MVA dose which reported the 
dose as safe and well tolerated ((23, 69),  The AEs reported in the studies were mild 
(Grade 1) and moderate (Grade 2) local and systemic reactions. Most reactions were 
reactogenic, involving pain at the injection site (local) and malaise and myalgia (systemic). 
There were very few treatment-related SAEs reported (19).  
By way of comparison, there were vaccine-related SAEs observed in a study of rMVA 
expressing malarial antigens conducted in healthy, malaria-naïve participants, dosed at 5 x 
108pfu (28). The majority (75%) of participants reported moderate (Grade 2) to severe 
(Grade 3 or more) pain at the vaccination site and 25% reported a systemic reaction. 
However, the participants tolerated the injections when the MVA given in combination 
with a recombinant simian adenovirus primer administered at 1-2 x 108 pfu (same dose as 
proposed in this study). At both doses, rMVA significantly boosted vaccine-specific T cell 
responses. 
Dosing Regimen: Single vaccination in HIV-pre-immune individuals 
4.4 
End of Study Definition 
A participant is considered to have completed the study if they have completed all study-
required visits including the last visit in the Schedule of Events (SOE), Section 1.3. 
5 STUDY POPULATION 
5.1 
Inclusion Criteria 
1. HIV infection documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and 
confirmed by a licensed Western blot or a second antibody test by a method other than 

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the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral 
assay. 
A reactive initial rapid test should be confirmed by either another type of rapid assay or 
an E/CIA that is based on a different antigen preparation and/or different test principle 
(e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral 
load. 
NOTE: The term “licensed” refers to a US FDA-approved kit, which is required 
for all IND studies.  
WHO (World Health Organization) and CDC (Centers for Disease Control and 
Prevention) guidelines mandate that confirmation of the initial test result must use 
a test that is different from the one used for the initial assessment.  
2.  
Ages ≥ 18 to ≤ 65 years old 
3. 
Able and willing to give written informed consent. 
4. 
Able and willing to provide adequate locator information.  
5. 
Able and willing to comply with time requirements for protocol-specified visits and 
evaluations. 
6. 
Able and willing to commit to all study visits including follow-up through Day 168 
(Week 24). 
7. 
Continuous ART prior to screening, defined as not missing more than 9 total days 
and never more than 4 consecutive days in the last 3 months. 
8.  
On a stable ART regimen defined as no changes in any ART medication within the 
30 days prior to screening.  
9.  
Permitted ART regimens include:  
1) At least 3 ART agents (not counting ritonavir or cobicistat as one of the agents 
if less than a 200mg total daily dose). One of the agents must include an 
integrase inhibitor, NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitors), 
or a boosted-PI (protease inhibitor).  
OR 
2) Two (2) ART agents in which one of the agents is either a boosted protease 
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NOTE: Other potent fully suppressive antiretroviral combinations will be 
considered on a case-by-case basis.  
NOTE: Changes in drug formulation or dose are allowed (e g, TDF to TAF, 
ritonavir to cobicistat or separate ART agent dosing to fixed-dose combination), 
but none within 30 days prior to screening.  
NOTE: Prior changes in, or elimination of, medications for easier dosing schedule, 
intolerance, toxicity, an improved side effect profile or within a drug class are 
permitted if an alternative suppressive regimen was maintained, but not within 30 
days prior to screening. 
10. 
Ability and willingness of participant to continue ART throughout the study. 
11.  
Plasma HIV-1 RNA <50 copies/mL at 3 time points in the previous 24 months 
prior to screening and never ≥50 copies/mL on 2 consecutive time points in the last 
24 months.  
NOTE: The documented plasma HIV-1 RNA must be performed by any US 
laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) 
certification or its equivalent. 
12. 
At least 1 documented HIV-1 RNA result <50 copies/mL ≥24 months but ≤ 36 
months prior to screening. 
13.       Plasma HIV-1 RNA level <50 copies/mL on an FDA-approved HIV RNA assay 
performed at a US CLIA Certified Laboratory (or its equivalent) at screening.  
14. 
CD4 cell count ≥ 350 cells/mm3, performed at any US laboratory that has a CLIA 
certification or its equivalent at screening. 
 
15. 
Hepatitis C (HCV) antibody negative result at screening or, if the participant is 
HCV antibody positive, a negative HCV RNA at screening. 
16. 
Hepatitis B surface antigen (HBsAg) negative at screening. 
17. 
Adequate vascular access for leukapheresis.  
18. 
Able and willing to receive IM injections without difficulty.  
19. 
All women must have a negative serum pregnancy test at screening regardless of 
reproductive potential.  

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Note: The serum pregnancy test must have a sensitivity of at least 25 mIU/mL.  
20. 
All participants must agree not to participate in a conception process (e.g., active 
attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization, 
egg donation) while on study and for 4 months after their vaccination.   
Note: Women of child bearing potential is defined as women who have not been 
post-menopausal for at least 24 consecutive months, i.e., who have had menses 
within the preceding 24 months, or women who have not undergone surgical 
sterilization, specifically hysterectomy and/or bilateral oophorectomy or bilateral 
salpingectomy 
21. 
All men and women participating in sexual activity that could lead to pregnancy 
must agree to consistently use at least one of the following forms of birth control 
for at least 21 days prior to Visit 4 (Day 0) and for 4 months after their  
vaccination: 
▪ Condoms (male or female) with or without a spermicidal agent  
▪ Diaphragm or cervical cap with spermicide 
▪ Intrauterine device (IUD) 
▪ Tubal ligation 
▪ Hormone-based contraceptive 
NOTE: For female participants receiving ritonavir or cobicistat, estrogen-based 
contraceptives are not reliable and an alternative method should be suggested. 
22. 
Men and women who are not of reproductive potential are eligible without 
requiring the use of contraceptives. Acceptable documentation detailing 
sterilization and menopause are specified below. 
Note: Men who have sex with men only will not be required to use contraception.  
Written or oral documentation communicated by clinician or clinician’s staff of one 
of the following: 
▪ Physician report/letter 
▪ Operative report or other source documentation in the patient record (a 
laboratory report of azoospermia is required to document successful vasectomy) 
▪ Discharge summary 
▪ Follicle stimulating hormone-release factor (FSH) measurement elevated into 
the menopausal range as established by the reporting laboratory 
23. 
Agrees not to enroll on another study of an investigational research agent during 
the study period. 

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NOTE: Investigational research agent is defined as any unlicensed investigational 
drug not yet approved for use in humans.  
24. 
Willingness to defer routine vaccination except for influenza and COVID-19 from 
within the previous 28 days of screening enrollment through 28 days after 
vaccination at Day 0.  
NOTE: Potential participants should delay enrollment on study until 14 days after 
receiving the influenza and/or COVID-19 vaccine. 
25. 
Adequate organ function as indicated by the laboratory values provided in Error! 
Reference source not found.. 
Table 7 Adequate Organ Function Values for Inclusion 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count 
≥ 1,000 /mcL 
Platelets 
≥ 100,000 / mcL 
Hemoglobin 
≥ 12 g/dL (male) and ≥ 11.5 g/dL (females)  
Coagulation 
Prothrombin Time or INR 
<1.1 x ULN  
Chemistry 
Serum potassium levels 
Within normal limits 
Serum magnesium levels1 
WNL 
Glucose 
Screening serum glucose ≤ Grade 1 (fasting or non-
fasting)  
Renal 
Creatinine clearance determined by the CKD-Epi 
equation found at: 
https://www.qxmd.com/calculate/calculator_251/egfr-
using-ckd-epi 
eGFR > 60mL/min 
Hepatic 
Serum total bilirubin 
Total bilirubin <1.1 x ULN.  
If total bilirubin is elevated, direct bilirubin must be 
<2 x ULN 
If the participant is on an atazanavir –containing 
therapy then a direct bilirubin should be measured 
instead of the total bilirubin and must be ≤1.0mg/dL. 
AST (SGOT) and ALT (SGPT) 
<1.25 X ULN 
Alkaline Phosphatase  
<1.25 X ULN 
Urinalysis  
 
Protein  
< 2+ 
Blood  
< 2+ (for women, before or after menses)  
1 LLN for Mg++ per the clinical laboratory’s normal range used for this study is a grade 1 event per the DAIDS Toxicity 
Table and is allowed for eligibility. 

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LLN = lower limit of normal                             ULN = upper limit of normal                        WNL = within limit of normal 
 
5.2 
Exclusion Criteria 
1. If the HIV provider or study investigator is unable, as assessed by the study PI or 
protocol team, to construct a fully active alternative regimen based on previous 
resistance testing and/or treatment history.  
2. Women of childbearing age/potential must not be breast feeding, pregnant, or planning 
pregnancy any time from enrollment to 4 months after vaccination at Day 0.  
3. Body Mass Index (BMI) ≥40 kg/m2 
4. Untreated syphilis infection (defined as a positive rapid plasma reagin (RPR) without 
clear documentation of treatment). 
NOTE: In cases of untreated syphilis, participant may rescreen following 
documentation of adequate treatment of syphilis. 
5. Current treatment for HCV with antiviral therapy or participants who have received 
HCV treatment within 6 months prior to screening. 
6.  HIV RNA ≥150 copies/mL in the 6 months prior to screening. 
7. Received any infusion blood product, immune globulin, or hematopoetic growth 
factors within 6 months prior to screening. 
8. Use of any of the following within 90 days prior to screening: immunomodulatory, 
cytokine, or growth stimulating factors such as systemic cytotoxic chemotherapy, 
immune globulin, interferon, cyclosporine, methotrexate, azathioprine, anti-CD25 
antibody, IFN, interleukins, interleukin-2 (IL-2), hydroxyurea, thalidomide, 
sargramostim (granulocyte macrophage-colony stimulating factor [GM-CSF]), growth 
factors, dinitrochlorobenzene (DNCB), thymosin alpha, thymopentin, inosiplex, 
polyribonucleoside, or diticarb sodium, coumadin, warfarin, or other Coumadin 
derivative anticoagulants. 
9. Intent to use immunomodulators (e.g., IL-2, IL-12, interferons or TNF modifiers) 
during the course of the study. 
10. Use of systemic corticosteroids or topical steroids over a total area exceeding 15 cm2 
within 30 days prior to screening, or anticipated need for periodic use of corticosteroids 
during the study.  

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NOTE: For participants receiving ritonavir or cobicistat, (either as a booster or 
protease inhibitor [PI]) as part of their ART regimen, the concomitant use of 
oral/systemic/topical/inhaled/intranasal corticosteroids is prohibited. 
11. Use of any prior HIV vaccine (prophylactic and/or therapeutic) or HIV 
immunotherapy. 
Note: exceptions allowed for antibody therapies per PI review and approval. 
12. Any experimental non-HIV vaccination within 1 year prior to screening.  
NOTE: the receipt of an FDA Emergency Use Authorization (EUA) sanctioned 
COVID-19 vaccine is not considered exclusionary and should be reviewed with the 
protocol PI on a case-by-case basis. 
13. Prior immunization with a recombinant Adenovirus or MVA vaccine  
Note: prior immunization with smallpox vaccine is not exclusionary.  
NOTE: This exclusion INCLUDES COVID-19 vaccines with adenovirus vector (i.e., 
Janssen and AstraZeneca). 
14. Live attenuated vaccines received within 60 days prior to screening (i.e., varicella; 
measles, mumps, rubella [MMR]; yellow fever, oral polio, shingles).  
NOTE: Individuals who require vaccination will delay screening for the study until 60 
days after receiving the injection. 
15. History of prior IgG therapy or immunization with any experimental immunogens 
(antibodies) within 6 months of screening. 
16. Use of any investigational treatment within 6 months prior to screening, with the 
exception of Phase II studies of antiretroviral agents. 
NOTE: Co-enrollment with other studies under an IND using an FDA approved 
medication that are not otherwise listed as prohibited will be considered on a case-by-
case basis.  
NOTE: The receipt of an FDA Emergency Use Authorization (EUA) sanctioned 
COVID-19 vaccine or treatment will be reviewed with the protocol PI and will be 
considered on a case-by-case basis.   

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17. For any serious illness requiring systemic treatment or hospitalization, the participant 
must either complete therapy or be clinically stable on therapy, in the opinion of the 
site investigator, for at least 90 days prior to screening.  
18. Treatment for an active HIV-related opportunistic infection within 90 days prior to 
screening.  
19. History of malignancy within the last 5 years. 
NOTE: A history of non-melanoma skin cancer (e.g., basal cell carcinoma or 
squamous cell skin cancer) is not exclusionary with documentation of topical treatment 
or of complete resection at least 3 months prior to screening). 
20. Immune deficiency other than that caused by HIV infection. 
21. Any medical, psychiatric, occupational or other condition that, in the judgment of the 
investigator, would interfere with, or serve as a contraindication to, protocol adherence 
or assessment of safety. 
22. Hypertension - Exclude for blood pressure consistently > 150 mm Hg systolic and 
>100 mm Hg diastolic.  
Note: Elevated BP occurring during research leukapheresis procedures completed 
within the past 12 months are excluded from this requirement. Isolated elevations must 
be noted as acceptable and signed by study PI or designee.  
23. History of auto-immune disease, including Type I diabetes mellitus, with specific 
exception of:  
• Vitiligo 
• Resolved childhood atopic dermatitis 
• Psoriasis (with the exception of psoriatic arthritis) not requiring systemic 
treatment (within the past 2 years).  
• Grave’s disease with subsequent return to a euthyroid state (clinically and by 
laboratory testing).  
24. Seizure disorder: History of seizure(s) within the past 3 years. Also exclude if 
participant has used medications in order to prevent or treat seizure(s) at any time 
within the past 3 years. 
25. History of unexplained syncope or fainting episodes within 12 months of study 
screening. 

