SARS-CoV-2 Immune Responses After COVID-19 Therapy and Subsequent Vaccine
Phase: PHASE4
Conditions: Covid19, SARS-CoV2 Infection
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
 
A5404 
 
 
SARS-CoV-2 Immune Responses after COVID-19 Therapy and  
Subsequent Vaccine  
 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
 
Sponsored by: 
National Institute of Allergy 
and Infectious Diseases 
 
 
Industry Support Provided by: 
Moderna, Inc. 
 
 
IND # 027376 
 
 
 
Protocol Chair: 
David (Davey) Smith, MD, MAS 
 
Protocol Vice Chairs: 
Kara Chew, MD, MS 
 
Eric Daar, MD 
 
David Wohl, MD 
 
DAIDS Clinical Representative:  
Arzhang Cyrus Javan, MD, MPH, DTM&H 
 
 
Clinical Trials Specialist:  
Preeti Dhillon, MPH 
 
 
 
 
 
 
 
 
FINAL VERSION 3.0 
November 30, 2022 
 

 
 
A5404 
 
 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
 
SARS-CoV-2 Immune Responses after COVID-19 Therapy and Subsequent Vaccine  
 
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 US 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.  
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
 Name/Title 
 
 
 

 
 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
 
 
TABLE OF CONTENTS 
 
 
Page 
SIGNATURE PAGE ...................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY ..................................................................................... 5 
PROTOCOL TEAM ROSTER ....................................................................................................... 6 
STUDY MANAGEMENT ............................................................................................................. 10 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ...................................................................... 13 
SCHEMA ..................................................................................................................................... 14 
1.0 
STUDY OBJECTIVES ..................................................................................................... 16 
1.1 
Primary Objective ................................................................................................ 16 
1.2 
Secondary Objectives ......................................................................................... 16 
1.3 
Other Objectives .................................................................................................. 16 
2.0 
INTRODUCTION ............................................................................................................. 18 
2.1 
Background ......................................................................................................... 18 
2.2 
Rationale ............................................................................................................. 19 
3.0 
STUDY DESIGN ............................................................................................................. 21 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................. 22 
4.1 
Inclusion Criteria .................................................................................................. 22 
4.2 
Exclusion Criteria ................................................................................................ 23 
4.3 
Study Enrollment Procedures .............................................................................. 23 
4.4 
Co-enrollment Guidelines .................................................................................... 24 
5.0 
STUDY TREATMENT ..................................................................................................... 24 
5.1 
Regimens, Administration, and Duration ............................................................. 24 
5.2 
Study Product Formulation and Preparation ....................................................... 25 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability ............................... 26 
5.4 
Concomitant Medications .................................................................................... 27 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ............................................................ 28 
6.1 
Schedule of Evaluations ...................................................................................... 28 
6.2 
Timing of Evaluations .......................................................................................... 36 
6.3 
Instructions for Evaluations ................................................................................. 39 
7.0 
ADVERSE EVENTS AND STUDY MONITORING.......................................................... 46 
7.1 
Definition of Adverse Events ............................................................................... 46 
7.2 
Adverse Event Collection Requirements for This Protocol .................................. 46 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ......................................... 47 
7.4 
Study Monitoring ................................................................................................. 48 
8.0 
CLINICAL MANAGEMENT ISSUES ............................................................................... 48 
8.1 
Toxicity ................................................................................................................ 48 
8.2 
Pregnancy ........................................................................................................... 49 

A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
 
CONTENTS (Cont’d) 
 
 
8.3 
Breastfeeding ...................................................................................................... 49 
8.4 
Allergic Reactions ................................................................................................ 50 
8.5 
Injection Site Reactions ....................................................................................... 50 
8.6 
New SARS-CoV-2 Infection ................................................................................ 50 
8.7 
Myocarditis and Pericarditis............................................................................. 51 
9.0 
CRITERIA FOR DISCONTINUATION............................................................................. 51 
9.1 
Permanent and Premature Vaccine Discontinuation for Participants Receiving 
Study-Provided Vaccine ................................................................................... 51 
9.2 
Premature Study Discontinuation for All Participants ....................................... 51 
10.0 
STATISTICAL CONSIDERATIONS ................................................................................ 52 
10.1 
General Design Issues ........................................................................................ 52 
10.2 
Outcome Measures ............................................................................................. 53 
10.3 
Randomization and Stratification ......................................................................... 54 
10.4 
Sample Size ........................................................................................................ 54 
10.5 
Data and Safety Monitoring ................................................................................. 57 
10.6 
Analyses .............................................................................................................. 57 
11.0 
PHARMACOLOGY PLAN ............................................................................................... 59 
12.0 
DATA COLLECTION AND MONITORING ...................................................................... 59 
12.1 
Records to Be Kept ............................................................................................. 59 
12.2 
Role of Data Management .................................................................................. 59 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 59 
13.0 
PARTICIPANTS .............................................................................................................. 60 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 60 
13.2 
Participant Information and Consent ................................................................... 60 
13.3 
Participant Confidentiality .................................................................................... 60 
13.4 
Study Discontinuation .......................................................................................... 61 
14.0 
PUBLICATION OF RESEARCH FINDINGS ................................................................... 61 
15.0 
BIOHAZARD CONTAINMENT ........................................................................................ 61 
16.0 
REFERENCES ................................................................................................................ 62 
INFORMED CONSENT FORM ................................................................................................... 65 
CONSENT FOR OPTIONAL USE OF EXTRA SAMPLES IN OTHER STUDIES ...................... 83 
 

 
5 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
SITES PARTICIPATING IN THE STUDY 
 
A5404 is a multicenter study open to select US and non-US clinical research sites that are 
participating in A5401, “Adaptive Platform Treatment Trial for Outpatients with COVID-19 (Adapt 
Out COVID).” 
 
 
 
 
 
 

 
6 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
PROTOCOL TEAM ROSTER 
 
Chair 
David (Davey) Smith, MD, MAS 
Antiviral Research Center 
University of California, San Diego 
220 Dickinson Street 
San Diego, CA 92103 
Phone: 619-543-7449 
Fax: 619-298-0177 
E-mail: d13smith@health.ucsd.edu 
 
Vice-Chairs 
Kara Chew, MD, MS 
Clinical AIDS Research and Education 
University of California, Los Angeles 
911 Broxton Avenue, Suite 200 
Los Angeles, CA 90024 
Phone: 310-825-0796 
Fax: 310-477-7657 
E-mail: kchew@mednet.ucla.edu 
 
Eric Daar, MD 
Harbor University of California Los Angeles 
CDCRC Building, Room 205 
1124 West Carson Street 
Torrance, CA 90502 
Phone: 424-201-3000 
Fax: 310-533-0447 
E-mail: edaar@lundquist.org 
 
David Wohl, MD 
Chapel Hill CRS 
Suite 2100, Bioinformatics Building 
130 Mason Farm Road 
Chapel Hill, NC 27514 
Phone: 919-843-2723 
Fax: 919-966-8928 
E-mail: wohl@med.unc.edu 
 
DAIDS Clinical Representative  
Arzhang Javan, MD, MPH, DTM&H 
TRP, DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9E41, MSC 9830 
Rockville, MD 20852 
Phone: 301-761-7710 
Mobile: 240-475-6683 
E-mail: arzhang.javan@nih.gov 
 
 
 
Clinical Trials Specialist 
Preeti Dhillon, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3017 
E-mail: preeti.dhillon@dlhcorp.com 
 
Statisticians 
Carlee Moser, PhD 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public 
Health  
615 Huntington Avenue, FXB 513 
Boston, MA 02115-6017 
Phone: 617-432-2526 
E-mail: cmoser@sdac.harvard.edu 
 
Isabelle Weir, PhD 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health  
615 Huntington Avenue, FXB 515 
Boston, MA 02115-6017 
Phone: 617-432-2998 
E-mail: iweir@sdac.harvard.edu 
 
Xingye (Shirley) Wu, MS 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health  
615 Huntington Avenue, FXB 601 
Boston, MA 02115-6017 
Phone: 617-432-1115 
Fax: 617-432-2843 
E-mail: xwu@sdac.harvard.edu

 
7 
A5404 
FINAL VERSION 3.0  
 
PROTOCOL TEAM ROSTER (Cont'd) 
30Nov2022 
 
Data Manager 
Sara Sieczkarski, PhD 
ACTG Data Management Center 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226-1056  
Phone: 716-834-0900, x7372 
E-mail: sieczka@frontierscience.org 
 
DAIDS Pharmacists 
Justine Beck, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9D39 
Rockville, MD 20852 
Phone: 301-761-5288 
E-mail: justine.beck@nih.gov 
 
Kelly Colsh, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, OCSO 
5601 Fishers Lane, 9D38 
Rockville, MD 20852 
Phone: 240-669-5721 
E-mail: kelly.parsons@nih.gov 
 
Immunologist 
Scott Sieg, PhD 
Case Western Reserve University 
Biomedical Research Building 
Room 1020 
2109 Adelbert Road 
Cleveland, OH 44106-4984 
Phone: 216-368-6594 
Fax: 216-368-5415 
E-mail: sfs2@case.edu
Virologist 
Jonathan Li, MD, MMSc 
Brigham and Women's Hospital 
Therapeutics (BWHT) CRS 
Harvard Medical School  
Department of Infectious Diseases 
65 Landsdowne Street, Room 421 
Boston, MA 02139 
Phone: 617-768-8476 
E-mail: jli@bwh.harvard.edu 
 
Pharmacologist 
Courtney Fletcher, PharmD 
University of Nebraska Medical Center 
College of Pharmacy 
986000 Nebraska Medical Center 
Omaha, NE 68198-6000 
Phone: 402-559-4333 
E-mail: cfletcher@unmc.edu 
 
Investigators 
Sandra Wagner Cardoso, MD, PhD 
Instituto de Pesquisa Clinica Evandro 
Chagas CRS 
Oswaldo Cruz Foundation 
Avenida Brasil 4365, Manguinhos 
Rio de Janeiro 21045--900 
BRAZIL  
Phone: 55-21-38659623 
E-mail: dra.wagner@gmail.com 
 
Judith Currier, MD, MSc 
Clinical AIDS Research and Education 
(CARE) Center CRS 
911 Broxton Avenue, Suite 200 
Los Angeles, CA 90024 
Phone: 310-825-9283 
Fax: 310-477-7657 
E-mail: jscurrier@mednet.ucla.edu 
 
Joseph Eron, MD 
University of North Carolina Global HIV 
Prevention and Treatment CTU 
Bioinformatics Building 
130 Mason Farm Road, Suite 210  
Chapel Hill, NC 27599-7215 
Phone: 919-843-2722 
Fax: 919-966-6714 
E-mail: jeron@med.unc.edu

 
8 
A5404 
FINAL VERSION 3.0  
 
PROTOCOL TEAM ROSTER (Cont'd) 
30Nov2022 
 
Investigators (Cont'd) 
Teresa Evering, MD, MS 
Weill Cornell Medicine 
Uptown CRS 
1300 York Avenue 
New York, NY 10065 
E-mail: evering@med.cornell.edu 
 
Pamela Grace Mukwekwerere, MBChB, MPH  
Milton Park CRS 
31 Lawson Avenue 
Milton Park, Harare 
ZIMBABWE 
Phone: 263-2422-57066 
E-mail: pmukwekwerere@uz-ctrc.org 
 
Cornelius Munyanga, MD 
Malawi CRS 
UNC-Project Malawi, Tidziwe Centre, 
along 100 Mzimba road 
KCH Campus, Lilongwe, Malawi 
P.O. Box A-104 
Lilongwe 0000 
MALAWI 
Phone: 265-1755-056 
E-mail: cmunyanga@unclilongwe.org 
 
Sydney Ramirez, MD, PhD 
La Jolla Institute for Immunology and 
University of California, San Diego 
9420 Athena Circle 
La Jolla, CA 92037 
Phone: 916-835-9080 
E-mail: sramirez@lji.org 
 
Immunology Investigators 
Shane Crotty, PhD 
La Jolla Institute for Immunology and 
University of California, San Diego 
9420 Athena Circle 
La Jolla, CA 92037 
Phone: 858-642-1620 
Fax: 858-752-6985 
E-mail: shane@lji.org
Immunology Investigators (Cont’d) 
Alessandro Sette, DrBiolSci 
La Jolla Institute for Immunology and 
University of California, San Diego 
9420 Athena Circle 
La Jolla, CA 92037 
Phone: 858-752-6902 
Fax: 858-752-6985 
E-mail: alex@lji.org 
 
Daniela Weiskopf, PhD 
La Jolla Institute for Immunology 
9420 Athena Circle 
La Jolla, CA 92037 
Phone: 858-752-6902 
Fax: 858-752-6985 
E-mail: dweiskopf@lji.org 
 
Field Representatives 
Matthew Newell, BSN, RN, CCRN 
UNC Global Research Group 
Bioinformatics Suite 2100,  
130 Mason Farm Road, CB #7215 
Chapel Hill, NC 27599-7215 
Phone: 919-843-6929 
Fax: 919-966-8928 
E-mail: matthew_newell@med.unc.edu 
 
Susan Pedersen, RN, BSN 
University of North Carolina Global HIV 
Prevention and Treatment CTU 
Bioinformatics Building, Suite 2100 
130 Mason Farm Road 
Chapel Hill, NC 27599-7215 
Phone: 919-966-6713 
Phone: 919-966-6712 
E-mail: spederse@med.unc.edu 
 
Laboratory Technologists 
Brian Greenfelder, BA 
Ohio State University CRS 
Division of Infectious Diseases 
Department of Internal Medicine 
Starling Loving B002 
320 West 10th Avenue 
Columbus, OH 43210 
Phone: 614-293-8938 
Fax: 614-293-5810 
E-mail: brian.greenfelder@osumc.edu

 
9 
A5404 
FINAL VERSION 3.0  
 
PROTOCOL TEAM ROSTER (Cont'd) 
30Nov2022 
 
Laboratory Technologists (Cont'd) 
Cheryl Jennings, BS 
Rush University Medical Center 
Research Core Laboratory - CRRL 
859 Jelke Building 
1750 West Harrison Street 
Chicago, IL 60612 
Phone: 312-942-5954 
E-mail: cheryl_jennings@rush.edu 
 
Community Scientific Subcommittee (CSS) 
Jan Kosmyna, MIS, RN, CCRP 
Case CRS 
10041 Brookside Circle 
North Royalton, OH 44133 
E-mail: jankosmyna@gmail.com 
 
International Site Specialist 
Akbar Shahkolahi, PhD 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3318 
E-mail: akbar.shahkolahi@dlhcorp.com 
 
Industry Representative 
Randall Hyer, MD, PhD, MPH 
SVP Global Medical Affairs 
Moderna Global Headquarters 
200 Technology Square 
Cambridge, MA 02139 
Phone: 202-330-1160 
E-mail: randall.hyer@modernatx.com 
 
Laboratory Data Managers 
Kevin Knowles, MA, PhD 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, Ext. 7238 
E-mail: knowles@frontierscience.org 
 
Laboratory Data Managers (Cont'd) 
Philip Marzinek 
ACTG Data Management Center 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 
E-mail: marzinek@frontierscience.org 
 
Laboratory Specialists 
Kathie Ferbas, PhD 
ACTG Laboratory Center 
University of California Los Angeles 
675 Charles E. Young Drive South 
MacDonald Research Laboratory 
Los Angeles, CA 90095 
Phone: 310-780-3639 
E-mail: kferbas@milabcentral.org 
 
William A. Murtaugh, MPH 
ACTG Laboratory Center 
University of California Los Angeles 
11075 Santa Monica Boulevard, Suite #200 
Los Angeles, CA 90025 
Phone: 310-794-9894 
E-mail: wmurtaugh@milabcentral.org 
 
 

 
10 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teama5404@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teama5404@fstrf.org. A 
response should generally be received within 24 hours (Monday through Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5404 e-mail group. 
Include the protocol number in the e-mail subject line.  
• 
Send an e-mail message to actg.user.support@fstrf.org.  
 
Clinical Management:  
For questions concerning entry criteria, toxicity management, concomitant medications, and co-
enrollment, contact the Clinical Management committee (CMC).  
• 
Send an e-mail message to actg.cmca5404@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to immunologic, virologic, or pharmacologic laboratory tests, 
contact the Protocol Immunologist, Virologist, or Pharmacologist.  
• 
Send an e-mail message to actg.teama5404@fstrf.org (ATTENTION: Scott Sieg, 
Immunologist; Jonathan Li, Virologist; Courtney Fletcher, Pharmacologist). 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the 
data manager. Completion guidelines for eCRFs and participant-completed CRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact [Sara 
Sieczkarski] directly.  
• 
For other questions, send an e-mail message to actg.teama5404@fstrf.org (ATTENTION: 
Sara Sieczkarski).  
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration  
For randomization/participant registration questions or problems and study identification number 
SID lists:  
• 
Send an e-mail message to rando.support@fstrf.org or call the DMC Randomization Desk at 
716-834-0900, extension 7301.  
 
DMC Portal and Medidata Rave Problems  
Contact DMC User Support. 
• 
Send an e-mail message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 

 
11 
A5404 
FINAL VERSION 3.0  
 
STUDY MANAGEMENT (Cont'd) 
30Nov2022 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist.  
• 
Send an e-mail message to actg.teama5404@fstrf.org (ATTENTION: Preeti Dhillon). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send an e-mail message to ACTGNCC@dlhcorp.com. 
Electronic copies can be downloaded from the ACTG website at https://www.actgnetwork.org. 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation at US sites contact the Clinical Trials Specialist.  
• 
Send an e-mail message to actg.teama5404@fstrf.org (ATTENTION: Preeti Dhillon). 
 
For questions related to protocol activation at non-US sites contact the ACTG Site Coordination 
Group.  
• 
Send an email message to actgsitecoordination@dlhcorp.com.  
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, 
contact [Justine Beck and Kelly Parsons], Protocol Pharmacists, at 301-496-8213 or send an e-
mail message to justine.beck@nih.gov and kelly.parsons@nih.gov.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
The IND number will be available on the protocol-specific web page (PSWP) within 30 days of 
the submission to the Food and Drug Administration (FDA). For any questions related to the 
IND submission, contact the DAIDS RSC at Regulatory@tech-res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Telephone Calls 
Sites are responsible for documenting telephone calls made to A5404 team members.  
• 
Send an e-mail message to actg.teama5404@fstrf.org. 
 

 
12 
A5404 
FINAL VERSION 3.0  
 
STUDY MANAGEMENT (Cont'd) 
30Nov2022 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 

 
13 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
Ab 
antibody 
ACTIV 
Accelerating COVID-19 Therapeutic Interventions and Vaccines  
AE  
adverse event  
AESI 
adverse event of special interest 
COVID-19 
coronavirus disease 2019 
CRS 
clinical research site 
EAE 
expedited adverse event 
eCRF 
electronic case report form 
EUA 
Emergency Use Authorization 
FDA 
US Food and Drug Administration 
Investigational therapy  
ACTIV-2/A5401 active treatment 
LPC 
lab processing chart 
MOPS 
Manual of Procedures 
mRNA 
messenger ribonucleic acid 
NAb 
neutralizing antibody 
NP 
nasopharyngeal 
PBMC 
peripheral blood mononuclear cell 
PID 
patient identification number 
PSWP 
protocol-specific web page 
SAE  
serious adverse event  
SARS-CoV-2  
Severe Acute Respiratory Syndrome coronavirus 2  
Select therapy 
ACTIV-2/A5401 investigational therapy or corresponding placebo 
SMC 
Study Monitoring Committee 
SOE 
Schedule of Evaluations 
 

 
14 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
SCHEMA 
 
A5404 
SARS-CoV-2 Immune Responses after COVID-19 Therapy and Subsequent Vaccine 
 
 
DESIGN 
A5404 is a phase IV, open-label study. The objective of A5404 is to 
evaluate how prior investigational therapy for COVID-19 versus 
comparator (placebo or active comparator) affects vaccine response. 
 
Eligible A5404 participants include:  
• 
Cohort 1 (ACTIV-2/A5401 cohort): Participants of ACTIV-2/A5401 
who received an investigational therapy or its comparator (placebo or 
active comparator).  
• 
Cohort 2 (SARS-CoV-2-naïve cohort): Persons without prior history 
of SARS-CoV-2 infection (non-A5401 participants).  
 
