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




IMPAACT 2018 
Randomized Phase I Study of the Infectivity, 
Safety, and Immunogenicity of a Single Dose of 
the Recombinant Live-Attenuated Respiratory 
Syncytial Virus (RSV) Vaccines RSV 
ΔNS2/Δ1313/I1314L or RSV 276 or Placebo, 
Delivered as Nose Drops to RSV-Seronegative 
Infants 6 to 24 Months of Age 
 
 
DAIDS ES #38405 
 
 
This file contains the current IMPAACT 2018 protocol, 
which is comprised of the following documents, 
presented in reverse chronological order: 
 
x Letter of Amendment #3, dated 10 June 2020 
x Clarification Memorandum #2, dated 27 March 2020 
x Letter of Amendment #2, dated 18 July 2018 
x Letter of Amendment #1, dated 15 March 2018 
x Clarification Memorandum #1, dated 1 September 2017 
x Protocol Version V1.0, dated 15 June 2017 

Letter of Amendment #3 
Page 1 of 6 
10 June 2020 
IMPAACT 2018 Protocol Version 1.0 
Letter of Amendment #3 for: 
 
IMPAACT 2018 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus 
(RSV) Vaccines RSV delta NS2/delta 1313/I1314L or RSV 276 or Placebo, 
Delivered as Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
Version 1.0, dated 15 June 2017 
 
DAIDS Study ID #38405 
IND #17587 
 
Letter of Amendment Date: 10 June 2020 
 
 
Table of Contents 
 
Information/Instructions to Study Sites from the Division of AIDS ............................................................ 1 
Letter of Amendment Signature Page ........................................................................................................... 2 
Summary of Modifications and Rationale .................................................................................................... 3 
Implementation ............................................................................................................................................. 3 
A. Updates of Protocol Team Roster  .................................................................................................... 3 
B. 
Operational Guidance from Protocol CM #2, dated 27 March 2020 ................................................ 5 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT 2018 study and 
must be submitted to site Institutional Review Boards and/or Ethics Committees (IRBs/ECs) as soon as 
possible for their review and approval. Approval must also be obtained from other site regulatory entities 
if applicable per the policies and procedures of the regulatory entities. All applicable IRB/EC and 
regulatory entity requirements must be followed. 
 
Upon obtaining all required IRB/EC approvals and any other applicable regulatory entity approvals, each 
site should immediately begin implementing this LoA. Sites are required to submit an LoA registration 
packet to the DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support Center. Sites 
will receive a registration notification for the LoA 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/EC and regulatory entity correspondence, and all correspondence 
with the DAIDS PRO in your essential document files for IMPAACT 2018. If the IMPAACT 2018 
protocol is amended in the future, applicable contents of this LoA will be incorporated into the next 
version of the protocol. 
 
 

Letter of Amendment #3 
Page 2 of 6 
10 June 2020 
IMPAACT 2018 Protocol Version 1.0 
IMPAACT 2018 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus 
(RSV) Vaccines RSV delta NS2/delta 1313/I1314L or RSV 276 or Placebo, 
Delivered as Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
DAIDS Study ID #38405 
 
 
Version 1.0, Letter of Amendment #3 
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 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 

Letter of Amendment #3 
Page 3 of 6 
10 June 2020 
IMPAACT 2018 Protocol Version 1.0 
Summary of Modifications and Rationale 
 
This LoA updates the protocol team roster and incorporates the contents of protocol Clarification 
Memorandum (CM) #2.  
 
Section A of this LoA includes the protocol team and site roster updates.  
 
Section B of this LoA incorporates the contents of CM #2, which was issued on 27 March 2020 to 
safeguard the health and well-being of study participants in the context of circulating SARS-CoV-2 and 
the associated COVID-19 pandemic. CM #2 provided operational flexibility for conducting study visits 
and procedures when needed to ensure continued close communications with participants’ families and to 
prioritize the conduct of clinically and scientifically important evaluations when possible. Consistent with 
the instructions provided in CM #2, implementation of Section B of this LoA is expected to be time-
limited in relation to the COVID-19 pandemic. In consultation with IMPAACT Network leadership and 
the study Sponsor, the IMPAACT 2018 Protocol Team will determine when, in the future, the guidance in 
Section B is no longer applicable. When such a determination is made, study sites will be formally 
notified and instructed to inform IRBs/ECs and other applicable regulatory entities. 
 
Implementation 
 
Updates of the protocol team roster are shown in Section A of this LoA, using strikethrough for deletions 
and bold type for additions where applicable. Operational guidance for conducting study visits and 
procedures during the COVID-19 pandemic is provided in Section B of this LoA; conventions for use of 
strikethrough and bolding do not apply in this section. 
  
A. Updates of Protocol Team and Site Rosters  
 
To reflect current membership, the protocol title page, protocol team roster, and site roster are updated as 
follows:  
 
Protocol Title Page 
 
Clinical Trials Specialists:  
Charlotte Perlowski, MSPH 
 
 
 
 
Jennifer Libous, MS, CCRP 
 
 
 
 
Shane Reynolds, MSHS 
 
Protocol Team Roster 
 
Clinical Trials Specialists 
Shane Reynolds, MSHS 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: 919054407040 x11941 
Email: shreynolds@fhi360.org 
 
Protocol Pharmacists 
Kelly Parsons, PharmD 
DAIDS/NIAID/NIH 
5601 Fishers Lane, Room 9E15 
Rockville, MD 20852 
Phone: 240-669-5721 
Email: kelly.parsons@nih.gov 
 

Letter of Amendment #3 
Page 4 of 6 
10 June 2020 
IMPAACT 2018 Protocol Version 1.0 
Clinical Investigators 
Amanda (Mandy) Dempsey, MD 
University Physicians, Inc. Building (UPI) 
13199 East Montview Boulevard 
Suite 300, Campus Box F443 
Aurora, Colorado 80045 
Phone: 303-724-6679 
Email: Amanda.dempsey@ucdenver.edu 
 
Protocol Statistician 
Petronella Muresan, MS 
Statistical & Data Analysis Center (SDAC)  
Harvard School of Public Health 
Statistical and Data Management Center 
(SDMC) 
Frontier Science Foundation 
1371 Beacon Street, Suite #203 
Brookline, MA 02446 
Phone: 617-632-2000, ext. 4031 
Email: petronm@sdac.harvard.edu 
 
Protocol Data Managers 
Kayla Denson, PhD 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Rd. 
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7211 
Email: denson@fstrf.org 
 
Linda Marillo, BA 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Rd. 
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7257 
Email: marillo@fstrf.org 
Benjamin Johnston, BS 
Frontier Science Foundation 
4033 Maple Rd. 
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7407 
Email: Johnston@frontierscience.org 
 
Jared Kneebone, PhD 
Frontier Science Foundation 
4033 Maple Rd. 
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7263 
Email: kneebone@frontierscience.org 
 
Protocol Laboratory Data Manager 
Frederic Bone 
Frontier Science and Technology Research 
Foundation (FSTRF) Frontier Science 
Foundation 
4033 Maple Rd. 
Amherst, NY 14226-1056 
Phone: 716-834-0900 ext. 7306 
Email: bone@fstrf.org 
bone@frontierscience.org  
 
Laboratory Center Representative 
Dale Dayton, RN, CCRA 
Children’s Hospital of Los Angeles 
4650 Sunset Boulevard 
Los Angeles, CA 90027 
Phone: 301-742-9077 
Email: ddayton@impaactlabcenter.org 
 
Nicole Tobin, MD 
University of California Los Angeles 
MacDonald Research Laboratory 
675 Charles E. Young Drive South 
Los Angeles, CA 90095 
Phone: (310) 825-7708 
Email: ntobin@impaactlabcenter.org 
 
IMPAACT Community Program Associate 
Marcus Bryan, MEd 
IMPAACT Operations Center 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701 
Phone: (919) 544-7040 x11678 
Email: mbryan@fhi360.org 
 
 
 

Letter of Amendment #3 
Page 5 of 6 
10 June 2020 
IMPAACT 2018 Protocol Version 1.0 
Site Roster 
 
Site 3801, Baylor College of Medicine/Texas Children’s Hospital 
William Shearer, MD, PhD 
Texas Children's Hospital 
1102 Bates Avenue, Suite 330 
Immunology, Allergy & Rheumatology 
Houston, TX, 77030-2399 
Phone: 832-824-1274 
Email: wtsheare@texaschildrens.org
Mary Paul, MD 
Texas Children's Hospital 
1102 Bates Avenue, Suite 330 
Houston, TX, 77030 
Phone: 832-822-1038 
Email: mepaul@texaschildrens.org 
 
 
B. Operational Guidance from Protocol CM #2, dated 27 March 2020 
 
This CM provides operational guidance to study sites from the IMPAACT 2018 Protocol Team. The 
Protocol Team acknowledges that the extent to which site operations may be disrupted by the COVID-19 
pandemic may vary across sites and over time. All sites should follow applicable government, health 
authority, and institutional policies with respect to conduct of study visits and procedures, with 
utmost importance placed on the health and well-being of study participants and study staff. Site 
investigators should continue to follow current protocol specifications for communication with the 
Protocol Team and/or Protocol Safety Review Team (PSRT) and should contact the PSRT 
(impaact.psrt2018@fstrf.org) with any questions or concerns regarding this CM or management of study 
participants.  
 
Visit Scheduling 
• 
Sites should continue to conduct weekly non-visit contacts per protocol with participants’ families 
during the remainder of RSV Season Surveillance (i.e., through 31 March 2020). 
• 
Sites should discontinue all in-person Illness Visits and instead use chart abstraction (i.e., from non-
study medical visits associated with the illness) and non-visit contacts with participants’ families to 
collect available data related to illnesses meeting protocol-specified illness criteria during the 
remainder of RSV Season Surveillance (i.e., through 31 March 2020). The Illness Visit nasal wash 
specimen will not be collected. 
• 
Sites should conduct Post-RSV Season Study Visits; effective with the issuance of this CM, the target 
window for the Post-RSV Season Study Visit is broadened to include 1 April to 31 July 2020 and the 
allowable window for this visit is broadened to include up to 30 September 2020.  
- Sites should utilize the broadened visit window as needed to permit continued completion of in-
person Post-RSV Season Study Visits. 
- Sites that anticipate operational disruptions or closures in the near future are advised to conduct 
visits early in the target window. Visits conducted prior to opening of the target window would 
also be preferred to completely missing a visit at a later date. 
- Sites that are currently experiencing operational disruptions or closures are advised to conduct 
visits late in the target window. Visits conducted after closing of the target window (i.e., after 31 
July 2020) but prior to the closing of the allowable window (i.e., by 30 September 2020) would 
also be preferred to completely missed visits. 
- Sites with no ability to conduct Post-RSV Season Study Visits in-person during any of the 
windows noted above should notify the protocol team. 
 

Letter of Amendment #3 
Page 6 of 6 
10 June 2020 
IMPAACT 2018 Protocol Version 1.0 
Prioritization of Post-RSV Season Study Visit Procedures 
• 
Sites with full capacity to conduct Post-RSV Season Study Visits in-person at the study clinic during 
the month of April 2020 should continue to do so in full compliance with the current protocol 
language. If it is not possible to conduct visits in April, the broadened windows noted above may be 
used. 
• 
Sites may also conduct in-person Post-RSV Season Study Visits off-site, in full or in part, if permitted 
by applicable government, health authority, and institutional policies during any of the windows 
noted above. Where this option is permitted, site staff should communicate with parents/guardians to 
determine in advance where and when such visits will take place, with adequate protections for 
safety, privacy, and confidentiality. Off-site visit procedures should be conducted by site staff who 
are adequately qualified and trained to conduct the procedures, as determined by the site Investigator 
of Record (IoR), with attention paid to occupational health, biohazard containment, and specimen and 
data chain of custody. These staff should also be adequately trained and qualified to immediately 
assess and/or manage any adverse events and/or social impacts that may occur during the visits. If 
adverse events requiring further evaluation or management are identified during an off-site visit, 
study staff conducting the visit should arrange for appropriate clinical management, in consultation 
with the IoR or designee, as needed. 
• 
Sites with limited capacity to conduct Post-RSV Season Study Visits in-person during any of the 
windows noted above should prioritize collection of blood for immunologic assays/serum antibodies 
to RSV and then blood for cellular immune assay (viable PBMCs); a secondary priority is collection 
of nasosorption SAM strip specimens.  
 