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26. History of Asplenia – absence of normal spleen function as indicated by: 
o Splenectomy 
o Sickle cell disease 
27. Bleeding disorder including factor deficiency, coagulopathy or platelet disorder that 
requires special precautions (easy bruising without a formal diagnosis is not 
exclusionary). 
28. Allergy to eggs and/or egg products. 
29. History of anaphylaxis or severe adverse reaction to vaccines including symptoms such 
as hives, respiratory difficulty, angioedema, and/or abdominal pain. 
30. History of hereditary angioedema, acquired angioedema or idiopathic angioedema. 
31. Known or suspected hypersensitivity to any vaccine component. 
32. Unstable asthma (e.g. sudden acute attacks occurring without an obvious trigger) or 
asthma requiring: 
o Daily steroid or long acting beta-agonist prevention 
o Hospitalization in the last two years 
33. Depo-provera injection at the site of administration (upper left or right medial deltoid 
muscles) within the 3 months prior to screening, if other deltoid is not an option.  
34. History of allergy to latex.  
35. Active chronic skin problems such as eczema or psoriasis.  
36. Known psychiatric or substance abuse disorder/dependence that, in the opinion of the 
site investigator, would interfere with cooperation with the requirements of the trial.  
37. Compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric 
illness or a physical illness, e.g., infectious disease.   
38. Prisoner recruitment and participation is not permitted.  
39. Inability to communicate effectively with study personnel. 

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5.3 
Screening 
5.3.1 
Failures 
Screening evaluations must occur prior to the participant starting any medications, 
treatments, or interventions. Screening visit can occur up to 60 days prior to the 
Enrollment/Baseline Visit.  
Demographic, clinical, and laboratory data is collected on persons at screening. The 
information collected on persons who fail screening and do not enroll will be retained in 
the screen failure section of the study file.  
Labs and/or procedures completed within the 14 days preceding the screening visit can be 
used to qualify the participant upon approval of the study PI (or designee). 
5.3.2 
Re-screening  
Potential participants who are unable to meet protocol-defined eligibility criteria at the 
Screening Visit may be eligible to re-screen again at the investigator’s (or designee’s) 
discretion.  
If a screen failure or the failure to enroll or proceed to Day 0 is due to the inability to meet 
one of the laboratory parameters (hematology, chemistry, HIV RNA level, or CD4+ T cell 
count), a retest of the failed criteria may be performed one time only. 
5.4 
Strategies for Recruitment and Retention 
5.4.1 
Recruitment 
There are several venues for recruitment available to the study team: 
• In the UNC ID Clinic and/or other local HIV clinics, there is a large pool of patients 
with long-term viral suppression on ART interested in participating in research.  Many 
have previously participated in clinical research studies. These individuals will be 
provided with the opportunity to discuss this study with their provider and the study 
coordinator.  
• Individuals who signed the UNC CFAR database consent, as well as those who signed 
the consent for the UNC Cure and PHI studies/database, will be identified and 
approached about the study. Primary care providers or the study coordinator, after 
consultation with their primary care provider, will provide information about the study 
and participation.  
• Advertisements and flyers in local clinics and with UNC HIV Community Outreach 
Organizations  

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5.4.2 
Co-enrollment Guidelines  
Co-enrollment on other studies will be addressed on a case-by-case basis with the study 
team. Due the potential interference with monitoring for the effects of this study’s 
treatments, participants will not be able to participate on other studies that provide 
medications, with the exception of Phase 2 or greater ARV studies. 
 
Co-enrollment in the ACTG 5332 REPRIEVE study (NCT023442900) using 
FDA approved pitavastatin is permitted provided the participant has taken the study 
provided medication ≥ 4 months. 
 
Although not a study, FDA EUA sanctioned COVID-19 treatments and vaccines are 
permitted and must be addressed on a case-by-case basis with the study team. 
6 STUDY INTERVENTION 
6.1 
Study Intervention(s) Administration 
6.1.1 
Study Intervention Description 
MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) have been manufactured in 
accordance with Good Manufacturing Process (GMP) by IDT Biologika, Am Pharmapark, 
06861 Dessau-Rosslau, Germany.  
Description of MVA.tHIVconsv3 (M3) 
The MVA.tHIVconsv3 vaccine is a second-generation HIV-1 conserved-region multi-
component vaccine employing tHIVconsv3 immunogens comprised of Mosaic-1 regions. 
MVA.tHIVconsv3 is a recombinant, non-replicating MVA expressing six conserved sub-
protein regions (regions 1-6) of HIV-1 as one chimeric protein designated tHIVconsv3. 
Description of MVA.tHIVcons4 (M4) 
The MVA.tHIVconsv4 vaccine is a second-generation HIV-1 conserved-region multi-
component immunization regimen employing tHIVconsv4 immunogens comprised of 
Mosaic-2 regions. MVA.tHIVconsv4 is a recombinant, non-replicating MVA expressing 
six conserved sub-protein regions (regions 1-6) of HIV-1 as one chimeric protein 
designated tHIVconsv4.  
6.1.2 
Dosing and Administration 
Dosing 

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All participants will receive a single vaccine/placebo administration on Day 0. Participants 
randomized to Arms 1 and 2 will receive 2108 pfu of M3 or M4, respectively.  
Participants randomized to Arm 3 will receive a 1108 pfu dose of both M3 and M4 (total 
dose 2x108 pfu M3+M4). Participants randomized to Arm 4 will receive placebo (Table 7).   
Table 7 
Arms in the Clinical Study 
Arm 
N 
Day 
Treatment 
Dose (pfu) 
Volume 
(mL) 
Route 
1 
7 
0 
M3 
2108 
.59 
IM 
2 
7 
0 
M4 
2108 
1.11 
IM 
3 
7 
0 
M3+M4 
1108, each vaccine 
.29 + .56 
(total 0.85) 
IM 
4 
3 
0 
Placebo/saline 
- 
1.0 
IM 
M3 = 
MVA.tHIVconsv3  
M4 = 
MVA.tHIVconsv4  
pfu = plaque forming 
units 
IM = intramuscular   
 
For the purpose of this study and safety management, a maximum of 2 study participants 
will be vaccinated each week.  
Study Treatment Administration 
Both M3 and M4 vaccines should be thawed to room temperature and administered within 
60 minutes of removal from the freezer. 
The combination dose of M3 and M4 (Arm 3) will be delivered as a single injection, with 
both products drawn up into a single syringe for administration in IDS.  
Administer all vaccines/placebo doses as a single injection at Day 0. 
Administer all vaccine/placebo doses as an IM injection in the deltoid muscle of the non-
dominant arm, unless a participant requests vaccination in their dominant arm.  
The study DOES NOT ALLOW any modifications to any vaccine doses.  

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6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and accountability 
The M3 and M4 vaccines will be manufactured and provided by IDT Biologika, Germany. 
Study products will be provided directly to the UNC Investigational Drug Services (IDS), 
and dispensed and administered according to site and study-specific SOPs.   
Both investigational products will be used as supplied by the manufacturer.   
The study site will supply the normal saline used for the placebo injections.   
The primary IDS pharmacist will be responsible to the Principal Investigator (PI) for 
maintaining study drug accountability, reconciliation, preparation, distribution, and record 
maintenance during the study, including documentation of the amount of both study 
treatments (M3 and M4) received in IDS and the amount administered to each participant.  
The cleanup and disposal of spilled, wasted, or unused medication and used syringes must 
be documented appropriately (i.e., witnessed) in accordance with applicable federal 
regulations, Good Clinical Practice (GCP) procedures, and the procedures for handling 
biohazardous substances. Any incidents related to M3 and M4 vaccines and 
employee/participant exposure or employee needle sticks must be reported immediately to 
the UNC Institutional Biosafety Committee (IBC) and NIH Office of Science Policy (OSP) 
as per the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid 
Molecules dated April 2016.  
An accountability form and dispensing log, documenting vial allocation number and date, 
will be kept during the study and will be available for monitoring and inspection/auditing 
as required. All unused vials will be stored in a designated local freezer at the end of each 
vaccination visit. Any used vials and expired pre-filled syringes should be disposed of in 
accordance with institutional or pharmacy policy. 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
MVA.tHIVconsv3 (M3) vaccine is a white cloudy solution, formulated in Tris-saline 
buffer (10 mM Tris HCl, 140 mM NaCl, pH 7.7) at a concentration of 3.4x108 pfu/ml. The 
extractable fill volume is 500 µl. The product is supplied in sterile rubber-stopped glass 
vials.  
MVA.tHIVconsv4 (M4) vaccine is a white cloudy solution, formulated in Tris-saline 
buffer (10 mM Tris HCl, 140 mM NaCl, pH 7.7) at a concentration of 1.8x108 pfu/ml. The 
extractable fill volume is 500 µl. The product is supplied in sterile rubber-stopped glass 
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M3 and M4 vaccines will be packaged and labeled at the manufacturing facilities.  
The vaccines will be labelled or have accompanying documentation indicating compliance 
with GMP and other regulatory requirements. The minimum information provided by the 
manufacturer includes:  
• Study product name and concentration 
• Manufacturer 
• Date of manufacture 
• Lot number 
• Volume 
• Expiration date (or re-test date) 
Investigational vaccine release will comply with procedures required by International 
Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use 
Good Clinical Practice (ICH)-GCP. The study PI provides written authorization for the 
shipment of the M3 and M4 vaccines to UNC after confirmation that all critical documents 
required for shipment authorization are completed. The investigational vaccines are 
shipped to UNC in cryoshippers with temperature monitoring capacity.  
6.2.3 
Product Storage and Stability 
M3 and M4 
The M3 and M4 vaccines are stored frozen at ≤ -65°C (nominal temperature) in a locked 
freezer at IDT Biologika according to good manufacturing practice (GMP). Upon QP 
certification to trial and associated labelling to trial, the vaccine will be transferred to the 
UNC IDS. 
Once received in the IDS at UNC, the study vaccines are transferred to temperature-
monitored storage at   ≤ -65°C in a locked freezer (IB, MVA.tHIVconsv3 version 2.0; IB, 
MVA.tHIVconsv4 version 2.0). The freezers must be temperature monitored and if 
temperature goes outside the normal range, appropriate action is required in accordance 
with previously agreed SOPs. The placebo (normal saline) will be stored at room 
temperature.   
A vaccine accountability log will be used to record the removal, including the time of 
removal, and use of each vaccine vial. Vaccine accountability, storage, shipment, and 
handling will be in accordance with the relevant IDS SOPs and forms.  
Preparation 
Dispensing and Handling 

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UNC IDS will prepare and dispense all study product according to UNC and/or study-
specific SOPs.  
M3 and M4 vaccines and placebo will be dispensed from the UNC IDS Pharmacy, where 
only the pharmacist(s) will be un-blinded.  
Following randomization in IDS, the designated vaccine product(s) will be thawed, 
without shaking, until completely liquid by holding the vial in a gloved hand.  
The vials will not be shaken.  
All syringes (vaccine and placebo) will be covered with opaque tape and a label in the 
UNC IDS Pharmacy to maintain blinding. 
Arm 1 - Using aseptic technique, withdraw the needed volume of M3 from the vial into a 
syringe.  Affix a needle suitable for IM injection for administration.  
Arm 2 - Using aseptic technique, withdraw the needed volume of M4 from the vial into a 
syringe.  Affix a needle suitable for IM injection for administration.  
Arm 3 - Using aseptic technique, withdraw the needed volume of M3 and M4 from each 
vial into a single syringe.  Affix a needle suitable for IM injection for administration.  
Arm 4 - Using aseptic technique, for placebo draw the appropriate amount of Sodium 
Chloride for Injection USP, 0.9% into a syringe. Affix a needle suitable for IM injection 
for administration. 
Following study product preparation, all vaccine/placebo study product should be kept at 
room temperature until administered. Vaccines must be administered within 60 minutes (1 
hour) of removal from the freezer. 
Any unused portion of entered vials and expired pre-filled syringes should be disposed of 
in accordance with institutional or pharmacy policy. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Randomization 
The 24 study participants will be randomly assigned to receive one vaccination with M3 
(n=7) or M4 (n= 7) or M3 + M4 (n=7) or placebo (n=3) through a blinded randomization 
schedule. When the participant’s eligibility is confirmed, the study specific identification 
numbers (SIDs) will be assigned sequentially as each participant enrolls at the study at the 
Enrollment Visit. Vaccine and placebo product will be indistinguishable. Site and 
laboratory personnel and participants will be blinded with respect to the allocation of 

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vaccine or placebo. A double-blind placebo-controlled design has been chosen to minimize 
bias in the reporting of safety and immunological data. 
Participants will be randomized and assigned an RID on Day 0 in the IDS pharmacy after 
receipt of vaccine/placebo prescription. The randomization plan will be generated centrally 
by the study statisticians at the UNC CFAR using computer software, and will be kept 
concealed from study personnel. 
Un-blinding 
Un-blinding of an individual participant is indicated in the event of a medical emergency 
where the clinical management would be altered by knowledge of the group assignment. 
The decision to un-blind will be taken in conjunction with the independent members of the 
Study Monitoring Committee (SMC). Procedures and contact details for un-blinding 
procedures will specified in a site-specific SOP. The site personnel will ensure that the 
reasons for un-blinding are documented in the clinical research chart. 
6.4 
Study Intervention Compliance 
Participants will keep a daily diary of solicited AEs for both local and systemic symptoms 
for 3 days after the vaccine/placebo administration. 
6.5 
Concomitant Medications 
Whenever a concomitant medication is initiated or the dose is changed for all participants 
after receipt of vaccine/placebo at Day 0 through Day 28 of the study, the PI (or designees) 
must review the concomitant medications’ most recent package inserts, investigator’s 
brochures, or updated information from DAIDS to obtain the most current information on 
drug interactions, contraindications, and precautions. 
Required Medications  
1. All participants will be required to have durable HIV suppression on ART for ≥ 24 
months prior to study screening and maintain ART therapy throughout the entire study. 
The study will not provide ART medications.  
The study team will consider alternate ART regimens on a case-by-case basis prior to 
enrollment per eligibility criteria. The study permits the use of all approved PIs, 
NNRTIs, NRTIs, and fusion and integrase inhibitors. Also permitted are changes to the 
participants’ ART during the study for dosing simplification, tolerability issues, and 
improved side effect profile or at the investigator’s discretion. If a participant develops 
toxicity related to his/her previously stable ART, consult the protocol team (preferably 
before appropriate therapy modification). 