Cohort 1 participants will be offered study-provided standard dosing of 
the Moderna mRNA-1273 vaccine, or will receive a community-provided 
mRNA-based COVID-19 vaccine (e.g., Moderna or Pfizer). Cohort 1 
participants will receive their mRNA-based COVID-19 vaccine 30-240 
days after receiving their last dose of a select ACTIV-2/A5401 
investigational therapy, or its comparator. Cohort 2 participants will 
receive study-provided standard dosing of the Moderna mRNA-1273 
vaccine. 
 
All participants will have blood collected and immune responses 
measured before first vaccine dose (if feasible), at second dose of 
vaccine (e.g., 28 days later; if feasible), and at 56 (if feasible), 140, 365, 
and 730 days after their first vaccine dose. 
 
DURATION 
 
730 days. 
 
SAMPLE SIZE 
Cohort 1: 70 participants from each ACTIV-2/A5401 select therapy group 
(combining recipients in ACTIV-2/A5401 on a particular investigational 
therapy, corresponding active comparator, or placebo).  
 
 
And 
 
Cohort 2: Up to 70 participants without prior history of SARS-CoV-2 
infection (SARS-CoV-2-naïve, non-A5401 participants) per select therapy 
group from ACTIV-2/A5401, based on vaccine supply at each A5404 site. 
For example, up to 350 SARS-CoV-2-naïve participants may enroll in 
A5404 if five A5401 select therapy groups are included.  
 
The total sample size will depend on how many select therapy groups are 
evaluated from ACTIV-2/A5401.  

 
15 
A5404 
FINAL VERSION 3.0  
 
SCHEMA (Cont'd) 
30Nov2022 
 
 
If up to 70 Phase II participants in the A5401/ACTIV-2 trial from each 
therapy group are not able to be enrolled, then Phase III participants in 
the A5401/ACTIV-2 trial from that select therapy group can be enrolled 
until full enrollment is achieved. However, Phase II participants are 
preferred.  
 
POPULATION 
Cohort 1: ACTIV-2/A5401 trial participants who received an 
investigational therapy or its active comparator/placebo.  
 
And 
 
Cohort 2: Persons without prior history of SARS-CoV-2 infection.  
 
REGIMEN  
Cohort 1: ACTIV-2/A5401 participants 
Participants will receive one of the following regimens:  
Cohort 1a: Moderna mRNA-1273 COVID-19 vaccine, 100 µg (0.5 mL) to 
be administered intramuscularly (IM) at Entry and Day 28. Both doses 
will be provided by the study. 
 
Or 
 
Cohort 1b: Participants will receive a two-dose series of a 
community-provided mRNA-based COVID-19 vaccine that has received 
FDA EUA or FDA approval (e.g., Moderna or Pfizer). Vaccine will not be 
provided by the study. 
 
NOTE: These participants may enter the study before their first 
vaccine dose, after their first vaccine dose, or after their second 
vaccine dose.  
 
Or 
 
Cohort 1c: Participants will receive their first Moderna mRNA-1273 
COVID-19 vaccine dose in the community. Their second Moderna 
mRNA-1273 dose will be provided by the study (100 µg [0.5 mL] to be 
administered IM 28 days after their first dose).  
 
NOTE: These participants may enter the study before or after their 
first vaccine dose.  
 
Cohort 2: Participants without prior history of SARS-CoV-2 infection  
Participants will receive the following study-provided regimen: 
Moderna mRNA-1273 COVID-19 vaccine, 100 µg (0.5 mL) to be 
administered IM at Entry and Day 28. 

 
16 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
 
1.0 
STUDY OBJECTIVES 
 
1.1 
Primary Objective 
 
1.1.1 To estimate the difference in neutralizing antibody (NAb) response to mRNA-
based COVID-19 vaccine among participants with prior SARS-CoV-2 infection 
who received investigational therapy exposure compared to participants without 
prior investigational therapy exposure (placebo for investigational therapy or 
active comparator). 
 
1.2 
Secondary Objectives 
 
To explore the safety of mRNA-based COVID-19 vaccines among participants with prior 
COVID-19 who received investigational therapy or its comparator for COVID-19 and 
persons who are SARS-CoV-2 naïve. 
 
1.3 
Other Objectives 
 
1.3.1 To explore the difference in humoral and cellular immune responses to 
mRNA-based COVID-19 vaccines among participants with prior COVID-19 
who received investigational therapy compared to participants without 
prior investigational therapy (placebo or corresponding active comparator) 
exposure and persons who are SARS-CoV-2 naïve. 
 
1.3.2 To explore the difference in humoral and cellular immune responses, 
including NAb levels, B and T cell responses, and serologic responses to 
COVID-19 vaccination by duration of time of vaccination from prior 
investigational therapy versus active comparator/placebo exposure and 
compared to persons who are SARS-CoV-2 naïve. 
 
1.3.3 To explore whether investigational therapy drug levels at time of first 
COVID-19 vaccination is associated with humoral and cellular responses in 
participants with prior COVID-19 who received investigational therapy or its 
comparator for COVID-19. 
 
1.3.4 To explore B and T cell exhaustion before and after COVID-19 vaccination 
in persons with prior COVID-19 who received investigational therapy or 
corresponding comparator for COVID-19 and persons who are SARS-CoV-2 
naïve. 
 
1.3.5 To explore whether vaccine-associated symptoms are associated with immune 
responses to the vaccine. 
 
1.3.6 To explore whether investigational therapy affects humoral and cellular 
responses to SARS-CoV-2 infection before first dose of vaccine is administered. 
 

 
17 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
 
1.3.7 In participants with prior COVID-19, to explore whether COVID-19 disease 
severity affects humoral and cellular responses to SARS-CoV-2 infection. 
 
1.3.8 In participants with prior COVID-19, to explore whether presence of viral 
resistance to the investigational therapy (measured in ACTIV-2/A5401) affects 
humoral and cellular responses to SARS-CoV-2 infection before and after 
vaccine. 
 
1.3.9 In participants with prior COVID-19, to explore whether presence of SARS-CoV-2 
IgG or IgM (measured in ACTIV-2/A5401) affects humoral and cellular responses 
to SARS-CoV-2 before and after vaccine administration. 
 
1.3.10 To explore whether host characteristics (i.e., age, race, ethnicity, history of 
immunosuppression, body mass index [BMI], co-morbidities) affect humoral and 
cellular responses to SARS-CoV-2 vaccination. 
 
1.3.11 In participants with prior COVID-19, to explore whether duration of COVID-19 
symptoms at time of ACTIV-2/A5401 enrollment affects humoral and cellular 
responses to SARS-CoV-2 vaccination. 
 
1.3.12 In participants with prior COVID-19, to explore dynamics of humoral and cellular 
immune responses after first and second vaccine dose in relation to 
demographic, treatment and COVID-19 symptom progression, and vaccine-
associated symptom covariates.  
 
1.3.13 To explore whether baseline immune signatures (e.g., gene expression, 
proteomic) predict humoral and cellular responses to the vaccine. 
 
1.3.14 To explore differences in change in humoral and cellular immune responses after 
COVID-19 vaccination between people who previously had COVID-19 and 
people who previously did not have COVID-19. 
 
1.3.15 To explore differences in change in humoral and cellular immune responses after 
COVID-19 vaccination between hospitalized (e.g., ACTIV-3) and non-
hospitalized (e.g., ACTIV-2) people who previously had COVID-19 and who 
received investigational therapy or comparator.  
 
1.3.16 In participants with prior COVID-19, to characterize and evaluate the role(s) of 
SARS-CoV-2 B and T cell adaptive immunity in protection versus pathogenesis 
in COVID-19 and subsequent vaccine response. 
 
1.3.17 To determine the durability of SARS-CoV-2 specific B and T cell memory 
immunity and its correlation with disease severity and vaccine response. 
 
1.3.18 To investigate the relationship between inflammatory markers measured just 
prior to COVID-19 vaccinations and immune responses to vaccine in participants 

 
18 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
with prior COVID-19 who had received prior investigational therapy or active 
comparator or placebo for COVID-19.  
 
1.3.19 In participants with prior COVID-19, to evaluate change in participant-reported 
symptoms of post-acute sequelae of SARS-CoV-2 (PASC) infection after COVID-
19 vaccination. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Antibody and Non-Antibody-Based Therapies for COVID-19 
COVID-19 has exacted a deadly toll on the US and the world. New treatments and 
vaccines are promising, but questions remain on how these biomedical interventions 
interact with each other. One of the first antiviral therapeutics to show promise has been 
antibody-based (Ab) therapies, such as monoclonal antibodies [1, 2]. Currently, a 
handful of monoclonal antibody therapies and vaccines have been granted emergency 
use authorization (EUA) by the FDA [3-6], and there are many more in development. 
Given their mechanism of action, such Ab therapies may impact the efficacy of 
subsequent SARS-CoV-2 vaccinations. Specifically, it remains unclear if treatment of 
COVID-19 with an Ab directed against SARS-CoV-2 proteins (e.g., Spike) impedes or 
blunts the development of humoral and cellular immune responses to a vaccine—
responses that can augment and prolong immune responses produced by natural 
infection.  
 
Other types of treatments (e.g., protease inhibitors, small molecule viral enzyme 
inhibitors, interferon) given during early COVID-19 may also impact immune responses 
to COVID-19 vaccination [7]. For example, abrogating a SARS-CoV-2 infection with a 
direct antiviral or modulating immune response with immunomodulatory drugs may have 
unexpected effects on future COVID-19 vaccine responses [8]. Therefore, we will 
examine the impact of vaccination after COVID-19 and treatment. 
 
ACTIV-2/A5401 
ACTIV-2/A5401 is a randomized, controlled adaptive platform trial to evaluate 
investigational therapies (Ab-therapies and non-Ab-therapies) for the treatment of 
outpatient COVID-19. The trial starts with a Phase II evaluation that transitions to a  
Phase III evaluation for therapies meeting safety and efficacy criteria in Phase II. The 
first therapy studied in this trial was a monoclonal antibody from Eli Lilly called 
bamlanivimab; 222 participants were enrolled in the Phase II portion of this trial. Half 
received bamlanivimab and half received placebo. Based on safety and efficacy data, 
this drug has received EUA for the treatment of outpatient COVID-19. Other Ab 
therapies being studied in the trial include those from Brii Biosciences, AstraZeneca, and 
SAB Biotherapeutics; in addition, non-Ab-therapies such as Camostat mesylate and 
SynAIRGen inhaled interferon beta (SNG001) are also being evaluated. 
 

 
19 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
2.2 
Rationale 
 
Immune Responses 
Early in the pandemic, it was unknown if natural infection with SARS-CoV-2 induced adaptive 
immune responses. Research by our collaborators found that people developed both viral-
specific antibodies and T cell responses [9]. Further investigations found that multiple SARS-
CoV-2 antigens were recognized by CD4+ and CD8+ T cells in these individuals [9]. The 
frequencies of viral antigen-specific T cells corresponded to predicted viral protein 
abundance in infected cells [9]. Analyses in persons followed from acute COVID-19 found 
that a coordinated adaptive immune response consisting of SARS-CoV-2-specific CD4+ and 
CD8+ T cells and NAb was associated with less severe disease [10]. This study also defined 
how most people with COVID-19 had measurable antibody (IgG, IgA, IgM) to the viral Spike 
(S) protein, the receptor binding domain (RBD) of S, and Nucleocapsid (N) protein, as well as 
neutralizing antibody (NAb). Similarly, most participants also had SARS-CoV-2-specific CD4+ 
T cells, CD8+ T cells, and T follicular helper cells to viral S, matrix (M), N, and other viral 
epitopes. Interestingly, correlation analyses demonstrated that viral-specific T cell responses, 
but not NAbs, were associated with COVID-19 severity [10]. Further studies found that most 
participants had durable adaptive immunity to SARS-CoV-2, although heterogeneity was 
observed in the adaptive immune responses including half-lives of SARS-CoV-2 specific 
antibody titers and memory B and CD4+ and CD8+ T cell responses [11]. The same assays 
used in these studies and others will be used in this study [9-15]. This A5404 study will also 
evaluate persons without prior SARS-CoV-2 infection as a comparison group (i.e., SARS-
CoV-2 naïve group) to evaluate vaccine-induced immune responses. Although persons ≥18 
years old may enroll into the SARS-CoV-2 naïve group, the age eligibility for PBMC collection 
is limited to those persons ≥40 years old. This criteria has been added to avoid skewing of 
cellular based assays toward younger participants who have more robust immune responses, 
and less likely to match the ages of participants in ACTIV-2/A5401. Including this SARS-CoV-
2 naïve group should also reduce waste of the Moderna mRNA-1273 COVID-19 vaccine, 
since doses must be delivered within a short timeframe after opening a multidose vial (see 
section 5.2.1 and Manual of Procedures [MOPS] for further description).  
 
We imagine a number of people will be enrolled in the SARS-CoV-2 naïve group with 
prior asymptomatic SARS-CoV-2 infection. These people will still be able to obtain an 
mRNA COVID-19 vaccine, as they would in the community, so they will not be pre-
screened for our study. The A5404 study will assess baseline serology in the context of 
the trial to determine if such participants are evaluable for the sub-analyses of the 
SARS-CoV-2 naïve group, but these analyses will be conducted after the participant has 
enrolled in the trial and received their vaccination. 
 
The team recognizes the value in studying all COVID-19 vaccine types, but increasing 
the types of COVID-19 vaccines in A5404 will decrease the overall number of 
participants receiving the same type of vaccine. This heterogeneity could be an issue as 
there seems to be different NAb dynamics between mRNA versus adenoviral vaccines 
and therefore analyses would be carried out separately. Smaller sample sizes may lead 
to a decrease in precision on the estimated neutralizing antibody (NAb) levels post-
vaccine. Since we will be providing the Moderna mRNA-1273 COVID-19 vaccine, we will 
only evaluate mRNA vaccines. 

 
20 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Reinfection 
As described above, initial SARS-CoV-2 infection elicits human immune responses, and 
it is likely that these responses offer some level of protection from reinfection for some 
time. NAb seems to be an important immune correlate of protection and subsequent 
disease severity [16-18]. It is unclear how these reinfections impact vaccine 
development and long-term efficacy [19]. However, people who have had SARS-CoV-2 
infection can subsequently be reinfected [20], and perhaps active viral infection 
generates a weaker immune response than what can be elicited by a COVID-19 vaccine 
[21]. Due to the lack of close molecular epidemiological surveillance, it remains unclear 
how frequently reinfection occurs [22]. Open questions that remain concerning initial 
infection include identifying exact correlates of immune protection, length of protection 
generated after initial SARS-CoV-2 infection, variability in protection, and whether a 
COVID-19 vaccine can improve a protective immune response generated from a 
previous SARS-CoV-2 infection. Additionally, the optimal time frame to immunize post 
COVID-19 infection has not been fully discerned nor is it known if predictors of immune 
responses to vaccination, such as baseline inflammation, are associated with immune 
responses to COVID-19 mRNA vaccination [23]. 
 
Currently, the CDC recommends that people with prior COVID-19 receive a currently 
authorized COVID-19 vaccine, even though recent data suggest that the risk of 
reinfection is low following initial infection [24]. It is noted, however, that the risk of 
reinfection may increase over time due to waning immunity [24]. The optimal timing of a 
vaccination to boost such waning immunity is unknown and is the rationale for the 30-
240-day window after receiving their last dose of ACTIV-2/A5401 select therapy (i.e., 
post-infection) for vaccination in the proposed study. Understanding how SARS-CoV-2 
immune responses develop and then wane after vaccination may be important for 
developing future guidelines for re-vaccination. 
 
Study Overview 
We will recruit ACTIV-2/A5401 participants (Cohort 1) and persons without prior history 
of SARS-CoV-2 infection (Cohort 2) into the A5404 study. We will enroll participants 
who elect to receive mRNA vaccines outside of A5404 to maximize the number of 
ACTIV-2 participants from whom we can measure vaccine responses following 
investigational agent therapy for ACTIV-2 study participants. Participants will be offered 
open-label standard dosing of Moderna COVID-19 vaccine [21] or will obtain mRNA-
based COVID-19 vaccination in the community outside of the study. Cohort 2 
participants will only be enrolled at sites enrolling Cohort 1 participants. People 
who participate in the study will be followed longitudinally for humoral and cellular 
immune dynamics.  
 
Closed to Accrual 
Accrual closed on February 25, 2022, due to slow enrollment and difficulty 
enrolling new participants into the various study cohorts. Vaccine responses will 
be studied in the 43 participants who enrolled. 
 

 
21 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
3.0 
STUDY DESIGN 
 
A5404 is a phase IV, open-label study. Eligible participants include: 
• 
Cohort 1: Participants of ACTIV-2/A5401 who received selected investigational 
therapy or its comparator (active or placebo). 
• 
Cohort 2: Persons without a prior history of SARS-CoV-2 infection (non-A5401 
participants) who have not yet received a COVID-19 vaccine. 
 
The objective of the study is to evaluate whether prior investigational therapy versus 
placebo or active comparator in ACTIV-2/A5401 affects vaccine response. Cohort 1 
participants will be offered the Moderna mRNA-1273 COVID-19 vaccine (Cohorts 1a 
[full series to be administered through study] and 1c [first dose received in the 
community, second dose to be administered through the study]) or receive an 
mRNA-based COVID-19 vaccine in the community (Cohort 1b [both doses received in 
the community] or Cohort 1c [first dose received in the community, second dose 
in the study]), with the first vaccine dose administered 30-240 days after receiving 
their last dose of ACTIV-2/A5401 select therapy (investigational agent or active 
comparator or placebo). Community-provided mRNA-based COVID-19 vaccines must 
have received FDA EUA or FDA approval. Cohort 2 participants will be offered standard 
dosing of the study-provided Moderna mRNA-1273 COVID-19 vaccine. Participants will 
have blood collected and immune responses measured before the first vaccine dose (if 
feasible), and before the second dose of vaccine (e.g., 28 days later for Moderna 
vaccine and 21 days later for Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine if 
given in the community) (if feasible), and 56 (if feasible), 140, 365, and 730 days after 
their first vaccine dose (Figure 3.0-1).  
 
 
Figure 3.0-1: This schema includes common assessments for ACTIV-2/A5401 
participants in both phases 2 and 3 (panel A). If possible, blood will be collected before 

 
22 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
each vaccine dose is administered and 56, 140, 365, and 730 days after their first 
vaccine dose (panel B). If possible, participants will be contacted 7 days after each 
vaccine dose to grade vaccine-associated symptoms. 
 
Up to 70 participants from Cohort 1 will be enrolled from each ACTIV-2/A5401 select 
therapy group along with 350 participants from Cohort 2 without prior SARS-CoV-2 
infection (i.e., SARS-CoV-2-naïve, non-ACTIV-2/A5401 participants). The total sample 
size will depend on how many select therapy groups are evaluated in ACTIV-2/A5401.  
 
If a sufficient number of Phase II participants in the A5401/ACTIV-2 trial from a select 
therapy group are not able to be enrolled, then Phase III participants in the 
A5401/ACTIV-2 trial from that select therapy group can be enrolled until full enrollment is 
achieved. However, Phase II participants are preferred. 
 
As available, PBMC from days 0, 7, 28, and week 24 from Cohort 1 participants will be 
used for this study. Plasma from each of the time points that blood for PBMC is collected 
will also be used for this study. Samples will be used to study the adaptive immune 
response to SARS-CoV-2 during acute and convalescent COVID-19 in the context of 
treatment versus active comparator/placebo receipt during acute COVID-19. This will 
also connect to the vaccination arm of the ACTIV-2/3 studies, as feasible.  
 
The study will provide important information on the use of mRNA-based COVID-19 
vaccines for persons after SARS-CoV-2 infection and for persons who received 
investigational therapy, including monoclonal antibodies, for COVID-19. Study outcome 
measures are provided in section 10.2 in line with the Study Objectives.  
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Ability and willingness of participant (or legally authorized representative) to 
provide informed consent prior to initiation of any study procedures.  
 
4.1.2 Individuals ≥18 years of age 
 
4.1.3  Cohort 1: Receipt of all selected investigational therapy or active 
comparator/placebo for that therapy.  
 
NOTES:  
• 
Selected investigational therapies will be posted on the A5404 PSWP. 
• 
For participants who received camostat or the active 
comparator/placebo for camostat: Receipt of ≥50% of the doses 
indicated in ACTIV-2/A5401. 
 
4.1.4 Cohort 1a: Receipt of the last dose of investigational therapy or active 
comparator/placebo for that therapy ≥30 days and ≤240 days prior to study 
entry. 