Documentation 
• 
Site-specific contingency plans, and the implementation thereof, should be documented in essential 
document files for IMPAACT 2018.  
• 
Documentation should be entered in participant study charts in real-time should any of the following 
occur: 
- Missed visits  
- Out-of-window visits 
- Off-site visits (document the location of the visit) 
- Incomplete or partial visits (document which procedures were performed and which were not) 
- Remote contacts (e.g., by telephone) performed in lieu of in-person visits (document method used 
to complete the contact and which procedures were performed) 
- Any other participant contacts  
- Non-standard laboratory assays 
• 
In consultation with the Division of AIDS, the IMPAACT Network is developing comprehensive 
guidance for documenting and/or reporting protocol deviations that may occur due to limited site 
capacity to conduct study visits or procedures during the COVID-19 pandemic. Once this Network-
level guidance is available, it will be provided in a separate communication to all sites.  
 
 

Clarification Memorandum #2 
Page 1 of 3 
27 March 2020 
IMPAACT 2018 Protocol Version 1.0 
 
Clarification Memorandum #2 for:  
 
IMPAACT 2018 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus 
(RSV) Vaccines RSV delta NS2/delta 1313/I1314L or RSV 276 or Placebo, 
Delivered as Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
Version 1.0, dated 15 June 2017 
 
DAIDS Study ID #38405 
IND #17587 held by DAIDS 
 
Clarification Memo Date: 27 March 2020 
 
 
Summary of Clarifications 
 
This Clarification Memorandum (CM) is being issued to safeguard the health and well-being of 
IMPAACT 2018 study participants in the context of circulating severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) and the associated the coronavirus disease (COVID-19) pandemic.  
 
As the study Sponsor, the Division of AIDS (DAIDS) has determined that this CM should be 
implemented immediately upon issuance. Consistent with United States Food and Drug Administration 
guidance, institutional review board/ethics committee (IRB/EC) approval of this CM is not required by 
the Division of AIDS prior to implementation. However, given the context of the COVID-19 pandemic 
and the importance of the guidance provided in this CM, sites should submit this CM to IRBs/ECs for 
their information or, if required by the IRBs/ECs, for their review and approval.  
 
The purpose of this CM is to provide operational flexibility for conducting study visits and procedures 
when needed to ensure continued close communications with participants’ families and to prioritize the 
conduct of clinically and scientifically important evaluations when possible. 
 
Implementation of this CM is expected to be time-limited in relation to the COVID-19 pandemic. In 
consultation with IMPAACT Network leadership and the study Sponsor, the IMPAACT 2018 Protocol 
Team will determine when, in the future, the guidance provided in this CM is no longer applicable. When 
such a determination is made, study sites will be formally notified and instructed to inform their 
IRBs/ECs. 
 
Please file this CM and any applicable IRB/EC correspondence in your essential document files for 
IMPAACT 2018. 
 
 
 
 

Clarification Memorandum #2 
Page 2 of 3 
27 March 2020 
IMPAACT 2018 Protocol Version 1.0 
Implementation 
 
This CM provides operational guidance to study sites from the IMPAACT 2018 Protocol Team. The 
Protocol Team acknowledges that the extent to which site operations may be disrupted by the COVID-19 
pandemic may vary across sites and over time. All sites should follow applicable government, health 
authority, and institutional policies with respect to conduct of study visits and procedures, with 
utmost importance placed on the health and well-being of study participants and study staff. Site 
investigators should continue to follow current protocol specifications for communication with the 
Protocol Team and/or Protocol Safety Review Team (PSRT) and should contact the PSRT 
(impaact.psrt2018@fstrf.org) with any questions or concerns regarding this CM or management of study 
participants.  
 
Visit Scheduling 
• 
Sites should continue to conduct weekly non-visit contacts per protocol with participants’ families 
during the remainder of RSV Season Surveillance (i.e., through 31 March 2020). 
• 
Sites should discontinue all in-person Illness Visits and instead use chart abstraction (i.e., from non-
study medical visits associated with the illness) and non-visit contacts with participants’ families to 
collect available data related to illnesses meeting protocol-specified illness criteria during the 
remainder of RSV Season Surveillance (i.e., through 31 March 2020). The Illness Visit nasal wash 
specimen will not be collected. 
• 
Sites should conduct Post-RSV Season Study Visits; effective with the issuance of this CM, the target 
window for the Post-RSV Season Study Visit is broadened to include 1 April to 31 July 2020 and the 
allowable window for this visit is broadened to include up to 30 September 2020.  
- Sites should utilize the broadened visit window as needed to permit continued completion of in-
person Post-RSV Season Study Visits. 
- Sites that anticipate operational disruptions or closures in the near future are advised to conduct 
visits early in the target window. Visits conducted prior to opening of the target window would 
also be preferred to completely missing a visit at a later date. 
- Sites that are currently experiencing operational disruptions or closures are advised to conduct 
visits late in the target window. Visits conducted after closing of the target window (i.e., after 31 
July 2020) but prior to the closing of the allowable window (i.e., by 30 September 2020) would 
also be preferred to completely missed visits. 
- Sites with no ability to conduct Post-RSV Season Study Visits in-person during any of the 
windows noted above should notify the protocol team. 
 
Prioritization of Post-RSV Season Study Visit Procedures 
• 
Sites with full capacity to conduct Post-RSV Season Study Visits in-person at the study clinic during 
the month of April 2020 should continue to do so in full compliance with the current protocol 
language. If it is not possible to conduct visits in April, the broadened windows noted above may be 
used. 
• 
Sites may also conduct in-person Post-RSV Season Study Visits off-site, in full or in part, if permitted 
by applicable government, health authority, and institutional policies during any of the windows 
noted above. Where this option is permitted, site staff should communicate with parents/guardians to 
determine in advance where and when such visits will take place, with adequate protections for 
safety, privacy, and confidentiality. Off-site visit procedures should be conducted by site staff who 
are adequately qualified and trained to conduct the procedures, as determined by the site Investigator 
of Record (IoR), with attention paid to occupational health, biohazard containment, and specimen and 
data chain of custody. These staff should also be adequately trained and qualified to immediately 
assess and/or manage any adverse events and/or social impacts that may occur during the visits. If 
adverse events requiring further evaluation or management are identified during an off-site visit, 

Clarification Memorandum #2 
Page 3 of 3 
27 March 2020 
IMPAACT 2018 Protocol Version 1.0 
study staff conducting the visit should arrange for appropriate clinical management, in consultation 
with the IoR or designee, as needed. 
• 
Sites with limited capacity to conduct Post-RSV Season Study Visits in-person during any of the 
windows noted above should prioritize collection of blood for immunologic assays/serum antibodies 
to RSV and then blood for cellular immune assay (viable PBMCs); a secondary priority is collection 
of nasosorption SAM strip specimens.  
 
Documentation 
• 
Site-specific contingency plans, and the implementation thereof, should be documented in essential 
document files for IMPAACT 2018.  
• 
Documentation should be entered in participant study charts in real-time should any of the following 
occur: 
- Missed visits  
- Out-of-window visits 
- Off-site visits (document the location of the visit) 
- Incomplete or partial visits (document which procedures were performed and which were not) 
- Remote contacts (e.g., by telephone) performed in lieu of in-person visits (document method used 
to complete the contact and which procedures were performed) 
- Any other participant contacts  
- Non-standard laboratory assays 
• 
In consultation with the Division of AIDS, the IMPAACT Network is developing comprehensive 
guidance for documenting and/or reporting protocol deviations that may occur due to limited site 
capacity to conduct study visits or procedures during the COVID-19 pandemic. Once this Network-
level guidance is available, it will be provided in a separate communication to all sites.  
 

Letter of Amendment #2       
Page 1 of 6 
18 July 2018 
IMPAACT 2018 Protocol Version 1.0 
 
Letter of Amendment # 2 for: 
 
IMPAACT 2018 
 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus (RSV) 
Vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 or Placebo, Delivered as Nose Drops 
to RSV-Seronegative Infants 6 to 24 Months of Age 
 
Version 1.0, dated 15 June 2017 
 
DAIDS Document ID 38405 
IND # 17587 held by DAIDS 
 
Letter of Amendment Date: 18 July 2018 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT 2018 study and must be 
submitted to site Institutional Review Boards (IRBs) as soon as possible for their review and approval. Approval 
must also be obtained from site regulatory entities if applicable per the policies and procedures of the regulatory 
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. Sites are required to submit an 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 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 2018. If the IMPAACT 2018 protocol is amended 
in the future, the contents of this LoA will be incorporated into the next version of the protocol.  
 
 
 
 

Letter of Amendment #2       
Page 2 of 6 
18 July 2018 
IMPAACT 2018 Protocol Version 1.0 
 
IMPAACT 2018 
 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus (RSV) 
Vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 or Placebo, Delivered as Nose Drops 
to RSV-Seronegative Infants 6 to 24 Months of Age 
 
DAIDS Document ID 38405 
 
Version 1.0, dated 15 June 2017 
 
Letter of Amendment #2, dated 18 July 2018 
 
 
LETTER OF AMENDMENT SIGNATURE PAGE 
 
 
I will conduct this study in accordance with the provisions of this protocol, including this Letter of Amendment, 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 

Letter of Amendment #2       
Page 3 of 6 
18 July 2018 
IMPAACT 2018 Protocol Version 1.0 
 
Summary of Modifications and Rationale 
 
This Letter of Amendment: 
 
1. Updates the Protocol Team Roster: Frederic Bone replaced Andee Fox as the Laboratory Data Manager. 
 
2. Updates the protocol-specified procedures for emergency unblinding: These changes have been made for 
compliance with international requirements that blinded studies allow rapid emergency unblinding by the 
site Investigator of Record, independently from the sponsor or Protocol Team. Specifically, Sections 5.8 
and 9.4.1 have been updated to remove requirements for non-site staff (e.g., Protocol Team members) to 
be involved in emergency unblinding. Instead, these sections refer to the IMPAACT Network Manual of 
Procedures (MOP), which will contain the most current guidance. 
 
3. Adjusts secondary and exploratory objectives and outcomes: These revisions have been made to more 
accurately reflect planned analysis timelines. Specifically, three objectives and two outcomes formerly 
designated as secondary have been recategorized as exploratory, as the Protocol Team anticipates that 
data related to these objectives/outcomes may not be available within the timeframe specified for 
reporting results from secondary objectives/outcomes to ClinicalTrials.gov. 
 
