Randomized Phase I/II Study of the Safety and Immunogenicity of a Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus (RSV) Vaccines RSV ΔNS2/Δ1313/I1314L, RSV 6120/ΔNS2/1030s, RSV 276 or Placebo, Delivered as Nose Drops to RSV-Seronegative Children 6 to 24 Months of Age
Phase: PHASE1
Conditions: Respiratory Syncytial Virus (RSV)
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Letter of Amendment # 1      
 Page 1 of 8 
25 September 2023 
IMPAACT 2021 Protocol Version 3.0 
Letter of Amendment # 1 for: 
 
IMPAACT 2021 
Randomized Phase I/II Study of the Safety and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory 
Syncytial Virus (RSV) Vaccines RSV ΔNS2/Δ1313/I1314L, RSV 
6120/ΔNS2/1030s, RSV 276 or Placebo, Delivered as Nose Drops to 
RSV-Seronegative Children 6 to 24 Months of Age 
 
Version 3.0, dated 28 April 2022 
 
 DAIDS ES # 38530 
IND # 018943 Held By DAIDS 
 
Letter of Amendment Date: 25 September 2023 
 
 
Table of Contents 
 
Information/Instructions to Study Sites from the Division of AIDS ............................................................ 1 
Letter of Amendment Signature Page ........................................................................................................... 3 
Summary of Modifications and Rationale .................................................................................................... 4 
Implementation ............................................................................................................................................. 4 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) impacts the IMPAACT 2021 study, 
including the sample informed consent form (ICF), and will be submitted to the single Institutional 
Review Board (sIRB), Advarra, centrally by the IMPAACT Operations Center as soon as possible for 
their review and approval. If applicable, sites must also obtain approval from site IRBs per the policies 
and procedures of those entities. All IRB and regulatory entity requirements must be followed. 
 
Upon obtaining IRB approval and any other applicable regulatory entity approvals, each site should 
immediately begin implementing this LoA. After all required approvals are obtained, the updated ICFs 
should be used for all new participants. In addition, all previously enrolled participants must reconsent to 
ongoing study participation using the updated site-specific ICF. Re-consenting should take place at each 
enrolled participant’s next study visit after all required approvals are obtained. 
 
Sites are required to submit a LoA registration packet to the DAIDS Protocol Registration Office (DAIDS 
PRO) at the Regulatory Support Center (RSC). Sites will receive a registration notification for the LoA 

Letter of Amendment # 1      
 Page 2 of 8 
25 September 2023 
IMPAACT 2021 Protocol Version 3.0 
after the DAIDS PRO verifies that all required registration documents have been received and are 
complete. Sites should not await this notification before implementing this LoA.  
 
Please file this LoA, all associated IRB and regulatory entity correspondence, and all correspondence with 
the DAIDS PRO in your essential documents files for IMPAACT 2021. If the IMPAACT 2021 protocol 
is amended in the future, the contents of this LoA will be incorporated into the next version of the 
protocol. 
 
 
 
 

Letter of Amendment # 1      
 Page 3 of 8 
25 September 2023 
IMPAACT 2021 Protocol Version 3.0 
IMPAACT 2021 
Randomized Phase I/II Study of the Safety and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory 
Syncytial Virus (RSV) Vaccines RSV ΔNS2/Δ1313/I1314L, RSV 
6120/ΔNS2/1030s, RSV 276 or Placebo, Delivered as Nose Drops to 
RSV-Seronegative Children 6 to 24 Months of Age 
 
DAIDS ES # 38530 
 
Version 3.0, Letter of Amendment #1 
Letter of Amendment Signature Page 
 
I will conduct this 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 Council for Harmonisation Guideline for Good Clinical Practice (ICH 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 
 

Letter of Amendment # 1      
 Page 4 of 8 
25 September 2023 
IMPAACT 2021 Protocol Version 3.0 
Summary of Modifications and Rationale 
The primary purpose of this LoA is to update the licensed RSV product information in the protocol and 
Informed Consent Form. In August 2023, the Centers for Disease Control and Prevention (CDC) director 
adopted the recommendation from the CDC Advisory Committee on Immunization Practices to approve 
nirsevimab, an FDA-licensed extended half-life monoclonal antibody active against RSV. Nirsevimab has 
been recommended by the CDC for all infants younger than eight months old who are born during or 
entering their first RSV season. For children between the ages of eight and 19 months who are at increased 
risk of severe RSV disease, a dose is recommended in their second RSV season. With the CDC director’s 
adoption of the recommendation, nirsevimab is now applicable for official CDC public health guidance and 
can be added to the childhood immunization schedule. Additionally, in August 2023, the FDA approved an 
RSV prefusion F vaccine for pregnant people between 32-36 weeks gestation. The vaccine is expected to 
prevent of lower respiratory tract disease (LRTD) or severe LRTD in infants from birth through six months 
of age. This LoA also includes updates to the Protocol Team and Study Site Rosters. 
Implementation 
The modifications included in this Letter of Amendment are listed below in order of appearance in the 
protocol and will be incorporated into the next protocol amendment as specified below.  Additions to the text 
are indicated in bold; deletions are indicated by strike-through.   
Note: In this LOA, all new references are identified with alphabetic identifiers, with full citations 
provided on page 8. In the next full amendment of the IMPAACT 2021 protocol, these references will be 
incorporated into the numeric listing of all references in protocol Section 15. 
 