 
23 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
4.1.5 Cohorts 1b and 1c: Receipt of the last dose of investigational therapy or active 
comparator/placebo for that therapy ≥30 and ≤240 days prior to receipt or 
planned receipt of the first dose of community-provided vaccine. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Cohort 1: Self-report of prior receipt of a non-mRNA-based COVID-19 vaccine. 
 
4.2.2 Cohort 1: Self-report of receipt of the first dose of an mRNA-based COVID-19 
vaccine 140 days or more before A5404 enrollment.  
 
4.2.3 Cohort 1: Self-report of a second SARS-CoV-2 infection after the infection that 
qualified the participant for ACTIV-2/A5401.  
 
4.2.4 Cohort 2: Self-report of receipt of any prior COVID-19 vaccine. 
 
4.2.5 Cohort 2: Known prior history of any SARS-CoV-2-positive test (e.g., PCR test, 
Nucleic Acid Amplification Test [NAAT], antigen test, serology test). 
 
4.2.6 Cohorts 1a and 1c and Cohort 2: Known allergy to any component of the 
Moderna COVID-19 vaccine. 
 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support 
Center (RSC). The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all of the required documents have been received.  
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by 
the DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all required documents have been received. Site-specific ICF(s) 
WILL NOT be reviewed or approved by the DAIDS PRO. Sites will receive an 
Amendment Registration Notification when the DAIDS PRO receives a complete  

 
24 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
registration packet. A copy of the Amendment Registration Notification should be 
retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual.  
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant (or, when necessary, the legal 
representative if the participant is under guardianship) will be asked to read and 
sign the approved protocol consent form.  
 
Participants from whom a signed informed consent has been obtained may be 
screened and enrolled, if they otherwise qualify. An ACTG Screening Checklist 
must be entered through the DMC Participant Enrollment System.  
 
4.3.2 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found 
on the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment.  
 
4.3.3 Participant Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database.  
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures.  
 
4.4 
Co-enrollment Guidelines  
 
For specific questions and approval for co-enrollment in other studies, sites should first 
check the PSWP or contact the protocol team via e-mail as described in the Study 
Management section. 
 
5.0 
STUDY TREATMENT 
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimen and Duration  
 
Cohort 1: ACTIV-2/A5401 participants 
Participants will receive one of the following regimens:  

 
25 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Cohort 1a: Moderna mRNA-1273 COVID-19 vaccine, 100 µg (0.5 mL) to be 
administered intramuscularly (IM) at Entry and Day 28. Both doses will be 
provided by the study. 
Or 
Cohort 1b: Participants will receive a two-dose series of a community-provided 
mRNA-based COVID-19 vaccine that has received FDA EUA or FDA approval 
(e.g., Moderna or Pfizer). Vaccine will not be provided by the study. 
NOTE: These participants may enter the study before their first vaccine 
dose, after their first vaccine dose, or after their second vaccine dose. 
Or 
Cohort 1c: Participants will receive their first Moderna mRNA-1273 COVID-
19 vaccine dose in the community. Their second Moderna mRNA-1273 dose 
will be provided by the study (100 µg [0.5 mL] to be administered IM 28 
days after their first dose).  
 
NOTE: These participants may enter the study before or after their first 
vaccine dose.  
Or 
Cohort 2: Participants without prior history of SARS-CoV-2 infection  
Participants will receive the following study-provided regimen: Moderna 
mRNA-1273 COVID-19 vaccine, 100 µg (0.5 mL) to be administered IM at 
Entry and Day 28. 
 
5.1.2  Administration of study-provided Moderna mRNA-1273: 
 
Moderna mRNA-1273 COVID-19 vaccine will be administered IM in the deltoid, 
using standard IM injection technique. 
 
Guidance for administration of the doses in each Moderna mRNA-1273 COVID-
19 vial is provided in the MOPS.  
 
5.2 
Study Product Formulation and Preparation 
 
5.2.1 Formulation and Storage 
 
The Moderna mRNA-1273 COVID-19 vaccine is supplied as a frozen suspension, 
stored between -50°C to -15°C, in multi-dose vials, and does not contain a 
preservative. Protect from light. Do not store on dry ice or below -50°C. The 
Moderna mRNA-1273 COVID-19 vaccine is white to off-white suspension. It may 
contain white or translucent product-related particulates.  
 
The Moderna mRNA-1273 COVID-19 vaccine must be thawed prior to 
administration. After thawing, a maximum of 10-11 doses (0.5 mL each) can be 

 
26 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
withdrawn from each vial, dependent on the syringes and needles used. Vials 
can be stored refrigerated between 2° to 8°C for up to 30 days prior to first use. 
Do not refreeze once thawed. Unpunctured vials may be stored between 8° to 
25°C for up to 24 hours. Do not refreeze. After the first dose has been withdrawn,  
the vial should be held between 2° to 25°C and discarded after 12 hours. Do not 
refreeze. 
 
5.2.2 Preparation 
 
Pharmacists must follow appropriate aseptic technique and consider sterile 
preparation procedures/guidance as outlined in USP. Pharmacists must also 
follow the requirements of their country, institution, and pharmacy regulatory 
authority regarding these procedures. Local regulations and site institutional 
policies and procedures for use of personal protective equipment, such as 
gloves, gowns, face masks and safety glasses, must be followed. 
 
Any empty vials or unused portion of entered vials of the Moderna mRNA-1273 
COVID-19 vaccine should be discarded in a biohazard containment bag and 
incinerated or autoclaved in accordance with institutional or pharmacy policy. 
 
1. Remove one vial of the Moderna mRNA-1273 COVID-19 vaccine from the 
freezer and thaw either in the refrigerator or at room temperature. If thawed in 
the refrigerator, the vial must be kept between 2°C and 8°C for two hours and 
30 minutes. If thawed at room temperature, the vial must be kept between 
15°C and 25°C for one hour. Once thawed, the vial may be kept between 8°C 
and 25°C for up to 24 hours. Do NOT refreeze.  
2. With the vial upright, gently swirl the vaccine. Do NOT shake. Do NOT dilute 
the vaccine. 
3. Examine the vaccine. It should be white to off-white in color and may contain 
white or translucent product-related particulates. Do not use if liquid contains 
other particulate matter or is discolored. 
4. Withdraw 0.5 mL of vaccine into an appropriately sized syringe. When the 
stopper of the vial is punctured to start preparation, record this as the vaccine 
preparation time. Assign a 12-hour beyond use date and time from the 
preparation time.  
 
The prepared vaccine should be administered immediately. If immediate 
administration is not possible, the prepared vaccine may be stored and 
refrigerated at 2°C to 8°C or left at ambient (room) temperature at 15°C to 
25°C for up to 12 hours. Keep out of direct sunlight.  
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
The Moderna mRNA-1273 COVID-19 vaccine will be provided through the US 
Government Response to COVID-19 and available through the NIAID Clinical 

 
27 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Research Products Management Center (CRPMC). The site pharmacist should 
obtain the study product(s) for this protocol by following the instructions in the 
manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks.  
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. At US clinical 
research sites (CRSs), all unused study products must be returned to the NIAID 
CRPMC (or as otherwise directed by the sponsor) after the study is completed or 
terminated. The procedures to be followed are provided in the manual Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks. At non-US CRSs, 
the site pharmacist must follow the instructions in the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks for the destruction of unused 
study products. 
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the ACTG Precautionary and Prohibited 
Medications Database located at http://tprc.pharm.buffalo.edu/home/di_search/. 
 
5.4.1 Required Medications 
 
None. 
 
5.4.2 Prohibited Medications 
 
None.  
 
5.4.3 Precautionary Medications 
 
Antipyretic or analgesic medications (e.g., acetaminophen, non-steroidal anti-
inflammatory drugs [NSAIDS]) or antihistamines can be taken for the 
symptomatic treatment of post-vaccination local or systemic symptoms, but 
prophylactic administration of these medications to prevent post-vaccination 
symptoms is not currently recommended by the CDC [24]. If such medications 
are used before or after vaccination, then they should be recorded as 
concomitant medications (see section 6.3.5). 

 
28 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
 
6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations 
 
Table 6.1-1: Study-provided Moderna COVID-19 Vaccine Schedule of Evaluations for ACTIV-2/A5401 Participants (Cohort 1a)  
Evaluation 
Screening 
Study Entry 
See section 6.2.2 
Post-Vaccination #1  
Follow-up/Day 7 
Day 28 
Post-Vaccination #2  
Follow-up/Day 35 
Day 56 
Day 140 
Day 365 (1 Year) 
Day 730 (2 Years) 
Premature Study D/C  
Event-Driven Evaluation: 
SARS-CoV-2 Infection 
Visit Window (days) 
-28 
 
7-14 days 
post-vaccine 
+7 
7-14 days 
post-
vaccine 
+7 ±7 
±28 
 
+14 
Visit Type 
(P: In Person, R: Remote) 
R/P 
P 
R 
P 
R 
P 
P 
P 
P 
P 
P 
Documentation of 
ACTIV-2/A5401 participation and receipt of 
investigational therapy or active comparator/placebo for 
investigational therapy 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testing 
 
X 
 
X 
 
If pregnancy 
suspected 
X 
X 
Vaccine Administration (1See section 6.2.3.2 See section 
6.2.4) 
 
X 
 
X1 
 
 
 
 
 
X2 
 

 
29 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Evaluation 
Screening 
Study Entry 
See section 6.2.2 
Post-Vaccination #1  
Follow-up/Day 7 
Day 28 
Post-Vaccination #2  
Follow-up/Day 35 
Day 56 
Day 140 
Day 365 (1 Year) 
Day 730 (2 Years) 
Premature Study D/C  
Event-Driven Evaluation: 
SARS-CoV-2 Infection 
Visit Window (days) 
-28 
 
7-14 days 
post-vaccine 
+7 
7-14 days 
post-
vaccine 
+7 ±7 
±28 
 
+14 
Visit Type 
(P: In Person, R: Remote) 
R/P 
P 
R 
P 
R 
P 
P 
P 
P 
P 
P 
Vaccine Symptom Screen 
 
 
X 
 
X 
 
 
 
 
 
 
Stored Plasma 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Stored Serum 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Stored PBMCs  
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Stored PAXgene RNA Tube 
 
X 
 
X 
 
 
 
 
 
 
 
Documentation of New Active SARS-CoV-2 Infection by 
Antigen or Nucleic Acid Test 
 
 
 
 
 
 
 
 
 
 
X 
Nasopharyngeal (NP) Swab Collection (See section 
6.3.11) 
 
 
 
 
 
 
 
 
 
 
X 
ACTIV-2/A5401 Investigational Therapy or Active 
Comparator/Placebo Questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 

 
30 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Table 6.1-2: Schedule of Evaluations for ACTIV-2/A5401 Participants Who Will Receive a Two-dose Series of a 
Community-provided mRNA-based COVID-19 Vaccine (Cohort 1b) 
Evaluation 
Screening 
See section 6.2.1 
Study Entry 
See section 6.2.2 
Post-Vaccination #1 
Follow-up 
See section 6.2.3 
Day of 2nd dose of 
vaccine 
Post-Vaccination #2  
Follow-up 
56 Days  
Post-Vaccination #1  
See section 6.2.3 
140 Days  
Post-Vaccination #1 
See section 6.2.3 
365 Days (1 Year) 
Post-Vaccination #1 
730 Days (2 Years) 
Post-Vaccination #1 
Premature Study D/C  
Event-Driven Evaluation: 
SARS-CoV-2 Infection 
Visit Window (days) 
-28 
 
7-14 
days 
post-1st 
dose of 
vaccine 
-3 
7-14 
days 
post-2nd 
dose of 
vaccine 
+7 
±7 
±28 
 
+14 
Visit Type 
(P: In Person, R: Remote) 
R/P 
P 
R 
P 
R 
P 
P 
P 
P 
P 
P 
Documentation of ACTIV-2/A5401 
participation and receipt of investigational 
therapy or active comparator/placebo for 
investigational therapy 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
X 
X 
 
X3 
 
X 
X 
X 
X 
X 
X 
Pregnancy Testing 
 
X 
 
X3 
 
If pregnancy suspected 
X 
X 
Documentation of Community-Provided 
COVID-19 Vaccination(s) (see section 
6.3.7) 
 
X1 
 
X2 
 
X3 
 
 
 
 
 
Vaccine Symptom Screen (see section 
6.3.8) 
 
X1 
X2 
 
X3 
 
 
 
 
 
 

 
31 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Evaluation 
Screening 
See section 6.2.1 
Study Entry 
See section 6.2.2 
Post-Vaccination #1 
Follow-up 
See section 6.2.3 
Day of 2nd dose of 
vaccine 
Post-Vaccination #2  
Follow-up 
56 Days  
Post-Vaccination #1  
See section 6.2.3 
140 Days  
Post-Vaccination #1 
See section 6.2.3 
365 Days (1 Year) 
Post-Vaccination #1 
730 Days (2 Years) 
Post-Vaccination #1 
Premature Study D/C  
Event-Driven Evaluation: 
SARS-CoV-2 Infection 
Visit Window (days) 
-28 
 
7-14 
days 
post-1st 
dose of 
vaccine 
-3 
7-14 
days 
post-2nd 
dose of 
vaccine 
+7 
±7 
±28 
 
+14 
Visit Type 
(P: In Person, R: Remote) 
R/P 
P 
R 
P 
R 
P 
P 
P 
P 
P 
P 
Stored Plasma 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Stored Serum 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Stored PBMCs 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Stored PAXgene RNA Tube 
 
X 
 
 
 
 
 
 
 
 
 
Documentation of New Active SARS-CoV-
2 Infection by Antigen or Nucleic Acid 
Test 
 
 
 
 
 
 
 
 
 
 
X 
Nasopharyngeal (NP) Swab Collection 
(See section 6.3.11) 
 
 
 
 
 
 
 
 
 
 
X 
ACTIV-2/A5401 Investigational Therapy or 
Active Comparator/Placebo Questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
1If one or both vaccine doses administered prior to entry; 2If vaccination #1 occurs after entry; 3If vaccination #2 occurs 
after entry 
 
 

 
32 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Table 6.1-3: Schedule of Evaluations for ACTIV-2/A5401 Participants Who Will Receive Their First Moderna mRNA-1273 
COVID-19 Vaccine Dose in the Community and Their Second Moderna mRNA-1273 Dose Will Be 
Provided by the Study (Cohort 1c) 
Evaluation 
Screening 
See section 6.2.1 
Study Entry 
See section 6.2.2 
Post-Vaccination #1  
Follow-up 
See section 6.2.3 
Day of 2nd dose of vaccine  
Post-Vaccination #2  
Follow-up 
56 Days  
Post-Vaccination #1 
140 Days  
Post-Vaccination #1 
365 Days (1 Year) 
Post-Vaccination #1 
730 Days (2 Years) 
Post-Vaccination #1 
Premature Study D/C  
Event-Driven Evaluation: 
SARS-CoV-2 Infection 
Visit Window (days) 
-28 
 
7-14 days 
post-1st 
dose of 
vaccine 
-3 
7-14 
days 
post-2nd 
dose of 
vaccine 
+7 
±7 
±28 
 
+14 
Visit Type 
(P: In Person, R: Remote) 
R/P 
P 
R 
P 
R 
P 
P 
P 
P 
P 
P 
Documentation of ACTIV-2/A5401 
participation and receipt of investigational 
therapy or active comparator/placebo for 
investigational therapy 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
X 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testing 
 
X 
 
X 
 
If pregnancy suspected 
X 
X 
Documentation of Community-Provided 
COVID-19 Vaccine Administration  
 
X2 
 
X1 
 
 
 
 
 
 
 
Vaccine Administration (See section 6.2.3)  
 
 
 
X 
 
 
 
 
 
 
 
Vaccine Symptom Screen 
 
 
X1 
 
X 
 
 
 
 
 
 

 
33 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Evaluation 
Screening 
See section 6.2.1 
Study Entry 
See section 6.2.2 
Post-Vaccination #1  
Follow-up 
See section 6.2.3 
Day of 2nd dose of vaccine  
Post-Vaccination #2  
Follow-up 
56 Days  
Post-Vaccination #1 
140 Days  
Post-Vaccination #1 
365 Days (1 Year) 
Post-Vaccination #1 
730 Days (2 Years) 
Post-Vaccination #1 
Premature Study D/C  
Event-Driven Evaluation: 
SARS-CoV-2 Infection 
Visit Window (days) 
-28 
 
7-14 days 
post-1st 
dose of 
vaccine 
-3 
7-14 
days 
post-2nd 
dose of 
vaccine 
+7 
±7 
±28 
 
+14 
Visit Type 
(P: In Person, R: Remote) 
R/P 
P 
R 
P 
R 
P 
P 
P 
P 
P 
P 
Stored Plasma 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Stored Serum 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Stored PBMCs 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Stored PAXgene RNA Tube 
 
X 
 
X 
 
 
 
 
 
 
 
Documentation of New Active SARS-CoV-2 
Infection by Antigen or Nucleic Acid Test 
 
 
 
 
 
 
 
 
 
 
X 
Nasopharyngeal (NP) Swab Collection (see 
section 6.3.11) 
 
 
 
 
 
 
 
 
 
 
X 
ACTIV-2/A5401 Investigational Therapy or 
Active Comparator/Placebo Questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
  1If vaccination #1 occurs after entry; 2If vaccination #1 occurs prior to entry 

 
34 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
 
Table 6.1-4: Study-provided Moderna COVID-19 Vaccine Schedule of Evaluations for Participants Without Prior History of 
SARS-CoV-2 Infection (Cohort 2) 
Evaluation 
Screening 
Study Entry 
See section 6.2.2 
Post-Vaccination #1  
Follow-up/Day 7 
Day 28 
Post-Vaccination #2  
Follow-up/Day 35 
Day 56 
Day 140 
Day 365 (1 Year) 
Day 730 (2 Years) 
Premature Study D/C  
Event-Driven Evaluation: 
SARS-CoV-2 Infection 
Visit Window (days) 
-28 
 
7-14 days 
post-
vaccine 
+7 
7-14 days 
post-
vaccine 
+7 ±7 
±28 
 
+14 
Visit Type 
(P: In Person, R: Remote) 
R/P 
P 
R 
P 
R 
P 
P 
P 
P 
P 
P 
Documentation of no prior history of SARS-CoV-2 
infection by participant self-report 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testing 
 
X 
 
X 
 
If pregnancy 
suspected 
X 
X 
Vaccine Administration (1See section 6.2.3.2 See section 
6.2.4) 
 
X 
 
X1 
 
 
 
 
 
X2 
 
Vaccine Symptom Screen 
 
 
X 
 
X 
 
 
 
 
 
 
Stored Plasma 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Stored Serum 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 

 
35 
A5404 
 
 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Evaluation 
Screening 
Study Entry 
See section 6.2.2 
Post-Vaccination #1  
Follow-up/Day 7 
Day 28 
Post-Vaccination #2  
Follow-up/Day 35 
Day 56 
Day 140 
Day 365 (1 Year) 
Day 730 (2 Years) 
Premature Study D/C  
Event-Driven Evaluation: 
SARS-CoV-2 Infection 
Visit Window (days) 
-28 
 
7-14 days 
post-
vaccine 
+7 
7-14 days 
post-
vaccine 
+7 ±7 
±28 
 
+14 
Visit Type 
(P: In Person, R: Remote) 
R/P 
P 
R 
P 
R 
P 
P 
P 
P 
P 
P 
Stored PBMCs for 35 total SARS-CoV-2-naïve 
participants (See section 6.3.9) 
 
X 
 
 
 
X 
 
X 
X 
 
X 
Documentation of New Active SARS-CoV-2 Infection by 
Antigen or Nucleic Acid Test 
 
 
 
 
 
 
 
 
 
 
X 
Nasopharyngeal (NP) Swab Collection (See section 
6.3.11) 
 
 
 
 
 
 
 
 
 
 
X 

 
36 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
 
6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
If the participant is in Cohorts 1a or 1c or Cohort 2 (receiving study-provided 
Moderna COVID-19 vaccine), then screening evaluations must occur prior to the 
participant receiving first dose of study vaccine. 
  
If the participant is in Cohorts 1b or 1c (receiving community-provided 
mRNA COVID-19 vaccine), it is preferred for these participants to have their 
screening evaluations before their first or second community-provided vaccine 
dose, if feasible. 
  