Implementation 
 
The modifications included in this LoA 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 in strikethrough.   
1. Updates to Protocol Team Roster, page 11: 
Protocol Laboratory Data Manager 
Andee Fox, MPH Frederic Bone 
Laboratory Data Manager 
Frontier Science and Technology Research Foundation (FSTRF)  
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 ext. 7276 7306 
Email: fox@fstrf.org bone@fstrf.org 
2. Updates to emergency unblinding procedures 
a. Section 5.8, Study Product Accountability, page 43, starting with fourth sentence: 
On a case-by-case basis If needed to guide management of a serious illness or medical emergency 
affecting a study participant, or if knowing the participant’s treatment assignment would 
otherwise affect decisions regarding the participant’s immediate medical management as 
determined by the site Investigator of Record (IoR) or treating clinician, the randomization code 
may only be released at the written request of the Protocol Chair(s) and only after discussion with the 
senior protocol statistician and the MO to the site IoR at his/her request for rapid unblinding of 
the participant’s treatment assignment, independently from the sponsor or Protocol Team, as 
described in protocol Section 9.4.1. Additional information is available in and the IMPAACT 
Network Manual of Procedures (MOP) Appendix I: Unblinding Procedures. [...] 
b. Section 9.4.1, Monitoring by the Protocol Team, Blinding/Unblinding, page 71, second paragraph:  
If the need arises to unblind a specific participant’s assignment in the event to guide management of 
a serious illness or medical emergency or if knowing the participant’s treatment assignment 

Letter of Amendment #2       
Page 4 of 6 
18 July 2018 
IMPAACT 2018 Protocol Version 1.0 
 
would otherwise affect decisions regarding the participant’s immediate medical management as 
determined by the site Investigator of Record (IoR) or treating clinician prior to completion of 
the RSV Season Surveillance Period, IMPAACT the procedures for emergency unblinding specified 
in the IMPAACT Network Manual of Procedures (MOP) will must be followed. In the event that 
unblinding is required, only that specific participant’s assignment will be unblinded. Whenever 
possible, the Protocol Chair will make a decision regarding early unblinding in collaboration with the 
Data and Safety Monitoring Board (DSMB). The sponsor and the DSMB Executive Secretary will 
also be notified of the event in real time. 
3. Adjustments to objectives and outcomes 
a. Schema, Secondary Objectives and Exploratory Objectives, page 15: note that, previously, 
exploratory objectives were not listed in the Schema per the IMPAACT protocol template. The 
template has since been updated to include exploratory objectives in the Schema; therefore, the three 
objectives that have been moved from secondary to exploratory, plus the existing exploratory 
objective from protocol Section 2.3, are now included in the Schema. 
Secondary Objectives 
[…] 
4. To characterize the B cell response to vaccine and to characterize these responses in the 
vaccine and placebo recipients who experience natural infection to wt RSV during the 
subsequent RSV season 
5. To characterize the mucosal antibody response to each vaccine  
6. To determine differences in infectivity and immunogenicity between the vaccines 
Exploratory Objectives 
1. To characterize the B cell response to vaccine and to characterize these responses in the 
vaccine and placebo recipients who experience natural infection to wt RSV during the 
subsequent RSV season 
2. To characterize the mucosal antibody response to each vaccine  
3. To identify differences in infectivity and immunogenicity between the vaccines 
4. Study samples may be used to compare to samples from other RSV vaccine studies 
initiated by the Laboratory of Infectious Diseases, NIAID, NIH or to evaluate other 
questions related to respiratory viral infections 
b. Section 1.4: Rationale, page 30, last paragraph, first sentence: 
As an exploratory secondary objective, additional details of the B cell response to RSV will be 
studied. 
c. Section 2: Objectives, page 31:   
2.2 
Secondary Objectives 
The secondary objectives of this study are to: 
[…] 
2.2.3 
To characterize the B cell response to vaccine and to characterize these responses in 
the vaccine and placebo recipients who experience natural infection to wt RSV 
during the subsequent RSV season 
2.2.4 
To characterize the mucosal antibody response to vaccine  
2.2.5 
To identify differences in infectivity and immunogenicity between the vaccines 

Letter of Amendment #2       
Page 5 of 6 
18 July 2018 
IMPAACT 2018 Protocol Version 1.0 
 
2.3 
Exploratory Objectives 
2.3.1 
To characterize the B cell response to vaccine and to characterize these 
responses in the vaccine and placebo recipients who experience natural infection 
to wt RSV during the subsequent RSV season 
2.3.2 
To characterize the mucosal antibody response to each vaccine  
2.3.3 
To identify differences in infectivity and immunogenicity between the vaccines 
2.3.14 Study samples may be used to compare to samples from other RSV vaccine studies 
initiated by the Laboratory of Infectious Diseases, NIAID, NIH or to evaluate other 
questions related to respiratory viral infections 
d. Section 9.2: Outcome Measures, page 66:   
9.2.2 
Secondary Outcome Measures 
• 
Types and grades of symptomatic, medically attended respiratory and febrile illness 
adverse events in the vaccine and placebo recipients who experience natural infection 
with wt RSV during the subsequent RSV season. 
• 
Antibody titers in the vaccine and placebo recipients who experience natural infection 
with wt RSV during the subsequent RSV season. 
• 
Frequency of B cell response to vaccine  
• 
Mucosal antibody titers to vaccine, in nasal wash or nasosorption samples 
9.2.3 
Other Outcome Measures 
Additional outcomes may be added once results for primary and secondary outcomes 
are completed. 
• 
Frequency of B cell response to vaccine  
• 
Mucosal antibody titers to vaccine, in nasal wash or nasosorption samples 
e. Section 9.5: Analyses, page 73:   
9.5.2 
Assessment of Secondary Objectives 
[…] 
A line listing of the individual RSV antibody titer pre- and post-RSV Season Surveillance 
Period will be prepared. In addition, the geometric mean and median antibody titers will be 
provided for each study product group. To address the criterion “Post-vaccination 
surveillance during the RSV season following vaccination should reveal substantial rises in 
RSV-neutralizing serum antibodies in a subset of vaccine recipients in the absence of RSV 
associated medically attended acute respiratory illness (RSV-MAARI), which would be 
indicative of exposure to wt RSV without illness,” the changes in median antibody titers 
between day 56 the Pre-RSV Season Visit (or the Day 56 Visit if this visit was conducted 
in lieu of the Pre-RSV Season Visit) and the Post-RSV surveillance time point Season Visit 
will be summarized in the subset of vaccine recipients who do not experience RSV-MAARI.   
 
The B cell responses to vaccine will be summarized for each study product group. A line 
listing of the mucosal antibody response detected in nasal wash specimens will be prepared. 
 
The two vaccine groups will be compared descriptively with respect to peak viral titers and 
antibody titers following vaccination. 

Letter of Amendment #2       
Page 6 of 6 
18 July 2018 
IMPAACT 2018 Protocol Version 1.0 
 
9.5.3 
Assessment of Exploratory Objectives 
The B cell responses to vaccine and the mucosal antibody responses detected in nasal 
wash specimens will be summarized for each study product group.  
The two vaccine groups will be compared descriptively with respect to peak viral titers 
and antibody titers following vaccination. 
Additional analyses may be added once results for primary and secondary outcomes are 
completed. 

Letter of Amendment #1       
Page 1 of 5 
15 March 2018 
IMPAACT 2018 Protocol Version 1.0 
Letter of Amendment # 1 for: 
 
IMPAACT 2018 
 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus 
(RSV) Vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 or Placebo, Delivered 
as Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
Version 1.0, dated 15 June 2017 
 
DAIDS Document ID 38405 
IND # 17587 held by DAIDS 
 
Letter of Amendment Date: 15 March 2018 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT 2018 study and 
must be submitted to site Institutional Review Boards (IRBs) as soon as possible for their review and 
approval. Approval must also be obtained from site regulatory entities if applicable per the policies and 
procedures of the regulatory 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 the IRB-approved updated site-specific informed 
consent form (ICF) is made available, all study participants still in follow-up must be re-consented at their 
next scheduled study visit, and all new participants must be consented using the updated site-specific ICF.  
 
Sites are required to submit an 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 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 2018. If the IMPAACT 2018 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 2 of 5 
15 March 2018 
IMPAACT 2018 Protocol Version 1.0 
IMPAACT 2018 
 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus 
(RSV) Vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 or Placebo, Delivered 
as Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
DAIDS Document ID 38405 
 
Version 1.0, Letter of Amendment #1 
Dated 15 March 2018 
 
 
LETTER OF AMENDMENT SIGNATURE PAGE 
 
 
I will conduct this study in accordance with the current version of this protocol, including this Letter of 
Amendment, 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 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 3 of 5 
15 March 2018 
IMPAACT 2018 Protocol Version 1.0 
Summary of Modifications and Rationale 
 
This Letter of Amendment: 
 
1. Updates the Team Roster and Site Roster: Contact information has been updated for 
Clinical Trials Specialist Jennifer Libous, and Ellen Chadwick has replaced Ram Yogev 
as the site investigator at site 4001. 
 
 
2. Specifies the inclusion of additional individuals in early unblinding: The NIAID RSV vaccine 
development program involves a Cooperative Research and Development Agreement (CRADA) 
between NIAID and Sanofi Pasteur, and the program includes a CRADA Scientific Advisory 
Board (SAB) comprising a number of experts from the field. The Protocol Team has obtained 
permission from the IMPAACT Management Oversight Group (MOG) and the NIAID Intramural 
Data and Safety Monitoring Board (DSMB) to confidentially share unblinded study data—which 
have already been provided to a subset of Protocol Team members per protocol Section 9.4.1—
with several members of the SAB and Sanofi Pasteur as needed to facilitate planning for the 
vaccine program. Protocol Section 9.4.1 has been updated accordingly and has also been revised 
to correctly refer to Ruth Karron as the Companion Protocol Chair, rather than the Protocol Vice 
Chair (her former title was inadvertently carried over from a prior IMPAACT RSV protocol). 
 
3. Updates language regarding regulatory entities that may review study records: Per ICH GCP E6 
4.8.10(n) and DAIDS requirements, it is mandatory that all DAIDS-sponsored and/or supported 
trials include language that informs participants that other US, local, and international regulatory 
entities may also review study records. Protocol Section 10.2 and the sample ICF have been 
updated accordingly. As noted in the instructions above, after the IRB-approved updated site-
specific informed consent form (ICF) is made available, all study participants still in follow-up 
must be re-consented at their next scheduled study visit, and all new participants must be 
consented using the updated site-specific ICF.  
 

Letter of Amendment #1       
Page 4 of 5 
15 March 2018 
IMPAACT 2018 Protocol Version 1.0 
Implementation 
The modifications included in this LoA 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 in strikethrough.   
4. Roster updates 
a. Team Roster, page 9: 
Clinical Trials Specialists 
[…] 
Jennifer Libous, MS, CCRP  
IMPAACT Operations Center  
FHI 360  
359 Blackwell Street, Suite 200  
Durham, NC 27701  
Phone: 919-544-7040 x11393  
1825 Connecticut Ave. NW, N958 
Washington, DC 20009 
Phone: 202-884-8131 x18131 
Email: jlibous@fhi360.org 
 
b. Site Roster, page 12: 
 
Site 4001, Lurie Children’s Hospital of Chicago 
Ram Yogev, MD 
Ann & Robert H. Lurie Children's Hospital of Chicago 
2300 Children's Plaza, Box #155 
Chicago, IL 60611 
Phone: 773-880-4757 
Email: ryogev@luriechildrens.org  
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 
 
5. Section 9.4.1, Monitoring by the Protocol Team, Blinding/Unblinding, page 71, third paragraph:  
 
A subset of protocol team members limited to the Protocol Statistician, the Companion Protocol 
Vice Chair, and the two Scientific Investigators of the Laboratory of Infectious Diseases will be 
unblinded to all data at the completion of the Post-Acute Phase of follow-up (Day 56) for the last 
participant enrolled in each calendar year. to  To request scientific advice, the subset of protocol 
team members may share the unblinded data with a limited number of representatives from 
Sanofi Pasteur and the CRADA Scientific Advisory Board. This unblinding will enable more 
efficient and timely study evaluation and planning for appropriate next steps with respect to RSV 
candidate vaccine development.  
 