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Prohibited Medications 
1. Ongoing use of investigational ART with the exception of Phase II studies of 
antiretroviral therapy.  
2. Concomitant use with oral or parental corticosteroids, immunosuppressive agents 
(including but not limited to chronic topical steroids or steroid containing inhalers, 
azathioprine, and cyclosporine) or any immunotherapy or immunomodulatory agents; 
3. Antihistamine from 7 days prior to vaccination through Day 14; 
4. Standard vaccines (e.g., pneumococcal, Hepatitis A, Hepatitis B) and live vaccinations 
(e.g., varicella, measles, mumps, rubella, MMR; yellow fever, oral polio) except 
influenza and COVID-19 are prohibited from 28 days prior to screening through Day 
28 (reference Sections 5.1 and 5.2);  
5. Any agent that suppresses lymphocytes or monocyte function; 
6. Chemotherapeutic agents, growth factors, cytokines, or chemokines, white lineage 
colony stimulating factors (e.g., granulocyte-colony stimulating factor [G-CSF] and 
GM-CSF);  
7. Chronic use of topical corticosteroids applied to large areas of the skin (exceeding the 
cumulative area of the palm of the participant’s hand); 
8. Sporadic topical use of corticosteroids (e.g. creams) to small areas of the skin (<15 
cm2) for participants who are receiving ritonavir or cobicistat as part of their current 
ART regimen; 
9. Any form of corticosteroid or antihistamine medications at or near the injection site, 
including for treatment of injection site reactions; 
10. Refer to exclusion criteria in Section 5.2. 
Rescue Medicine 
Not applicable. 
7 STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
Premature Treatment Discontinuation Evaluations 

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There is only one study treatment intervention visit at Day 0. The collection of safety labs, 
virologic, immunologic, SCA, and the 2nd leukapheresis will continue to be collected per 
SOE, section 1.3.  
Participants who complete the vaccine/placebo injection but do not complete the Day 7 
study visit will be replaced, provided the inability to complete the Day 7 visit is not due to 
a study-related AE. 
Participants who complete the vaccine/placebo injection but do not complete the Day 28 
study visit and 2nd leukapheresis procedure will be replaced, provided the inability to 
complete the Day 28 visit is not due to a study-related AE. 
Participants who receive vaccine/placebo but are unable to complete the Day 7 or 2nd 
leukapheresis should be encouraged to continue on study for safety assessments per the 
SOE. 
Discontinuation of Antiretroviral Therapy  
If the participant discontinues ART prior to DAY 0, DO NOT give the vaccine/placebo 
injection. DO NOT collect research labs for the time points after the participant 
discontinued ART. This participant will be replaced.  
If the participant discontinues ART after the vaccine or placebo administration (Day 0), the 
participant should continue on study for safety follow-up as noted in the SOE. Collection 
of virologic, immunologic, SCA, and the 2nd leukapheresis samples will be determined on 
a case-by-case basis in discussion with the protocol team. This participant may be 
replaced. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
1. Enrolled Participants, who are not Randomized and Do Not Start Study Treatment  
a. Participants who withdraw or who are withdrawn from the study after the 
Enrollment Visit but prior to receipt of vaccine/placebo: 
▪ DO NOT re-use the SID.  
▪ REPLACE the participant. 
b. A participant who is unable to complete the leukapheresis procedure or from whom 
< 40 ml is collected prior to Day 0 will be terminated from the study. 
▪ DO NOT re-use the SID.  
▪ REPLACE the participant. 
▪ Termination can occur due to complications at the leukapheresis procedure as 
determined by the Clinical PI (or designee) and the Apheresis Medical Director 
and can include contraindications for further leukapheresis procedures. 

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c. Participants who complete the first leukapheresis procedure pre-vaccine but do not 
want to do the second leukapheresis procedure will be withdrawn from the study.  
▪ DO NOT re-use the SID.  
▪ REPLACE the participant. 
2. Evaluations for Randomized Participants Who Do Not Start Study Treatment 
a. Participants who withdraw or are withdrawn after randomization but prior to 
starting study treatment (vaccine or placebo) will have no further evaluations or 
follow-up.  
▪ Notify IDS of the withdrawal and the randomization assignment.  
▪ RE-ASSIGN the Randomization Identification (RID).  
▪ DO NOT re-use the SID.  
▪ REPLACE the participant.  
3.  Evaluations for Randomized Participants Who Received Study Product and are 
Discontinued or Withdrawn from Study Participation.  
a. Participants who withdraw or are withdrawn after randomization and prior to Day 
28, will have no further research evaluations or follow-up (based on review by PIs) 
but will be encouraged to complete EOS safety evaluation visit.  
▪ Notify IDS of the withdrawal and the randomization assignment.  
▪ REASSIGN the RID.  
▪ DO NOT re-use the SID.  
 
4. A participant may withdraw or be withdrawn from the study if any of the following 
occurs: 
 
• Request by the participant to withdraw from the study and study procedures. 
• Development of an illness that requires treatment with medications prohibited in 
this study. 
• Change in the participant’s medical condition that might make continuation in the 
study harmful to participant. 
• Participant does not continue to meet eligibility requirements. 
• Participant does not complete Day 7 research assays.  
• Request of the participant’s primary care provider if she/he thinks the study is no 
longer in the best interest of the participant. 
• Participant judged by the study Principal Investigator (or designee) to be at 
significant risk of failing to comply with the provisions of the protocol, as to cause 
harm to self or seriously interfere with the validity of the study results. 
• At the discretion of the IRB/Ethics Committee, FDA, NIH, and other government 
agencies as part of their duties, Principal Investigator (designee), or vaccine 
supplier. 

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Premature Study Discontinuation (D/C) Evaluations  
Participants who prematurely discontinue study participation after completing the 
vaccine/placebo at Day 0 but before Day 70 will have premature study discontinuation 
(D/C visit) evaluations performed per the SOE for Day 70. Participants who discontinue 
the study prior to the 2nd leukapheresis without having met the primary safety outcome 
measure will be replaced, provided the discontinuation from study was not due to a study- 
related AE. 
7.3 
Lost to Follow-Up 
Participants classified as lost to follow-up (LTFU) need to meet both of the following 
criteria:  
o Failure to respond or reply to 3 documented phone contact attempts, followed by  
o Failure to respond to a certified letter sent to the address provided by the 
participant.  
Only after documentation of these failed attempts to connect with the participant, will they 
be determined as LTFU. In scenarios in which a participant is relocated after 3 failed 
attempts, the study PI will address continued participation on a case-by-case basis.  
8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Efficacy Assessments  
Remote Data Collection  
Study visits may be conducted remotely (e.g., telephone, facetime) in the following 
situations: 
o a participant is unable to attend a visit because of a debilitating illness; the site must 
inform the protocol team in advance 
o the site is temporarily unable to conduct non-essential visits in the clinic per 
University policies at the time of the visit; the site must inform the protocol team in 
advance 
o at the discretion of the protocol team if the risk of an on-site visit is felt to pose 
more risk than potential benefit to the participant; a message from the team will be 
sent to the study team 
Regardless of the situation, the study team should designate which visits were conducted 
remotely and attempt to obtain as much of the visit-specific required information, based on 
the Schedule of Events, and record it on the relevant study specific checklist. The reason 
for conducting the visit remotely must also be recorded and documented in the 
participant’s study file. 

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Visit Windows:  
o Perform visits scheduled ≤ 7 days apart per window listed in SOE. There is no 
window around Day 7 visit. There is a ± 2 days window around the Day 14 Visit.  
o All windows after Day 14 visit are +/- 7 days (6 in the case of overlapping visits). 
Please reference SOE. The protocol allows scheduling the Day 28 Leukapheresis 
outside the parameters of the visit window. Please reference SOE and sections 4.1 
and 8.2.3. 
Medical History:  
The medical history must include all signs and symptoms and all diagnoses regardless of 
grade within the past 30 days prior to entry. Assessment and documentation of the medical 
history evaluation occurs at the screening visit. Update to medical history will occur at all 
clinical visits. 
Document: 
o All allergies to any medications and their formulations 
o Date of birth, gender, race and ethnicity of participant   
o Nadir CD4 and pre-ART HIV-1 RNA level, if available (if nadir documentation is 
not available, collect and record participant recall) 
o Targeted Reproductive Assessment includes:  
▪ For women and men participating in activities that could lead to pregnancy, 
verify use of birth control for a minimum of 21 days prior to vaccination date 
(see Section 5.1) through the 4 months following vaccination. 
▪ Assess the date of the last menstrual period (LMP) for all women of 
childbearing potential (WOCBP) at all study visits as part of the complete PE or 
the targeted assessment. 
Medication History: 
Complete a medication history, include medication start and stop dates. Document the 
vaccine/placebo administration as in Table 8.   
Table 8 
Medication Complete History or Timeframe 
Medication Category  
Complete History or Timeframe 
Antiretroviral Therapy  
Complete History  
Immune-based Therapy  
Current & within 105 days prior to enrollment  

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HCV antiviral therapy  
Complete history  
Prescription Drugs  
Within 30 days prior to enrollment 
Systemic Corticosteroids  
Within 30 days prior to enrollment 
HIV-1 related vaccines 
Complete History 
Experimental non-HIV vaccine 
Within the 12 months prior to enrollment 
Live attenuated vaccines  
Within 4 weeks prior to enrollment  
IgG therapy or immunization w/experimental Abs 
Within 6 months prior to enrollment 
Non-prescription drugs (OTC)  
Within 30 days of enrollment 
Clinical Assessments 
Complete Physical Exam (PE): A complete PE will be performed at screening and Day 28. 
This complete PE is to include at a minimum an examination of the skin, head, mouth, and 
neck; auscultation of the chest; cardiac exam; abdominal exam; and examination of the 
lower extremity for edema. The complete PE will also include signs and symptoms, 
diagnosis, weight (kg), temperature (T°C, oral), respiratory rate (RR), pulse (P), and blood 
pressure (BP). 
Targeted Physical Assessment: A targeted physical assessment is done at all other visits 
and includes vital signs. The targeted or directed physical assessment addresses any 
previously identified or new event that the participant experiences since the last study visit 
or any unresolved signs or symptoms previously experienced. In addition to the vital signs, 
this assessment includes updates to signs and symptoms, and clinical assessment of HIV 
disease. 
Vital Signs (VS): Perform VS at all clinical visits. VS include P, BP, RR, T, and weight. 
Height: Measurement of height (cm) that is required at the screening and baseline visits 
should be performed with shoes off. 
BMI Assessment: Performed at screening for eligibility and again at Day -7 for dosing 
purposes.  
EKG: Perform an EKG at screening for baseline assessment. The study PI (or designee) 
reviews the results documented in the participant’s chart. 
ART Adherence Assessment: This protocol requires participants take all required doses of 
ART. Document all missed doses, even if the reason/s for missing the doses are outside the 
participant’s control. Report missed doses to study PI (or designee). Study participation 
can be terminated if HIV medication is missed.  

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For the purpose of this study, non-adherence is defined as missing doses for more than two 
(2) consecutive days or more than four (4) cumulative days in the prior 12 weeks (3 
months) prior to screening visit. Assess and document any missed doses while on study 
and discuss missed ART doses with study PI (or designee). Continuation on study will be 
contingent on adherence. 
Antiretroviral Medication Assessments: During the study, all modifications to the 
participant’s ART regimen, including any ARV interruptions, dose modifications, 
formulations modifications, starts, and permanent discontinuations since the last study visit 
or at the study visit must be recorded. 
Signs and Symptoms Assessments: At entry, all signs and symptoms, regardless of grade, 
that occurred within the 30 days before entry must be recorded.  
Active solicitation of AEs will be done at every study visit. Post-entry signs and 
symptoms, Grade ≥ 2, will be recorded. All signs or symptom, definitely, possibly, or 
probably related to study interventions will be recorded, regardless of grade. Additionally, 
all signs and symptoms that lead to a change in study treatment or change in ART or 
discontinuance of the leukapheresis procedure, regardless of grade, must be recorded.  
Diagnoses: After entry, record all diagnoses identified. 
Concomitant Medication Assessments: At screening and entry, record all medications 
taken per medical history guidelines. Thereafter, record all new or discontinued 
concomitant medications, including prescription, dietary supplements, and over-the-
counter medications taken or stopped since the last visit. 
Laboratory Studies 
CD4+/CD8+: All study required absolute CD4+/CD8+ count and percentages must be 
obtained from a laboratory that possesses a CLIA certification or equivalent. Eligibility 
will be determined based on a CD4+ ≥ 350 at screening. 
Plasma HIV-1 RNA: All study required HIV-1 RNA assays must be performed by a 
laboratory that possesses a CLIA certification or equivalent. Eligibility will be determined 
based on an HIV-1 RNA value <50 at screening. 
Research Assays 
Blood will be collected for the following research laboratory evaluations: 
FNA and Matching Blood Sample  