For all participants, screening evaluations to determine eligibility must be 
completed within 28 days prior to study entry unless otherwise specified. 
 
Screening and Entry can happen on the same day. The screening visit may be 
conducted remotely, over the phone, or via telemedicine systems approved for 
use at the site if necessary. 
 
In addition to data being collected on participants who enroll into the study, 
demographic and clinical data on screening failures will be captured in a 
Screening Failure Results form and entered into the ACTG database.  
 
6.2.2 Entry Evaluations 
 
For all participants, entry evaluations must occur ≤28 days after screening 
evaluations unless otherwise specified.  
 
Screening and Entry can happen on the same day. 
 
Cohort 1 participants are expected to receive the first dose of study vaccine 30-
240 days after receiving the last dose of an investigational therapy or 
corresponding active comparator/placebo in ACTIV-2/A5401.  
 
Entry Evaluations for Cohort 1a and Cohort 2 Participants (both vaccine 
doses provided by the study) 
Entry evaluations may be performed up to 72 hours before the first study-
provided vaccine dose. Participants must have their blood collected before the 
first study-provided vaccine dose is administered. Entry pregnancy test results 
must be available before the study-provided vaccine dose is administered for 
participants of reproductive potential (see section 6.3.6 for definition of 
reproductive potential). 
 

 
37 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Entry Evaluations for Cohort 1b (both vaccine doses received in the 
community) 
Participants who enroll prior to receiving a community-provided vaccine 
dose should have their Entry evaluations within 72 hours prior to the 
administration of the dose. Participants who enroll after receiving the 
second community-provided vaccine dose must have their blood collected 
within 14 days of the second community-provided dose. 
 
Entry Evaluations for Cohort 1c (first dose in the community, second dose 
through the study) 
Participants who enroll prior to receiving a community-provided Moderna 
mRNA-1273 vaccine dose should have their Entry evaluations within 72 
hours prior to the administration of the dose. Participants who enroll after 
receiving their first community-provided Moderna mRNA-1273 vaccine 
dose must have their blood collected within 72 hours prior to the 
administration of the second study-provided dose. 
 
6.2.3 Post-Entry Evaluations 
 
On-Treatment and Post-Treatment Evaluations 
Evaluations should occur in the visit windows described in section 6.1.  
 
In-person visits will take place at the clinic, at the participant’s home, or at 
another non-clinic location if the site is able to accomplish all of the scheduled 
study visit evaluations. 
 
Remote visits can take place over the phone or via telemedicine systems 
approved for use at the site.  
 
Community-Provided mRNA-based COVID-19 Vaccine, Post-Vaccination #1 
Follow-up (Cohorts 1b and 1c)  
This visit will only be performed if the participant enters the study ≤14 days after 
their first vaccine dose. This visit may be combined with the entry visit. 
 
Study-Provided Moderna COVID-19 Vaccine: Second Vaccine Dose (Cohorts 
1a and 1c and Cohort 2) 
Evaluations may be performed up to 72 hours before the receipt of the second 
vaccine dose. Blood must be drawn before the second vaccine dose is 
administered. Pregnancy test results must be available before the study-provided 
vaccine dose is administered for participants of reproductive potential (see 
section 6.3.6 for definition of reproductive potential). 
 
To be in the study window, the second dose of the study vaccine should be 
received at least 28 days and no later than 35 days after the first administration. 
Post-vaccination #1 follow-up should occur at least 7 days and no more than 14 
days after the first vaccine dose, and post-vaccination #2 follow-up should occur 
at least 7 days and no more than 14 days after the second vaccine dose. 

 
38 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
If the second vaccine dose window is missed, and a participant still wishes to 
receive it, then the second dose can be administered anytime between 36 days 
and 140 days after the first dose. Participants who receive their second vaccine 
between 36 and 140 days will have a post-vaccination visit between 7 and 14 
days after second vaccine dose and then continue following the protocol 
schedule of evaluations. Documentation of timing of dose of second vaccine will 
be documented in the eCRF (see section 6.3.7). 
 
Community-Provided Vaccine: Day of Second Dose of Vaccine (Cohort 1b) 
This visit will only be performed if the participant enters the study before 
their second vaccine dose. 
 
Evaluations may be performed up to 72 hours before the receipt of the second 
vaccine dose. Blood must be drawn before the second vaccine dose is 
administered. 
 
Participants receiving a Moderna mRNA-1273 COVID-19 vaccine in the 
community may receive their second dose through the study (Cohort 1c). If the 
second vaccine dose window is missed, and a participant still wishes to receive 
it, then the second dose can be administered anytime between 36 days and 140 
days after the first dose. Participants who receive their second vaccine between 
36 and 140 days will have a post-vaccination visit between 7 and 14 days after 
the second vaccine dose and then continue following the protocol schedule of 
evaluations. Documentation of timing of dose of second vaccine will be 
documented in the eCRF (see section 6.3.7). 
 
56 and 140 Days Post-Vaccination #1 for Cohort 1b Participants Who 
Received Both Vaccine Doses before Entry 
• 
56 days post-vaccination #1 time point: 
o This visit will not be conducted if the participant enrolls more than 
56 days after their first vaccine dose. 
o This visit may be combined with the Entry visit if the participant 
enrolls between 56 and 63 days after their first mRNA COVID-19 
vaccine dose. Evaluations indicated at both time points will be 
conducted only once.  
• 
140 days post-vaccination #1 time point: This visit may be combined 
with the Entry visit if the participant enrolls between 133 and 139 days 
after their first mRNA COVID-19 vaccine dose. Evaluations indicated at 
both time points will be conducted only once.  
 
Study Completion Evaluations  
Participants will be evaluated at Day 730, as described in section 6.1. 
 
Event-Driven Evaluation: SARS-CoV-2 Infection  
Evaluations should occur within 14 days after the positive SARS-CoV-2 test (for 
new SARS-CoV-2 diagnoses after study enrollment only). Participants who report 
new COVID-19 symptoms should be tested or referred for testing with a PCR or 

 
39 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
antigen-based FDA authorized test for SARS-CoV-2, and the results recorded. 
Should a new SARS-CoV-2 infection occur, participants are not discontinued 
from the study and will be asked to remain on the study until the final evaluation 
(Day 730). See section 8.6 for instructions for administering the second vaccine 
dose for participants who contract SARS-CoV-2 infection between their first and 
second scheduled vaccine dose.  
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Registered Participants Who Do Not Receive First Dose of Study- 
or Community-Provided Vaccine 
All eCRFs must be keyed for the period up to and including the entry visit and 
participants will be discontinued from the study.  
 
Evaluations for Participants Who Do Not Receive Second Dose of Study-
Provided Vaccine (Cohorts 1a and 1c and Cohort 2) 
Participants who do not receive the second dose of the Moderna mRNA-1273 
vaccine within 140 days of study entry should remain on study. All evaluations 
should be performed, as described in section 6.1. 
 
If the participant discontinues the study after 28 days and did not receive the 
second study-provided Moderna mRNA-1273 vaccine dose, they may receive it 
at their premature study discontinuation visit.  
 
Evaluations for Participants Who Do Not Receive Second Dose of Community-
Provided Vaccine (Cohort 1b) 
Participants who do not receive the recommended second dose of the COVID-19 
vaccine provided in the community should remain on study, and all evaluations 
should be performed, as described in section 6.1.  
 
Cohort 1c participants may receive their second dose through the study at their 
premature study discontinuation visit. 
 
Premature Study Discontinuation Evaluations  
Participants who prematurely discontinue study participation should have 
premature study discontinuation evaluations, as outlined in section 6.1, prior to 
being taken off the study, unless the reason for premature study discontinuation 
was that the participant did not receive study vaccine or was lost to follow-up. 
 
6.3 
Instructions for Evaluations 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy on 
Requirements for Laboratories Performing Testing for DAIDS-Supported and/or Sponsored Clinical 
Trials, which is available at: https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf. 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the DAIDS Site Clinical Operations and Research 

 
40 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Essential (SCORE) Manual: Source Documentation on the DAIDS website for 
information about what must be included in the source documents: 
https://www.niaid.nih.gov/sites/default/files/score-source-documentation.pdf.  
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events (DAIDS AE Grading Table) and AE reporting of 
adverse events requirements. 
 
6.3.1 Documentation of ACTIV-2/A5401 participation, including the Participant ID  
 
ACTIV-2/A5401 Subject ID Number and receipt of investigational therapy or 
active comparator/placebo for investigational therapy for ACTIV-2/A5401 
participants will be captured in the eligibility checklist. This information will not be 
recorded on the eCRF.  
 
6.3.2 Documentation of no prior history of SARS-CoV-2 infection by participant self-report 
 
Documentation of no prior history of SARS-CoV-2 infection will be captured for 
non-ACTIV-2/A5401 participants in the eligibility checklist. This information will 
not be recorded on the eCRF. 
 
6.3.3 Medical History 
 
At Screening and updated at Study Entry, a complete medical history for the 
preceding 120 days should be recorded. Any signs or symptoms associated 
with an mRNA-based COVID-19 vaccine administration prior to study entry 
(including Grade 1 or higher allergic reactions and Grade 2 or higher 
injection site reactions) should be recorded, regardless of when the 
diagnosis was made. 
 
Additionally, the following diagnoses should be recorded regardless of when the 
diagnosis was made, except where noted:  
• 
Autoimmune disease 
• 
Pulmonary embolus 
• 
Deep venous thrombosis 
• 
HIV infection 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Acute viral respiratory infection (influenza, parainfluenza, respiratory syncytial 
virus, rhinovirus) within the previous 14 days (if known by participant) 
• 
Chronic lung disease 
• 
Asthma requiring daily inhaled medication 
• 
Obesity (BMI >35) 
• 
Hypertension 
• 
Cardiovascular disease  
• 
Diabetes 

 
41 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
• 
Chronic kidney disease 
• 
History of cirrhosis  
• 
Exogenous or endogenous immunosuppression 
 
Any allergies to any medications and vaccines and their formulations must also 
be documented.  
 
6.3.4 Medication History 
 
A medication history must be present, including start and stop dates.  
Table 6.3.4-1 lists the medications that must be included in the history at 
screening and updated at entry. 
 
Table 6.3.4-1: Medication History 
Medication/Category 
Timeframe 
All prescription drugs 
Last 7 days 
Corticosteroids, anabolic steroids 
Last 30 days 
Non-steroidal anti-inflammatory drugs (NSAIDS) 
Last 30 days 
Acetaminophen, Paracetamol 
Last 30 days 
Prescription drugs for high blood pressure 
Last 3 months 
Prescription drugs for diabetes and pre-diabetes 
Last 3 months 
Prescription drugs for lung disease 
Last 3 months 
Prescription drugs for heart disease 
Last 3 months 
Prescription drugs for autoimmune disease 
Last 3 months 
Cancer chemotherapy 
Last 3 months 
Antiretroviral therapy 
Last 3 months 
Immune-based therapy 
Last 3 months 
Blinded investigational agent (including ACTIV-
2/A5401 treatment) 
Last 12 months 
SARS-CoV-2 treatments  
Complete history 
Hydroxychloroquine 
Complete history 
Antibiotics 
Last 3 months 
Anti-parasitics 
Last 3 months 
Alternative therapies 
Last 3 months 
Dietary supplements 
(including zinc and vitamins C and D) 
Last 3 months 
 
6.3.5 Clinical Assessments 
 
Targeted Physical Examination 
A targeted physical examination should be conducted at all in-person visits, 
including vital signs and examinations driven by any previously identified or new 
adverse event (AE)/targeted condition (as described in section 7.2) that the 
participant has experienced since the last visit.  
 

 
42 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
At Entry, a physical examination will include cardiac exam, pulmonary exam, 
weight, height, and vital signs (temperature, pulse, blood pressure, respiration 
rate, and resting peripheral oxygen saturation.  
 
Post entry, see section 8.2 for collection requirements for pregnancy. 
 
Assessment for Adverse Events 
Beginning at entry, participants will be assessed at every visit (remote or in-
person) for any new signs or symptoms and the relationship to study vaccine. 
 
Refer to section 7.2 for AE collection requirements.  
 
Concomitant Medications 
Post-entry, the following new, modified, or discontinued concomitant medications 
must be recorded: 
• 
All prescription drugs 
• 
Corticosteroids, anabolic steroids 
• 
Cancer chemotherapy 
• 
Antiretroviral therapy 
• 
Immune-based therapy 
• 
Blinded investigational agent  
• 
SARS-CoV-2 treatments  
• 
Vaccines (experimental or standard of care, including COVID-19 booster 
vaccines); Note that 1st and 2nd doses of mRNA COVID-19 vaccines 
should be recorded per section 6.3.7. 
• 
Hydroxychloroquine 
• 
Antibiotics 
• 
Anti-parasitics 
• 
Alternative therapies 
• 
Dietary supplements (including zinc and vitamins C and D) 
 
6.3.6 Pregnancy Testing 
 
For participants of reproductive potential: Serum or urine β-HCG. (Urine test 
must have a sensitivity of ≤25 mIU/mL.) Pregnancy testing should be performed 
per the SOE and sections 6.2.2 and 6.2.3. 
 
NOTE: Reproductive potential is defined as: 
• 
Participants who have reached menarche 
• 
Participants who have not been post-menopausal for at least 12 consecutive 
months with follicle-stimulating hormone (FSH) ≥40 IU/mL or 24 consecutive 
months if an FSH is not available 
• 
Participants who have not undergone surgical sterilization (e.g., 
hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or bilateral 
salpingectomy)  

 
43 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
• 
Participants with no other clinical conditions (such as anorexia nervosa) that 
could induce amenorrhea 
• 
Participants not taking medications such as oral contraceptives, hormones, 
gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor 
modulators (SERMs) or chemotherapy that could induce amenorrhea  
• 
For individuals with permanent infertility due to an alternate medical cause 
(e.g., Mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied. 
 
In the event of pregnancy occurring during the study, record pregnancy and 
pregnancy outcome per section 8.2. 
 
6.3.7 Vaccine Administration 
 
All first and second doses of mRNA COVID-19 vaccines, whether given by 
the study or outside of the study, will be recorded on the study treatment 
log eCRF. 
 
Documentation of Community-Provided COVID-19 Vaccination (Cohorts 1b 
and 1c) 
The date and type of vaccine administered to participants who received a 
community-provided COVID-19 vaccine will be recorded. Participants will be 
asked to bring their vaccine cards to the Entry Visit (both cohorts, if Entry 
Visit occurs after administration of a community-provided dose), Day of 2nd 
Dose of Vaccination (both cohorts, if not already provided at Entry Visit), and 
56 Days Post-Vaccination #1 Visit (Cohort 1b only) for verification of date of 
vaccine administration, type of vaccine, and vaccine lot number. Record any 
permanent vaccine discontinuation.  
 
Study-Provided COVID-19 Vaccination Administration 
• 
Pre-Medication: Pre-medication is not planned. However, if the participant 
has a medical history suggesting a potential benefit from pre-medication, the 
study investigator(s) should determine the appropriate pre-medication. Any 
pre-medications given will be documented as a concomitant medication. 
• 
IM Administration: Each dose of the Moderna COVID-19 vaccine will be 
administered as one IM injection per the MOPS. 
• 
Study Vaccine Modifications: Record all study vaccine modifications, 
including first and second doses, participant-initiated and/or protocol-
mandated modifications. Record any permanent vaccine discontinuation. 
• 
After Vaccine Administration: All participants should be monitored closely for 
30 minutes following IM administration of the vaccine, as there is a risk of 
systemic reaction (including anaphylaxis) with any vaccine.  
 
Symptoms and signs that may occur as part of an administration reaction include, but 
are not limited to, fever, chills, nausea, headache, bronchospasm, hypotension, 
angioedema, throat irritation, rash including urticaria, pruritus, myalgia, and dizziness. 

 
44 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
The severity of systemic reactions will be assessed and reported using the criteria 
for infusion-related reactions in the DAIDS AE Grading Table, corrected Version 
2.1, July 2017, which can be found on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. 
 
The clinical site should have necessary equipment and medications for the 
management of any administration reaction, which may include but is not limited 
to oxygen, IV fluid, epinephrine, acetaminophen and antihistamine. 
 
Investigators should determine the severity of the reaction and manage reactions 
based on standard of care and their clinical judgment. If an administration 
reaction occurs, then supportive care should be provided in accordance with the 
signs and symptoms. 
 
Only AEs that meet AE reporting requirements will be recorded.  
 
Participants may register with the CDC V-safe to report side effects after getting 
the vaccine. See the MOPS. 
 
6.3.8 Vaccine Symptom Screen 
 
For Cohorts 1b and 1c participants: If the participant enrolls >14 days after the 
first or second dose of their vaccine, then a Vaccine Symptom Screen is not 
collected for the doses provided prior to enrollment. Otherwise, 7 to 14 days 
after each vaccine, participants will be contacted and asked about their symptoms 
and signs post-vaccination. Symptoms should be recorded on the Adverse Events 
eCRF for symptoms meeting AE reporting criteria per section 7.2.  
 
See the MOPS for further detail. 
 
6.3.9 Stored Samples 
 
Plasma, sera or PBMCs will be used to assess SARS-CoV-2 virologic and 
immunologic responses. Refer to the A5404 LPC for processing information. 
Entry samples must be collected for all participants. Entry samples must be 
collected before the first vaccine dose is administered, if the participant has not 
already received their first dose of vaccine through the community prior to entry. 
Samples for Day 28/Day of 2nd dose of vaccine must be collected as indicated in 
the SOE before the second vaccine dose is administered. All other blood 
samples must be collected as outlined in the SOE. 
 
Stored Plasma 
Blood plasma will be collected and stored for future testing, including: 
• 
Total and antigen-specific SARS-CoV-2 IgA, IgG, and IgM levels 
• 
Plasma protein, cytokine, and metabolomic analysis 
 

 
45 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Stored Serum 
Blood sera will be collected and stored for future testing, including: 
• 
Serologic responses to SARS-CoV-2 and other circulating coronavirus viral proteins 
• 
Total and NAb assays 
 
Stored PBMCs 
PBMCs will be collected from all Cohort 1 participants and 35 (in total) Cohort 2 
participants (see the MOPS). PBMCs for SARS-CoV-2-naïve participants should 
only be collected for those who are ≥40 years old on the day of collection. PBMC 
processing must be done in an IQA-approved lab. PBMCs will be stored for 
future testing, including: 
• 
Antigen-specific, including Memory T cell assays 
• 
Antigen-specific Memory B cell assays 
 
Stored PAXgene Blood RNA Tube 
Blood will be collected in a PAXgene tube and stored for future testing, including: 
• 
To evaluate gene expression via RNASeq technology 
 
6.3.10 Documentation of New Active SARS-CoV-2 Infection by Antigen or Nucleic Acid 
Test  
 
In the case of new COVID-19 symptoms occurring at any time following vaccine 
administration while on study, participants should be tested or referred to testing 
with an antigen or nucleic acid test for SARS-CoV-2 infection. If a participant 
already received a new diagnosis of new SARS-CoV-2 infection by an antigen or 
nucleic acid test, then a test does not need to be repeated if a copy of the test 
result can be obtained. If a participant is found to have active SARS-CoV-2 
infection, then additional blood samples should be collected. See section 6.1 and 
the LPC for further detail. 
 
6.3.11 Nasopharyngeal (NP) Swab Collection 
 
If feasible, NP swabs will be collected by staff after any documented new active 
SARS-CoV-2 infection within 14 days after onset of symptoms. Collection as early 
as possible after symptom onset is preferable. See the MOPS for further detail.  
 
6.3.12 ACTIV-2/A5401 Investigational Therapy or Active Comparator/Placebo Questionnaire  
 
Per the SOE, Cohort 1 participants will be asked whether they believe they received 
the ACTIV-2/A5401 investigational therapy or the active comparator/placebo and 
whether this belief influenced their decision to join this study. 
 
The questionnaire is posted on the DMC Portal in the Forms Management Utility. 
 

 
46 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Events 
 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or diagnosis that occurs in a study participant during the 
conduct of the study after enrollment REGARDLESS of the attribution (i.e., relationship 
of event to medical treatment/study product/device or procedure/intervention). This 
includes any occurrence that is new in onset or aggravated in severity or frequency from 
the pre-enrollment baseline condition. 
 