Protocol Team and Site Study Rosters 
 
1. Protocol Team  
 
To reflect current membership, John Binkowski and Nicole Tobin have been removed from the roster 
and Grace Malonga, Helty Adisetiyo, and Maggie Albano are added: 
 
Protocol Statisticians  
Mark Giganti, PhD  
Center for Biostatistics in AIDS Research  
Harvard TH Chan School of Public Health  
651 Huntington Avenue  
Boston, MA 02115  
Phone: 617-432-3233  
Email: mgiganti@sdac.harvard.edu  
 
Rachel Ketchum, SM  
Center for Biostatistics in AIDS Research  
Harvard TH Chan School of Public Health  
651 Huntington Avenue  
Boston, MA 02115  
Phone: 617-432-2899  
Email: rketchum@sdac.harvard.edu 
 
Grace Malonga, MPH, MS 
Center for Biostatistics in AIDS Research  
Harvard TH Chan School of Public 
Health  
651 Huntington Avenue  
Boston, MA 02115  
Phone: 617-432-3171 
Email: gmalonga@sdac.harvard.edu 
 
Protocol Data Managers 
Benjamin Johnston, BS 
Frontier Science Foundation 
4033 Maple Rd.  
Amherst, NY 14226-1056  
Phone: 716-834-0900 x7407  
Email: johnston@frontierscience.org  
 

Letter of Amendment # 1      
 Page 5 of 8 
25 September 2023 
IMPAACT 2021 Protocol Version 3.0 
John Binkowski, MA  
Frontier Science Foundation  
4033 Maple Road  
Amherst, NY 14226  
Phone: 716-834-0900 ext. 7371  
Email: binkowski@frontierscience.org 
 
Carly Hoffmann, BA  
Frontier Science Foundation  
4033 Maple Road 
Amherst, NY 14226  
Phone: 716-834-0900 ext. 7396  
Email: hoffmann@frontierscience.org 
 
Laboratory Center Representatives 
Helty Adisetiyo, PhD 
IMPAACT Laboratory Center 
University of California Los Angeles 
10990 Wilshire Boulevard, Suite 260  
Los Angeles, CA 90024 
Phone: 424-946-5724 
Email: hadisetiyo@milabcentral.org 
 
Nicole Tobin, MD 
University of California Los Angeles  
MacDonald Research Laboratory  
675 Charles E. Young Drive South  
Los Angeles, CA 90095 
Phone: 310-889-4786 
Email: ntobin@milabcentral.org 
 
IMPAACT Community Program Associates 
Maggie Albano, MA 
IMPAACT Operations Center  
FHI 360  
359 Blackwell Street, Suite 200  
Durham, NC 22701  
Phone: 202-464-3753 
Email: malbano@fhi360.org 
 
Michelle Haber, CMSW  
IMPAACT Operations Center  
FHI 360  
359 Blackwell Street, Suite 200  
Durham, NC 22701  
Phone: 919-321-3472  
Email: mhaber@fhi360.org 
 
2. Study Site Roster 
 
To reflect the current Investigators of Record, Ellen Chadwick has been replaced by Jennifer Jao (site 
4001), Sharon Frey has been replaced by Heidi Sallee (site 30344), and Evan Anderson (site 5030) 
and Jennifer Schuster (site 32017) have been removed from the Study Site Roster:
Site 4001, Lurie Children’s Hospital of 
Chicago 
Ellen Chadwick, MD 
Ann& Robert H. Lurie Children’s Hospital 
of Chicago  
225 E. Chicago Ave  
Chicago, IL 60611 
Phone: 312-227-4080 
Email: egchadwick@luriechildrens.org 
 
Jennifer Jao, MD, MPH  
Ann & Robert H. Lurie Children’s 
Hospital of Chicago  
225 E. Chicago Ave  
Chicago, IL 60611 
Phone: 312-227-4080 
Email: jjao@luriechildrens.org 
 