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Analyzed for T-cell specificity, phenotype and function, and virologic measurements per 
the SOE. Performance of assays is dependent on cell yield and viability. Specific testing 
may include the following: 
o Quantification of T cell memory frequencies and activation pre- and post-treatment 
o Cell-associated viral RNA in CD4+ T cells pre- and post-treatment 
Measurements of HIV specific T cell responses pre- and post-treatment Human Leukocyte 
Antigen (HLA) Typing  
HLA testing will be performed at one time point in the study; however, if HLA type is 
already available in the medical record, it does not need to be repeated. The result will be 
used for research purposes. 
Stored Plasma/PBMC for Immunology Studies: Plasma and cryopreserved PBMC will be 
stored for analysis of low level viremia, T-cell specificity, phenotype and function, and 
virologic measurements per the SOE. Specific testing will include the following: 
o Low-level HIV-1 RNA assays pre- and post-treatment 
o Measurement of T cell responses pre- and post-treatment 
o Measurement of T cell virus inhibition pre- and post-treatment 
o Phenotyping of both total and specific CD4+ and CD8+ T cell activation, homing 
and memory differentiation using flow cytometry pre- and post- treatment 
o Functional analysis (e.g., anti-viral cytokine and lytic molecule release) of both 
total and specific T cells pre- and post-treatment using flow cytometry  
o Cell-associated viral RNA in CD4+ T cells pre- and post-treatment 
Site laboratory standardized protocols will guide the performance of all research assays.  
NOTE: See Section 7.2.6 regarding collection of stored Plasma/PBMC for Immunology 
Studies for participants who discontinue ART or do not complete study treatment. 
8.2 
Safety and Other Assessments 
8.2.1 
Screening  
Screening takes place in a stepwise manner and includes the completion of the following 
prior to enrollment:  
 

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o Informed consent (completed prior to screening assessments) 
o Determination of HIV infection status 
o Documentation of stable continuous ART  
o Documentation of HIV RNA values that are <50 copies/mL for eligibility  
o Participant locator information  
o Assessment of baseline laboratory testing for continued safety monitoring 
8.2.2 
Participant Enrollment  
Enrollment occurs within the 60 days following screening. Participants not meeting 
eligibility requirements will not continue on study. The completion of the following occurs 
prior to enrollment: 
o Inclusion/exclusion criteria met 
Once eligibility is confirmed, participant study identification numbers (SIDs) will be 
assigned sequentially as each participant enters the study.  
8.2.3 
Leukapheresis 
Participants undergo 2 leukapheresis procedures.  The first study-required leukapheresis 
procedure occurs at or after Enrollment/Baseline (Visit 2) but prior to Day 0. This 
leukapheresis provides the cells needed to perform baseline research assays and 
measurements required to establish pre-treatment immune responses. 
NOTE: Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS) do not need to be held 
prior to the procedure.  
The Baseline Leukapheresis  
This procedure can occur at any time point within the 60 days following the Screening 
visit. It can occur at or after the Enrollment/Baseline (Visit 2). 0.  
 
o If Leukapheresis procedure is scheduled on a date other than the 
Enrollment/Baseline visit, 
• The procedure should be scheduled after the Enrollment/Baseline visit. 
• Safety labs will be performed with the leukapheresis and not at the 
Enrollment/Baseline visit. 
• Complete VS and BMI assessment 

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• The assessments listed under the Enrollment/Baseline Visit will be done at 
Visit 2. Leukapheresis procedures done at UNC will have a CBC with 
differential done prior to the procedure (unless result available within the 
past 24 hours) as this is required for the Apheresis Lab.  
  
If the leukapheresis procedure is done on the Enrollment/Baseline visit, collect the 
leukapheresis product in addition to the research labs. (Reference the Study Specific Lab 
Manual.) 
The Day 28 Leukapheresis 
o If Leukapheresis cannot be done within the Day 28 Visit window due to scheduling 
conflicts or unforeseen issues, please contact study PI for option to see person 
outside the visit window, either 1 week earlier or up to 2 weeks after the Day 28 
Visit window. 
8.2.4 
Randomization  
Participants are randomized to the study Arms, assigned a RID, and receive 
vaccine/placebo at Day 0. Study Arm assignment is double-blinded and all randomized 
participants will receive either vaccine or placebo. The administration of the vaccination or 
placebo designates Day 0 and the calculation of the remaining visits are identified by 
consecutive days starting with Day 0.   
Vaccine and placebo product will be indistinguishable. Site and laboratory personnel and 
study participants will be blinded with respect to the allocation of vaccine or placebo. The 
randomization plan will be generated centrally by the study statisticians at the UNC CFAR 
using computer software, and will be kept concealed from the study personnel. 
8.2.5 
Participants randomized to receive study product and do not 
receive the vaccine/placebo or are withdrawn from the study after receipt of 
the vaccine (reference protocol sections 7.2 and 7.3) will be replaced and the 
RID re-assigned at the time of next eligible participant randomization. Study 
Un-blinding  
Study un-blinding will occur following an independent SMC review commencing 
approximately 28 days after the last participant receives their vaccine/placebo injection and 
completes the 2nd leukapheresis.  
8.2.6 
Unscheduled Visits 
Visit windows are defined in the protocol and SOE. For a visit not performed within the 
window period, the interim visit will be completed and documented as a protocol 
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study staff should attempt to bring the participant in for an interim visit as soon as possible. 
Safety evaluations should be completed per SOE for the missed visit.  
Should a participant require an unscheduled visit between visits, procedures performed at 
these visits are usually toxicity/safety assessments (including local safety labs). The 
procedures completed at the unscheduled visit should be performed only if clinically 
indicated. 
8.2.7 
Vaccine or Placebo Administration Visit:  
Vaccine (M3 or M4 or M3+M4) or placebo injections are given at Day 0.  
1. Complete required pre-vaccine/placebo assessments and blood draws (per SOE) prior 
to the administration of the vaccine/placebo. 
2. Record the RID and the vaccine/placebo injection, including dose, and time of 
administration. Record where the injection was given (location). If unable to 
administer the entire dose for any reason, notify the study PI (or designee) and 
document the reason. 
3. Complete the following: 
o During administration of the vaccines, medicines and resuscitation equipment will 
be immediately available for the management of anaphylaxis. 
o Two licensed staff will verify and confirm the vaccine/placebo for administration. 
o Two licensed staff will confirm the research chart PID /SID to the PID/SID on the 
blinded study treatment label.  
o Document the verification process. 
o Have participant seated in a secure chair prior to injection to avoid the risk of fall 
due to possible dizziness/lightheadedness, or in rare cases, syncope. 
o Administer vaccine/placebo as a single IM injection in the deltoid muscle, 
preferably in the non-dominant arm, unless a participant requests vaccination in 
their dominant arm.  
o The study DOES NOT ALLOW any modifications to any vaccine doses.  
o Study staff will wear gloves and eye protection when handling the vaccine/placebo 
product.  

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8.2.8 
Post Vaccination/Injection Management:  
1. Observe participant and injection site for 60 minutes following each vaccine/placebo 
injection for clinical AEs. 
o Assess for injection site reaction every 15 minutes  4, document observed 
reactions 
o Observe and assist participant when coming to a standing position for the first time 
following each administration of vaccine/placebo  
o Obtain vital signs (BP, P, RR, and T) prior to discharge home 
2. Instruct participant to contact the study coordinator immediately with any concerns 
about the injection site after leaving the clinic. 
3. Provide post vaccination symptom log and instructions for completion prior to leaving 
the clinic. 
o Review symptom log at the Day 2 and Day 7 visits following the vaccination 
o Symptom logs are collected at the Day 7 visit 
4. Contact participant the day after the injection in the manner pre-determined by the 
study coordinator and participant. 
o Assess for signs and symptoms resulting from vaccine or placebo administration 
5. Following receipt of vaccine/placebo, participants will be followed with study visits 
through Day 70 and the Days 84 and 168 visits will be completed via phone contact.  
6. Participants will be contacted by phone at Days 84 and 168 to assess for and document 
new adverse events.  
7. If the participant reports any AEs possibly related to treatment at either the Day 84 or 
Day 168 assessments, an additional unscheduled visit may be needed to further 
evaluate the participant and attribution to treatment. 
8.2.9 
Post Vaccination Symptom Log 
Participants will be given a “Post vaccination symptom log” to use as a memory aid for 
tracking adverse events that occur during the 3 days following the injection. Participants 
will record daily temperature and systemic symptoms.  

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1. For this study, solicited AEs occurring during the 3 days after the vaccine/placebo 
injection will include:  
o unusually tired/feeling unwell  
o muscles aches  
o headache 
o chills 
o nausea  
o joint pain 
2. Instruct participants to take their temperature at least once daily, starting with the day 
of injection (Day 0), after leaving the clinic and through Day 3 post-injection. 
3. Temperature should be taken orally in the evening whenever possible. If more than one 
measurement is made in a day (for example due to feeling unwell), then the highest 
temperature taken that day should be recorded.  
4. The symptoms and assignment of grades will be reviewed with participants to assure 
an understanding of how to use and evaluate each symptom during these first 3 days.  
The study coordinator will discuss the symptom logs for accuracy and completeness at Day 
2 and review and collect the completed symptom log at the Day 7 Visit. The study 
coordinator will review symptoms with participants for each identified symptom and 
clarify the grading assigned at the time. Additionally, active solicitation of AEs will be 
done at every visit. Participants will also be asked to contact the study coordinator, study 
PI, or designee should they experience any adverse events at any time points during the 
study.   
8.2.10 
Solicited AE Assessments:  
The study coordinator will assess for Solicited AEs (expected) symptoms at Day 2 and 
Day 7 following each injection. 
Assessments will consist of a standard series of questions administered at approximately 
48 hours post vaccination (Day 2) and at the Day 7 Visit. The following local reaction 
evaluations (Table 9) and systemic reaction evaluations (Table 10) are part of each 
assessment. 
Table 9 
Local Reaction Solicited AE Assessments 
Injection site erythema (redness) 
Injection site pruritus (itching) 
Injection site tenderness  
Injection site swelling 

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Warmth at injection site 
Skin discoloration 
Injection site pain 
Skin damage (vesiculation or ulceration) 
Induration (hardening or formation of a crust or scab) 
Table 10 
Systemic Reaction Solicited AE Assessments 
Vomiting 
Fatigue (extreme tiredness)  
Malaise  
Headache 
Flu like symptoms  
Temperature (fever >37.7°C or 99.9°F) 
Sweating 
Chills  
Diarrhea 
Nausea 
Dizziness 
Myalgia (muscle pain) 
Anorexia 
Abdominal pain 
Syncope 
 
Study staff will follow new or unresolved vaccine-related AEs to resolution. In general, 
participants self-reporting any post-injection reaction greater than mild are to be evaluated 
by the study PI (or designee) within 72 hours after onset, unless the reaction is improving 
and/or has completely resolved. 
Institute appropriate countermeasures, including medical intervention or procedures, if 
clinically indicated. 
8.2.11 
Laboratory Evaluations 
Details of specimen collection are found in the Lab Procedures Manual for this study.   
Labs utilized for processing and resulting the clinical evaluations are the UNC McLendon 
Lab and LabCorp. The study PI (or designee) assesses the results of all clinical laboratory 
tests to determine continuing eligibility or AE relatedness at specified visits. Lab results or 
values outside the normal reference range require the investigator (or designee) to 
determine if the abnormal value is clinically significant and/or related to a study 
intervention.  All confirmed abnormal laboratory values that the investigator deems 
clinically significant and/or related to a study intervention must be reported as AEs, 
regardless of grade. Post-entry laboratory values, Grade ≥2, will be recorded. Participants 
and/or their primary care provider will be informed of any clinically significant laboratory 
test result or clinical event that occurs throughout the study. Participants will be referred 
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Hematology: Perform hemoglobin, hematocrit, white blood cell count (WBC), differential 
WBC, absolute neutrophil count (ANC), and platelet count in real time at the local 
laboratory. 
Note: CBC with differential for Leukapheresis procedures:  
o A STAT CBC with differential is required prior to each leukapheresis performed at 
the UNC Apheresis Lab unless results completed within 24 hours of the procedure 
are available to the Apheresis Lab performing the procedure.  
o Leukapheresis procedures performed at a local apheresis collection center require a 
CBC within 30 days of procedure.  
Liver Function Tests: Perform total bilirubin, AST (SGOT), ALT (SGPT), and alkaline 
phosphatase in real time at the local laboratory. 
NOTE: For participants on ritonavir boosted atazanavir, total and direct bilirubin should 
be measured. 
Blood Chemistries  
Screening lab evaluation includes electrolytes (sodium, chloride, potassium, 
CO2/bicarbonate), glucose, blood urea nitrogen (BUN), creatinine, calcium, phosphate, 
albumin, magnesium, LDH, and total protein in real time at the local laboratory.  
Safety lab evaluations throughout the study include electrolytes (sodium, potassium, 
chloride, CO2/bicarbonate), BUN, creatinine, calcium, magnesium, and glucose (also 
reference Pre-Vaccine Safety Lab Assessment).  
Creatinine and Creatinine Clearance  
Creatinine clearance (eGFR) calculations will use the CKD-EPI equation. This calculation 
can be found at https://www.qxmd.com/calculate/calculator_251/egfr-using-ckd-epi  
The creatinine clearance (eGFR) will be required for study enrollment eligibility. The 
study assesses serum creatinine level at all the safety lab checks and uses the serum 
creatinine value for toxicity grading and as confirmation to receive vaccine or placebo 
doses. 
The creatinine clearance (eGFR) value reported as part of the lab report of serum creatinine 
level will be re-assessed and re-calculated if incidental finding indicates a value ≥ Grade 3. 
The re-calculated value using the CKD-EPI equation will be used to determine the severity 
of the lab abnormality.  