7.2 
Adverse Event Collection Requirements for This Protocol 
 
All AEs must be recorded on the eCRFs if any of the following criteria have been met: 
• 
If any of the following targeted conditions occur, regardless of grade: 
o Allergic or hypersensitivity reactions to COVID-19 vaccine observed by study 
staff or reported by the participant. See section 6.3.7 for instructions for 
monitoring participants after vaccination.  
o Myocarditis 
o Pericarditis 
o Participant reported acute viral respiratory infection. If a diagnosis is known, then 
record on the eCRF 
• 
Grade ≥2 AEs  
• 
All AEs that led to a change in study treatment/intervention regardless of grade  
• 
AEs meeting SAE definition or EAE reporting requirement 
 
NOTE A: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System (DAERS), an Internet-based reporting 
system. 
 
NOTE B: Participants reporting acute chest pain, shortness of breath, palpitations, or 
other signs or symptoms of myocarditis or pericarditis within 4 to 6 weeks after 
vaccination must be referred to a cardiologist for evaluation and management. Cases 
should be followed until resolution of symptoms and abnormal test findings. 
 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above. 
 

 
47 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Suspected Unexpected Serious Adverse Events 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as a serious 
adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g., Investigator’s Brochure for an unapproved investigational product). 
 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS 
 
7.3.1 Expedited Reporting of Adverse Events to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/manual-expedited-reporting-adverse-events-daids.  
 
The DAIDS Adverse Experience Reporting System (DAERS), an Internet-based 
reporting system, must be used for EAE reporting to DAIDS. In the event of 
system outages or technical difficulties, EAEs may be submitted using the DAIDS 
EAE Form. This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting.  
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Please note that site queries may also be sent 
from within the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety 
Office at DAIDSRSCSafetyOffice@tech-res.com. 
 
7.3.2 Reporting Requirements for this Study 
 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
• 
The study agents for which expedited reporting is required are the Moderna 
mRNA-1273 COVID-19 vaccine and the Pfizer-BioNTech BNT162b2 
mRNA COVID-19 vaccine. 
 
7.3.3 Grading Severity of Events 
 
The DAIDS AE Grading Table, corrected Version 2.1, July 2017, must be used, 
and is available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-tables.  
 
7.3.4 Expedited AE Reporting Period 
• 
The expedited AE reporting period for this study is per the EAE manual.  
• 
After the protocol-defined AE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs), as defined in Version 

 
48 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
2.0 of the EAE Manual, will be reported to DAIDS if the study staff become aware of 
the events on a passive basis (from publicly available information). 
 
7.4 
Study Monitoring 
 
The protocol team will monitor the conduct and safety of the study via regular summaries 
of accrual, study discontinuation, stored sample and data completeness, and AEs as 
described in the Study Progress, Data, and Safety Monitoring Plan (SPDSMP). These 
reports will be summarized among participants with no prior history of SARS-CoV-2 
infection and pooled among Cohort 1 participants. 
 
The DAIDS Clinical Representative will review and assess select EAE reports for 
potential impact on the study participant safety and protocol conduct as per DAIDS 
policies, guidance documents, and SOPs as applicable. Additionally, the DAIDS clinical 
representative will routinely review aggregated AE summaries pooled across the 
blinded ACTIV-2/A5401 arms prepared by the Statistical and Data Analysis Center 
(SDAC) on a schedule as defined in the SPDSMP. 
 
The study will undergo interim safety reviews by an ACTG-appointed Study Monitoring 
Committee (SMC) at least annually. The first interim review will occur when 10 
participants have enrolled to one select therapy group, received their first dose 
of vaccine after study entry, and their data through study Day 7 (7 days after the first 
vaccine dose) are available, or 3 months after the first participant enrolls, whichever occurs 
first. Subsequent reviews will occur annually unless otherwise recommended by the SMC 
or requested by the study team. It is not intended that the SMC will review data on 
immunologic outcomes. An interim review may also be convened if a concern is identified 
by the DAIDS clinical representative, the study chairs, or study statistician in consultation 
with the team. Enrollment will pause and the SMC will review any death that occurs on 
study that is deemed related to study product as determined by the site investigator. A 
pause in enrollment will also occur and the SMC will review if two participants experience a 
Grade 4 AE that is deemed related to study product as determined by the site investigator. 
See section 10.0 for statistical and other considerations related to interim monitoring. 
 
Detailed plans for study monitoring are outlined in an SPDSMP developed by the SDMC 
prior to enrollment of the first participant. 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity  
 
Only toxicities related to study medication provided through this study will be 
considered in the toxicity management section. Participants who receive 
community-provided COVID-19 vaccine should manage toxicity for that medication 
per SOC. The grading system for vaccine toxicities is located in the DAIDS AE Grading 
Table, corrected Version 2.1, July 2017, which can be found on the DAIDS RSC website 
at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. 
 

 
49 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
For the vaccine evaluated in this trial, if a participant develops a Grade 4 AE that is 
related to the study product as determined by the site investigator, no further doses of 
the study vaccine should be administered by the site.  
 
It is possible that some participants will experience transient or prolonged AEs during the 
study. As some of the visits will be conducted remotely, AEs will often be assessed remotely 
and unplanned study visits scheduled if deemed necessary by the site investigator. For any 
concerning AEs that are felt to require clinical intervention, participants should be instructed 
to contact their health care provider or seek urgent or emergent care, or 911 should be 
called, as appropriate.  
 
Vaccine may be discontinued without contacting the protocol team in advance, but the 
protocol team should be notified within 48 hours of vaccine discontinuation or 
interruption (follow the directions described in the Study Management section). 
 
8.2 
Pregnancy  
 
There is limited data regarding the use of mRNA COVID-19 vaccines in participants who 
are pregnant. The American College of Obstetrics and Gynecology (ACOG) suggests 
offering vaccination to pregnant and breastfeeding individuals if they meet the criteria for 
vaccination based on the Advisory Committee on Immunization Practices (ACIP) 
recommending priority groups for vaccination [25, 26]. The Centers for Disease Control 
and Prevention (CDC) has recently classified pregnant and breastfeeding individuals at 
increased risk of severe illness or death from COVID-19 [27]. Therefore, pregnant 
individuals are eligible to participate in this study. 
 
Participants who become pregnant after the first dose of the vaccine but prior to the second 
dose are eligible to receive the second dose of the vaccine. If pregnant participants choose 
not to receive the second dose of the vaccine, they will be encouraged to continue on study 
and complete the evaluations indicated in the Schedule of Evaluations. At the end of the 
pregnancy, outcome and adverse events for participant and infant will be recorded on the 
outcome eCRF. 
 
If a participant has completed the study or chooses to discontinue from the study before 
the end of the pregnancy, then site staff should request permission to contact them  
regarding pregnancy outcomes at the end of pregnancy. If the information is obtained, 
pregnancy outcomes will be submitted on an eCRF at the end of the pregnancy.  
 
8.3 
Breastfeeding 
 
There are no data regarding the use of mRNA COVID-19 vaccines in participants who 
are breastfeeding. See section 8.2 for further rationale to allow individuals who are 
breastfeeding to participate in this study. 
 

 
50 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
8.4 
Allergic Reactions 
 
All participants should be monitored closely, as there is a risk of systemic reaction 
(including anaphylaxis) with any vaccine.  
 
Symptoms and signs that may occur as part of an administration reaction include, but 
are not limited to, fever, chills, nausea, headache, bronchospasm, hypotension, 
angioedema, throat irritation, rash including urticaria, pruritus, myalgia, and dizziness. 
 
The severity of systemic reactions will be assessed and reported using the criteria for 
infusion-related reactions in the DAIDS AE Grading Table, corrected Version 2.1, July 
2017, which can be found on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-tables. 
 
The clinical site should have necessary equipment and medications for the management 
of any administration reaction, which may include, but is not limited to, oxygen, IV fluid, 
epinephrine, acetaminophen, and antihistamine. 
 
Investigators should determine the severity of the reaction and manage reactions based 
on standard of care and their clinical judgment. If an administration reaction occurs, then 
supportive care should be provided in accordance with the signs and symptoms. 
 
8.5 
Injection Site Reactions 
 
Injection-site reactions (ISRs) will be differentiated from the above generalized allergic 
reactions by definition as localized pain/tenderness, induration, erythema, and/or 
formation of an ulceration or infection at the injection site. ISRs will be graded per the 
DAIDS AE Grading Table, corrected Version 2.1, July 2017, which can be found on the 
DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-
event-grading-tables. 
 
8.6 
New SARS-CoV-2 Infection 
 
Participants who are found to have new SARS-CoV-2 infection after study enrollment will have 
the measures detailed in section 6.2.3 (Post-Entry Evaluations), Event-Driven Evaluations.  
 
If the new SARS-CoV-2 infection occurs after the first dose but before the second 
scheduled dose of the COVID-19 vaccine, then sites should follow CDC guidance which 
is available at https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-
considerations.html#CoV-19-vaccination when administering the second vaccine dose to 
participants who contract SARS-CoV-2 infection between their first and second 
scheduled vaccine dose. For such participants, the second vaccine dose should not be 
given until the participant has recovered from the acute phase of their infection and 
completed quarantine. Participants will have evaluations per section 6.2.3 and Schedule 
of Evaluations (section 6.1) and continue with the rest of planned evaluations. If the new 
SARS-CoV-2 infection happens after the second COVID-19 vaccine dose, then 
participants will continue with the planned Schedule of Evaluations. 

 
51 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
8.7 
Myocarditis and Pericarditis 
 
Participants reporting acute chest pain, shortness of breath, palpitations, or other 
signs or symptoms of myocarditis or pericarditis within 4 to 6 weeks after 
vaccination must be referred to a cardiologist for evaluation and management 
(see section 7.2). Cases of myocarditis and pericarditis should be followed until 
resolution of symptoms and abnormal test findings. Participants with events of 
myocarditis and/or pericarditis should be discontinued from the study and 
complete premature study discontinuation evalutations per section 6.1.  
 
NOTE: The Centers for Disease Control and Prevention (CDC) provide guidelines 
on case definition and criteria for myocarditis and pericarditis 
(https://www.cdc.gov/mmwr/volumes/70/wr/mm7027e2.htm) 
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
Participants may discontinue or withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the investigator or at the study site. 
Every effort should be made to keep participants in the study. The reasons for 
participants discontinuing the vaccine series and/or withdrawing from the study will be 
recorded on the eCRF. 
 
9.1 
Permanent and Premature Vaccine Discontinuation for Participants Receiving Study-
Provided Vaccine 
• 
Vaccine-related toxicity (see section 8.1 Toxicity). 
• 
Request by participant to terminate vaccine. 
• 
Clinical reasons believed life-threatening by the physician, even if not addressed in 
section 8.1 Toxicity of the protocol. 
• 
Any clinically significant medical condition that, in the opinion of the 
investigator, poses an additional risk to the participant if they continue to 
participate in the study. 
• 
Confirmed cases of myocarditis and/or pericarditis (see section 8.1 Toxicity). 
 
9.2 
Premature Study Discontinuation for Any Participant 
• 
Failure to receive the first dose of study- or community-provided mRNA vaccine.  
• 
Request by the participant to withdraw. 
• 
Request of the primary care provider if they think the study is no longer in the best 
interest of the participant. 
• 
At the discretion of the IRB/EC, FDA, NIAID, Office for Human Research Protections 
(OHRP), other government agencies as part of their duties, investigator, or industry 
supporter.  
• 
Development of myocarditis or pericarditis. 
 

 
52 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
10.0 
STATISTICAL CONSIDERATIONS  
 
10.1 
General Design Issues 
 
The aim of this study is to describe immunologic responses to mRNA-based SARS-CoV-
2 vaccine among individuals who previously received investigational therapy in ACTIV-
2/A5401 for SARS-CoV-2 infection in comparison to individuals who received a placebo. 
As ACTIV-2/A5401 is expected to change from using a placebo control to an active 
control, this study’s aim will also evolve to describe immunologic responses to mRNA-
based SARS-CoV-2 vaccine among individuals who previously received investigational 
therapy in ACTIV-2/A5401 for SARS-CoV-2 infection in comparison to individuals who 
received an active control. Results will need to be interpreted in the context of available 
information from outside the study when analyses are completed. 
 
ACTIV-2/A5401 is evaluating multiple investigational agents with randomized 
comparison of a given investigational agent to a placebo control group which includes 
participants who were eligible to receive that investigational agent but who were 
concurrently randomized to receive the placebo for that specific agent or a placebo to 
another agent being evaluated at the same time. This combined placebo control group 
(or its equivalent combined active control group when ACTIV-2/A5401 changes to use 
an active control group) will be used in comparisons in this study. The randomization 
system in ACTIV-2/A5401 is designed so that the number of participants in the 
combined placebo group for evaluating a given investigational agent is approximately 
the same as the number of participants who received that investigational agent. Based 
on the select investigational agents likely to be included in this study, it is anticipated that 
the ratio of these numbers in this study will be close to 1:1. However, even if this is not 
achieved, the combined placebo group used in this study will still include participants 
who were eligible to receive the investigational agent and who were concurrently 
randomized to receive a placebo. 
 
Although participants in this study were randomized to receive select therapy or 
corresponding active comparator/placebo in the ACTIV-2/A5401 study, the exposure 
comparison in this study is not a pure randomized comparison. Outcomes experienced 
in the ACTIV-2/A5401 study, including differential experiences by receipt of 
investigational therapy versus active comparator/placebo, may influence a participant’s 
decision to enroll in this study (even though participants will still be blinded to their select 
therapy group assignment in ACTIV-2/A5401). Differences in mortality between the 
investigational therapy and active comparator/placebo exposures may also lead to 
differences in enrollment to this study. With the caveat of limited sample size, adjusted 
analyses and or analyses using propensity scores or other approaches for causal 
inference may be used to explore potential biases in exposure comparisons induced by 
selective enrollment. 
 
Note that for the purposes of statistical analysis of this study, unblinded statisticians will 
have access to the treatment assignments from ACTIV-2/A5401 but the participants and 
other investigators in the study will not be unblinded.  
 

 
53 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
10.2 
Outcome Measures 
 
Primary and secondary outcome measures listed below will be addressed in the study’s 
primary Statistical Analysis Plan, which will define the content of the Primary Analysis 
Report. This report will form the basis for the primary study manuscript and results 
reporting to https://ClinicalTrials.gov. Outcome measures will be analyzed as 
originally pre-specified if accrual is sufficiently high to provide meaningful 
estimates. Otherwise, analyses will instead be reported as descriptive estimates 
within participant groups rather than as comparisons between groups. Additional 
details are pre-specified in the primary Statistical Analysis Plan.  
 
10.2.1 
Primary Outcome Measure  
 
10.2.1.1 Neutralizing antibody (NAb) level at least 140 days after the first dose 
of the study- or community-provided vaccine. 
 
10.2.2 
Secondary Outcome Measures  
 
10.2.2.1 Relative pre-vaccine to post-vaccine change in NAb response 
defined as the ratio of post-vaccine level/pre-vaccine level. The pre-
vaccine NAb measurement will be obtained before the first dose of 
the vaccine, and the post-vaccine measurement will be obtained at 
least 56 days after the first dose of the vaccine. 
 
10.2.2.2 New Grade 3 or higher AE, or SAE, or AE leading to change or 
discontinuation in vaccine receipt from first dose of the mRNA-based 
COVID-19 vaccine and through 140 days after the first dose of 
vaccine. 
 
10.2.2.3 Grade 1 or higher allergic reaction from first dose of the mRNA-
based COVID-19 vaccine through the visit 56 days after the first dose 
of the vaccine 
 
10.2.2.4 Grade 2 or higher injection site reaction from first dose of the mRNA-
based COVID-19 vaccine through the visit 56 days after the first dose 
of the vaccine. 
 
10.2.2.5 Relative pre-vaccine to post-vaccine change in NAb response 
defined as the ratio of post-vaccine level/pre-vaccine level by 
received vaccine, i.e., Moderna versus Pfizer. The pre-vaccine NAb 
measurement will be obtained before the first dose of the vaccine, 
and the post-vaccine measurement will be obtained at least 56 days 
after the first dose of the vaccine. 
 

 
54 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
10.2.3 
Other Outcome Measures  
 
10.2.3.1 CD4+ and CD8+ T cell responses to SARS-CoV-2 spike protein and 
IgG serologic responses to SARS-CoV-2 spike protein at receptor 
binding domain (RBD) and N terminal domain (NTD) at study 
entry/Day 0 and 56 days after the first vaccine dose.  
 
10.2.3.2 Flow cytometry of PBMC for markers of exhaustion on B and T cells at 
study entry/Day 0, 56, and 140 days after the first vaccine dose.  
 
10.3 
Randomization and Stratification 
 
There is no randomization or stratification in this study. 
 
10.4 
Sample Size 
 
The following considers sample size for a comparison of responses among participants 
who previously received an investigational agent versus among participants who 
previously received placebo. Similar considerations apply if instead the comparison is of 
responses among participants who previously received an investigational agent versus 
among participants who previously received an active control. It was originally 
intended to consider the following sample sizes for each investigational therapy 
group separately. Due to lower than anticipated enrollment numbers, revisions to 
the protocol and SAP now consider combining the active arms from some 
investigational therapy groups together for comparisons against the pooled 
placebo group or active comparator. 
 
To inform sample size and precision of estimates, we use data from a recent study of 
outpatients with symptomatic COVID-19 followed longitudinally [8] to provide information 
about variability in NAb levels and changes in NAb levels (in the absence of both Ab 
therapy and vaccine). These data include samples taken up to 180 days after symptom 
onset. NAb levels in that study were measured using the pseudotyped virus reported 
from a single-round-of-infection neutralization assay (PsVNA or PSV), the same assay 
as will be used in this study. The standard deviation of log NAb levels was 0.48 among 
54 participants with samples taken between 120 and 180 days after symptom onset. 
These data represent a similar time interval after select COVID-19 therapy or placebo to 
the post-vaccine NAb measurement in this study). The extended time interval up to 240 
days in this study might result in reduced variability (lower standard deviation) and thus 
the estimate of 0.48 to inform our anticipated precision is conservative. 
 
For the primary outcome measure of NAb levels 140 days after the first vaccine dose, 
we will calculate the ratio of geometric mean responses (GMRs) for participants with 
prior select investigational therapy exposure versus participants who received placebo. 
A ratio of GMRs (GMR for investigational therapy exposed divided by GMR for placebo) 
of one indicates no difference in NAb response. A ratio of less than 1 indicates lower 
NAb response among those who received prior select investigational therapy exposure 
compared to those who received placebo. The main analysis is descriptive: to provide an 

 
55 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
estimate of the ratio of GMRs and associated confidence interval. If the study does not 
enroll enough participants to provide meaningful estimates and/or precision, then 
NAb levels at 140 days after the first vaccine dose will be reported as separate 
descriptive results among participants exposed to ACTIV-2/A5401 active 
therapies, participants exposed to ACTIV-2/A5401 placebo, and participants 
exposed to ACTIV-2/A5401 active comparator.  
 
The statistical analysis will be undertaken on a log (base 10) scale as is conventional for 
NAb measurements (as the distribution of log responses is generally closer to a normal 
distribution). The estimate and confidence interval will be anti-logged to provide an 
estimate and confidence interval for the ratio of GMRs. For the purposes of evaluation of 
precision and sample size, we assume that the confidence intervals can be calculated 
using standard methods assuming that responses are approximately normally distributed 
on a log scale.  
 
Table 10.4-1 shows the anticipated precision in this study of estimates of the ratio of 
GMRs (after anti-logging) for participants with versus without prior exposure to 
investigational agents and assuming that the observed ratio of GMRs is one (i.e., under 
the null hypothesis of no difference between groups), for a range of standard deviations 
encompassing the value of 0.5. For a standard deviation of 0.5 and a sample size of 70 
participants who receive vaccine (35 with prior investigational therapy and 35 who 
received active comparator/placebo [a 1:1 ratio]), the 90% confidence interval for the 
ratio of GMRs is (0.63, 1.58) and the 95% confidence interval is (0.58, 1.73). These 
confidence intervals suggest reasonable precision to rule out reductions in response 
associated with prior investigational therapy of about 40% or more or increases of about 
60% or more. If there are investigational agents included in ACTIV-2/A5401 but not in 
this study, it is possible that the ratio of number of participants with prior exposure to a 
given agent to the number of participants in the combined placebo group will differ from 
1:1. Table 10.4-1 shows confidence intervals for various ratios of participants in this 
study with prior investigational therapy versus placebo. There is some loss of precision 
(wider confidence intervals) as the ratio increases from 1:1 to 4:1 for fixed sample size 
but the precision is still reasonable (note 4:1 is likely a very extreme ratio based on the 
select investigational agents likely to be included in this study). There is also some loss 
of precision for standard deviations larger than 0.5 and some gain in precision for 
smaller standard deviations. In protocol version 3.0, we revised the scenarios shown 
in Table 10.4-1 to show precision for expected sample sizes of 10, 20, 30, 50, and 
70 to reflect lower than anticipated observed enrollment numbers. With a total 
sample size less than 30, expected precision on the GMR ratio is low, and 
therefore if total enrollment numbers do not exceed this level, descriptive 
analyses may be preferred. 
 