Letter of Amendment #1       
Page 5 of 5 
15 March 2018 
IMPAACT 2018 Protocol Version 1.0 
6. Section 10.2, Essential and Source Documents and Access to Source Data, page 75, fourth paragraph, 
first sentence:  
 
All study records must be accessible for inspection, monitoring, and/or auditing during and after the 
conduct of the study by authorized representatives of the study sponsors and their contracted 
monitors, IMPAACT, the US Food and Drug Administration, the European Medicines Agency 
(EMA), site drug regulatory authorities, site IRBs/IBCs, OHRP, and other applicable US, local, and 
international regulatory entities.  
 
7. Appendix VI: Sample Informed Consent Form, What about confidentiality?, page 101, sixth 
paragraph: 
 
Other groups of people who may be involved in the study and may need to see your baby’s 
information are: 
• 
The government agency “Office for Human Research Protections,” that makes sure that we are 
conducting the research as planned, and the U.S. FDA, and the European Medicines Agency 
(EMA) 
• 
The sponsor of the study and people with whom the sponsor may contract for the study, such 
as study monitors. 
• 
Other US, local, and international regulatory groups 
 

Clarification Memorandum #1       
Page 1 of 4 
1 September 2017 
IMPAACT 2018 Protocol Version 1.0 
Clarification Memorandum #1 for: 
 
IMPAACT 2018 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus 
(RSV) Vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 or Placebo, Delivered as 
Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
Version 1.0, dated 15 June 2017 
 
 DAIDS ES # 38405 
IND # 17587 Held By DAIDS 
 
Clarification Memorandum Date: 1 September 2017   
 
 
Summary of Clarifications and Rationale 
 
This Clarification Memorandum (CM) adds the IND number to the protocol, specifies that Lactated 
Ringer’s will be used as the vaccine diluent and placebo following observation of precipitate in the 2X L-
15 Leibovitz medium that was intended to be used for this purpose, and clarifies a reference to infection 
with wild-type RSV.  
 
 
Implementation 
 
This CM has been approved by the NIAID and NICHD Medical Officers. Institutional Review Board 
(IRB) approval of this CM is not required by the study sponsor prior to implementation. However, sites 
may submit this CM to the responsible IRBs for their information or, if required by the IRBs, for their 
approval prior to implementation. 
 
The content of the CM does not impact the sample informed consent forms for the study or the benefit-to-
risk ratio for study participants. 
 
This CM should be maintained in each site’s essential documents file for IMPAACT 2018. It is the 
responsibility of the Investigator of Record to ensure that all study staff are made aware of this CM. The 
content of this CM will be incorporated into any future amendment of the IMPAACT 2018 protocol. 
 
The modifications included in this CM are listed below in order of appearance within a specified 
clarification in the protocol. Additions to the text are indicated in bold; deletions are indicated in 
strikethrough. 
 
 

Clarification Memorandum #1       
Page 2 of 4 
1 September 2017 
IMPAACT 2018 Protocol Version 1.0 
1. Addition of the IND number to the title page. The IND number (17587) has been added as follows. 
 
DAIDS ES # 38405 
IND # [TBD] 17587 Held by DAIDS 
 
2. Updates to the product to be used as the vaccine diluent and placebo. Following observation of 
precipitate in the 2X L-15 Leibovitz medium that was intended for use as the vaccine diluent and 
placebo, the Protocol Team determined that Lactated Ringer’s Solution for Injection, USP should 
instead be used for this purpose. (Note that Lactated Ringer’s is also used for the protocol-specified 
nasal washes.) A pause in enrollment/inoculation was initiated prior to enrollment of any 
participants in IMPAACT 2018; thus, no participants have received vaccine diluent or placebo 
containing L-15 Leibovitz medium through this study. The protocol has been updated as follows. 
 
a. ABBREVIATIONS AND ACRONYMS, page 8. 
 
[…] 
L-15  
Leibovitz-15 medium 
[…] 
SWFI  
Sterile Water For Injection 
[…] 
 
b. Section 5.1, Study Products, third bullet point, page 39.  
 
• 
Placebo for RSV vaccine will be 1X L-15 Leibovitz medium (1X L-15) Lactated 
Ringer’s Solution for Injection, USP 0.5ml 
 
c. Section 5.3.2, Diluent for RSV ΔNS2/Δ1313/I1314L and RSV 276, page 40.  
 
The diluent for RSV ΔNS2/Δ1313/I1314L and RSV 276 is 1X Leibovitz L-15 medium 
Lactated Ringer’s Solution for Injection, USP.  
 
Sterile Water For Injection, USP (SWFI) and 2X Leibovitz L-15 medium are required to prepare 
the diluent for the vaccine. 2X Leibovitz L-15 medium is a specific lot of Leibovitz L-15 
medium. It is a solution of amino acids, sugar, and salt that has been safety tested as described in 
a Master File (MF 12959), which has been submitted to the FDA. 
 
d. Section 5.3.3, Placebo for RSV ΔNS2/Δ1313/I1314L and RSV 276, page 40.  
The placebo for RSV ΔNS2/Δ1313/I1314L and RSV 276 is 1X Leibovitz L-15 medium 
Lactated Ringer’s Solution for Injection, USP.  
 
Sterile Water For Injection, USP (SWFI) and 2X Leibovitz L-15 medium are required to prepare 
the Placebo for the vaccine. 
 

Clarification Memorandum #1       
Page 3 of 4 
1 September 2017 
IMPAACT 2018 Protocol Version 1.0 
e. Section 5.4, Study Product Storage, second paragraph, page 40. 
 
Leibovitz L-15 medium will be stored in a secure refrigerator at 2°C to 8°C. Lactated Ringer’s 
Solution for Injection, USP should be stored at room temperature in accordance with the 
manufacturer’s recommendation and transferred to a secure 2°C to 8°C refrigerator at 
least 24 hours before use. Vaccine diluent/placebo will be prepared from new, unopened 
containers for each use. 
Sterile Water for Injection, USP (SWFI) must also be stored in the refrigerator at 2°C to 8°C. 
  
f. Section 5.5.1, Preparation of Diluent for RSV ΔNS2/Δ1313/I1314L and RSV 276, page 41. 
 
The diluent is prepared by mixing concentrated 2X Leibovitz L-15 medium with sterile water for 
injection in 1:1 ratio Lactated Ringer’s Solution for Injection, USP. The prepared vaccine 
diluent will be 1X Leibovitz L-15 medium.  
 
Please follow the MOP for detailed instructions on diluent preparation. 
  
g. Section 5.5.2, Preparation of Placebo for RSV ΔNS2/Δ1313/I1314L and RSV 276, page 41. 
 
Placebo for RSV ΔNS2/Δ1313/I1314L and RSV 276 will be prepared by mixing the 
concentrated 2X Leibovitz L-15 medium with sterile water for injection in 1:1 ratio. The 
prepared product will be 1X Leibovitz L-15 medium. Lactated Ringer’s Solution for 
Injection, USP. 
 
Placebo will be drawn up to a volume of 0.5 mL in a sterile 1 mL oral syringe and labeled per 
instructions in MOP. An auxiliary label stating “FOR INTRANASAL ADMINISTRATION 
ONLY” will be affixed to the syringe or outside bag. The labeled, filled syringe(s) will be 
transported in a cooler monitored and maintained at 2ºC to 8ºC with ice or cold packs to the 
clinical site for administration. Placebo must be administered within 4 hours of concentrated 2X 
Leibovitz L-15 Lactated Ringer’s Solution for Injection, USP being removed from the 
refrigerator.  
 
Please follow the MOP for detailed instructions on preparation of placebo. 
 
h. Section 5.5.3, Preparation of Live Recombinant Respiratory Syncytial Virus RSV 
ΔNS2/Δ1313/I1314L and RSV 276, page 41.  
 
Diluent must be prepared prior to removal of the RSV vaccine from the freezer.  
 
[…] 
 
At least two vials of undiluted vaccine are needed to prepare the vaccine dose. When 
manipulating the undiluted vaccine, use as small a gauge needle as possible to avoid loss of 
vaccine in the needle and syringe hub. The frozen vaccine will be thawed and diluted with 1X L-
15 Lactated Ringer’s Solution for Injection, USP to the indicated dose of either 106 (RSV 
ΔNS2/Δ1313/I1314L) or 105 PFU (RSV 276) in 0.5 mL prior to administration.  
 
The diluted vaccine will be drawn up […] However, the expiration time is assigned based on 
the time the concentrated 2X Leibovitz L-15 Lactated Ringer’s Solution for Injection, USP 
is removed from the refrigerator in order to maintain the blind. 
 

Clarification Memorandum #1       
Page 4 of 4 
1 September 2017 
IMPAACT 2018 Protocol Version 1.0 
[…] 
 
i. 
Section 5.7, Study Product Acquisition, page 42.  
 
The clinical lots of RSV ΔNS2/Δ1313/I1314L and RSV 276 were generated by Charles River 
Laboratories using the seed virus provided by the National Institutes of Health (NIH).  
 
A specific lot concentrated 2X L-15 Leibovitz Medium that Lactated Ringer’s Solution for 
Injection, USP will be used to prepare as the Diluent and Placebo is provided by the National 
Institutes of Health (NIH). 
 
Sterile Water for Injection, USP (SWFI) must be obtained by each site.  
 
Upon successful completion of protocol registration procedures, the clinical research site (CRS) 
pharmacists can order the vaccine, the 2X L-15 Leibovitz Medium (which is used to make the 
diluent and placebo), diluent/placebo, sterile oral 1ml syringes (commercially available, 
individually packaged), sterile syringe caps and yellow overlays from the CRPMC by following 
the instructions in Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks.  
 
Please refer to the MOP for details on shipment of the vaccines and diluent/placebo study 
products. 
 
j. 
Section 5.8, Study Product Accountability, page 43.  
 
The site pharmacist is responsible for maintaining an accurate inventory and accountability 
record of vaccine and Leibovitz L-15 medium diluent/placebo supplies for this study. […] 
Partially used vials of vaccine and Leibovitz L-15 medium components diluent/placebo may 
not be saved and reused at a later time. 
 
3. Clarification of definition of infection with the study vaccine virus. In their initial review of 
IMPAACT 2018, the DSMB recommended that the team use consistent terminology throughout the 
protocol for the definition of infection with vaccine virus. The team confirmed that a consistent 
definition of infection with vaccine virus is already used throughout the protocol; however, it was 
noted that a reference to infection with wild-type (wt) RSV in the protocol could be updated to clarify 
that a fourfold or greater rise in RSV-specific antibody titer would indicate infection with wt RSV. 
 
Section 6.12.2, Specimen Preparation, Testing, Storage, and Shipping, Virologic and 
Immunologic Assays, first paragraph, third sentence, page 54. 
 
These samples will be used to determine whether a fourfold or greater rise in RSV-specific 
serum antibody titer has occurred during the RSV season, which would signify infection with 
wt RSV. 
 