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Pre-Vaccine Safety Lab Assessments 
Participants will have a Pre-Dose Safety Lab Assessment completed at either Visit 2 or the 
leukapheresis and within the 10 days prior to the vaccine/placebo dosing visit. These safety 
lab results must be within the eligibility criteria parameters established for this study. Labs 
that fall outside the parameters can be repeated one time only to qualify the participant to 
proceed on study.  
After repeat testing, any lab value that remains outside the guidelines but considered 
clinically non-significant and documented as such by the study clinical PI (or designee), 
must be reviewed and approved by the protocol and/or safety committee prior to the 
vaccination. 
Serum and Point of Care (POCT) Urine Pregnancy Test:  A negative serum pregnancy 
test (to rule out pregnancy) is required on all women at screening, and a negative urine 
pregnancy test on Day 0, regardless of documented procedures that prohibit pregnancy.  
The use of the POCT urine pregnancy test as confirmation of negative pregnancy status is 
acceptable for vaccination visit at Day 0, unless pregnancy is suspected. If pregnancy is 
suspected, a serum pregnancy test must be done to rule out pregnancy. The test must be 
negative within 48 hours of the dose.  
In addition, a POCT pregnancy test should be performed at any visit post vaccination, if 
pregnancy is suspected. Because the study has no direct clinical benefit, this added 
protection is warranted. 
The study will use the date of LMP to rule out suspected pregnancy.  Pregnancy will be 
suspected if >35 days since first day of last menstrual period in pre-menopausal women 
has elapsed. Hepatitis Screen: Both hepatitis tests (HCV AB and HBsAg) must be 
negative or non-detected to be included on the study. A positive HCV AB test reflexed to 
Hepatitis C RNA revealing a negative result is acceptable. 
Eligibility will be determined based on negative testing, per above definition at screening.  
RPR: Complete at screening to rule out clinically active untreated syphilis. 
Participant may participate on study following documentation of adequate treatment of 
syphilis at screening (Visit 1). Participants diagnosed with syphilis at screening, will be 
referred for and require documentation of treatment. The participant may rescreen 
following a minimum of 14 days post syphilis treatment.  
HIV Ag/Ab Test: Complete HIV testing at screening if documentation of HIV infection is 
not available from prior records.  

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Fasting Lipid Panel:  Obtain total cholesterol, HDL, LDL calculation, VLDL 
calculations, and triglycerides at screening. 
Prothrombin time (PT), INR, and APTT: Evaluate at the Screening Visit.  
Urinalysis: Do dipstick testing (including protein, glucose, hemoglobin, pH, and ketone) 
at select visits. Do microscopic analysis only in the event of abnormal results from dipstick 
testing. 
Estimated Blood Volumes Associated with Study Visits: Estimated blood volumes 
associated with each study visit is provided in Table 11. 
Table 11 
Blood Volumes Associated with Study Visits 
Day # 
Approximate Blood 
Volume (mL)  
Day #  
Approximate Blood 
Volume (mL) 
Screen  
100 
Day 7 
115 
Enrollment/Baseline  75 
FNA (optional) 
3 
Leukapheresis  
20 
Day 14 
110 
 
 
Day 28 
75 
 
 
Day 56 
100 
FNA (optional)  
3 
Day 70 
130 
Day 0  
85 
Day 84 
0 
Day 2 
0 
Day 168  
0 
8.3 
Adverse Events and Serious Adverse Events 
8.3.1 
Definition of Adverse Events (AE) 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 
(a)). 
An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product. 
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities. 

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Definition of Serious Adverse Events (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view 
of either the investigator or sponsor, it results in any of the following outcomes:  
o death,  
o a life-threatening adverse event,  
o inpatient hospitalization or prolongation of existing hospitalization,  
o a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or  
o a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant 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. 
8.3.2 
Classification of an Adverse Event 
8.3.2.1 
Severity of Event 
Event severity will be assigned according to the Investigator’s (or designee’s) assessment.  
Severity Grade for Parameters Not Identified in the Grading Table:  
The functional table ( 
Table 12) should be used to grade the severity of an AE that is not specifically identified in 
the grading table. In addition, all deaths related to an AE are to be classified as Grade 5. 
Table 12 
Severity Grade for Parameters 
PARAMETER  GRADE 1 MILD  
GRADE 2 
MODERATE  
GRADE 3 
SEVERE  
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING  

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Clinical 
adverse event 
NOT identified 
elsewhere in 
the grading 
table  
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated  
Moderate 
symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention 
indicated  
Severe symptoms 
causing inability 
to perform usual 
social & 
functional 
activities with 
intervention or 
hospitalization 
indicated  
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-
care functions with 
intervention indicated 
to prevent permanent 
impairment, persistent 
disability, or death  
8.3.2.2 
Relationship to Study INTERVENTION 
Attribution/Assessment of Causality is a determination that describes the relationship or 
association of the study product with an adverse event.  
This assessment of causality or relationship of AEs to the study product is provided by the 
Investigator and is determined by 1) temporal relationship of the event to the 
administration of study product, 2) whether an alternative etiology has been identified, and 
3) biological plausibility. Causality must be assessed separately for each study product.  
The causality assessment categories that will be used for this study are described below.  
1. Causality assessments that are considered not related to study product: 
a. Not related: 
 
The event is related to an etiology other than the study product (the alternative 
etiology must be documented in the participant’s medical record). 
If an SAE is considered "unrelated" to study product, the Investigator should offer 
his/her clinical opinion as to what factor(s), agent(s), or process(s) were the likely 
causative mechanism for the event.  
2. Causality assessments that are considered related to study product: 
a. Possible: 
 
There is an association between the event and the administration of the study 
product and there is a plausible mechanism for the event to be related to study 
product; but there may also be alternative etiology, such as characteristics of the 
participant’s clinical status or underlying disease. 
b. Probable: 
 

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There is an association between the event and the administration of study product, a 
plausible mechanism for the event to be related to the study product, and the event 
could not be reasonably explained by known characteristics of the participant’s 
clinical status or an alternative etiology is not apparent. 
c. Definite: 
There is an association between the event and the administration of study product; a 
plausible mechanism for the event to be related to the study product, causes other 
than the study product have been ruled out, and/or the event re-appeared on re-
exposure to the study product. 
8.3.2.3 
Expectedness  
The study PI (or designee) will be responsible for determining whether an adverse event 
(AE) is expected or unexpected.  An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously 
described for the study intervention or is not listed in the most current IBs for the study 
intervention. 
8.3.3 
Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant 
presenting for medical care, or upon review of medical record. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured in the research record on the appropriate form. Information collected includes:  
• Event description,  
• Time of onset,  
• Study PI’s (or designee’s) assessment of severity, relationship to study product and 
expectedness,  
• Time of resolution/stabilization of the event.  
All AEs occurring while on study must be documented appropriately regardless of 
relationship. All study- related AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be 
considered baseline and not reported as an AE. However, if the study participant’s 
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Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
The study research coordinator will record all reportable events with start dates occurring 
any time on or after the enrollment visit until 7 days (for non-serious AEs) or 30 days (for 
SAEs) after the last day of study participation.  At each study visit, the research 
coordinator will inquire about the occurrence of AE/SAEs since the last visit.  Vaccine-
related and/or reportable events will be followed for outcome information until resolution 
or stabilization. 
Clinical Laboratory Changes:  
Safety laboratory assessments will be carried out locally at UNC and evaluated by the 
Investigator (or designee) to ensure participant safety. The Investigator (or designee) is 
responsible for reviewing the results of all laboratory tests as they become available.  
• Laboratory values that fall outside of a clinically accepted reference range or differ 
significantly from previous values must be evaluated for clinical significance by the 
Investigator (or designee). The Investigator (or designee) may repeat the laboratory test 
or request additional tests to verify the results of the original laboratory tests.  
• If the Investigator (or designee) determines the laboratory value is an abnormal change 
from baseline and is of clinical significance for that participant, it is considered an AE.  
• Generally, Grade 1 and Grade 2 laboratory findings need not be reported as AEs unless 
deemed clinically significant by the Investigator (or designee).  
• Consistent with the DAIDS designation of Grade 3 events as severe or medically 
significant and Grade 4 events as life-threatening, Grade 3 and Grade 4 laboratory 
findings should be reported as AEs or SAEs, as appropriate.  
• The test result or finding should be reported as the AE. Such laboratory values should 
generally be recorded as “increased” or “decreased” (e.g., change from baseline 
potassium of 5.0 to 3.5 mEq/L = potassium decreased). 
The study PI (or designee) is responsible for appropriate reporting of AEs to the regulatory 
authorities. The study PI (or designee) will also report all suspected unexpected serious 
adverse reactions. The study PI (or designee) must report suspected unexpected serious 
adverse reactions to the FDA if applicable and to the UNC IRB, per the UNC IRB 
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8.3.4 
Adverse Event Reporting  
Adverse events will be graded according to the DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, 
July 2017, on the DAIDS RSC website at http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/daids-grading-tables. 
The study will monitor participants for adverse events. Toxicities will be characterized in 
terms including duration, intensity, and time to onset. Safety endpoints will include all 
adverse experiences, in addition to laboratory safety assessments, and vital signs. All AEs 
will be recorded on the appropriate study form.  
AEs will be recorded in the database if any of the following criteria have been met:   
o Study-related Grade ≥ 1 AEs 
o Grade ≥ 3 AEs  
o Autoimmune-related AEs regardless of grade 
o HIV viral loads ≥ 50 copies/mL 
o Injection reactions regardless of grade  
o AEs that led to a change in study intervention regardless of grade 
o AEs meeting SAE definition or EAE (Expedited Adverse Event) reporting 
requirement 
Grade 1 or 2 Toxicity  
Participants who develop a Grade 1 or 2 AE or lab toxicity that occurs following a 
vaccine/placebo injection that is thought to be possibly, probably, or definitely related to 
the study treatment should be discussed with the study team. Grade 1 or 2 AEs that may be 
related to the vaccine/placebo injection will be handled according to standard clinical 
practice and documented.  
Grade 3 Toxicity 
For participants who develop a Grade 3 AE following the administration of 
vaccine/placebo judged by the study PI (or designee) to be at least possibly study 
treatment-related, the protocol team must be notified within 24 hours. Participants 
experiencing Grade 3 AEs should be followed closely and if the AE does not return to 

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Grade ≤ 2 within 2 weeks, the study team should again be notified within 24 hours and the 
SMC will be notified.  
For participants who experience a Grade 3 AE judged not related to the study treatment by 
the investigator, continued study participation is at the discretion of the study PI (or 
designee) in consultation with the protocol team and SMC.  
Grade 4 Toxicity   
For participants who develop a Grade 4 AE following administration of vaccine/placebo 
judged by the study PI (or designee) to be at least possibly study treatment-related, the 
protocol team and SMC must be notified within 24 hours. Participants experiencing Grade 
4 AEs should be followed closely with additional clinical assessments and laboratory 
testing as clinically indicated. If the AE does not return to Grade ≤ 2 within 2 weeks, the 
protocol team and SMC should again be notified within 24 hours. 
All study treatments will be discontinued in the event of Grade 4 AEs possibly related to 
study treatment. 
Local or Systemic Reactions to Vaccine/Placebo Injections 
Grade 1 or 2  
Local reactions of mild (Grade 1) or moderate (Grade 2) severity will usually resolve 
spontaneously. If needed, they may be managed with local application of cold packs, oral 
acetaminophen, oral non-steroidal anti-inflammatory agents, or a combination of these 
measures as appropriate. 
NOTE: Topical steroids should not be applied to the injection site. 
Grade 3 or 4  
For severe (Grade 3) or potentially life-threatening (Grade 4) local reactions, the protocol 
team must be notified within 24 hours. For Grade 4 local reactions, definitive medical 
and/or surgical intervention should be undertaken as appropriate.  
Systemic Reactions  
The protocol team must be contacted within 24 hours for any non-local Grade 3 or 4 
systemic reactions thought definitely, possibly, or probably related to the vaccine/placebo 
injections. 
The common systemic adverse events usually seen with MVA vectored vaccines, M3 and 
M4, include headache, feverishness, myalgia, arthralgia, fatigue, malaise, nausea, transient 

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flu like illness within 24 hours of vaccination, which usually resolves within 48 hours. It is 
anticipated that the majority of systemic adverse events post vaccination will be mild in 
intensity. However, there is a possibility of moderate or severe headache or malaise. 
If an adverse event of special interest (AESI) occurs (see section 8.3.8), the study 
coordinator, in collaboration with the study PI (or designee), will evaluate the severity and 
seriousness of the AE and the relationship to the study treatment, and will document the 
findings. The protocol team should be contacted within 24 hours of notification of any 
reactions thought definitely, possibly, or probably related to the vaccine/placebo injections. 
Injection Site Reaction 
Injection Site Erythema or Redness and Injection Site Induration or Swelling will not be 
considered an AE if there is no interference with usual social and functional activities such 
that:  
o Grade 1 is: 2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area;  
o Grade 2 is: ≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface area;  
o Grade 3 is: ≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR Ulceration OR 
Secondary infection OR Sterile abscess OR Drainage;  
o Grade 4 is: Potentially life-threatening consequences (e.g., abscess, exfoliative 
dermatitis, necrosis involving dermis or deeper tissue) 
Allergic or Hypersensitivity Reactions 
Record all allergic and hypersensitivity reactions with both grade severity and attribution.  
Serious allergic or hypersensitivity reactions (≥ Grade 3) that are deemed possibly related 
to the study treatment by the study PI (or designee) will be reported to the protocol team 
and SMC within 24 hours of notification and to the NIH/DAIDS, UNC IRB, FDA, and 
study product sponsors within 48 hours per their reporting requirements. 
Dose Limiting Toxicity (DLT)  
o Hematologic dose-limiting toxicity will be defined as any confirmed toxicity ≥ 
Grade 2, that cannot clearly be attributed to another reversible cause.  
o Follow participants per protocol schedule of events until the lab abnormality or 
toxicity resolves to ≤ Grade 1 or the participant’s baseline.  

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o Non-hematologic dose-limiting toxicity will be defined as any confirmed 
symptomatic ≥ Grade 3, if related (definitely, probably, or possibly) to 
vaccine/placebo. 
Monitoring HIV RNA levels 
In the event of viremia of ≥ 50 copies/mL the following should occur per standard of care: 
o Adherence to ART should be carefully assessed and documented.  
o A standard HIV RNA assay should be repeated within 1-4 weeks. 
o HIV resistance testing will be performed at the time of drawing a confirmatory 
sample and as indicated for persistent viremia. 
o For HIV RNA confirmed >200 copies/mL on repeat testing, stored samples may be 
tested for the presence of one or more ARV drugs in the participant’s regimen. 
o HIV RNA will be repeated every 2 weeks, or sooner as clinically indicated, until 
<50 copies/mL and the participant can continue on study. 
o In the event of confirmed viremia and documented adherence to ART, ART should 
be managed by the primary care provider in discussion with the study team. The 
results of the HIV resistance tests will be shared with the participants and their care 
providers. 
The Protocol Core Team will monitor the conduct and safety of the study via monthly 
meetings and regular summaries. Accrual, baseline characteristics, conduct of the study 
(including premature study discontinuations), any interruptions of ART, virologic failures, 
and all reported toxicities and events will be monitored during the study and discussed 
with the protocol team on a monthly basis or more frequently, if needed.  
The study protocol team will review the individual safety data monthly to assess relation of 
all reported toxicities and AEs to the study treatment. A study unique independent Safety 
Monitoring Committee (SMC) will receive monthly study progress and safety monitoring 
reports. Study feasibility and the achievement of study milestones will be assessed in these 
reports. 
The DAIDS program and medical officers will review and assess the monthly safety 
reports, as well as EAE reports for potential impact on the study participant safety and 
protocol conduct as per DAIDS policies, guidance documents, and SOPs, as applicable. 