 
56 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Table 10.4-1: Confidence Intervals for an Observed Ratio of GMRs Comparing Participants 
With Versus Without Prior Investigational Therapy for a Range of Sample Sizes 
and Standard Deviations (SDs: for log base 10 values) 
A key secondary outcome measure evaluates relative change in NAb level pre-vaccine 
to post-vaccine. The statistical analysis for this outcome measure will use change in log 
(base 10) NAb level pre-vaccine to post-vaccine. The outpatient study provides 
information about the variability in change in log NAb level over time. Forty-three of the 
participants in that study had an additional measurement earlier in follow-up. The 
median time of the first measurement was 63 days after onset of symptoms and the 
median time of the second measurement was 159 days after onset of symptoms. The 
median duration of time between measurements was 96 days (similar to the time interval 
between the pre-vaccine and post-vaccine measurements in this study). The standard 
deviation of changes in log NAb level among these 43 participants was 0.35. Assuming 
that the variability of changes in this study is similar (standard deviation of 0.4 and 
recognizing that the vaccine should alter the mean change), then Table 10.4-1 shows 
that with a sample size of 70 participants receiving vaccine with equal numbers with 
versus without prior investigational therapy, the 90% confidence interval is (0.69, 1.44) 
and the 95% confidence interval is (0.64, 1.55) when the observed ratio of GMRs 
comparing participants with versus without prior select therapy is 1. Similar 
considerations as noted above for the primary outcome measure apply if the ratio of 
Allocation 
Ratio
Total 
N
n Ab, 
n Placebo
SD=0.3
SD=0.4
SD=0.5
SD=0.6
SD=0.3
SD=0.4
SD=0.5
SD=0.6
1 to 1
10
5, 5
(0.44, 2.25) (0.34, 2.95)
(0.26, 3.87)
(0.20, 5.08)
(0.36, 2.74) (0.26, 3.83)
(0.19, 5.36)
(0.13, 7.50)
20
10, 10 
(0.58, 1.71) (0.49, 2.04)
(0.41, 2.44)
(0.34, 2.92)
(0.52, 1.91) (0.42, 2.38)
(0.34, 2.95)
(0.27, 3.66)
30
15, 15
(0.65, 1.53) (0.56, 1.77)
(0.49, 2.05)
(0.42, 2.36)
(0.60, 1.67) (0.50, 1.99)
(0.42, 2.37)
(0.36, 2.81)
50
25, 25
(0.72, 1.39) (0.65, 1.55)
(0.58, 1.73)
(0.52, 1.93)
(0.67, 1.48) (0.59, 1.69)
(0.52, 1.92)
(0.46, 2.19)
70
35, 35
(0.76, 1.32) (0.69, 1.44)
(0.63, 1.58)
(0.58, 1.73)
(0.72, 1.39) (0.64, 1.55)
(0.58, 1.73)
(0.52, 1.93)
2 to 1
10
7, 3
(0.41, 2.43) (0.31, 3.26)
(0.23, 4.39)
(0.17, 5.89)
(0.33, 3.00) (0.23, 4.34)
(0.16, 6.25)
(0.11, 9.02)
20
13, 7
(0.57, 1.75) (0.47, 2.11)
(0.39, 2.55)
(0.33, 3.08)
(0.51, 1.97) (0.40, 2.48)
(0.32, 3.10)
(0.26, 3.90)
30
20, 10
(0.63, 1.58) (0.54, 1.84)
(0.47, 2.13)
(0.40, 2.48)
(0.58, 1.73) (0.48, 2.07)
(0.40, 2.49)
(0.33, 2.99)
50
34, 16
(0.70, 1.42) (0.63, 1.60)
(0.56, 1.79)
(0.50, 2.02)
(0.66, 1.52) (0.57, 1.75)
(0.50, 2.02)
(0.43, 2.32)
70
47, 23
(0.75, 1.34) (0.68, 1.48)
(0.61, 1.63)
(0.56, 1.80)
(0.70, 1.42) (0.63, 1.60)
(0.56, 1.80)
(0.50, 2.02)
3 to 1
10
8, 2
(0.36, 2.76) (0.26, 3.87)
(0.18, 5.43)
(0.13, 7.62)
(0.28, 3.52) (0.19, 5.36)
(0.12, 8.17)
(0.08, 12.42)
20
15, 5
(0.54, 1.86) (0.44, 2.28)
(0.36, 2.81)
(0.29, 3.44)
(0.47, 2.11) (0.37, 2.72)
(0.29, 3.48)
(0.22, 4.48)
30
23, 7
(0.60, 1.66) (0.51, 1.97)
(0.43, 2.33)
(0.36, 2.76)
(0.54, 1.84) (0.44, 2.26)
(0.36, 2.77)
(0.29, 3.40)
50
38, 12
(0.68, 1.47) (0.60, 1.67)
(0.53, 1.90)
(0.46, 2.15)
(0.63, 1.58) (0.54, 1.85)
(0.47, 2.15)
(0.40, 2.51)
70
53, 17
(0.73, 1.38) (0.65, 1.53)
(0.59, 1.71)
(0.53, 1.90)
(0.68, 1.47) (0.60, 1.67)
(0.53, 1.90)
(0.46, 2.16)
4 to 1
10
8, 2
(0.36, 2.76) (0.26, 3.87)
(0.18, 5.43)
(0.13, 7.62)
(0.28, 3.52) (0.19, 5.36)
(0.12, 8.17)
(0.08, 12.42)
20
16, 4
(0.51, 1.95) (0.41, 2.44)
(0.33, 3.05)
(0.26, 3.82)
(0.44, 2.25) (0.34, 2.95)
(0.26, 3.86)
(0.20, 5.07)
30
24, 6
(0.58, 1.71) (0.49, 2.05)
(0.41, 2.44)
(0.34, 2.92)
(0.52, 1.91) (0.42, 2.37)
(0.34, 2.93)
(0.27, 3.64)
50
40, 10
(0.66, 1.51) (0.58, 1.73)
(0.51, 1.98)
(0.44, 2.27)
(0.61, 1.63) (0.52, 1.92)
(0.44, 2.26)
(0.37, 2.67)
70
56, 14
(0.71, 1.41) (0.63, 1.58)
(0.56, 1.77)
(0.50, 1.99)
(0.66, 1.51) (0.58, 1.73)
(0.50, 1.99)
(0.44, 2.28)
90% CI for a true ratio of GMR of 1
95% CI for a true ratio of GMR of 1

 
57 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
participants with versus without prior investigational select therapy increases from 1:1, or 
if the standard deviation increases from 0.4. If total enrolment numbers are low, we 
may consider reporting descriptive analyses of change in NAb level without the 
comparisons of investigational therapy exposure to placebo/active comparator. 
 
10.5 
Data and Safety Monitoring  
 
The study will undergo safety reviews by an ACTG-appointed SMC as described in 
section 7.4. There are no formal statistical stopping guidelines for these planned safety 
reviews. It is not intended that the SMC review immunologic outcome data or that the 
study be stopped early based on the magnitude of immune responses. 
 
10.6 
Analyses 
 
Statistical analysis plans will be developed describing analyses to address the primary 
and secondary objective of the study.  
 
The primary outcome analysis is descriptive and was originally intended to be carried 
out separately for each investigational therapy and associated combined placebo group 
or investigational agent and associated active comparator group. Due to lower than 
anticipated enrollment into the study, the primary outcome analysis may be 
amended to be carried out in a combined group of participants exposed to 
particular ACTIV-2/A5401 investigational agents. Additional details are described 
in the Statistical Analysis Plan. The analysis will combine participants regardless of 
which mRNA-based COVID-19 vaccine they received. An exploratory analysis may be 
carried out separately for each mRNA-based COVID-19 vaccine if sample size 
permits. 
 
The following description focuses on the comparison of outcomes among participants 
who received an investigational agent in ACTIV-2/A5401 compared with participants in 
the combined placebo control group. Similar analyses will be undertaken if the 
comparison is to participants in an active control group. 
 
For the primary outcome measure, we will evaluate the ratio of GMRs for participants 
with prior investigational therapy versus participants who received placebo. A ratio of 
GMRs (GMR for investigational therapy exposed divided by GMR for placebo) of one 
indicates no difference in NAb response. A ratio less than 1 indicates lower NAb 
response among those who received prior investigational therapy exposure compared to 
those who received placebo. If the study does not enroll enough participants to 
provide meaningful estimates and/or precision, then NAb levels at 140 days after 
the first vaccine dose will be reported as separate descriptive results among 
participants exposed to ACTIV-2/A5401 active therapies, participants exposed to 
ACTIV-2/A5401 placebo, and participants exposed to ACTIV-2/A5401 active 
comparator. 
 
The primary analysis population will include all participants who received at least one 
vaccine dose and provided NAb responses at least 140 days after the first vaccine dose. 

 
58 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Participants reinfected with SARS-CoV-2 after receiving the first dose of the vaccine will 
be excluded from the primary analysis. Similarly, participants reinfected with SARS-
CoV-2 between receipt of the second dose of vaccine and 140 days after the first 
vaccine dose will be excluded from the primary analysis. The primary analysis is 
descriptive: to provide estimates of NAb and if sample size allows, the ratio of GMRs 
and associated confidence interval. No formal statistical tests will be performed. 
Estimates and confidence intervals will be obtained from linear regression with an 
indicator variable for prior investigational therapy exposure versus placebo using 
standard methods assuming that NAb responses are approximately normally distributed 
on a log (base 10) scale. To allow for the possibility that the distribution of time from 
receipt of investigational therapy or placebo to the first dose of vaccine may vary, an 
analysis adjusted for this time will also be undertaken. A supplemental analysis will be 
conducted among participants who received both doses of the vaccine. An exploratory 
analysis will be conducted by mRNA-based COVID-19 vaccine.  
 
The analysis population for the secondary outcome measure exploring change in NAb 
levels from pre- to post-vaccine will include all participants who received at least one 
vaccine dose and provided NAb responses within 7 days prior to the first dose of the 
vaccine and at least 56 days after the first vaccine dose. Participants reinfected with 
SARS-CoV-2 after receiving the first dose of the vaccine will be excluded from this 
analysis. Similarly, participants reinfected with SARS-CoV-2 between receipt of the 
second dose of vaccine and 140 days after the first vaccine dose will be excluded. 
The analysis is descriptive: To provide estimates of change in NAb and if sample size 
allows, the ratio of GMRs and associated confidence interval. No formal statistical tests 
will be performed. Estimates and confidence intervals will be obtained from linear 
regression with an indicator variable for prior investigational therapy exposure versus 
placebo using standard methods assuming that NAb responses are approximately 
normally distributed on a log (base 10) scale. To allow for the possibility that the 
distribution of time from receipt of investigational therapy or placebo to the first dose of 
vaccine may vary, an analysis adjusted for this time may also be undertaken. A 
sensitivity analysis will be conducted among participants who received both doses of the 
vaccine. An exploratory analysis will be conducted by mRNA-based COVID-19 vaccine 
if sample size allows.  
 
Outcomes among participants without prior COVID-19 will be analyzed in the same way 
as for participants with prior COVID-19 and is intended to be descriptive. In the event 
that there are differences in outcomes between participants with prior COVID-19 
(including taking account of exposure to ACTIV-2/A5401 investigational agent, placebo, 
or active control) and participants without prior COVID-19, which are considered large, 
exploratory analyses may be undertaken taking account of information available at the 
time of analysis about participant characteristics that might affect the magnitude of 
vaccine response. 
 
The safety analysis population will include all participants who receive at least the first 
vaccine dose. The analysis of safety outcome measures will be descriptive by whether 
participants had been exposed to investigational therapy or active comparator/placebo in 
ACTIV-2/A5401, and separately for participants without prior COVID-19. We will 

 
59 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
summarize each safety outcome measure (estimate of proportion and corresponding 
95% confidence interval) at the pre-specified time points detailed in section 10.2.2. 
 
Outcomes experienced in the ACTIV-2/A5401 study, including differential experiences 
by receipt of investigational therapy versus active comparator/placebo, may influence a 
participant’s decision to enroll in this study even though participants will still be blinded to 
their assignment in ACTIV-2/A5401. If sample size permits, adjusted analyses or 
analyses using propensity scores or other causal inference methods may be used to 
explore potential biases in exposure comparisons induced by selective enrollment. 
 
11.0 
PHARMACOLOGY PLAN 
 
Not applicable. 
 
12.0 
DATA COLLECTION AND MONITORING  
 
12.1 
Records to Be Kept 
 
Electronic case report form screens will be made available to sites for data entry. 
Participants must not be identified by name on any data submitted to the DMC. 
Participants will be identified by the patient identification number (PID) and study 
identification number (SID) provided by the ACTG DMC upon registration. 
 
12.2 
Role of Data Management 
 
12.2.1 
Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.2.2 
It is the responsibility of the ACTG DMC to ensure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
12.3 
Clinical Site Monitoring and Record Availability 
 
12.3.1 
Monitoring visits may be conducted on-site or remotely. Remote visits may 
include remote source document verification using methods specified for this 
purpose by NIAID. Remote monitoring visits may be performed in place of, or in 
addition to, onsite visits to ensure the safety of study participants and data 
integrity [28]. The site must make available study documents for site monitors 
to review utilizing a secure platform that is HIPAA and 21 CFR Part 11 
compliant. The Data Management Center will configure Medidata Remote 
Source Review (RSR) and make it available to all sites. We encourage 
Sites to use the DMC provided Medidata RSR platform but other potential 
platform options include: Veeva SiteVault, site-controlled SharePoint or cloud-
based portal, direct access to Electronic Medical Record (EMR), and Medidata 
Rave Imaging Solutions. Other secure platforms that are 21 CFR Part 11 

 
60 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
compliant may be utilized, as allowed by the DAIDS Office of Clinical Site 
Oversight (OCSO). 
 
12.3.2 
The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, eCRFs) and pertinent hospital or clinic records readily 
available for inspection by the local IRB, the site monitors, the FDA, the NIAID, 
the OHRP, the industry supporter or designee, other local, US, and 
international regulatory entities for confirmation of the study data.  
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (INFORMED CONSENT FORM) and 
any subsequent modifications will be reviewed and approved by the IRB or EC responsible 
for oversight of the study. A signed consent form will be obtained from the participant (or 
parent, legal guardian, or person with power of attorney for participants who cannot 
consent for themselves, such as those below the legal age of consent). The consent form 
will describe the purpose of the study, the procedures to be followed, and the risks and 
benefits of participation. A copy of the consent form will be given to the participant, parent, 
or legal guardian, and this fact will be documented in the participant’s record. 
 
13.2 
Participant Information and Consent 
 
Informed consent in compliance with US Title 21 CFR Part 50 and US Title 45 CFR Part 
46 shall be obtained from each participant before entering the study or performing any 
unusual or nonroutine procedure that involves risk to the participant.  
 
Before recruitment and enrollment, each prospective participant or their legal guardian 
will be given a full explanation of the study, be allowed to read the approved ICF, and 
have any questions answered. Once the investigator is assured that the participant/legal 
guardian understands the implications of participating in the study, the participant/legal 
guardian will be asked to give consent to participate in the study. A witness may be used 
for the informed consent process if remote consent is performed and it is not possible to 
obtain a copy of the signed consent form from the participant (or legal guardian or 
person with power of attorney for participants who cannot consent for themselves).  
 
The Informed Consent Form will include a description of the risks and benefits of the 
COVID-19 vaccine. There is increasing evidence that COVID-19 vaccination has the 
potential of direct benefit whether participants have been infected previously or not, 
because it offers high levels of protection against future SARS-CoV-2 infection. 
 
13.3 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified by coded number only to maintain participant confidentiality. All records will be kept 
locked. All computer entry and networking programs will be done with coded numbers only. 

 
61 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
Clinical information will not be released without written permission of the participant, except as 
necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, OHRP, other local, US, and 
international regulatory entities as part of their duties, or the industry supporter or designee.  
 
13.4 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
other government agencies as part of their duties to ensure that research participants 
are protected, or the industry supporter. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any presentation, 
abstract, or manuscript will be made available for review by the industry supporter prior to 
submission.  
 
15.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the CDC and the 
National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations. 

 
62 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
 
16.0 
REFERENCES 
 
1. Rogers TF, Zhao F, Huang D, et al. Isolation of potent SARS-CoV-2 neutralizing 
antibodies and protection from disease in a small animal model. Science 2020;369:956-
63. doi:10.1126/science.abc7520. 
2. Chen P, Nirula A, Heller B, et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in 
outpatients with Covid-19. N Engl J Med 2020 Oct 28;NEJMoa2029849. 
doi:10.1056/NEJMoa2029849. 
3. [No authors listed]. An EUA for bamlanivimab--a monoclonal antibody for COVID-19. 
JAMA 2021;325:880-1. doi:10.1001/jama.2020.24415. 
4. Haynes BF, Corey L, Fernandes P, et al. Prospects for a safe COVID-19 vaccine. Sci 
Transl Med 2020 Nov 4;12(568):eabe0948. doi:10.1126/scitranslmed.abe0948. 
5. Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA vaccine against SARS-CoV-2 
-- preliminary report. N Engl J Med 2020;383:1920-31. doi:10.1056/NEJMoa2022483. 
6. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA 
Covid-19 vaccine. N Engl J Med 2020;383:2603-15. doi:10.1056/NEJMoa2034577. 
7. Fragkou PC, Belhadi D, Peiffer-Smadja N, et al. Review of trials currently testing 
treatment and prevention of COVID-19. Clin Microbiol Infect 2020;26:988-98. doi: 
10.1016/j.cmi.2020.05.019. PMID: 32454187. 
8. Lariccia V, Magi S, Serfilippi T, Toujani M, Gratteri S, Amoroso S. Challenges and 
opportunities from targeting inflammatory responses to SARS-CoV-2 infection: a 
narrative review. J Clin Med 2020;9:4021. doi: 10.3390/jcm9124021. PMID: 33322733. 
9. Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T cell responses to SARS-CoV-2 
coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 
2020;181:1489-1501. doi:10.1016/j.cell.2020.05.015. 
10. Rydyznski Moderbacher C, Ramirez SI, Dan JM, et al. Antigen-specific adaptive 
immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease 
severity. Cell 2020;183:996-1012. doi:10.1016/j.cell.2020.09.038. 
11. Tarke A, Sidney J, Kidd CK, et al. Comprehensive analysis of T cell immunodominance 
and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases. bioRxiv 2020 Dec 
9;2020.12.08.416750. doi:10.1101/2020.12.08.416750. 
12. Dan JM, Havenar-Daughton C, Kendric K, et al. Recurrent group A Streptococcus 
tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant 
TFH cells. Sci Transl Med 2019;11(478):eaau3776. doi:10.1126/scitranslmed.aau3776. 
13. Lipsitch M, Grad YH, Sette A, Crotty S. Cross-reactive memory T cells and herd 
immunity to SARS-CoV-2. Nat Rev Immunol 2020;20:709-13. doi:10.1038/s41577-020-
00460-4. 
14. Mateus J, Grifoni A, Tarke A, et al. Selective and cross-reactive SARS-CoV-2 T cell 
epitopes in unexposed humans. Science 2020;370:89-94. doi:10.1126/science.abd3871. 