 

 
 
IMPAACT 2018  
 
 
Randomized Phase I Study of the Infectivity, Safety, and 
Immunogenicity of a Single Dose of the Recombinant Live-Attenuated 
Respiratory Syncytial Virus (RSV) Vaccines RSV ΔNS2/Δ1313/I1314L 
or RSV 276 or Placebo, Delivered as Nose Drops to RSV-Seronegative 
Infants 6 to 24 Months of Age 
 
A Study of the International Maternal Pediatric Adolescent  
AIDS Clinical Trials Network  
 
 
 
Sponsored by: 
National Institute of Allergy and Infectious Diseases  
Eunice Kennedy Shriver  
National Institute of Child Health and Human Development  
National Institute of Mental Health 
 
 
 
 
DAIDS ES # 38405 
IND # [TBD] Held by DAIDS 
 
 
 
Protocol Chair: 
Coleen Cunningham, MD 
 
Protocol Vice Chairs: 
Elizabeth J. McFarland, MD 
 
Matthew Kelly, MD, MPH 
 
NIAID Medical Officer:  
Patrick Jean-Philippe, MD 
 
NICHD Medical Officer: 
Jack Moye, Jr., MD 
 
Clinical Trials Specialists: 
Charlotte Perlowski, MSPH 
Jennifer Libous, MS, CCRP 
 
Version 1.0 
15 June 2017 

IMPAACT 2018, Version 1.0 
Page 2 of 106 
15 June 2017 
IMPAACT 2018 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus 
(RSV) Vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 or Placebo, Delivered as 
Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
TABLE OF CONTENTS 
 
TABLE OF CONTENTS ............................................................................................................. 2 
LIST OF TABLES ....................................................................................................................... 5 
LIST OF FIGURES .................................................................................................................... 5 
PROTOCOL SIGNATURE PAGE .............................................................................................. 6 
ABBREVIATIONS AND ACRONYMS ........................................................................................ 7 
PROTOCOL TEAM ROSTER .................................................................................................... 9 
SITE ROSTER ..........................................................................................................................12 
SCHEMA ..................................................................................................................................14 
1 
INTRODUCTION ...........................................................................................................17 
1.1 
Overview ......................................................................................................................................... 17 
1.2 
Background ..................................................................................................................................... 21 
1.3 
Prior Research................................................................................................................................. 24 
1.3.1 Experimental Vaccines against Respiratory Syncytial Virus ....................................................... 24 
1.3.2 Preclinical Studies ....................................................................................................................... 24 
1.3.3 Previous Clinical Experience ....................................................................................................... 26 
1.4 
Rationale ......................................................................................................................................... 29 
1.5 
Hypotheses ..................................................................................................................................... 30 
2 
OBJECTIVES ................................................................................................................31 
2.1 
Primary Objective ............................................................................................................................ 31 
2.2 
Secondary Objectives ...................................................................................................................... 31 
2.3 
Exploratory  Objective ..................................................................................................................... 32 
3 
STUDY DESIGN ...........................................................................................................32 
4 
STUDY POPULATION ..................................................................................................34 
4.1 
Inclusion Criteria .............................................................................................................................. 34 
4.2 
Exclusion Criteria............................................................................................................................. 35 
4.3 
Co-Enrollment Considerations ......................................................................................................... 37 
4.4 
Recruitment, Screening, and Enrollment Process ........................................................................... 37 
4.5 
Participant Retention ....................................................................................................................... 38 
4.6 
Participant Withdrawal or Termination from the Study .................................................................... 38 
5 
STUDY PRODUCT CONSIDERATIONS .......................................................................39 
5.1 
Study Products ................................................................................................................................ 39 
5.2 
Study Product Regimens ................................................................................................................. 39 
5.3 
Study Product Formulation .............................................................................................................. 39 
5.3.1 Vaccines ...................................................................................................................................... 39 
5.3.2 Diluent for RSV ΔNS2/Δ1313/I1314L and RSV 276 ................................................................... 40 
5.3.3 Placebo for RSV ΔNS2/Δ1313/I1314L and RSV 276 .................................................................. 40 
5.4 
Study Product Storage .................................................................................................................... 40 
5.5 
Study Product Preparation .............................................................................................................. 41 
5.5.1 Preparation of Diluent for RSV ΔNS2/Δ1313/I1314L and RSV 276 ............................................ 41 
5.5.2 Preparation of Placebo for RSV ΔNS2/Δ1313/I1314L and RSV 276 .......................................... 41 
5.5.3 Preparation of Live Recombinant Respiratory Syncytial Virus RSV ΔNS2/Δ1313/I1314L and 
RSV 276 ...................................................................................................................................... 41 
5.6 
Study Product Administration/ Inoculation Procedure ..................................................................... 42 
5.7 
Study Product Acquisition ................................................................................................................ 42 

IMPAACT 2018, Version 1.0 
Page 3 of 106 
15 June 2017 
5.8 
Study Product Accountability ........................................................................................................... 43 
5.9 
Disposition of Used/Unused Study Product ..................................................................................... 43 
5.10 
Final Disposition of Study Products ................................................................................................. 43 
5.11 
Concomitant Medications ................................................................................................................ 43 
5.11.1 Prohibited Concomitant Medications ........................................................................................... 43 
5.11.2 Precautionary Concomitant Medications ..................................................................................... 43 
6 
STUDY VISITS AND PROCEDURES............................................................................44 
6.1 
Screening Visit................................................................................................................................. 44 
6.2 
Enrollment Visit................................................................................................................................ 45 
6.3 
Acute Phase Visits and Contacts .................................................................................................... 48 
6.3.1 Acute Phase Visits: Study Days 3, 5, 7, 10, 12, 14, 17, and 28 (all are ±1 day) ......................... 48 
6.3.2 Acute Phase Contacts: Study Days 1, 2, 4, 6, 8, 9, 11, 13, 15,16, 18, 19, 20, 21, 22, 23, 24, 25, 
26, and 27 (±1 day) ..................................................................................................................... 49 
6.4 
Day 29 Contact (+ 1 day) ................................................................................................................ 49 
6.5 
Post-Acute Phase (Days 30 to 56) .................................................................................................. 50 
6.5.1 Day 56 Visit (+7 Days) ................................................................................................................ 50 
6.6 
Period after Day 56 Visit until October 31st or as specified in the MOP ........................................... 51 
6.7 
Pre-RSV Season Study Visit (October 1st to 31st or as specifiedin the MOP) .................................. 51 
6.8 
RSV Season Surveillance (November 1st through March 31st following inoculation or as specified in 
the MOP) ......................................................................................................................................... 51 
6.9 
Post-RSV Season Study Visit (April 1st to 30th) ............................................................................... 52 
6.10 
Illness Visit ...................................................................................................................................... 52 
6.11 
Early Discontinuation Study Visit ..................................................................................................... 53 
6.12 
Additional Considerations for Laboratory Procedures ..................................................................... 53 
6.12.1 Specimen Collection ................................................................................................................... 53 
6.12.2 Specimen Preparation, Testing, Storage, and Shipping.............................................................. 54 
6.12.3 Biohazard Containment ............................................................................................................... 55 
7 
SAFETY ASSESSMENT, MONITORING, AND REPORTING .......................................55 
7.1 
Safety-Related Roles and Responsibilities ...................................................................................... 56 
7.1.1 Site Investigators ......................................................................................................................... 56 
7.1.2 Protocol Safety Review Team ..................................................................................................... 56 
7.1.3 Data Safety Monitoring Board ..................................................................................................... 56 
7.1.4 Sponsor Reporting ...................................................................................................................... 56 
7.2 
Safety-Related Recording on Case Report Forms .......................................................................... 57 
7.3 
Expedited Adverse Event (EAE) Reporting ..................................................................................... 59 
7.3.1 Adverse Event Reporting to DAIDS ............................................................................................ 59 
7.3.2 Reporting Requirements for this Study ....................................................................................... 59 
7.3.3 Expedited AE Reporting Period................................................................................................... 59 
7.4 
Grading Severity of Events .............................................................................................................. 60 
8 
PARTICIPANT MANAGEMENT ....................................................................................62 
8.1 
Management of Adverse Events ..................................................................................................... 62 
8.1.1 Solicited Adverse Events ............................................................................................................ 62 
8.1.2 Serious Adverse Event ................................................................................................................ 63 
8.2 
Pausing and Stopping Rules ........................................................................................................... 64 
9 
STATISTICAL CONSIDERATIONS ...............................................................................65 
9.1 
General Design Issues .................................................................................................................... 65 
9.2 
Outcome Measures ......................................................................................................................... 65 
9.2.1 Primary Outcome Measures........................................................................................................ 65 
9.2.2 Secondary Outcome Measures ................................................................................................... 66 
9.3 
Sample Size and Accrual ................................................................................................................ 66 
9.3.1 Sample Size and Randomization ................................................................................................ 66 
9.3.2 Sample Size Limitations with Respect to Safety ......................................................................... 66 
9.3.3 Sample Size Limitations with Respect to Infectivity and Immunogenicity ................................... 67 

IMPAACT 2018, Version 1.0 
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9.4 
Monitoring ........................................................................................................................................ 70 
9.4.1 Monitoring by the Protocol Team ................................................................................................ 70 
9.4.2 Monitoring by the NIAID Intramural Data and Safety Monitoring Board ...................................... 71 
9.5 
Analyses .......................................................................................................................................... 72 
9.5.1 Assessment of Primary Objectives .............................................................................................. 72 
9.5.2 Assessment of Secondary Objectives ......................................................................................... 73 
10 
DATA HANDLING AND RECORD KEEPING ................................................................74 
10.1 
Data Management Responsibilities ................................................................................................. 74 
10.2 
Essential and Source Documents and Access to Source Data ....................................................... 74 
10.3 
Clinical Investigator’s Brochure ....................................................................................................... 75 
10.4 
Quality Control and Quality Assurance ............................................................................................ 75 
11 
CLINICAL SITE MONITORING .....................................................................................76 
12 
HUMAN SUBJECTS PROTECTIONS ...........................................................................76 
12.1 
Institutional Review Board/Ethics Committee Review and Approval ............................................... 76 
12.2 
Vulnerable Participants .................................................................................................................... 77 
12.3 
Informed Consent ............................................................................................................................ 77 
12.4 
Potential Benefits............................................................................................................................. 78 
12.5 
Potential Risks ................................................................................................................................. 78 
12.5.1 Venipuncture ............................................................................................................................... 78 
12.5.2 Nasal Wash ................................................................................................................................. 78 
12.5.3 Receipt of Study Product ............................................................................................................ 78 
12.6 
Reimbursement/Compensation ....................................................................................................... 78 
12.7 
Privacy and Confidentiality .............................................................................................................. 78 
12.8 
Management of Incidental Findings ................................................................................................. 79 
13 
ADMINISTRATIVE PROCEDURES ..............................................................................79 
13.1 
Regulatory Oversight ....................................................................................................................... 79 
13.2 
Protocol Registration ....................................................................................................................... 79 
13.3 
Study Implementation ...................................................................................................................... 80 
13.4 
Protocol Deviation Reporting ........................................................................................................... 80 
13.5 
ClinicalTrials.gov ............................................................................................................................. 81 
14 
PUBLICATIONS ............................................................................................................81 
15 
REFERENCES ..............................................................................................................82 
APPENDICES ...........................................................................................................................85 
Appendix I: Tables Referenced in the Background Section .......................................................85 
Appendix II: Schedule of Events: Screening, Acute Phase, and Post-Acute Phase ...................91 
Appendix III: Schedule of Events: RSV Pre-season Sampling, seasonal surveillance, and Post-
season Sampling ...........................................................................................................92 
Appendix IV: Definitions of Solicited Adverse Events ................................................................93 
Appendix V: RSV Seasonality in Baltimore ...............................................................................94 
Appendix VI: Sample Informed Consent Form ..........................................................................95 
 
 
 
 
 
 
 
 

IMPAACT 2018, Version 1.0 
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15 June 2017 
 
 
 