Site 5030, Emory University School of 
Medicine 
Andres Camacho-Gonzalez, MD, MSc  
Emory University  
2015 Uppergate Drive  
Atlanta, GA 30322  
Phone: 404-727-5642  
Email: acamac2@emory.edu 
 
Evan Anderson, MD  
Emory University  
2015 Uppergate Drive  
Atlanta, GA 30322  
Phone: 404-727-1746  
Email: evanderson@emory.edu 
 

Letter of Amendment # 1      
 Page 6 of 8 
25 September 2023 
IMPAACT 2021 Protocol Version 3.0 
Site 30344, Saint Louis Center for Vaccine 
Development 
Sharon Frey, MD 
Edward A. Doisy Research Center 
1100 S. Grand Boulevard, 1st Floor 
St. Louis, MO 63104 
Phone: 314-977-9032 
Email: sharon.frey@health.slu.edu 
 
Heidi Sallee, MD 
1465 South Grand Boulevard 
Room 1710 Glennon Hall 
St. Louis, MO 63104 
Phone: 314-577-5643 
Email: heidi.sallee@health.slu.edu 
Site 32017, The Children’s Mercy Hospital  
James Christopher Day, MD  
Children's Mercy Kansas City  
2401 Gillham Road  
Kansas City, MO 64108  
Phone: 816-234-3207  
Email: ccday@cmh.edu  
 
Jennifer Schuster, MD  
Children’s Mercy Kansas City  
2401 Gillham Road  
Kansas City, MO 64108  
Phone: 816-234-3061  
Email: jeschuster@cmh.edu
 
Section-Specific 
 
3. Section 1.2, Background 
 
a) Page 22, third paragraph, starting with first sentence: Currently, no licensed vaccine against RSV 
is available, although there is broad consensus that such a vaccine is urgently needed and should 
be a global health priority to protect healthy older infants and toddlers. Although passive 
immunoprophylaxis with the RSV-neutralizing monoclonal antibody palivizumab 
(Synagis®;MedImmune) is available for high-risk infants, this approach is not feasible for 
general use. In addition, in August 2023, the Centers for Disease Control and Prevention 
(CDC) director adopted the recommendation from the CDC Advisory Committee on 
Immunization Practices (ACIP) to approve nirsevimab (1). Nirsevimab is an FDA-licensed 
monoclonal antibody active against RSV to provide passive immunity to healthy infants up 
to eight months old during their first RSV season and to high-risk children eight to 19 
months during their second RSV season (2). Additionally, on 21 August 2023, licensure of 
the RSVpreF maternal vaccine was approved for use at 32 through 36 weeks gestational age 
of pregnancy (3). While both products are expected to provide passive immunity to younger 
infants, they do not provide active, durable immunity and are not expected to protect 
healthy older infants and toddlers against RSV disease. Pursuit of vaccines for active 
immunization against RSV is important because protection from passive antibodies (from 
either nirsevimab or maternal immunization) is short-lived- lasting no more than 6 months. 
There is significant burden of RSV disease in children who are older than eight months of 
age during RSV season who will not be recommended to receive nirsevimab. For example, 
globally, the incidence in 6-12 months-old children of RSV lower respiratory illness is 
estimated at 82 per 1000 per year, with an estimated 4.1 to 8 million episodes annually in 
this age group, resulting in a rate of hospitalization of about 1% annually (estimated 
numbers: 500,000 – 970,000 hospital admissions) (4), In the United States, for children from 
7 to 20 months of age, rates of inpatient RSV infections were ~3 per 1000, emergency room 
RSV ~30 per 1000, and outpatient visits ~60 per 1000 (5, 6). In contrast to the passive 
immunity provided by nirsevimab or maternal RSV preF, live-attenuated vaccines studied 
in this protocol prime the infants’ immune system and induce active RSV immunity, which 
should provide long-lasting immunity with potent memory responses. […] 
 
 

Letter of Amendment # 1      
 Page 7 of 8 
25 September 2023 
IMPAACT 2021 Protocol Version 3.0 
4. Section 4.2, Exclusion Criteria 
 
a) 4.2.6, Page 38: Previous enrollment in this trial, previous maternal or pediatric receipt of a 
licensed or investigational RSV vaccine, or previous maternal or pediatric receipt of or planned 
administration of any other anti-RSV product (such as ribavirin or RSV IG or RSV mAb) within 
four months of screening or planned administration of an anti-RSV product between 
screening and day 56 after enrollment.  
 