 
63 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
15. Reiss S, Baxter AE, Cirelli KM, et al. Comparative analysis of activation induced marker 
(AIM) assays for sensitive identification of antigen-specific CD4 T cells. PLoS One 
2017;12:e0186998. doi:10.1371/journal.pone.0186998. 
16. Kim Y-I, Kim S-M, Park S-J, et al. Critical role of neutralizing antibody for SARS-CoV-2 
reinfection and transmission. Emerg Microbes Infect 2021;Jan 7;1-28. doi: 
10.1080/22221751.2021.1872352. PMID: 33407005. 
17. Wu F, Liu M, Wang A, et al. Evaluating the association of clinical characteristics with 
neutralizing antibody levels in patients who have recovered from mild COVID-19 in 
Shanghai, China. JAMA Intern Med 2020;180:1356-62. doi: 
10.1001/jamainternmed.2020.4616. PMID: 32808970. 
18. Selhorst P, Van Ierssel S, Michiels J, et al. Symptomatic SARS-CoV-2 reinfection of a 
health care worker in a Belgian nosocomial outbreak despite primary neutralizing 
antibody response. Clin Infect Dis 2020 Dec 14;ciaa1850. doi: 10.1093/cid/ciaa1850. 
PMID: 33315049. 
19. Nainu F, Abidin RS, Bahar MA, et al. SARS-CoV-2 reinfection and implications for 
vaccine development. Hum Vaccin Immunother 2020;16:3061-73. doi: 
10.1080/21645515.2020.1830683. PMID: 33393854. 
20. Tillett RL, Sevinsky JR, Hartley PD, et al. Genomic evidence for reinfection with SARS-
CoV-2: a case study. Lancet Infect Dis 2021;21:52-58. doi: 
https://doi.org/10.1016/S1473-3099(20)30764-7. 
21. Widge AT, Rouphael NG, Jackson LA, et al.; mRNA-1273 Study Group. Durability of 
responses after SARS-CoV-2 mRNA-1273 vaccination. N Engl J Med 2021;7;384:80-2. 
doi: 10.1056/NEJMc2032195. 
22. Dan J, Mehta S. SARS-CoV-2 immunity and reinfection. Clin Infect Dis 2021;02 January 
2021;ciaa1936. https://doi.org/10.1093/cid/ciaa1936. 
23. Shive CL, Judge CJ, Clagett B, et al. Pre-vaccine plasma levels of soluble inflammatory 
indices negatively predict responses to HAV, HBV, and tetanus vaccines in HCV and 
HIV infection. Vaccine 2018;36:453-60. PMID: 29254840. 
24. CDC. Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines Currently 
Authorized in the United States. Centers for Disease Control and Prevention; Updated 
February 21, 2021. https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-
considerations.html 
25. ACOG. Practice Advisory. Vaccinating Pregnant and Lactating Patients Against COVID-
19. American College of Obstetricians and Gynecologists; December 2020. 
https://www.acog.org/clinical/clinical-guidance/practice-
advisory/articles/2020/12/vaccinating-pregnant-and-lactating-patients-against-covid-19 
26. CDC. COVID-19 ACIP Vaccine Recommendations. The Advisory Committee on Immunization 
Practices’ Updated Interim Recommendation for Allocation of COVID-19 Vaccine - United 
States, December 2020. Centers for Disease Control and Prevention; December 2020. 
MMWR 2020;69. https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm695152e2-H.pdf 

 
64 
A5404 
FINAL VERSION 3.0  
 
 
30Nov2022 
 
27. CDC. COVID-19. Pregnancy, Breastfeeding, and Caring for Newborns. Centers for 
Disease Control and Prevention; December 2020. 
https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/pregnancy-
breastfeeding.html  
28. FDA Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 
Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review 
Boards, March 2020, Updated on January 27, 2021. Accessed at: 
https://www.fda.gov/media/136238/download 
 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 1 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
INFORMED CONSENT FORM 
 
 
Sponsor / Study Title: 
  
National Institute of Allergy and Infectious Diseases / “SARS-
CoV-2 Immune Responses after COVID-19 Therapy and 
Subsequent Vaccine” 
Protocol Number: 
A5404 
Principal Investigator: 
(Study Doctor) 
«PiFullName» 
Telephone: 
«IcfPhoneNumber» 
Address: 
«PiLocations» 
 
This form is for use in a research study that may involve participants who may or may not have 
the capacity to consent to take part in the study. When the participant cannot legally consent to 
take part, pronouns “you” and “your” should be read as referring to the participant rather than 
the person (legally authorized representative) who is signing and dating this form for the 
participant. In cases where the participant’s representative gives consent, the participant should 
be informed about the study to the extent possible given his/her understanding. During the 
course of the study, if the participant regains the capacity to consent, informed consent will be 
obtained from the participant, and the participant offered the ability to leave the study if desired. 
 
SUMMARY 
 
PURPOSE 
This is a research study and your participation in this study is voluntary. 
The purpose of this study is to evaluate the safety and efficacy of mRNA 
COVID-19 vaccines in: 
• 
People with prior COVID-19 (SARS-CoV-2 infection) who were in the 
ACTIV-2/A5401 study. 
And  
• 
People who have never had COVID-19 (SARS-CoV-2 infection). 
 
VACCINE 
Study-provided Moderna mRNA-1273 COVID-19 vaccine, or  
 
Community-provided mRNA COVID-19 vaccine (from a local clinic or 
vaccination site, for example). 
 
NUMBER OF  
PARTICIPANTS 
This study planned to enroll 70 people who were in ACTIV-2/A5401 from 
each ACTIV-2/A5401 study treatment group, and up to 70 people who 
have never had COVID-19 per each ACTIV-2/A5401 study treatment  
group. Enrollment into this study closed on February 25, 2022, due to 
slow enrollment. A total of 43 participants were enrolled. 
 
LENGTH OF  
STUDY  
You will be on this study for up to 730 days, which is about 2 years.  
 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 2 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
REQUIRED  
ACTIVITIES 
If you enter the study before you have the first vaccination, you will have 
blood drawn from a vein in your arm before your first and second mRNA 
COVID-19 vaccinations. If you enter the study before you have the 
second vaccination, you will have blood drawn before your second 
mRNA COVID-19 vaccination. If you enter the study after you have 
two doses of vaccine, you will have blood drawn on the day you 
enroll in the study. This blood will be used to measure immune and 
genetic (determined by inherited factors) responses to your initial SARS-
CoV-2 (the virus that causes COVID-19) infection and to the mRNA 
COVID-19 vaccine.  
 
If you are receiving study-provided Moderna mRNA-1273 COVID-19 
vaccine, the study vaccine will be given by needle into the muscle of your 
arm on study days 0 and 28. 
 
Phone Visits 7 to 14 Days after Vaccinations 
If you enter the study before your first or second mRNA COVID-19 
vaccination, you will be contacted by phone by the study team between 
7 and 14 days after each vaccine to see whether or not you have had 
any new symptoms or medical events. If you enter the study more than 
14 days after your first vaccination, you will only be contacted after the 
second vaccine. If you enter the study more than 14 days after your 
second vaccination, you will not have a scheduled phone visit. 
 
Study Visits 2 Months, 5 Months, 1 Year, and 2 Years After Your First 
mRNA COVID-19 Vaccine 
You will have blood drawn. This blood will be used to measure immune 
responses to your study-provided or community-provided mRNA COVID-
19 vaccine. 
 
RISKS 
Taking blood may cause some discomfort, bleeding, or bruising where the 
needle enters the body, lightheadedness, and in rare cases, fainting or 
infection.  
 
If You Are Receiving the Study-Provided Moderna mRNA-1273 COVID-
19 Vaccine  
Side effects that have been reported with the Moderna mRNA-1273 
COVID-19 vaccine include: 
• 
Injection site reactions: pain, itching, tenderness and swelling of the 
lymph nodes in the same arm of the injection, swelling and hardness 
around the injected area, and redness. 
• 
General side effects: fatigue (tiredness), headache, muscle pain, joint 
pain, chills, nausea and vomiting, fever, and mild abdominal pain. 
• 
Other: facial flushing (redness), generalized itching, tingling of face or 
extremities, runny nose, sneezing, hypotension (low blood pressure), 
hives, and pruritus (itching). 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 3 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
• 
There is increased risk of myocarditis and pericarditis. 
Myocarditis is inflammation of the heart muscle, and pericarditis 
is inflammation of the lining outside the heart. 
 
There is a very small chance that the study-provided Moderna mRNA-
1273 COVID-19 vaccine could cause a severe allergic reaction. A severe 
allergic reaction would usually occur within a few minutes to one hour 
after being vaccinated. For this reason, you will be asked to stay at the 
study site for monitoring after vaccination. Signs of a severe allergic 
reaction can include: 
• 
Difficulty breathing or swallowing 
• 
Chest tightness 
• 
Shortness of breath 
• 
Coughing 
• 
Wheezing 
• 
Swelling of your face and throat 
• 
A fast heartbeat 
• 
A bad rash all over your body 
• 
Vomiting 
• 
Abdominal pain 
• 
Dizziness and weakness 
• 
Fainting (loss of consciousness), convulsions (like a seizure) 
 
If You are Receiving Community-Provided mRNA COVID-19 Vaccine 
This is an observational study of the community-provided mRNA COVID-
19 vaccine that you are receiving locally, so the risks of taking those 
vaccines are not part of this study. Your medical provider or vaccine 
administrator should give you that information. 
 
BENEFITS 
There is increasing evidence that COVID-19 vaccination has the potential 
of direct benefit because it offers high levels of protection against future 
COVID-19 (SARS-CoV-2 infection), whether you have been infected 
previously or not. 
 
OTHER CHOICES  
Instead of being in this study, you have the choice of obtaining a COVID-
19 vaccine in the community, obtaining an experimental COVID-19 
vaccine in another study, if you qualify, or no vaccination.  
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you:  
 
1. Have previously had COVID-19 (SARS-CoV-2 infection) and received an experimental 
treatment, placebo (a look-alike product that has no active substance), or a standard of care 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 4 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
COVID-19 treatment (the usual care for COVID-19 at the time) in a clinical trial known as 
ACTIV-2/A5401. 
 
Or 
 
2.  You have not previously been diagnosed with a COVID-19 (SARS-CoV-2 infection) infection 
and have not previously been vaccinated for COVID-19. 
 
The current study is sponsored by the National Institutes of Health (NIH). The study doctor in 
charge of this study at this site is listed on the first page of this form. Before you decide if you 
want to be a part of this study, we want you to know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign and date this consent form. You will get a copy 
to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
SARS-CoV-2 is a recently identified virus that has caused a widespread outbreak of an illness 
called COVID-19. New treatments and vaccines are being developed for this virus. Some of 
these treatments and vaccineshave received Emergency Use Authorization (EUA) from the 
FDA. This means that they became available for use more quickly than usual. The Moderna 
mRNA-1273 vaccine received full FDA approval. Some of these treatments and vaccines are 
being evaluated in clinical trials, such as ACTIV-2/A5401 and this study (A5404). 
 
People who have previously experienced SARS-CoV-2 infection can get it again, and it is not 
known if active viral infection generates a weaker immune response than what can be elicited 
by a COVID-19 vaccine.  
 
This study is for people who had COVID-19 and participated in ACTIV-2/A5401 and received 
either experimental treatment, a standard of care COVID-19 treatment, or placebo. This study is 
also for people who have not previously had a COVID-19 infection. The study is designed to 
evaluate how the immune system responds to mRNA-COVID-19 vaccines in these participants. 
The safety of mRNA COVID-19 vaccines in persons with prior COVID-19 who did and did not 
receive prior experimental treatment for COVID-19 will be explored. Prior infection with or 
without treatment could increase, decrease, or have no significant effect on the response to 
mRNA COVID-19 vaccines, as well as the risk of side effects from these vaccines. Immune 
responses of participants who have not previously been infected with COVID-19 will be 
compared to those who have previously had COVID-19. 
 
Enrollment for this study closed on February 25, 2022, due to slow enrollment. Vaccine 
responses will be studied in the 43 participants enrolled. Your continued participation is 
appreciated.  
 
 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 5 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Location of Study Visits 
Your study visits will take place in person or remotely. You and the study staff at your study 
site will discuss the location for each visit.  
• 
In-person visits will take place at the clinic, at your home, or at another non-clinic location. 
• 
Remote visits will take place over the phone or via telemedicine systems approved for use at 
your study site. 
 
Information Collected at Screening 
There is some information that we collect on everyone who is screened for an AIDS Clinical 
Trials Group (ACTG, part of the National Institute of Allergy and Infectious Diseases, an institute 
of the NIH) study. As part of your screening visit, some demographic (for example, age, gender, 
race) and clinical (for example, disease condition, diagnosis) information will be collected from 
you. We also collect information on whether you use (or have used) injection drugs. 
  
We will collect this information even if you do not enroll in this study. This information is 
collected so that ACTG researchers may determine whether there are patterns and/or common 
reasons why people do not join a study. 
 
Blood Drawn 
The study site staff can tell you how much blood will be collected at any particular visit.  
 
Screening Visit 
If you would like to be in this study, after you have read, signed, and dated this consent form, 
you will have a screening visit to make sure you meet the requirements for joining the study. 
This visit will take about 1 hour. You may come to the clinic, or if it is possible or necessary, this 
visit might be done remotely (for example, by telephone). 
 
At this visit: 
• 
Study staff will tell you more about the study. 
• 
If you will receive the study-provided Moderna mRNA-1273 COVID-19 vaccine, then study 
staff will tell you about that study vaccine. 
• 
If you are receiving a community-provided mRNA COVID-19 vaccine, then study staff will ask 
you which vaccine (for example, Pfizer or Moderna) you are getting and when you received 
or are scheduled to receive your first and (if applicable) second vaccine doses. 
• 
If you were a participant in the A5401/ACTIV-2 study: Study staff will review your history and 
confirm your participation in ACTIV-2/A5401.  
• 
You will be asked about any symptoms you are experiencing. 
• 
Study staff will ask you about your allergy history, any health conditions you have, and 
questions about your health in general. 
• 
Study staff will ask you about your medication history and any medications you are taking. 
• 
You may have a brief physical exam if your screening visit takes place at the clinic.  
 
Entry Visit 
If you qualify for the study, you will have an entry visit. This visit might occur on the same day as 
your screening visit.  

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 6 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
 
• 
You will have a physical exam and answer questions about your medical and allergy history 
and any medications you are taking or have taken in the past.  
• 
If you have already received a community-provided mRNA COVID-19 vaccine dose 
before the Entry visit, you will be asked to bring your vaccine card to this visit. 
• 
If you have already received a community-provided mRNA COVID-19 vaccine dose 
before the Entry visit, you will be asked to bring your vaccine card to this visit. 
• 
If you were a participant in the A5401/ACTIV-2 study, your information collected from 
A5401/ACTIV-2 will also be used in this trial. 
• 
If you were a participant in the A5401/ACTIV-2 study, you will be asked some questions 
about ACTIV-2/A5401 experimental treatment and about your interest in this study. 
• 
You will be asked about symptoms you are experiencing.  
• 
You will have a pregnancy test, if applicable. 
• 
You will have blood collected. This blood will be tested to measure any responses that your 
genes and immune system have had to your previous SARS-CoV-2 infection.  
• 
If you are receiving the study-provided Moderna mRNA-1273 COVID-19 vaccine, you will 
receive the first dose of the vaccine. You will be asked to remain at the clinic for 
approximately 30 minutes for monitoring after you receive the Moderna mRNA-1273 COVID-
19 vaccine. 
• 
If you are receiving both COVID-19 vaccine doses outside of the study (“in the 
community”) and enroll prior to receiving the first or second dose, you should have 
your entry visit within 72 hours prior to receiving the dose. If you enroll after 
receiving the second dose, you must have blood collected within 14 days of that 
second dose. 
• 
If you are receiving the first vaccine dose outside of the study, and the second dose 
through the study (this is for people who receive Moderna mRNA-1273 vaccine only), 
and enroll prior to receiving the first dose, you should have your entry visit within 72 
hours prior to receiving that first dose. If you enroll after receiving the first vaccine 
dose, you must have blood collected within 72 hours prior to the second dose you 
receive through the study. 
 
Phone Visits 7 to 14 Days after Vaccinations 
If you enter the study before your first or second mRNA COVID-19 vaccination, between 7 
and 14 days after the vaccine(s), you will be contacted by phone by the study team to see 
whether or not you have had any new symptoms or medical events. If you enter the study 
more than 14 days after your first vaccination, then you will only be contacted after the second 
vaccine. If you enter the study more than 14 days after your second vaccination, then you 
will not be contacted. 
 
Study Visit on Day of 2nd Dose of Vaccine 
• 
If you are receiving the study-provided Moderna mRNA-1273 COVID-19 vaccine, you will 
return to the clinic around 28 days (about 4 weeks, or 1 month) after your first vaccine dose 
to receive your second dose. You will be asked to remain at the clinic for approximately 30 
minutes for monitoring after you receive the vaccine. If you do not receive the second dose 
of the vaccine at this time (and you still want to receive it), you may still get the second dose 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 7 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
through the study up to 140 days after your first vaccine dose. You will still be contacted by 
phone 7 to 14 days after you receive the vaccine. 
• 
If you are receiving the community-provided mRNA COVID-19 vaccine and enter the study 
before receiving your second dose: 
o If you received the Moderna mRNA-1273 COVID-19 vaccine, you will receive your 
second dose about 28 days after your first dose. If you received the Pfizer-BioNTech 
BNT162b2 mRNA COVID-19 vaccine, you will receive your second dose about 21 
days after your first dose. You will be asked to bring your vaccine card to this visit.  
o If you received the Moderna mRNA-1273 COVID-19 vaccine for your first dose, you may 
be able to get the second dose of the Moderna mRNA-1273 COVID-19 vaccine through 
the study, if you want to.  
• 
If you do not receive your 2nd dose of the vaccine, you may still remain on the study and 
have the remaining study visits performed.  
• 
If you enter the study after receiving both doses of mRNA COVID-19 vaccine in the 
community, then you will not have this visit.  
• 
If your first community-provided mRNA-based COVID-19 vaccine dose occurred after 
entry, you will be asked to bring your vaccine card to this visit. 
 
At this visit:  
• 
You will have a physical exam and answer questions about current medications you are 
taking.  
• 
You will have a pregnancy test, if applicable. 
• 
You will be asked about symptoms you are experiencing. 
• 
You will have blood collected. This blood will be tested to measure any responses that your 
genes and immune system have had to your previous SARS-CoV-2 infection.  
 
Study Visit 8 Weeks (56 days, or about 2 months) after Your First mRNA COVID-19 Vaccine 
Dose  
You will have a physical exam and answer questions about medications you are currently 
taking. You will have blood drawn. This blood will be used to measure immune responses to the 
vaccine you took. If you think you may be pregnant, you will have a pregnancy test. If you 
received the second community-provided mRNA COVID-19 vaccine dose after entering the 
study, you will be asked to bring your vaccine card to this visit. If you enroll more than 56 
days after your first mRNA COVID-19 vaccine dose, you will not have this visit. If you 
enroll between 56 and 63 days after your first mRNA COVID-19 vaccine dose, then this 
study visit may be combined with your entry visit. 
 
Study Visit 20 Weeks (140 days, or about 5 months) after Your First mRNA COVID-19 Vaccine 
Dose 
You will have a physical exam and answer questions about medications you are currently 
taking. You will have blood collected. This blood will be tested to measure immune responses to 
the vaccine you took. If you think you may be pregnant, you will have a pregnancy test.  
 
If you enroll between 133 and 139 days after your first mRNA COVID-19 vaccine dose, 
then this study visit may be combined with your entry visit.  
 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 8 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
Study Visit 1 Year (365 days) after Your First mRNA COVID-19 Vaccine Dose 
You will have a physical exam and answer questions about medications you are currently 
taking. You will have blood collected. This blood will be tested to measure immune responses to 
the vaccine you took. If you think you may be pregnant, you will have a pregnancy test. 
 
Study Visit 2 Years (730 days) after Your First mRNA COVID-19 Vaccine Dose – FINAL VISIT 
You will have a physical exam and answer questions about medications you are currently 
taking. You will have blood collected. This blood will be tested to measure immune responses to 
the vaccine you took. If you think you may be pregnant, you will have a pregnancy test.  
 
Additional Study Visit 
If you think you have contracted COVID-19, you will be asked to come in for an extra study visit.  
 
At this visit: 
• 
You will have a physical exam. 
• 
Diagnosis and documentation of new active SARS-CoV-2 infection with an antigen or 
nucleic acid test (these tests that can detect active SARS-CoV-2 infection from your nose or 
throat) will be done or you will be referred to a site that can do this testing  
• 
If you are found to have an active SARS-CoV-2 infection, you may have nasopharyngeal 
swabs (for example, deep nasal swabs) collected by a study staff person as early as 
possible within 14 days after your symptoms begin. Your current medications will also be 
reviewed. 
• 
You will be asked about symptoms you are experiencing. 
• 
You will have blood drawn. This blood will be stored for future study-required testing. 
• 
You will have a pregnancy test, if applicable. 
 