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8.3.5 
Serious Adverse Event Reporting  
All SAEs at least probably related to M3 or M4 will be considered unexpected and be 
reported as SUSARs within the regulatory timelines.  
All SAEs occurring during the study must be reported to the UNC IRB per the UNC IRB 
reporting requirements. A written report (Serious Adverse Event Report Form) will be 
submitted to DAIDS and DAIDS MO within 24 hours of site becoming aware of the SAE. 
Additional information will be supplied as requested. All SAEs occurring during the study 
will be reported to DAIDS following guidelines for expedited AE reporting and to the 
FDA according to their regulatory guidelines. 
After 30 days following the last dose of vaccine/placebo, only SAEs the study PI (or 
designee) considers related to study product or a protocol procedure, should be reported. 
Information regarding SAEs will be submitted to the DAIDS on required SAE reporting 
forms, which must be completed and signed by the study PI or designee, and sent within 
24 hours of the site becoming aware of the SAE.  
All Grade 3 or Grade 4 AE/SAEs considered related to study product must be followed 
until recovery to baseline or Grade 1 with the date of resolution recorded in the source 
documents. In addition, the investigator should report all follow-up for reportable Grade 3 
or Grade 4 AE/SAEs to the UNC IRB. Resolution of an event is defined as the return to 
pre-treatment status or stabilization of the condition with the expectation that it will remain 
chronic. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the participant's participation in the study, must be followed until any of 
the following occurs: 
o The event resolves 
o The event stabilizes 
o The event returns to baseline, if a baseline value/status is available 
o The event can be attributed to etiology other than the vaccine/placebo or to factors 
unrelated to study conduct 
o It becomes unlikely that any additional information can be obtained (participant’s 
or health care practitioner’s refusal to provide additional information, or lost to 
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Any event requiring hospitalization (or prolongation of hospitalization) that occurs during 
the course of a participant's participation in a study must be reported as an SAE, except 
hospitalizations for the following: 
o Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term facility) 
o Surgery or procedure planned before entry into the study (must be documented in 
the source document) 
The study PI (or designee) will be responsible for notifying the UNC IRB, FDA, the 
University of Oxford, and DAIDS of any unexpected fatal or life-threatening suspected 
adverse reaction as soon as possible, but in no case later than 7 calendar days after the 
sponsor's initial receipt of the information.  In addition, the sponsor must notify FDA in an 
IND safety report of potential serious risks, from clinical trials or any other source, as soon 
as possible, but in no case later than 15 calendar days.  
8.3.6 
Reporting Events to Participants  
We are engaged in a number of similar studies of novel immunotherapies for HIV, 
persistent HIV infection, monoclonal antibodies, latency reversing agents, and other 
interventions. We report the scientific findings of our work in the literature, and have 
regular (annual or more frequent) presentations with the local and national HIV-infected 
and affected community. Due to the lack of evidence thus far that our studies have a 
clinical impact, we discuss the scientific findings in a general way with each participant 
after EOS visits. Our studies have extremely stringent stopping criteria, and thus far, we 
have had no relevant or study-related SAEs to report. We would inform all study 
participants by letter or electronic messaging of any AEs determined by the External Study 
Safety Monitoring Committee to merit such notice. 
8.3.7 
Events of Special Interest  
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and 
medical concern specific to the protocol team, for which ongoing monitoring and rapid 
communication to the protocol team is required. These events might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the protocol team to the UNC IRB, FDA, NIH, and product 
manufacturers (i.e., regulators) might also be warranted. 
AESI for this protocol include those listed below.  
o Grade 3 or higher Injection site reactions  
o Immune-related AEs attributed to study treatment of any grade 

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8.3.8 
Reporting of Pregnancy  
If the participant becomes pregnant during the study, vaccine/placebo will not be 
administered. Although not considered an adverse experience, it is the responsibility of 
investigators or their designees to report any pregnancy in a participant or participant’s 
partner (spontaneously reported to them) that occurs during the study or within 4 months 
after vaccination. All participants or their partners who become pregnant must be followed 
to the completion/termination of the pregnancy. If the pregnancy continues to term, the 
outcome (health of infant) must also be reported the UNC IRB, the DAIDS Medical 
Officer, and the FDA (US Food and Drug Administration). 
If a male participant impregnates his partner while he is participating in this study, the 
pregnancy must be reported and the study PI (or designee) should make a concerted effort 
to follow the pregnancy and outcome. The study PI (or designee) will make every effort to 
obtain a medical release and a separate pregnancy outcome consent from the pregnant 
partner granting permission to follow the health of both the pregnant partner and her 
unborn child to the UNC IRB, DAIDS, study product sponsor, and FDA without delay and 
within 24 hours if the outcome is an SAE (e.g. death, abortion, congenital anomaly, or 
other disabling or life-threatening complication to the mother or newborn). 
Pregnancy and pregnancy outcome will be recorded. Pregnancies that occur on study 
should be reported prospectively to the Antiretroviral Pregnancy Registry. More 
information is available at www.apregistry.com. Telephone: 800-258-4263; Fax: 800-800-
1052.  
Pregnancy Outcomes and Reporting 
If a woman has completed the study or chooses to discontinue from the study before the 
end of the pregnancy, then site study staff should request permission via a separate 
pregnancy outcome consent to contact her regarding pregnancy outcomes at the end of 
pregnancy. If the information is obtained, pregnancy outcomes will be submitted at the end 
of the pregnancy. 
Pregnant women will discontinue study treatment and will be encouraged to continue on 
study and complete the evaluations included in the post-treatment evaluation section. At 
the end of the pregnancy, outcome and adverse events for participant and infant will be 
recorded. If pregnancy is suspected in a woman on study after study treatment, then a 
pregnancy test should be obtained. If pregnancy is confirmed, then further study treatment 
will be discontinued and the woman should continue on study (off study product) safety 
follow-up visits as noted in the SOE. Stored plasma/PBMC for stored plasma for virologic 
studies should not be obtained to minimize blood volume. 
The site study staff should request permission via a separate pregnancy outcome consent to 
contact her regarding pregnancy outcomes at the end of pregnancy. A visit 6 months 

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following the end of pregnancy will be conducted to assess for evidence of adverse events 
(AEs) in the participant and infant and documented. 
8.4 
New Safety Information  
8.4.1 
Definition of New Safety Information (NSI) 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to participants or others as NSI and this includes, in general, any incident, 
experience, or outcome that meets all of the following criteria: 
o Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures/study treatment that are described in the protocol-related documents, 
such as the Institutional Review Board (IRB)-approved research protocol, the 
informed consent document, and Investigator’s Brochure (IB); and (b) the 
characteristics of the participant population being studied; 
o Related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures/treatment involved in the research); and 
o Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
8.4.2 
NSI Reporting  
The investigator will report NSI to the UNC IRB. The NSI report will include the 
following information: 
o Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
o A detailed description of the event, incident, experience, or outcome;  
o An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an NSI;  
o A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the NSI. 
To satisfy the requirement for prompt reporting, NSI reports will be reported using the 
following timeline:   

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o NSI that are serious adverse events (SAEs) will be reported to the IRB and the 
DAIDS MO within 3 business days of the investigator becoming aware of the 
event.  
o Any other NSI will be reported to the IRB and to the DAIDS MO within 7 business 
days of the investigator becoming aware of the event.  
o All NSI should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the NIH MO (or designee), and the 
Office for Human Research Protections (OHRP) within 30 business days of the 
IRB’s review and determination that the report of the problem from the investigator 
imposed a safety risk. 
8.4.3 
Reporting NSI to Participants  
We would inform all study participants by letter or electronic messaging of any NSI if it is 
determined by the UNC IRB to merit such notice. 
9 STATISTICAL CONSIDERATIONS  
This is a phase I, single-site, pilot study to evaluate the safety of M3 and M4 given 
individually or in combination to HIV-infected individuals suppressed on ART.  There are 
two secondary analyses and multiple exploratory objectives to measure the effect of this 
therapy on HIV-specific T cell responses and on persistent HIV infection.  
9.1 
Statistical Hypotheses 
Hypothesis 
Intramuscular (IM) vaccination with M3 or M4, given individually or in combination 
(M3+M4) in adult HIV-infected participants on suppressive combination antiretroviral 
therapy (ART) will be safe and increase HIV-1-specific T cell responses targeting 
conserved regions of HIV-1.  
The simultaneous administration of M3 with M4 (M3+M4) will result in a greater increase 
in the breadth of HIV-1-specific T cells targeting conserved regions of HIV-1 than with the 
individual administration of M3 or M4 alone. 
9.2 
Sample Size Determination 
9.2.1 
Primary Sample Size Consideration  
From previous publications employing MVA- vectored vaccines, the proposed number of 
participants (7 vaccinees per arm and 3 placebo controls) is sufficient to evaluate the risk 

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of SAEs or severe local or systemic reactions in the study population. Descriptive analyses 
will be used to summarize AEs or SAEs in each arm as well as combined MVA arms.  
Enrollment into the trial will be suspended if two participants experience a study 
treatment-related toxicity of Grade 3 or higher or if one or more participants experience an 
SAE possibly related to study treatment (See Section 10.1.6). If zero of 7 participants 
experience a safety event, a 95% 1-sided exact binomial upper confidence limit for the 
probability of a safety event will be 35%. If one participant experiences a safety event, the 
corresponding 95% 1-sided upper confidence limit will be 52%. Each safety endpoint will 
be estimated with an exact binomial 95% 1-sided upper confidence limit. If zero safety 
events are observed in the three vaccine arms and data are pooled across arms (n=24), then 
the upper limit of the exact, 1-sided 95% confidence interval (CI) will be 13%. 
9.2.1.1 
Procedure for accounting for missing and unused data  
 
Based on previous experience with similar trials, we anticipate that the amount of missing 
or invalid data will be small. All participants who are evaluable for adverse event assessment 
will be included in the safety analyses, regardless of whether they are replaced or missing 
for additional endpoints. Participants who do not start study treatment or are unable to 
provide the first or second leukapheresis will be replaced to achieve the planned evaluable 
sample size. Given the small size of this study, formal imputation methods will not be used. 
To assess whether key findings are sensitive to missing data, missing values can be replaced 
with worst possible outcomes as a sensitivity analysis (e.g., by replacing missing values in 
the M3 and M4 only arms with the best rank and replacing missing values in the M3+M4 
arm with the worst rank, to assess if a finding regarding the M3+M4 arm is sensitive to 
missing data).  
9.2.1.2 
Study Duration and Accrual 
Participants will be screened approximately 75 days prior to vaccination and will be 
followed for 168 days after vaccination. The total study duration from screening to 
completion of follow-up per participant will be approximately 33.5 weeks (~8.4 months). 
We will recruit and screen up to 40 participants to obtain 24 participants with evaluable 
data to study. Given the focus of this study is on safety and potential adverse events, 
accrual will be staggered such that enrollment and treatment administration will include a 
maximum of 1 participant per week.  
9.2.1.3 
Randomization  
Following enrollment, the 24 study participants will be randomly assigned to receive one 
vaccination with either M3 (n=7), M4 (n=7), M3+M4 (n=7) or placebo (n=3) through a 
blinded randomization schedule. 