 
LIST OF TABLES 
 
Table 1: Overview of recent RSV vaccine candidates with M2-2 deletion.................................. 19 
Table 2: Overview of RSV vaccine candidates with NS2 or M2-2 deletion to be studied in 
IMPAACT 2018........................................................................................................... 20 
Table 3: AE eCRF Recording Requirements ............................................................................. 58 
Table 4: EAE Reporting ............................................................................................................ 60 
Table 5: Grading Table for Solicited AEs................................................................................... 61 
Table 6: Fever Grading* ............................................................................................................ 61 
Table 7: The Probability of Observing LRI events in Vaccinees ................................................ 67 
Table 8: Percent of Participants Experiencing AEs with Exact 90% Confidence Intervals ......... 67 
Table 9: Magnitude of Difference in Responses Detectable with 80% Power ............................ 68 
Table 10: Percent of Vaccinees who are Infected with Vaccine Virus with Exact 90% Confidence 
Intervals ...................................................................................................................... 70 
Table 11: Viral Titers of Nasopharyngeal Swab Samples from African Green Monkeys 
Inoculated with the CTM RSV ΔNS2/Δ1313/I1314L, Lot#006A, or with recombinant wt 
RSV rA2 ..................................................................................................................... 85 
Table 12: Viral Titer of Tracheal Lavage samples from African Green Monkeys Inoculated with 
the CTM RSV ΔNS2/Δ1313/I1314L, Lot RSV#006A, or with recombinant wt RSV rA2a
 ................................................................................................................................... 86 
Table 13:  Neutralizing antibody titers of AGMs inoculated with CTM RSV ΔNS2/Δ1313/I1314L, 
Lot RSV#006Aa, or with recombinant wt RSV rA2b ..................................................... 87 
Table 14:  Viral titers of nasopharyngeal swab samples from African green monkeys (AGMs) 
inoculated with recombinant wildtype RSV A2, MEDI/M2-2, or RSV 276a ................. 88 
Table 15: Viral titers of tracheal lavage samples from AGMs inoculated with recombinant 
wildtype RSV A2,  MEDI/M2-2, or RSV 276a ............................................................ 89 
Table 16: Neutralizing antibody titers of AGMs inoculated with recombinant wildtype RSV A2, 
MEDI/M2-2, or RSV 276a .......................................................................................... 90 
 
 
 
LIST OF FIGURES 
Figure 1: Study Overview .......................................................................................................... 16 
Figure 2: Study Phases and Periods of Evaluation .................................................................... 33 
Figure 3: Investigational Product Label (Enlarged Sample) ....................................................... 40 
Figure 4: Power curves for comparisons between responses to either vaccine to responses to 
placebo ....................................................................................................................... 69 
 
 
 

IMPAACT 2018, Version 1.0 
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15 June 2017 
IMPAACT 2018 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus 
(RSV) Vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 or Placebo, Delivered as 
Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
 
Version 1.0 
Dated 15 June 2017 
 
DAIDS Study ID #38405 
 
PROTOCOL 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 Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record 
 
Signature of Investigator of Record   
Date 
 
 
 
 

IMPAACT 2018, Version 1.0 
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15 June 2017 
IMPAACT 2018  
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus 
(RSV) Vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 or Placebo, Delivered as 
Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
ABBREVIATIONS AND ACRONYMS 
 
ACIP 
Advisory Committee on Immunization Practices (CDC) 
AE 
adverse event  
AGM 
African green monkey 
AIDS 
Acquired Immunodeficiency Syndrome 
cDNA 
complementary deoxyribonucleic acid 
cGMP 
current good manufacturing practice 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIR 
Center for Immunization Research 
cp 
Cold Passaged  
CRADA 
Cooperative Research and Development Agreement 
CRL 
Charles River Laboratories 
CRPMC 
Clinical Research Products Management Center 
CSO 
Clinical Safety Office 
CTM 
clinical trial material 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS  
DAIDS PRO 
Division of AIDS Protocol Registration Office 
DC 
discontinuation 
DCR 
Division of Clinical Research 
DHHS 
Department of Health and Human Services 
DMC 
Data Management Center 
DMEM 
Dulbecco’s Modified Eagle Medium 
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
EAE 
Expedited Adverse Event 
eCRF  
electronic case report form 
 ELISA 
enzyme-linked immunosorbent assay 
EENT 
ears, eyes, nose, throat 
F protein 
fusion protein (of RSV) 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FSTRF 
Frontier Science & Technology Research Foundation, Inc. 
GCP 
good clinical practices 
HEENT 
head, ears, eyes, nose, throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HJF 
Henry M. Jackson Foundation for the Advancement of Military Medicine 
HVTN 
HIV Vaccine Trials Network 
IBC 
Institutional Biosafety Committee 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IgA, IgG, IgE 
immunoglobulin A, G, E 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
IND 
investigational new drug 
IoR 
Investigator of Record  
IRB  
institutional review board 

IMPAACT 2018, Version 1.0 
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15 June 2017 
JHSPH 
Johns Hopkins Bloomberg School of Public Health 
L-15 
Leibovitz-15 medium 
LDMS 
Laboratory Data Management System 
LID 
Laboratory of Infectious Diseases 
LPC 
laboratory processing chart 
LRI 
lower respiratory illness 
LRT 
lower respiratory tract 
MA-LRI 
medically attended lower respiratory illness 
MOP 
manual of procedures 
mRNA 
messenger Ribonucleic Acid 
NHP 
nonhuman primate 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIAID CRMS NIAID Clinical Research Management System 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
nt 
nucleotide 
OCRPRO 
Office of Clinical Research Policy and Regulatory Operations 
OHRP 
Office for Human Research Protections 
ORF 
open reading frame 
OTC 
over-the-counter 
PBMC 
Peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PE 
physical exam 
PFU 
plaque-forming unit 
PID 
participant identification number 
PMTCT 
prevention of mother-to-child HIV transmission 
PRNT 
plaque reduction neutralization titer 
PSRT 
Protocol Safety Review Team 
r 
recombinant 
RE 
regulatory entity 
RNA 
ribonucleic acid 
rRT-PCR 
Reverse transcription polymerase chain reaction 
RSC 
Regulatory Support Center 
RSV 
respiratory syncytial virus 
RSV-MAARI  RSV-associated medically attended acute respiratory illness 
SAE 
Serious Adverse Event 
SAM 
synthetic adsorptive matrix 
SDAC 
Statistical & Data Analysis Center, Harvard School of Public Health 
SDMC 
Statistical and Data Management Center 
SES 
Subject Enrollment System 
SFM 
serum-free medium 
SID 
Study Identification Number 
SOP 
standard operating procedure 
SPG 
sucrose-phosphate-glutamate buffer 
SUSAR 
Serious and unexpected suspected adverse reactions 
SWFI 
Sterile Water For Injection 
TL 
Tracheal lavage  
URI 
upper respiratory illness 
URT 
upper respiratory tract 
US 
United States 
VAR 
vaccine administration record 
wt 
 
wild-type 
 

IMPAACT 2018, Version 1.0 
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IMPAACT 2018 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus 
(RSV) Vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 or Placebo, Delivered as 
Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
PROTOCOL TEAM ROSTER 
 
Protocol Chair 
Coleen Cunningham, MD  
Vice-Chair Research, Department of Pediatrics, 
Children’s Health Center Box 3499 DUMC  
Durham, NC 27710  
Phone: 919-668-4851  
Email: coleen.cunningham@duke.edu 
 
Protocol Vice Chairs  
Elizabeth (Betsy) J. McFarland, MD  
Children’s Hospital Colorado Pediatric 
Infectious Diseases, Box B055  
13123 East 16th Ave.  
Aurora, CO 80045  
Phone: 303-724-3447  
Email: betsy.mcfarland@ucdenver.edu 
 
Matthew Kelly, MD, MPH 
Division of Pediatric Infectious Diseases 
Duke University Medical Center 
Box 3499 DUMC 
Durham, NC 27710  
Phone: 919-668-4855  
Email: matthew.kelly@dm.duke.edu  
 
Companion Protocol (CIR 321) Chair 
Ruth Karron, MD 
Center for Immunization Research (CIR)  
Johns Hopkins Bloomberg School of Public 
Health (JHSPH)  
624 N. Broadway, Room 217  
Baltimore, MD 21205  
Phone: 410-614-0319  
Email: rkarron@jhu.edu 
 
Clinical Trials Specialists 
Charlotte Perlowski, MSPH 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: 919-544-7040 x11480 
Email: cperlowski@fhi360.org 
 
Jennifer Libous, MS, CCRP 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: 919-544-7040 x11393 
Email: jlibous@fhi360.org 
 
NIAID Medical Officer 
Patrick Jean-Philippe, MD  
DAIDS/NIAID/NIH 
Maternal, Adolescent and Pediatric Research 
Branch  
Prevention Sciences Program  
5601 Fishers Lane, Room 8B49 
Rockville, MD 20852 
Phone: (240) 292-4790  
Email: jeanphilippep@niaid.nih.gov   
 
NICHD Medical Officer 
Jack Moye, Jr. MD 
Eunice Kennedy Shriver National Institute of 
Child Health & Human Development 
National Institutes of Health,  
DHHS Bldg. 6710B Rm. 2146 MSC 7002 
6710B Rockledge Drive  
Bethesda, MD 20817 
Phone: 301-594-8624 
Email: john.moye@nih.hhs.gov 
 
Clinical Research Oversight Managers 
Kelly Cahill, RN, CCRC, RAC (US) 
NIH/NIAID/DCR/OCRPRO 
5601 Fishers Lane, Rm 4B23 
Rockville, MD 20852 
Mail Stop Code: 9820  
Email: cahillke@niaid.nih.gov 
 
Susan Vogel, RN, BSN 
OCRPRO/DCR/NIAID/NIH  
5601 Fishers Lane, Room 4B42, MSC 9820  
Bethesda, MD 20817-20892  
Phone: 240-669-5224 
Email: svogel@niaid.nih.gov 

IMPAACT 2018, Version 1.0 
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15 June 2017 
 
John Tierney, RN, MPM 
OCRPRO/DCR/NIAID/NIH  
5601 Fishers Lane, Room 4B11, MSC 9820 
Bethesda, MD 20892 
Phone: 301-451-5136 
Email: jtierney@niaid.nih.gov 
 
Protocol Pharmacist 
Lynette Purdue, PharmD  
DAIDS/NIAID/NIH 
5601 Fishers Lane, Room 9E28 
Rockville, MD 20852  
Phone: 240-627-3061  
E-mail: lpurdue@niaid.nih.gov 
 
Site-Based Pharmacist 
Vivian Rexroad, PharmD 
Investigational Drug Service Pharmacy 
Carnegie 180, Johns Hopkins Hospital 
600 North Wolfe St. 
Baltimore, MD 21287-6180 
Phone: 410-955-4505 
Email: vrexroa@jhmi.edu 
 
Clinical Investigators 
Elizabeth Schappell, RN, MSN, CCRP  
CIR, JHSPH  
624 N. Broadway, Room 205  
Baltimore, MD 21205  
Phone: 410-614-9114 
Email: eschapp1@jhu.edu 
 
Amanda (Mandy) Dempsey, MD 
University Physicians, Inc. Building (UPI) 
13199 East Montview Boulevard 
Suite 300, Campus Box F443 
Aurora, Colorado 80045 
Phone: 303-724-6679 
Email: Amanda.dempsey@ucdenver.edu 
 
Scientific Investigators 
Ursula Buchholz, PhD (Project Officer) 
Laboratory of Infectious Diseases (LID), 
National Institute of Allergy and Infectious 
Diseases (NIAID),  
NIH Building 50, Room 6503  
50 South Dr., MSC 8007  
Bethesda, MD 20892  
Phone: 301-594-1533  
Email: ubuchholz@niaid.nih.gov 
 
Peter Collins, PhD  
LID, NIAID, NIH  
Building 50, Room 6517  
50 South Dr., MSC 8007  
Bethesda, MD 20892  
Phone: 240-669-5917  
Email: pcollins@niaid.nih.gov 
 