5. Section 5.11, Concomitant Medications 
 
a) 5.11.2, Precautionary Concomitant Medications, Page 46, new bullet point:  
 
Due to their potentially confounding effect on immunogenicity results, the following treatments 
should be avoided after study product administration unless clinically indicated: 
 
• 
Systemic corticosteroids for more than 14 days at a dosage equivalent to prednisone at >2 
mg/kg or 20 mg daily or other immune-modifying drugs 
• 
Immunoglobulins and/or any blood products 
• 
Anti-RSV products (such as ribavirin or RSV IG or RSV mAb) 
 
6. Section 7.2, Safety-Related Data Collection 
a) Laboratory Test Results, Page 62, Table 5: AE eCRF Entry Requirements, Row Throughout 
Study, Column Concomitant Medications to enter into eCRFs:  
 
Study Phase at the time 
of event onset 
Calendar Date 
AEs to enter into eCRFs 
Concomitant Medications to 
enter into eCRFs 
Throughout study 
ANY 
• Updated data on unresolved AEs 
or serious AEs with onset date 
during the timeframe from study 
product administration (Day 0) to 
midnight on the 28th day after Day 
0 
• Updated data on unresolved 
serious AEs with onset date prior 
to midnight on the 56th day 
following Day 0 
• Updated data on unresolved 
serious AEs with onset date during 
RSV Surveillance Period or related 
to the Post-RSV Season Study 
Visit 
 
Note: unresolved events should be 
followed to resolution or until no 
further change is expected. 
• All concomitant 
medications   
administered to treat the 
entered event 
• All prohibited and 
precautionary 
medications (see Section 
5.11) 
 
Informed Consent Forms 
 
7. Appendix VI, Informed Consent Form for Study Participation 
 
a) Key Information, Page 96, last bullet: You may choose to not allow your child to take part in this 
study. Two products have been developed to protect young infants against RSV disease. 

Letter of Amendment # 1      
 Page 8 of 8 
25 September 2023 
IMPAACT 2021 Protocol Version 3.0 
However, Tthere are is currently no licensed vaccines to protect against RSV illness product 
available to provide long-lasting protection against RSV disease to healthy older infants and 
children. 
 
b) Why Is This Study Being Done?, Page 96, third paragraph: RSV can cause serious lung infections 
such as pneumonia and wheezing. Two products have been developed to protect young 
infants against RSV disease. At this time However, there is currently no approved vaccine to 
prevent RSV illness  licensed product available to provide long-lasting protection against 
RSV disease to healthy older infants and children. 
 
c) What Other Choices Does My Child Have Besides This Study?, Page 102: Two products have 
been developed to protect young infants against RSV disease. If your child is younger than 
eight months of age at the start of their first RSV season, your child may be eligible to receive an 
FDA-licensed product for short-term protection against RSV during your child’s first RSV 
season. However, Tthere are is currently no licensed vaccines to protect against RSV illness at 
this time product available to provide long-lasting protection against RSV disease to healthy 
older infants and children. There is no other similar study or approved vaccine that we can offer 
your child. You may choose to not allow your child to take part in this study. 
 
References 
1. 
Centers for Disease Control and Prevention. CDC Recommends a Powerful New Tool to Protect 
Infants from the Leading Cause of Hospitalization 2023. [cited 2023 9 Aug ]. Available from: 
https://www.cdc.gov/media/releases/2023/p-0803-new-tool-prevent-infant-hospitalization-.html.  
2. 
US Food and Drug Administration. FDA Approves New Drug to Prevent RSV in Babies and 
Toddlers 2023. [cited 2023 9 Aug]. Available from: https://www.fda.gov/news-events/press-
announcements/fda-approves-new-drug-prevent-rsv-babies-and-
toddlers#:~:text=Today%2C%20the%20U.S.%20Food%20and,remain%20vulnerable%20to%20s
evere%20RSV.  
3. 
Food and Drug Administration. FDA Approves First Vaccine for Pregnant Individuals to Prevent 
RSV in Infants 2023. [cited 2023 22 Aug]. Available from: https://www.fda.gov/news-
events/press-announcements/fda-approves-first-vaccine-pregnant-individuals-prevent-rsv-
infants#:~:text=Abrysvo%20is%20approved%20for%20use,years%20of%20age%20and%20olde
r.  
4. 
Network RVGE, Li Y, Wang X, Blau DM, Caballero MT, Feikin DR, et al. Global, regional, and 
national disease burden estimates of acute lower respiratory infections due to respiratory syncytial 
virus in children younger than 5 years in 2019: a systematic analysis. The Lancet. 
2022;399(10340):2047-64. 
5. 
Rha B, Curns AT, Lively JY, Campbell AP, Englund JA, Boom JA, et al. Respiratory syncytial 
virus–associated hospitalizations among young children: 2015–2016. Pediatrics. 2020;146(1). 
6. 
Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, et al. The burden of 
respiratory syncytial virus infection in young children. N Engl J Med. 2009;360(6):588-98.