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9.2.1.4 
Un-blinding procedures  
Un-blinding of an individual participant is indicated in the event of a medical emergency 
where the clinical management would be altered by knowledge of the group assignment. 
The decision to un-blind will be taken in conjunction with the independent members of the 
SMC. Procedures and contact details for un-blinding procedures will be held in a site-
specific SOP. The site study personnel will ensure that the reasons for un-blinding are 
documented in the CRF. 
All study participants will be un-blinded when the last vaccinated participant has 
completed the Day 28 Visit and the second leukapheresis. 
9.3 
Statistical Analyses 
9.3.1 
General Approach 
We plan a double blind, randomized, placebo-controlled, parallel design study to evaluate 
the safety and immunogenicity of viral-vector, MVA, expressing immunogens, 
tHIVconsv3 (M3) and tHIVconsv4 (M4), derived from conserved yet immunogenic 
regions of HIV-1. The study population is HIV-1 infected adults on c-ART with plasma 
HIV-1 RNA <50 copies/mL.  
Participants will be randomized to receive M3 or M4 alone, M3+M4 together, or placebo 
at Day 0 and continue baseline ART.  At Day 28, all participants undergo a 2nd 
leukapheresis to evaluate for an increase in the breadth of T cells targeting conserved 
regions of HIV-1. Unblinding will occur after the last participant has completed the Day 28 
visit and leukapheresis. Participants will be followed for safety assessments through Day 
168. 
9.3.2 
Immunological and Virologic Analysis  
Given the small sample size in this study, exact methods that do not rely on large sample 
assumptions will be used for statistical inference and will always be presented with 
corresponding descriptive statistics and/or data visualization. Because this is a Phase 1 
study with a small sample size and exploratory endpoints, results will be presented without 
adjustment for multiple hypothesis testing; a statistical significance level of 0.05 will be 
used. Whenever feasible, data visualization will present individual-level data points as well 
as summary statistics. Emphasis will be placed on estimated effect sizes and descriptive 
summaries. The sample size was chosen to evaluate safety and the primary efficacy 
outcome; this study includes a small total number of participants and thus may not detect 
all scientifically meaningful effects at a .05 statistical significance level. All study results 
should be interpreted within the context of the study eligibility criteria and the population 
available and willing to participate in this double-blinded, placebo-controlled randomized 
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9.3.3 
Analysis of the Primary Endpoint(s) 
The probability of a primary safety event through Day 28 following vaccination will be 
estimated with a proportion and a corresponding 95% 1-sided exact binomial upper 
confidence limit.  
9.3.4 
Analysis of the Secondary Endpoint(s) 
9.3.5 
Immunological and Virologic Analysis  
To evaluate changes in HIV-1 epitope-specific CD8+ T cell responses detected in IFN-γ 
ELISpot assays before and after vaccination, the relative change within participants (from 
Day 0 to both Day 7 and Day 14) will be estimated using a geometric mean ratio and 
evaluated with an exact 2-sided Wilcoxon signed-rank test. If the symmetry assumption for 
change in natural log-transformed summed HIV-1 specific T cell response appears 
violated, a sign test will be conducted as a sensitivity analysis. Efficacy and exploratory 
endpoints defined as a proportion of participants will be analyzed with a 2-sided binomial 
95% CI. Within a vaccination arm, changes in continuous measurements over time (e.g., 
change in an immune parameter from baseline to post-vaccination) will be summarized 
graphically and evaluated with an exact 2-sided Wilcoxon signed-rank test, or a sign test 
for endpoints that appear to violate assumptions of the Wilcoxon test.  
Observed immunologic measurements, such as the change in breadth following 
vaccination, may not be normally distributed or may be partially censored due to assay 
limits of quantification, and thus, an exact Wilcoxon rank-sum test will be used for 
between-arm comparison. 
The focus of our secondary objectives is to examine the effect of vaccination on within-
participant T cell magnitude and between-arm breadth of HIV-specific T cell responses.  
9.3.6 
T cell Magnitude:  
The primary within arm outcome will be the summed HIV-specific T cell response, 
either to peptides pools spanning the immunogen or pools of optimal HIV CD8+ 
epitopes. HIV specific T cell responses will be measured at baseline, Day 7, and 
Day 14 (following M3, M4, or M3+M4 vaccination). An average fold change of at 
least 2 (comparing T cell responses within participant) was anticipated to be 
scientifically meaningful. The specific alternative hypothesis is a geometric mean 
ratio (GMR) of 2. The assumed between-participant standard deviation (SD) for 
natural log-transformed HIV-specific T cell response was estimated from previous 
baseline data derived from HIV-infected participants durably suppressed by ART 
sampled weekly or monthly. Data were provided by Dr Goonetilleke (66). 
Empirical power for the exact Wilcoxon signed-rank test was calculated using 
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response follows a normal distribution, and the effect size under the alternative 
hypothesis was a GMR of 2 on the raw HIV-specific T cell response measures. A 
between-participant SD of 0.8 at baseline was observed using log-
transformed HIV-specific T cell response from previous baseline data; the 
same SD for both pre-vaccination and post-vaccination measurements was 
assumed to calculate power. The estimated correlation within a participant 
was >0.9 between paired log-transformed HIV-specific T cell response 
measures. Using a 2-sided exact Wilcoxon signed-rank test and a 0.05 significance 
level, n=7 vaccinated participants provides >95% power to detect a GMR of 2 or 
greater for a pre- and post-vaccine paired measurement correlation of 0.9 and a 
between-individual SD of 0.8. For a smaller within-individual correlation of 0.8 
and the same assumptions otherwise, the estimated power is 82%. 
Comparison of peak HIV specific T cell responses between arms (M3+M4 vs M3, 
M3+M4 vs M4) will be compared using a 2-sided exact Wilcoxon rank-sum test. 
With n=7 per vaccination group it is possible to achieve an exact p-value <0.05. 
Assuming a 90% probability that the peak HIV specific T cell responses for any 
given participant in the M3+M4 arm is higher than for any given individual in the 
M3 arm, there is >80% power to detect a difference between arms. This same 
power calculation applies for the M3+M4 vs M4 comparison. Power for the exact 
Wilcoxon rank-sum test was calculated in R version 3.4.3 using the wmwpow 
package. 
9.3.7 
T cell Breadth:   
Observed immunologic measurements, such as the change in breadth following 
vaccination, may not be normally distributed, and thus, a 2-sided exact Wilcoxon 
rank-sum test will be used for comparisons between arms.  
We anticipate zero change in T-cell breadth for the M3 and M4 arms. For the 
M3+M4 arm, we anticipate change of breadth ranging from 0-6 epitopes (Table 
13). Data in Table 13 describes the distribution of HIV-specific T-cell responses 
identified in 20 HIV-infected, durably suppressed participants provided by Dr 
Goonetilleke.  
Table 13 
Distribution of Regions of HIV Epitopes Targeted by T-Cells in HIV-1 
Infected Participants Durably Suppressed with ART 
# Epitopes found in tHIVconsvX 
% distribution 
0 
15 
1 
15 
2 
30 

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3 
20 
4 
5 
5 
10 
6 
5 
Given the assumptions in Table 13 and above (zero change in T cell breadth for the M3 
and M4 only arms), n=7 evaluable participants per arm provides >90% power to detect a 
difference between arms (M3+M4 vs M3, M3+M4 vs M4) using a 2-sided exact Wilcoxon 
rank-sum test and a 0.05 significance level. 
9.3.8 
Safety Analyses 
For the safety endpoints, we will describe all study treatment-related AEs through Day 28 
(primary endpoint) and the end of study (secondary endpoint). AEs will be coded per the 
Medical Dictionary for Regulatory Activities (MedDRA). Events prior to treatment (e.g., 
due to study-related procedure) will be listed separately in an appendix to the final clinical 
study report. The following tables of AE data will be created to summarize the number and 
percent of participants who experience at least one event of each of the following types: 
o Study treatment-related AEs by severity grade 
o All SAEs (this may be a listing if there are few events) 
o Study treatment-related SAEs 
o Fatal AEs (this may be a listing if there are few events) 
o AEs that result in study discontinuation or study treatment discontinuation 
o AEs categorized as AESI  
o AEs with severity Grade 3 or greater 
o Study treatment-related AEs with severity Grade 3 or greater 
o All treatment-related AEs with severity Grade 1 or greater 
All of these tables will display the number and percent of participants that experience the 
given event and will display events by System Organ Class (SOC) and Preferred Term 
(PT). Events will be displayed alphabetically for SOC and in descending order of overall 
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9.3.9 
Tabulation of Individual Participant Data 
Individual participant data will be listed by measure and time point. 
9.3.10 
Exploratory Analyses 
Other objectives or exploratory analysis can be grouped into additional immunological 
measures and virologic measures. 
Immunologic measures: Kinetic data will be analyzed by descriptive statistics and 
graphical displays. Other observed immunologic measurements such as virus inhibition 
may not be normally distributed or may be partially censored due to assay limits of 
quantification, and thus, an exact Wilcoxon signed-rank test will be used for within-
participant comparisons.  
Virologic measures: Virologic measures such as cell-associated HIV-1 RNA will be log-
transformed prior to analyses. Appropriate analysis method will be used for plasma HIV-1 
RNA by SCA depending on the amount of results below assay limit. For example, if a 
substantial fraction (~50%) are below the assay limit, the analysis will focus on estimating 
the proportion of participants with detectable SCA at various time points and comparison 
between arms will use Fisher’s exact test; otherwise, changes within participants will be 
summarized and compared between arms using Wilcoxon rank-sum tests.  
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Informed Consent Process 
10.1.1.1 
Consent/assent and Other Informational Documents Provided to 
Participants 
Consent forms describing in detail the study intervention, study procedures, and risks are 
given to the participant and written documentation of informed consent is required prior to 
any screening procedures and prior to starting study intervention/administering study 
intervention.   
10.1.1.2 
Consent Procedures and Documentation 
Informed consent is a process initiated prior to individuals agreeing to participate in the 
study and continues throughout the individual’s study participation. The consent forms are 
UNC IRB -approved and the participant will be asked to read and review the document. 
The study investigator (or designee) and/or study coordinator will explain the research 

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study to the participant and answer any questions that may arise. A verbal explanation will 
be provided in terms suited to the participant’s comprehension of the purposes, procedures, 
and potential risks of the study and of their rights as research participants. Participants will 
have the opportunity to carefully review the written consent form and ask questions prior 
to signing. The participants are provided the opportunity to discuss the study with their 
family, primary care provider, or significant other or to just think about the study and its 
requirements prior to agreeing to participate. The participant signs the informed consent 
document prior to any procedures being done specifically for the study. Participants are 
informed that participation is voluntary and that they may withdraw from the study at any 
time, without prejudice. A copy of the informed consent document will be given to the 
participants.  
The informed consent process will be conducted and documented in the source document, 
and the consent form signed, before the participant undergoes any study-specific 
procedures. The study PI (or designee) or the research coordinator will inform participants 
that the quality of their medical care will not be adversely affected if they decline to 
participate in this study, thus emphasizing the protection of the rights and welfare of the 
participants. 
10.1.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
funding agency (NIH), the FDA, the University of Oxford, and the UNC IRB. If the study 
is prematurely terminated or suspended, the study PI (or designee) will promptly inform 
study participants, the UNC IRB, and DAIDS and will provide the reason(s) for the 
termination or suspension.  Study participants will be contacted, as applicable, and be 
informed of changes to the study visit schedule. 
Circumstances that may warrant termination or suspension include but are not limited to: 
o Determination of unexpected, significant, or unacceptable risk to participants 
o Demonstration of efficacy that would warrant stopping    
o Insufficient compliance to protocol requirements 
o Data that are not sufficiently complete and/or evaluable 
o Determination that the primary endpoint has been met 
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Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, the UNC IRB, DAIDS, and/or the Food and Drug 
Administration (FDA). 
10.1.3 
Confidentiality and Privacy  
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, their study staff, and the sponsor(s)/funding source(s) and their 
representatives. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
UNC IRB, regulatory agencies, or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the study PI, including but 
not limited to, medical records and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. 
The study participants’ contact information will be securely stored at the clinical study site 
for internal use during the study. At the end of the study, all records will continue to be 
kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional 
policies, or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the UNC HIV Cure Center. This will not include the 
participants’ contact or identifying information. Rather, individual participants and their 
research data will be identified by a unique study identification number. The study data 
entry and study management systems used by the clinical staff of the UNC HIV Cure 
Center and by research staff will be secured and password protected. At the end of the 
study, all study databases will be de-identified and archived.  
10.1.3.1 
Certificate of Confidentiality  
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
issued by the National Institutes of Health (NIH). This certificate protects identifiable 
research information from forced disclosure. It allows the investigator and others who have 
access to research records to refuse to disclose identifying information on research 
participation in any civil, criminal, administrative, legislative, or other proceeding, whether 
at the federal, state, or local level. By protecting researchers and institutions from being 
compelled to disclose information that would identify research participants, Certificates of 

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Confidentiality help achieve the research objectives and promote participation in studies by 
helping assure confidentiality and privacy to participants. 
10.1.4 
Future Use of Stored Specimens and Data  
Data collected for this study will be analyzed and stored at the Goonetilleke Laboratory in 
the UNC HIV Cure Center. After the study is completed, the de-identified, archived data 
will be stored in the UNC HIV Cure Center Database, for use by the Goonetilleke 
Research Laboratories and their collaborators. Permission to transmit data to researchers 
outside the Goonetilleke Collaboration will require review and approval by the UNC IRB. 
In some circumstances, we will need to obtain additional consent from participants to share 
samples collected for the purpose of this study.   
With the participants’ approval and as approved by the UNC IRB, de-identified biological 
samples will be stored at the Goonetilleke and Archin/Margolis Laboratories both in the 
UNC HIV Cure Center and/or the UNC Chapel Hill HIV/STD Laboratory Core. These 
samples could be used to research the causes of HIV cure for which individuals with HIV 
infection can greatly benefit. These samples may also be used for genetic testing. The 
Goonetilleke Research Laboratory will also be provided with a code-link that will allow 
linking the biological specimens with the phenotypic data from each participant, 
maintaining the blinding of the identity of the participant. 
During the conduct of the study, an individual participant can choose to withdraw consent 
to have biological specimens stored for future research. However, withdrawal of consent 
with regard to biosample storage may not be possible after the study is completed.  
When the study is completed, access to study data and/or samples will be provided through 
the Goonetilleke Laboratory in the UNC HIV Cure Center Laboratory. 
10.1.5 
Key Roles and Study Governance 
Key roles and study governance will be provided as in  
Table 14. 
Table 14 
Key Roles 
Protocol Principal Investigator 
Grant Principal Investigator 
Cynthia Gay, MD, MPH 
Nilu Goonetilleke, PhD 
Associate Professor, Medical Director HIV Cure 
Center 
Assistant Professor, Dept. of Microbiology & 
Immunology/Medicine 
University of North Carolina at Chapel Hill  
University of North Carolina at Chapel Hill  

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130 Mason Farm Road, Suite 2112 Bioinformatics 
Building, Campus Box 7030  
120 Mason Farm Road, 2017 Genetic Medicine Building, 
Campus Box 7042 
Chapel Hill, NC 27599-7030 
Chapel Hill, NC 27599-7042 
10.1.6 
Safety Oversight 
Safety oversight will be under the direction of a Safety Monitoring Committee (SMC) 
composed of individuals with the appropriate expertise. Members of the SMC are 
independent from the study conduct and free of conflict of interest.   
The SMC advises the study PI and protocol team for this First in Man, Phase I study. The 
primary responsibility of the SMC is to monitor human subject safety. The SMC considers 
study-specific data as well as relevant background information about the disease, test 
agents, and target population under study. 
During the trial, the SMC will review:   
o Real-time and cumulative safety data for evidence of study-related adverse events;   
o Adherence to the protocol;  
o Factors that might affect the study outcome or compromise the trial data (such as 
protocol violations, losses to follow-up, etc.). 
o Review the achievement of enrollment benchmarks  
The SMC will receive monthly reports via email for review and comments. The SMC will 
be contacted directly via email (and possibly via teleconferencing) for any event or 
situation that impacts participant safety throughout the study and specified interventions or 
study participation will be suspended or terminated dependent on the response of the SMC. 
The study will undergo review at least annually by the SMC. The SMC will review 
information on accrual, baseline characteristics, conduct of the study (including premature 
study discontinuations and premature study treatment discontinuations), AEs by treatment 
arm (including protocol team assessment of relationship to study treatment), virologic 
failures, and HIV-1 RNA levels over time, and completeness of follow-up. 
Safety Pause 
Enrollment into the study and treatment injections will be temporarily suspended and the 
Study Monitoring Committee (SMC), unblinded to treatment assignment, will be asked to 
review all safety data. Review will include the relation to study treatment of the event(s) 
thought by the blinded core team to be a primary safety outcome, if any of the following 
occur: 
 

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a) Two or more participants experience a primary safety outcome measure that is a 
Grade ≥3 AE possibly related to study treatment (as judged by the core team, 
blinded to treatment arm); or  
 
b) One or more participants experience an SAE possibly related to study treatment 
(as judged by the core team, blinded to treatment arm). 
 