Protocol Statistician 
Petronella Muresan, MS 
Statistical & Data Analysis Center (SDAC) 
Harvard School of Public Health 
1371 Beacon Street, Suite #203 
Brookline, MA 02446 
Phone: 617-632-2000, ext. 4031  
Email: petronm@sdac.harvard.edu 
 
Protocol Data Managers 
Kayla Denson, PhD 
Frontier Science & Technology Research 
Foundation (FSTRF)  
4033 Maple Rd.  
Amherst, NY 14226-1056  
Phone: 716-834-0900 x7211 
Email: denson@fstrf.org  
 
Linda Marillo, BA 
Frontier Science & Technology Research 
Foundation (FSTRF)  
4033 Maple Rd.  
Amherst, NY 14226-1056  
Phone: 716-834-0900 x7257  
Email: marillo@fstrf.org 
 

IMPAACT 2018, Version 1.0 
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15 June 2017 
Protocol Laboratory Data Manager 
Andee Fox, MPH 
Laboratory Data Manager 
Frontier Science and Technology Research 
Foundation (FSTRF)  
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 ext. 7276 
Email: fox@fstrf.org 
 
Laboratory Center Representative 
Dale Dayton, RN, CCRA 
Children’s Hospital of Los Angeles 
4650 Sunset Boulevard 
Los Angeles, CA 90027 
Phone: 301-742-9077 
Email: ddayton@impaactlabcenter.org  
 
Protocol Laboratory Technologist 
Paul Harding, MS 
Pediatric Infectious Diseases  
University of Colorado Denver  
Mail Stop 8604, Building P15  
12700 East 19th Ave., Room 11460-A  
Aurora, CO 80045  
Phone: 303-724-3404 
Email: paul.harding@ucdenver.edu 
 
Westat Clinical Research Associate  
Scott Watson, BS, RN 
Westat, Inc. 
1441 W. Montgomery Ave 
Rockville, MD 20850 
 
Phone: 415-494-5575 
Email: ScottWatson@westat.com 
 
Field Representative 
Emily Barr, CPNP, CNM, MSN 
Children’s Hospital Colorado 
13123 East 16th Ave., Box B055 
Aurora, CO 80045 
Phone: 720-777-6752 
Email: Emily.barr@childrenscolorado.org 
 
 
 
 
 

IMPAACT 2018, Version 1.0 
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15 June 2017 
SITE ROSTER 
 
Site 3801, Baylor College of Medicine/Texas 
Children’s Hospital 
William Shearer, MD, PhD 
Texas Children's Hospital 
1102 Bates Avenue, Suite 330 
Immunology, Allergy & Rheumatology 
Houston, TX, 77030-2399 
Phone: 832-824-1274 
Email: wtsheare@texaschildrens.org  
 
Site 4001, Lurie Children’s Hospital of Chicago 
Ram Yogev, MD 
Ann & Robert H. Lurie Children's Hospital of 
Chicago 
2300 Children's Plaza, Box #155 
Chicago, IL 60611 
Phone: 773-880-4757 
Email: ryogev@luriechildrens.org  
 
Site 4601, University of California San Diego 
Stephen Spector, MD 
9500 Gilman Drive 
Stein Clinical Research Building 
Room 430, Mail Code 0672 
La Jolla, CA 92093 
Phone: 858-534-7361 
Email: saspector@ucsd.edu  
 
Site 5011, Boston Medical Center 
Ellen Cooper, MD 
Boston Medical Center  
Division of Pediatric Infectious Diseases  
670 Albany Street, Room 623  
Boston, MA, 02118 
Phone: 617-414-5588 
Email: ercooper@bu.edu  
 
Site 5013, Jacobi Medical Center 
Andrew Wiznia, MD 
Jacobi Medical Center 
1400 Pelham Parkway South 
JACP room 5c15, Building #5 
Bronx, NY 10461 
Phone: 718-918-4664 
Email: andrew.wiznia@einstein.yu.edu  
 
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: acamac@emory.edu  
 
Site 5040, SUNY Stony Brook 
Sharon Nachman, MD 
Stony Brook University Hospital 
HSC T-11 RM 060 
Department of Pediatric Infectious Disease 
Stony Brook, NY 11794-8111 
Phone: 631-444-7692 
Email: Sharon.Nachman@stonybrookmedicine.edu  
 
Site 5048, University of Southern California 
Mikhaela Cielo, MD 
Keck School of Medicine of USC 
HSA 10220, Bldg A10N 
Los Angeles, CA 90089 
Phone: 323-226-4726 
Email: mikhaela.cielo@usc.edu  
 
Site 5052, University of Colorado Denver 
Elizabeth (Betsy) J. McFarland, MD  
Children’s Hospital Colorado Pediatric 
Infectious Diseases, Box B055  
13123 East 16th Ave.  
Aurora, CO 80045  
Phone: 303-724-3447  
Email: betsy.mcfarland@ucdenver.edu 
 
Site 5083, Rush University/Cook County 
Hospital 
Mariam Aziz, MD 
Rush University Medical Center 
600 South Paulina St., Suite 140-142 
Chicago, IL 60612 
Phone: 312-942-4265 
Email: mariam_aziz@rush.edu  
 

IMPAACT 2018, Version 1.0 
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15 June 2017 
Site 5112, David Geffen School of Medicine at 
UCLA 
Jaime Deville, MD 
University of California, Los Angeles 
Department of Pediatrics  
Division of Infectious Diseases 
10833 Le Conte Ave., MDCC 22-442 
Los Angeles, CA 90095 
Phone: 310-825-9660 
Email: jdeville@mednet.ucla.edu  
 
Site 6501, St. Jude Children’s Research Hospital 
Nehali Patel, MD 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Phone: 901-595-4646 
Email: Nehali.Patel@stjude.org  
 
Site 31779, Johns Hopkins University Center for 
Immunization Research 
Ruth Karron, MD 
Center for Immunization Research (CIR)  
Johns Hopkins Bloomberg School of Public 
Health (JHSPH)  
624 N. Broadway, Room 217  
Baltimore, MD 21205  
Phone: 410-614-0319  
Email: rkarron@jhu.edu 
 

IMPAACT 2018, Version 1.0 
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15 June 2017 
IMPAACT 2018 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus 
(RSV) Vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 or Placebo, Delivered as 
Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
SCHEMA 
 
Purpose: 
To assess whether the RSV ΔNS2/Δ1313/I1314L and RSV 276 vaccines are 
safe, infectious and immunogenic in this age group. 
 
Design: 
A double-blind, randomized, placebo-controlled study design will be used to 
evaluate the safety and immunogenicity of the vaccines in RSV-seronegative 
infants. Participants will be randomized to receive RSV ΔNS2/Δ1313/I1314L 
vaccine, RSV 276 vaccine, or placebo in a 2:2:1 ratio. This protocol, 
IMPAACT 2018, is a companion protocol to the Johns Hopkins University, 
Center for Immunization Research (CIR) protocol CIR 321. 
 
 
Study Population: 
Healthy RSV-seronegative* infants ≥6 months (180 days) to <25 months 
(750 days) of age  
 
 
 
* Throughout the protocol and informed consent documents, seronegativity 
refers to RSV antibody status, which is defined as a serum RSV-neutralizing 
antibody titer <1:40. 
 
Sample Size: 
Approximately 80 (IMPAACT 2018 and CIR 321 combined) 
 
Study Product: 
Eligible RSV-seronegative infants will receive a single dose of RSV 
ΔNS2/Δ1313/I1314L vaccine, RSV 276 vaccine, or placebo intranasally at 
entry. 
 
 
         
 
 
 
 
**plaque-forming units (PFU) 
 
Study Duration: 
Approximately 20 months total. Accrual is expected to be completed in 
approximately 14 months from first enrollment, and all participants will be 
followed through April of the year following enrollment. Therefore, expected 
duration of follow up for a given participant is between 6 and 13 months 
depending on time of enrollment. 
 
Participants will be enrolled in the study outside of RSV season, i.e., between 
April 1st and October 14th  for most sites or—for sites with local RSV seasons 
that start earlier—as specified on a site-by-site basis in the MOP. All 
participants will remain on study until they complete the post-RSV season 
visit between April 1st and April 30th in the calendar year following 
N 
Product 
Dose 
32 
RSV ΔNS2/Δ1313/I1314L 
Vaccine 
106 PFU** 
32 
RSV 276 Vaccine 
105 PFU** 
16 
Placebo 
0 

IMPAACT 2018, Version 1.0 
Page 15 of 106 
15 June 2017 
enrollment. For example, a participant enrolled on August 1st, 2017 will 
remain on study approximately 8-9 months (completing a final visit in April 
2018) while a participant enrolled on October 14th, 2017 will remain on study 
approximately 6 months (also completing a final visit in April 2018). 
 
Primary Objectives 
1. Safety: To assess the frequency and severity of study product-related solicited and unsolicited 
adverse events (AEs), from Day 0 through midnight of the 28th day following inoculation.  
2. Safety: To assess the frequency of study product-related serious adverse events (SAEs) from Day 
0 through midnight on the 56th day following inoculation  
3. Infectivity: To determine the peak titer of vaccine virus shed and duration of virus shedding by 
each participant, where the primary aim is to check if the mean peak titer of shed virus in nasal 
washes is approximately 2.5 log10  
4. Infectivity: To assess the proportion of vaccinated infants infected* with study vaccine, where the 
primary aim is to check whether >90% of vaccinees are infected with vaccine virus 
5. Immunogenicity: To characterize antibody responses (Day 56) to the study product in each 
treatment group, where the primary aim is to check if the RSV-neutralizing antibody titers in the 
vaccine groups are similar to or better than MEDI/∆M2-2 (geometric mean titer of 1:97)  
 
* Infected with vaccine virus as defined by shedding vaccine virus, detected by infectivity assay 
and/or RT-qPCR, and/or ≥4-fold rise in RSV-specific serum antibodies, detected by ELISA against 
the RSV F protein and/or an RSV plaque reduction neutralization assay (RSV-PRNT) 
 
Secondary Objectives 
1. To characterize clinical outcomes (frequency and severity of symptomatic, medically attended 
respiratory and febrile illness) in the vaccine and placebo recipients who experience natural 
infection with wild-type (wt) RSV during the subsequent RSV season  
2. To characterize antibody responses in the vaccine and placebo recipients who experience natural 
infection with wt RSV during the subsequent RSV season, where the primary aim is to check if 
substantial rises in RSV-neutralizing serum antibodies are present in a subset of vaccine 
recipients in the absence of RSV-associated medically attended acute respiratory illness (RSV-
MAARI), which would be indicative of exposure to wt RSV without illness 
3. To characterize the B cell response to vaccine and to characterize these responses in the vaccine 
and placebo recipients who experience natural infection to wt RSV during the subsequent RSV 
season 
4. To characterize the mucosal antibody response to each vaccine  
5. To determine differences in infectivity and immunogenicity between the vaccines 
 
 
 
 

IMPAACT 2018, Version 1.0 
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15 June 2017 
IMPAACT 2018 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a 
Single Dose of the Recombinant Live-Attenuated Respiratory Syncytial Virus 
(RSV) Vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 or Placebo, Delivered as 
Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
Figure 1: Study Overview 
Panel A: Randomization Scheme 
 
Panel B: Study Procedures (All Study Product Arms) 
 

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1 
INTRODUCTION  
 
1.1 
Overview 
 
Human respiratory syncytial virus (RSV) is the most common viral cause of serious acute lower 
respiratory illness (LRI) in infants and children under 5 years of age worldwide (1). There is 
broad consensus that a vaccine is needed. Attenuated live virus vaccines are a promising strategy 
for RSV since they have not been associated with vaccine enhanced diseases (2) and they have 
the potential of inducing a spectrum of immune responses similar to responses induced by wild 
type infection (3). This protocol is part of a multi-year development plan aimed at identifying a 
candidate RSV vaccine that is sufficiently attenuated but still immunogenic. 
 