Genetic Testing  
Your body, like all living things, is made up of cells. Cells contain deoxyribonucleic acid, also 
known as “DNA.” DNA is like a string of information put together in a certain order. Parts of the 
string make up “genes.” Genes contain instructions on how to make your body work and fight 
disease. These genes direct the cells to make particular sequences or types of ribonucleic acid, 
also known as “RNA.” Differences or changes in DNA and RNA explain some of the physical 
differences among people. These differences partly explain why some people get diseases 
such as cancer or diabetes while others do not. Genetic testing looks at the differences in 
people’s DNA and RNA. This testing also looks at how differences affect health and the body’s 
response to disease, treatment, and vaccination.  
 
If you agree, some of your blood that is collected will be used to study whether there are genetic 
differences in how people respond to study drugs. This genetic testing might include whole 
genome sequencing (WGS) for DNA and gene expression for RNA. “Sequencing” is looking at 
the order of a person’s genes to see how this order is different from the order of other people to 
see if these differences are associated with different disease states or immune responses. You 
must agree to participate in this genetic testing in order to participate in this study. 
 
Please put your initials below to indicate your choice: 
 
________ (initials) I understand and I agree to this use of my samples. 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 9 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
OR 
________ (initials) I understand but I do not agree to this use of my samples, and I understand 
that this means I cannot participate in this study.  
 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE 
USED FOR? 
 
Your information and samples from ACTIV-2/A5401 and data generated from your information 
and samples from ACTIV-2/A5401 will be used for this study. Some of your blood will be stored 
and used for study-required testing.  
 
Your samples and any private information that has been collected about you will be coded. 
This means that no one looking at the labels or at other information will be able to know that the 
samples or information came from you.  
 
The tests described above are required by this study. If you do not agree to the storage or 
testing that has been described above, you should not join this study. Your samples may be 
used for commercial profit and you will not share in this commercial profit.  
 
Please refer to the separate consent at the end of this document to consent for use of your 
samples in other studies. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
This study planned to enroll 70 people who were in ACTIV-2/A5401 from each ACTIV-2/A5401 
study treatment group, and up to 70 people who have never had a COVID-19 infection per each 
ACTIV-2/A5401 study treatment group. In total, the study enrolled 43 participants. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 730 days.  
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
The study is stopped or cancelled. 
• 
You are not able to attend the study visits as required by the study. 
• 
You do not receive the first dose of mRNA COVID-19 vaccine, or other community–provided 
mRNA vaccine, such as the Pfizer BioNTech BNT162b2 mRNA COVID-19 vaccine.  
 
If you received the study- or community-provided Moderna mRNA-1273 COVID-19 vaccine for 
your first dose: 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 10 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
• 
You may still be able to get the second dose of the Moderna mRNA-1273 COVID-19 
vaccine through the study (up to 140 days after your first dose) at the premature study 
discontinuation visit if you are taken off of the study early.  
 
If you are receiving the study-provided Moderna mRNA-1273 COVID-19 vaccine, the study 
doctor may need to take you off the Moderna mRNA-1273 COVID-19 vaccine without your 
permission if: 
• 
Continuing the Moderna mRNA-1273 COVID-19 vaccine may be harmful to you. 
• 
You are not able to take the Moderna mRNA-1273 COVID-19 vaccine as required by the 
study. 
 
If you must stop taking the Moderna mRNA-1273 COVID-19 vaccine before the study is over, 
the study doctor may ask you to continue to be part of the study and return for some study visits 
and procedures.  
 
If you leave the study early, you will have a physical exam, pregnancy test (if applicable), and 
blood collection. 
 
If I have to permanently stop taking study-provided Moderna mRNA-1273 COVID-19 vaccine, or 
once I leave the study, how would the Moderna mRNA-1273 COVID-19 vaccine be provided? 
 
During the study: 
If you must permanently stop receiving study-provided Moderna mRNA-1273 COVID-19 vaccine 
before your study participation is over, the study staff will discuss other options that may be of 
benefit to you. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The study-provided Moderna mRNA-1273 COVID-19 vaccine used in this study may have side 
effects, some of which are listed below. Please note that these lists do not include all the side 
effects seen with this vaccine. These lists include the more serious or common side effects with 
a known or possible relationship. If you have questions concerning the additional Moderna 
mRNA-1273 COVID-19 vaccine side effects please ask the medical study staff at your site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the Moderna mRNA-1273 COVID-19 vaccine. For your safety, you must tell the study 
doctor or nurse about all medications you are taking before you start the study and also before 
starting any new medications while on the study. Also, you must tell the study doctor or nurse 
before enrolling in any other clinical trials while on this study. 
 
Since we do not fully understand the Moderna mRNA-1273 COVID-19 vaccine’s effectiveness 
in participants who have previously had COVID-19, it is recommended that you continue to take 
general precautions (for example, physical distancing, wearing a mask) to reduce the risk of 
infection.  
 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 11 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
Risks of the Study-provided Moderna mRNA-1273 COVID-19 Vaccine 
There are risks to taking part in any research study.  
 
There is a risk that the study-provided Moderna mRNA-1273 COVID-19 vaccine may not stop 
you from acquiring COVID-19.  
 
Additionally, if you have previously had COVID-19 and received an experimental treatment, 
placebo, or a standard of care COVID-19 treatment in the ACTIV-2/A5401 study: 
• 
The study-provided Moderna mRNA-1273 COVID-19 vaccine has received full FDA approval. 
It has been shown in a clinical trial to be effective in preventing COVID-19 following two doses 
given at least 1 month apart, but it is not known if it is effective in people who have had 
COVID-19 previously and if being treated with experimental treatment has any effect. 
 
Side effects that have been reported with the study-provided Moderna mRNA-1273 COVID-19 
vaccine include:  
• 
Injection site reactions: pain, itching, tenderness and swelling of the lymph nodes in the 
same arm of the injection, swelling (hardness) redness, and formation of an ulceration (a 
break in the skin) or infection. 
• 
General side effects: fatigue (tiredness), headache, muscle pain, joint pain, chills, nausea, 
vomiting, fever, and mild abdominal pain. 
• 
Other: facial flushing (redness), generalized itching, tingling of face or extremities, runny 
nose, sneezing, hypotension (low blood pressure), hives, and pruritus (itching). 
 
There is a very small chance that the study-provided Moderna mRNA-1273 COVID-19 vaccine 
could cause a severe allergic reaction. A severe allergic reaction would usually occur within a 
few minutes to 1 hour after getting a dose of the study-provided Moderna mRNA-1273 COVID-
19 vaccine. For this reason, you will be asked to stay at the study site where you received your 
vaccine for about 30 minutes after vaccination. Signs of a severe allergic reaction can include:  
• 
Difficulty breathing or swallowing 
• 
Chest tightness 
• 
Shortness of breath 
• 
Coughing 
• 
Wheezing 
• 
Swelling of your face and throat 
• 
A fast heartbeat 
• 
A bad rash all over your body 
• 
Vomiting 
• 
Abdominal pain 
• 
Dizziness and weakness 
• 
Fainting (loss of consciousness), convulsions (like a seizure)  
 
There is an increased risk of myocarditis and pericarditis after getting the study-provided 
Moderna mRNA-1273 COVID-19 vaccine. Myocarditis is inflammation of the heart muscle, 
and pericarditis is inflammation of the lining around the heart. In both cases, the body’s 
immune system is causing inflammation in response to the vaccine. Symptoms can 
include chest pain, shortness of breath, or palpitations. Symptoms usually start within a 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 12 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
few days after receipt of the Moderna mRNA-1273 COVID-19 vaccine. Most individuals who 
have sought medical care have responded well to medications and rest, and symptoms 
have resolved for most persons who experienced this side effect. It is not known if either 
myocarditis or pericarditis from the vaccine causes long-term health effects.  
 
Myocarditis and pericarditis have been reported in greatest numbers in males under the 
age of 40 years following a second dose of mRNA vaccines (including the COVID-19 
vaccine), but cases have been reported in older males and in females as well, and also 
following other doses. Risk for myocarditis and pericarditis has been observed to be 
highest in males between 12 to 17 years of age. While some cases required intensive care 
support, data suggests that symptoms got better in most people with some management. 
Information is not yet available about the potential long-term affects of myocarditis and 
pericarditis in these people. While there is limited data on the risk of myocarditis and 
pericarditis in children younger than 12 years old (especially compared to the risk data that 
is available in adolescents and adults), it is an area of science that is currently being 
studied.  
 
Please let a member of the study staff know if you experience any of the following 
symptoms of myocarditis or pericarditis, following vaccination provided through the 
study:  
• 
Chest pain 
• 
Shortness of breath 
• 
A fast heartbeat, fluttering, or pounding heart 
 
Study staff will provide you with appropriate contact information so that you can reach 
out should you experience any of these symptoms.  
 
You should not get the study-provided Moderna mRNA-1273 COVID-19 vaccine if you:  
• 
Had a severe allergic reaction after a previous dose of this vaccine. 
• 
Had a severe allergic reaction to any ingredient of this vaccine. 
 
Serious and unexpected side effects may also occur. 
 
Risks of Blood Collection 
Having blood collected may cause some discomfort, bleeding, bruising, and/or swelling where 
the needle enters the body, and in rare cases it may result in fainting. There is a small risk of 
infection. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY AND BREASTFEEDING? 
 
Pregnancy 
If at any point during the study you think you may be pregnant, you should let the staff at your 
site know so that a pregnancy test can be done.  
 
If you become pregnant after the first dose of the mRNA COVID-19 vaccine but prior to the 
second dose, you are eligible to receive the second dose. If you choose not to receive the 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 13 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
second dose of the vaccine, you will be encouraged to continue on study and complete the 
study.  
 
At the end of the pregnancy, study staff will contact you to ask about the pregnancy outcome. 
 
If you have completed the study or choose to discontinue from the study before the end of the 
pregnancy, then study staff will request permission to contact you regarding pregnancy 
outcomes at the end of pregnancy.  
 
If you are receiving the study-provided Moderna mRNA-1273 COVID-19 vaccine: 
There is limited data regarding the use of mRNA COVID-19 vaccines in people who are 
pregnant. The American College of Obstetrics and Gynecology (ACOG suggests offering 
vaccination in pregnant and breastfeeding individuals if they are at risk for COVID-19 if they 
meet the criteria for vaccination based on the Advisory Committee on Immunization Practices 
(ACIP) recommending priority groups for vaccination. The Centers for Disease Control and 
Prevention (CDC) has recently classified pregnant and breastfeeding individuals at increased 
risk of severe illness or death from COVID-19. Therefore, pregnant individuals are eligible to 
participate in this study. 
 
The study-provided Moderna mRNA-1273 COVID-19 vaccine may involve risks to you (or to the 
embryo or fetus, if you or your partner become pregnant), which are currently unforeseen.  
 
Breastfeeding 
If you are receiving the study-provided Moderna mRNA-1273 COVID-19 vaccine: It is not 
known if the Moderna mRNA-1273 COVID-19 vaccine is safe to use in people who are 
breastfeeding; however, you are eligible to receive this vaccine if you are breastfeeding. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
There is increasing evidence that COVID-19 vaccination has the potential of direct benefit 
because it offers high levels of protection against future COVID-19 (SARS-CoV-2 infection), 
whether you have been infected previously or not.  
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
• 
Obtaining a COVID-19 vaccine in the community. 
• 
Obtaining an experimental COVID-19 vaccine, if you qualify. 
• 
No vaccination. 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices. 
 
 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 14 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
WHAT ABOUT CONFIDENTIALITY? 
 
For sites in the US 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the US Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally. Having a Certificate of Confidentiality does not prevent you from releasing 
information about yourself and your participation in the study. Even with the Certificate 
of Confidentiality, if the study staff learns of possible child abuse and/or neglect or a risk 
of harm to yourself or others, we will be required to tell the proper authorities. 
 
Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the 
US Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties, Advarra IRB institutional review board (a committee 
that protects the rights and safety of participants in research), National Institutes of Health 
(NIH), study staff, study monitors, drug companies supporting this study, and their designees. 
Having a Certificate of Confidentiality does not prevent you from releasing information about 
yourself and your participation in the study. 
 
All information collected about you as part of the study will be sent securely to the ACTG 
Statistical and Data Management Center in the United States for combining with information from 
other study participants and statistical analysis of study results. Your name and other personal 
identifiers will not be sent. Your research site is responsible for sending your information in 
accordance with the laws, regulations, and policies of your country and research site. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.  
 
For sites outside the US 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. Any 
publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the 
US Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties, (insert name of site) institutional review board (IRB) or 
Ethics Committee (a committee that protects the rights and safety of participants in research), 
National Institutes of Health (NIH), study staff, study monitors, drug companies supporting this 
study, and their designees.  
 
All information collected about you as part of the study will be sent securely to the ACTG statistical 
and data management center in the United States for combining with information from other study 
participants and statistical analysis of study results. Your name and other personal identifiers will 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 15 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
not be sent. Your research site is responsible for sending your information in accordance with the 
laws, regulations, and policies of your country and research site. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
US law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time 
 
 
WHAT ARE THE COSTS TO ME? 
 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases, it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study.  
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You will be paid up to a total of $xx.xx if you complete this study. You will be paid for the visits 
you complete according to the following schedule: 
• 
$xx.xx for Visits xxx.  
• 
$xx.xx for Visits xxx.  
• 
$xx.xx for Visits xxx. 
 
If you do not complete the study, for any reason, you will be paid for each study visit you do complete. 
 
You will be paid ___________ [“following each completed visit,” “monthly,” “quarterly,” “at the end 
of your participation in the research study,” “following each completed visit or at the end of your 
participation in the research study, whichever you prefer”]. 
  
If you have any questions regarding your compensation for participation, please contact the 
study staff. 
  
[OR] 
  
You will not receive any monetary compensation for your participation in this study. 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for your 
injuries. The US National Institutes of Health (NIH) does not have a mechanism to provide direct 
compensation for research-related injury. 
 
[For sites outside the US: Please modify (if necessary) and insert one of these two statements, 
as appropriate to your site. If your site is required to carry CTI, this must be indicated in the 
informed consent. 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 16 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
• 
This site has clinical trials insurance. This insurance will allow the site to provide you with 
monetary compensation if you suffer harm as a result of participating in this research study.  
OR 
• 
The cost for this treatment will be charged to you or your insurance company. There is no 
program for compensation either through this institution or the NIH]. 
 
The US federal government has a program that may provide compensation to you or your family 
if you experience serious physical injuries or death and these costs are not covered by other 
payors. To find out more about this “Countermeasures Injury Compensation Program” go to 
https://www.hrsa.gov/cicp/about/index.html or call 1-855-266-2427. 
 
For sites in the US: To pay medical expenses, the sponsor will need to know some information 
about you such as your name, date of birth, and Medicare Beneficiary Identifier (MBI). This is 
because the sponsor has to check to see if you receive Medicare and if you do, report the 
payment it makes to Medicare. 
 
Due to the coronavirus public health crisis, the US federal government has issued an order that 
may limit your right to sue and recover for losses if you are injured or harmed while 
participating in this COVID-19 clinical study. If the order applies, it limits your right to sue and 
recover for losses from the researchers, healthcare providers, any study sponsor, or 
manufacturer or distributor involved with the study. However, the order does not limit your right 
to seek compensation for injuries that result from conduct or activities of the researchers, 
health care providers, study sponsors, manufacturers, and distributors that is unrelated to the 
study. Review the Public Readiness and Emergency Preparedness Act (PREP): 
https://www.phe.gov/Preparedness/legal/prepact/Pages/default.aspx. 
You will not be giving up any of your legal rights by signing and dating this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled.  
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. Clinically relevant research results, including individual research results, will not be 
provided to you. If applicable, pregnancy test results will be provided to you.  
 
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns, or complaints about the study, please contact the study doctor at the 
telephone number listed on the first page of this consent document. 
 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 17 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
If you seek emergency care, or hospitalization is required, alert the treating physician that you 
are participating in this research study.  
  
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants.  
 
[Sites: Select the contact information of your IRB below.] 
 
If you have any questions about your rights as a research participant, and/or concerns or 
complaints regarding this research study, contact: 
  
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
Or call toll free:    877-992-4724 
• 
Or by email:         adviser@advarra.com 
  
Please reference the following number when contacting the Study Subject Adviser: 
Pro00050357. 
 
[OR] 
 
If you have any questions about your rights as a research participant, and/or concerns or 
complaints regarding this research study, contact:  
• 
Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site. 
• 
Telephone number of above. 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 18 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered, and you agree to take part in this study, please sign your name below and date it. 
 
 
 
__________________________________ 
Printed Name of Participant 
 
__________________________________ 
 
 
 
__________ 
Signature of Participant  
 
 
 
 
 
Date 
 
__________________________________ 
Printed Name of Legally Authorized Representative (As Appropriate) 
 
 
__________________________________ 
 
 
 
__________ 
Signature of Legally Authorized Representative  
 
 
Date 
 
 
__________________________________ 
Printed Name of Study Staff Conducting Consent Discussion (print) 
 
__________________________________ 
 
 
 
__________ 
Signature of Study Staff Conducting Consent Discussion  
Date 
 
__________________________________ 
Printed Name of Witness (As Appropriate) 
 
__________________________________ 
 
 
 
__________ 
Signature of Witness 
Date 
 
 
 
 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 19 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
CONSENT FOR OPTIONAL USE OF EXTRA SAMPLES IN OTHER STUDIES 
Everything in the main study consent you signed and dated above still applies to your 
participation unless otherwise noted below. 
 
When samples are no longer needed for this study, the AIDS CLINICAL TRIALS GROUP 
(ACTG) may want to use them in other studies and share them with other researchers. These 
samples are called “extra samples.” The ACTG will only allow your extra samples to be used in 
other studies if you agree to this. If you have any questions, please ask. 
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will 
know that the samples or information came from you.  
 
Extra samples are stored in a secure central place called a repository. Your samples will be 
stored in the ACTG repository located in the United States. 
 
There is no limit on how long your extra samples will be stored. [Site: Revise the previous 
sentence to insert limits, if your regulatory authority imposes them.] 
 
When a researcher wants to use your samples and information, their research plan must be 
approved by the ACTG. Also, the researcher’s Institutional Review Board (IRB) or ethics 
committee (EC) will review their plan. [Site: If review by your institution’s IRB/EC/RE is 
also required, insert a sentence stating this.] IRBs and ECs protect the rights and well-being 
of people in research. If the research plan is approved, the ACTG will send your samples to the 
researcher’s location. This means that researchers who are not part of the study team may use 
your samples without asking you again for your consent.  
 
You will not be paid for your samples. Also, a researcher may make a new scientific discovery or 
product based on the use of your samples. If this happens, there is no plan to share any money 
with you.  
 
You may withdraw your consent for research on your extra samples at any time, and the 
specimens will be discarded. 
 
Please choose the response that matches what you want by putting your initials in the space 
provided. Please ask the study staff any questions that you have before you indicate your 
selection. 
 
Research without Human Genetic Testing  
If you agree, your extra samples may be stored (as described above) and used for ACTG-
approved research that does not include human genetic testing. 
____ (initials) I understand and I agree to this storage and possible use of my samples.  
OR 
____ (initials) I understand but I do not agree to this storage and possible use of my samples. 
 

National Institute of Allergy and Infectious Diseases / Protocol Number A5404 / FINAL VERSION 3.0  
Page 20 of  20 
 
«PiFullName» 
Advarra IRB Approved Version 30 Nov 2022 
Revised «PIApprovalDate» 
 
SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have 
been answered, and you agree to take part in this study, please sign your name below 
and date it. 
 
____________________________________ 
Printed Name of Participant 
 
____________________________________ 
 
 
__________ 
Signature of Participant 
 
 
 
 
 
Date 
 
___________________________________________________________ 
Printed Name of Legally Authorized Representative (As Appropriate)  
 
____________________________________________ 
 
__________ 
Signature of Legally Authorized Representative   
 
Date 
 
 
____________________________________________________ 
Printed Name of Study Staff Conducting Consent Discussion 
 
_________________________________________________ 
__________ 
Signature of Study Staff Conducting Consent Discussion 
Date 
 
____________________________________________ 
Printed Name of Witness (As Appropriate) 
 
____________________________________________ 
 
__________ 
Signature of Witness  
 
 
 
 
 
Date