Following the review, the SMC will recommend if and how the study should proceed with 
respect to resuming enrollment and continuing study treatment. 
10.1.7 
Clinical Monitoring 
To ensure the safety of participants in the study, compliance with applicable regulations, 
and to ensure accurate, complete, and reliable data, the study PI will keep records of 
laboratory tests, clinical notes, and participant medical records in the participant files as 
source documents for the study. 
An independent study monitor will monitor the study on a regular basis throughout the 
study period according to the study monitoring plan. The study PI (or designee) will 
allocate adequate time for such monitoring activities. The study monitor periodically will 
conduct a review of a sample of the participant data recorded on source documents at the 
study site. The study PI (or designee) will also ensure that the monitor is given access to all 
the above noted study-related documents, source documents (regardless of media), and 
study-related facilities (e.g., IDS pharmacy, etc.), and has adequate space to conduct the 
monitoring visit. Queries may be raised if any datum is unclear or contradictory. The study 
PI and site study personnel must address all queries in a timely manner. 
Participation as an Investigator in this study implies acceptance of the potential for 
inspection by the study Funder and its Representatives, US or non-US government 
regulatory authorities, IRB, and applicable compliance and quality assurance offices. The 
study PI (or designee) will permit study-related audits and inspections and will provide 
access to all study-related documents (e.g., source documents, regulatory documents, data 
collection instruments, study data, etc.). The study PI will ensure the capability for 
inspections of applicable study-related facilities (e.g., IDS pharmacy, CTRC, etc.). 
10.1.7.1 
Minimizing risk to participants 
Procedures to minimize risk to participants in the conduct of this study include:  
▪ Informing participants about risks so they can recognize and report harms in 
partnership with the study team;  
▪ respecting local/national blood draw limits;  

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▪ direct observation of participants after vaccine/placebo administration and collection of 
information regarding side effects for several days post product administration;  
▪ having study staff properly trained in administering study procedures that may cause 
physical harm or psychologic distress, such as blood draws and injections; and 
▪ providing study monitoring. 
10.1.8 
Quality Assurance and Quality Control 
UNC will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion.  A quality management plan was 
developed to describe the quality management program. 
UNC follows Standard Operating Procedures (SOPs) for quality management. Clinical 
research files verify and insure that the clinical trial is conducted per protocol and that data 
is generated and biological specimens collected, documented (recorded), and reported in 
compliance with the protocol, International Conference on Harmonization Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)). Data Quality is monitored per the 
data quality management plan with routine and specific research chart review. 
The study staff will be educated on the protocol and training will be provided as needed to 
implement protocol procedures. The study data management team will be responsible for 
addressing QA issues (e.g., correcting procedures that are not in compliance with the 
protocol) and QC issues (e.g., correcting errors in data entry). Documentation, as required, 
will be maintained in the regulatory files. 
UNC will provide direct access to all trial-related sites, source data/documents, and reports 
for the purpose of monitoring and auditing by the funding sponsor, and inspection by local 
and regulatory authorities. 
10.1.9 
Data Handling and Record Keeping  
10.1.9.1 
Data Collection and Management Responsibilities  
The clinical research staff is responsible for data collection under the supervision of the 
site study PI (or designee). The study PI (or designee) is responsible for ensuring the 
accuracy, completeness, legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
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Hard copies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study.  Data recorded in 
the electronic case report form derived from source documents should be consistent with 
the data recorded on the source documents.  
Clinical data (including adverse events (AEs), concomitant medications, and expected 
adverse reactions data) and clinical laboratory data will be entered into a UNC School of 
Medicine Database. The data system includes password protection. Clinical data will be 
entered directly from the source documents. 
10.1.9.2 
Study Records Retention  
Per ICH guidelines, all essential documents, including source documents (regardless of 
media), signed ICFs, and laboratory test results, should be retained by the study PI (or 
designee) for at least 2 years after last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH 
region or until at least 2 years have elapsed since formal discontinuation of clinical 
development of the investigational products. 
10.1.10 
Protocol Deviations  
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonization Good Clinical Practice (ICH GCP), or Manual of 
Procedures (MOP) requirements. The noncompliance may be on the part of the participant, 
the investigators, or the study site staff. As a result of deviations, corrective actions will be 
developed and implemented promptly, when necessary.  
These practices are consistent with ICH GCP:  
It is the responsibility of the site PI (or designee) to use continuous vigilance to identify 
and report deviations at the annual renewal of the protocol, provided there is no impact on 
participant safety as a result of the deviation. All deviations must be addressed in study 
source documents. Protocol deviations are sent to the UNC IRB per their policies. The site 
PI is responsible for knowing and adhering to reviewing the IRB requirements. Further 
details about the handling of protocol deviations will be included in the SOP. 
10.1.11 
Publication and Data Sharing Policy 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
o National Institutes of Health (NIH) Public Access Policy, which ensures that the 
public has access to the published results of NIH-funded research. It requires 

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scientists to submit final peer-reviewed journal manuscripts that arise from NIH 
funds to the digital archive PubMed Central upon acceptance for publication. 
o NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical 
Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov, if 
required.  
o NIH Genomic Data Sharing Policy, which applies to all NIH-funded research that 
generates large-scale human or non-human genomic data, as well as the use of 
these data for subsequent research. Large-scale data include genome-wide 
association studies (GWAS), single nucleotide polymorphisms (SNP) arrays, and 
genome sequence, transcriptomic, epigenomic, and gene expression data. 
10.1.12 
Conflict of Interest Policy 
The University of North Carolina at Chapel Hill recognizes that conflicts of interest will 
arise from the research enterprise, from technology transfer activities, and from the many 
facets of our investigators’ professional activities. UNC seeks to identify and manage these 
conflicting relationships, restricting activities where necessary, to preserve transparency, 
independent decision-making, protection of research participants, and integrity of the 
educational experience. UNC’s Conflict of Interest Program will have oversight over this 
study. 
 
10.2 
Abbreviations 
4A4OA 
4-anilino-4oxobutanoic acid 
ACD 
Acid Citrate Dextrose 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AHA 
Autoimmune Hemolytic Anemia 
AHI 
Acute HIV Infection  
Alk Phos 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ANA 
Antinuclear Antibody 
ANC  
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance 
Anti-dsDNA 
Anti-double-stranded DNA, IgG 

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APTT 
Activated Partial Thromboplastin Time 
ART 
Antiretroviral Therapy  
AST 
Aspartate Transaminase 
ATI 
Analytic Treatment Interruption 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BP  
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CBF 
Clinical Biomanufacturing Facility 
CBC 
Complete Blood Count 
CEF 
Chicken Embryo Fibroblast 
CFAR 
Center for AIDS Research  
CFR 
Code of Federal Regulations 
ChAd 
Simian Adenovirus 
CLIA 
Clinical Laboratory Improvement Amendments 
CM 
Clarification Memo 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19  
SARS-CoV-2 virus  
CPK 
Creatine Phosphokinase or Creatine Kinase (CK) 
CRF 
Case Report Form 
CSRC 
(DAIDS) Clinical Science Review Committee 
CTRC 
Clinical and Translational Research Center 
DAIDS 
Division of AIDS 
D/C 
Discontinue 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DNCB 
Dinitrochlorobenzene 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
E/CIA 
Enzyme or Chemiluminescence Immunoassay 

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EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Forms 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
EUA 
Emergency Use Authorization  
FNA 
Fine Needle Aspiration 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
FSH 
Follicle Stimulating Hormone 
GBS 
Guillian-Barré Syndrome 
G-CSF 
Granulocyte-Colony Stimulating Factor  
GM-CSF 
Granulocyte Macrophage-Colony Stimulating Factor 
GCP 
Good Clinical Practice 
GFP 
Green Fluorescent Protein 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HCVAb 
Hepatitis C Virus Antibody 
HIPAA 
Health Insurance Portability and Accountability Act  
HLA 
Human Leukocyte Antigen 
IB 
Investigator’s Brochure 
IBC 
Institutional Biosafety Committee 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
ICMJE 
International Committee of Medical Journal Editors 
ID 
Intradermal 
ID Clinic 
Infectious Diseases Clinic 
IFNγ 
Interferon gamma 

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IgG 
Immunoglobulin G 
IDS 
Investigational Drug Services  
IL-1 
Interleukin - 2 
IL-12 
Interleukin - 12 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
IUD 
Intrauterine device 
IV 
Intravenous  
LAN-HSD 
Los Alamos National Laboratory HIV Sequence Database 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein 
LMP  
Last Menstrual Period 
LOA 
Letter of Amendment  
LRA 
Latency Reversing Agent 
LSMEANS 
Least-Squares Means 
LTFU 
Lost to Follow-up 
M3 
MVA.tHIVconsv3 
M4 
MVA.tHIVconsv4 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/dL 
milligram per deciliter 
ml/min 
milliliter per minute 
mm Hg 
millimeters of mercury 
MMR 
Measles, Mumps, Rubella 
MO 
Medical Officer 
MOI 
Multiplicity of Infection 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 

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MVA 
Modified Vaccinia virus (Ankara strain) 
MVA.HIVA 
MVA expressing the HIVA immunogen, comprising p24 and HIV epitope string 
MVA.HIVconsv 
MVA expressing the 1st generation conserved HIV immunogen, HIVconsv  
MVA.tHIVconsv3 
MVA expressing a 2nd generation conserved HIV immunogen, tHIVconsv3  
MVA.tHIVconsv4 
MVA expressing a 2nd generation conserved HIV immunogen, tHIVconsv4 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
NRTI 
Nucleoside Reverse Transcriptase Inhibitor 
NNRTI 
Non-nucleoside Reverse Transcriptase Inhibitor 
NSI 
New Safety Information 
OHRP 
Office for Human Research Protections 
OSP 
Office of Science Policy 
OTC 
Over the Counter 
P 
Pulse 
PBMC 
Peripheral Blood Mononuclear Cells 
PE 
Physical Exam 
pfu 
Plaque-forming units 
PHI 
Primary HIV Infection 
PI 
Principal Investigator 
PID 
Participant Identification Number 
PI 
Protease Inhibitor 
POCT 
Point of Care Test 
PT 
Preferred Term  
PT 
Prothrombin time  
QA 
Quality Assurance 
QC 
Quality Control 
RID  
Randomization Identification Number 
rMVA 
Recombinant MVA 
RFP 
Red Fluorescent Protein 
RPR 
Rapid Plasma Reagent 
RR 
Respiratory Rate 

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SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SFU 
Spot-forming units 
SID 
Study Identification Number 
SMC 
Safety Monitoring Committee 
SNP 
Single Nucleotide Polymorphism  
SOE 
Schedule of Events 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Serious unexpected serious adverse reaction 
T 
Temperature 
TAF 
Tenofovir Alafenamide 
TDF 
Tenofovir 
TNF 
Tumor Necrosis Factor 
tPA-LS 
Human tissue activator sequence  
ULN 
Upper Limit of Normal 
UNC 
University of North Carolina  
UP 
Unanticipated Problem 
US 
United States 
VS 
Vital Signs 
WHO 
World Health Organization  
WOCBP 
Women of Child Bearing Potential 
 
10.3 
Protocol Amendment History 
 
Version 
Date 
Description of Change  
Brief Rationale 
Draft 
20 April 2018 
Original version  
To DAIDS CSRC 
1.0 
10 Sept 2018 
Incorporation of DAIDS CSRC and 
FDA suggested changes   
DAIDS CSRC and FDA review 
1.1  
14 Nov 2018 
Incorporation of UNC IRB and 
DAIDS RSC suggested changes and 
UNC Protocol Team changes  
DAIDS RSC and UNC IRB and 
UNC Protocol Team review 

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2.0  
02 July 2019 
Incorporated CM#1 & CM#2; 
decreased number of participants to 
24; decreasing each active arm 
(Arm 1, 2 & 3) to n=7.  
Modifications to Inclusion and 
Exclusion Criteria and terms 
regarding the re-assignment of 
randomization ID  
To DAIDS MO and RSC 
Review 
3.0  
06 January 2021 
Incorporated CMs #1 – 5 and LOAs 
#1 and 2 into this amendment. 
Additional information added to 
protocol to address COVID-19 
vaccines and treatments received by 
potential participants. Also modified 
exclusion criteria to allow topical 
treatment of non-melanoma cancer; 
to remove exclusion of tattoos on 
deltoid area of arms; and modified 
text pertaining to the receipt of 
depo-provera injections. Modified 
Dosing and Administration section 
to allow administration of 2 
vaccines per week.    
To DAIDS MO and RSC 
Review 
 
 
 
 
 
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HIV Persistence, HIV Reservoirs and Strategies Towards HIV Cure. 2017: Miami, 
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