One attenuation strategy that has shown great promise is the deletion of the viral interferon 
antagonist NS2, resulting in an NS2 deletion mutant. The most promising NS2 deletion candidate, 
RSV ∆NS2/∆1313/I1314L, contains a second attenuating element, a deletion of a single codon of 
the polymerase ORF, in addition to the NS2 deletion. The resulting vaccine candidate is 
attenuated and moderately temperature sensitive. In a Phase I trial (NCT01893554), this 
candidate vaccine was evaluated in RSV-seropositive children 12-59 months of age at a dose of 
106 PFU [10 vaccinees (V), 5 placebo recipients (P)], and no shedding or immune response was 
detected, indicative of attenuation. Next, it was evaluated in seronegative children 6-24 months of 
age at two sequential dose levels. At the lower dose of 105 PFU (15V, 7P), the vaccine was poorly 
infectious (7% and 80% of recipients shed virus detected by culture and RT-qPCR, respectively) 
and immunogenicity was low. At the higher dose of 106 PFU (20V, 10P), 80% and 90% of 
recipients shed virus detected by culture and RT-qPCR, respectively, and 94% had an F-ELISA 
serum antibody response greater or equal to a 4-fold rise in titer.  
 
Another very promising strategy is deletion of a large section of the M2-2 open reading frame, 
resulting in an M2-2 deletion mutant. This mutation is associated with increased mRNA 
production linked with reduced RNA replication (4). The increase in mRNA production results in 
increased synthesis of viral antigen, with the potential for increased immunogenicity, and the 
decreased RNA replication results in delayed assembly of new virus particles, resulting in 
attenuation. A large deletion mutation effectively reduces the potential for reversion to wild type, 
an important concern for a live-attenuated vaccine. The first candidate RSV vaccine using this 
strategy, MEDI/ΔM2-2, was studied sequentially in adults, seropositive children, and then 
seronegative infants and children (age 6 to 24 months) (5). This study found that the vaccine had 
excellent immunogenicity, associated with very low viral replication; at a 105 PFU dose, only 
60% of RSV-seronegative vaccinees shed vaccine virus (detectable by viral culture in nasal wash 
(NW) samples) at a low mean peak titer of only 1.5 log10 PFU/ml NW. MEDI/∆M2-2 had a very 
promising phenotype; it is possible that a dose of 106 PFU might increase infectivity and possibly 
replication and further enhance immunogenicity. However, MEDI/∆M2-2 was evaluated as part 
of a Collaborative Research and Development Agreement (CRADA) with Medimmune, LLC, 
that has been terminated, and this material was not available for further study. Therefore, a close 
facsimile, RSV 276, was generated to replace MEDI/∆M2-2, as described in greater detail below.  
 
Based on infectivity, safety, and immunogenicity data to date, these two candidate vaccines—
RSV ∆NS2/∆1313/I1314L and RSV 276, a facsimile of RSV MEDI/∆M2-2—appear to be the 
strongest candidates to move into an expanded Phase IB trial. This expanded Phase IB study is 
being planned to initiate in 2018 and will be designed to evaluate safety and immunogenicity of 
these two lead candidates. However, before the Phase IB trial can be designed, there are some 
remaining unanswered questions about these candidates that require the present Phase I study. 
The gaps in data necessitating the proposed trial include: 

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• 
RSV ∆NS2/∆1313/I1314L requires additional safety data. While initial data are promising, 
only 20 participants received vaccine at the dose to be used. Evaluation of additional 
participants will be needed to evaluate immunogenicity and safety.  
• 
The ∆M2-2 vaccine candidate, MEDI/∆M2-2, is not available for further study. A close 
facsimile of this virus (differing at the cDNA level by only 2 marker nucleotides in a 
restriction site in a non-coding region), called RSV 276, has now been prepared. RSV 276 
will be studied in parallel to RSV∆NS2/∆1313/I1314L. It is anticipated that RSV 276 will be 
equivalent to MEDI/∆M2-2. This first-in-human study of RSV 276 is needed to confirm 
infectivity, safety and immunogenicity of RSV 276. 
 
Table 1 includes an overview about recent RSV studies involving related candidates. The 
candidates of IMPAACT 2018 are described in Table 2. 
 
 

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Table 1: Overview of recent RSV vaccine candidates with M2-2 deletion  
 
IMPAACT 
Protocol 
Vaccine 
name 
Attenuating mutations, key 
features 
Expected effect 
Study status 
CIR 
protocol 
CIR 275 
MEDI/ 
∆M2-2 
• Deletion of the RSV RNA 
regulatory M2-2 protein ΔM2-2 
• Contains SH noncoding region that 
is deleted in “LID” versions;  
• differs from LID versions by one 
point mutation each in the NS2 and 
N proteins 
• Attenuation 
• Increased 
immunogenicity 
 
• Achieved target 
enrollment (n=30)  
• Highly attenuated 
• Highly immunogenic 
(Karron et al., 2015) 
2000 
LID 
∆M2-2 
• Deletion of the RSV RNA 
regulatory M2-2 protein ΔM2-2 
• Attenuation 
• Increased 
immunogenicity 
 
• Closed to accrual (n=29)  
• Manuscript in 
preparation 
• Peak titers higher than 
expected,  
> MEDI/∆M2-2 
2011 
LID 
∆M2-2 
1030s 
• Deletion of the RSV RNA 
regulatory M2-2 protein ΔM2-2 
• genetically stable "1030" 
attenuating point mutation 
• Attenuation 
• Temperature 
sensitivity 
• Increased 
immunogenicity 
• Closed to accrual 
• Achieved target 
enrollment (n=33)  
• Analysis pending 
2012 
LID cp 
∆M2-2 
• Deletion of the RSV RNA 
regulatory M2-2 protein ΔM2-2 
• five point mutations (derived from 
cold-passaged RSV) in the RSV 
nucleoprotein, fusion protein, and 
polymerase protein 
• Attenuation 
(increased by 
addition of cp 
mutations) 
• Increased 
immunogenicity 
• Closed to accrual 
• n = 17  
• Interim analysis: vaccine 
will not meet at least one 
of the desired 
characteristics 
2013 
D46/NS
2/N/ 
∆M2-2-
HindIII 
• Deletion of the RSV RNA 
regulatory M2-2 protein ΔM2-2; 
design based on MEDI/∆M2-2. 
• Contains SH noncoding region that 
is deleted in “LID” versions;  
• one point mutation in NS2, N 
proteins; identical on amino acid 
level to MEDI/∆M2-2 
• Attenuation 
• Lower level of 
replication than 
LID ∆M2-2 due 
to the presence 
of SH non-
coding region  
• Increased 
immunogenicity 
• Planned accrual: n=33 
Projected to complete 
enrollment in summer 
2017 based on prior 
experience  
 
 
 

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Table 2: Overview of RSV vaccine candidates with NS2 or M2-2 deletion to be 
studied in IMPAACT 2018 
IMPAACT 
Protocol 
Vaccine name 
Attenuating mutations, key 
features 
Expected effect 
Study status 
2018 
 
RSV 276 
• Deletion of the RSV RNA 
regulatory M2-2 protein ΔM2-2; 
design based on MEDI/∆M2-2. 
• Contains the SH noncoding 
region that is deleted in “LID” 
versions; 
• RSV 276 replaces MEDI/∆M2-2, 
differing only by two nucleotides 
in the 5’ noncoding region of the 
M2 gene (nt 8198/99; GC in 
MEDI/∆M2-2; CG in RSV 276) 
• Attenuation 
• Lower level of 
replication than 
LID ∆M2-2 due 
to the presence of 
SH non-coding 
region 
• Increased 
immunogenicity 
• Planned accrual: 
n=80 
• Projected to open in 
July 2017 
 
RSV ∆NS2/ 
∆1313/I1314L 
• Deletion of the RSV interferon 
antagonist NS2 (ΔNS2) 
• Deletion of codon 1313 of the 
polymerase gene (Δ1313), 
Codon 13114 was genetically 
stabilized (I1314L) 
• Attenuation 
• Temperature 
sensitivity 
• Increased 
immunogenicity 
 
In the proposed study, the lead candidates from each attenuation strategy, RSV 
∆NS2/∆1313/I1314L and RSV 276, will be evaluated side-by-side, and the results will guide the 
design of the planned Phase 1B study. A placebo group is included because of the high 
background of respiratory/febrile illness in this age group in RSV-seronegative infants. 
 
It is hoped that one or both candidates will have the following characteristics:  
• 
>90% of vaccinees should be infected with vaccine virus as defined by shedding vaccine 
virus, detected by infectivity assay and/or RT-qPCR and/or ≥4-fold rise in RSV-specific 
serum antibodies, detected by ELISA against the RSV F protein and/or an RSV plaque 
reduction neutralization assay (RSV-PRNT);  
• 
The vaccines will be safe;  
• 
The mean peak titer of shed virus in nasal washes should be approximately 2.5 log10 PFU;  
• 
RSV-neutralizing serum antibody titers (measured 56 days post inoculation) should be similar 
to or better than MEDI/∆M2-2 (geometric mean titer of >1:97); and   
• 
Post-vaccination surveillance during the RSV season following vaccination should reveal 
substantial rises in RSV-neutralizing serum antibodies in a subset of vaccine recipients in the 
absence of RSV-associated medically attended acute respiratory illness (RSV-MAARI), 
which would be indicative of exposure to wt RSV without illness. 
 
RSV∆NS2/∆1313/I1314L was previously evaluated at both 105 PFU and 106 PFU; both doses 
were well tolerated, but only the 106 PFU dose was sufficiently infectious and immunogenic. For 
this reason, RSV∆NS2/∆1313/I1314L will only be tested at the 106 dose level. RSV 276 will be 
evaluated at a dose of 105 PFU, the dose used in the previous study of MEDI/∆M2-2. The results 
from this Phase I study will guide the design of the Phase IB study. 
 
 

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1.2 
Background  
 
Epidemiology, Disease Burden, and the Need for a Vaccine 
 
In the United States alone, RSV is responsible for 75,000 to 125,000 hospitalizations of infants 
yearly (6), and worldwide, RSV infects at least 34 million children under 5 years, resulting in an 
estimated 3.4 million RSV LRI hospitalizations and 66,000 to 199,000 RSV-attributable deaths 
each year (1). In temperate climates, annual RSV epidemics occur in late winter and early spring, 
and nearly all children are infected within the first 2 years of life.  RSV illness can range from 
mild upper respiratory tract illness (URI), including rhinitis, pharyngitis, and coryza, to severe 
LRI, including bronchiolitis and pneumonia. Beyond the acute burden of disease caused by RSV, 
severe RSV disease in infancy may predispose to reactive airways disease during childhood (7, 
8). 
 
RSV is an enveloped RNA virus that is a member of the newly organized Pneumoviridae family, 
genus Orthoneumovirus (9). RSV has a single negative-sense strand RNA genome of 15.2 
kilobases encoding 10 mRNAs. Each mRNA encodes a single protein, with the exception of the 
M2 mRNA, which contains 2 overlapping open reading frames (ORFs). The 11 RSV proteins are: 
the viral RNA-binding nucleoprotein N, the phosphoprotein P, the large polymerase protein L, the 
attachment glycoprotein G, the fusion glycoprotein F, the small hydrophobic surface glycoprotein 
SH, the internal matrix protein M, the 2 nonstructural proteins NS1 and NS2, and the M2-1 and 
M2-2 proteins encoded by the M2 mRNA. The gene order is: 3'-NS1-NS2-N-P-M-SH-G-F-M2-
L-5'. RSV transcription and genome replication take place exclusively in the cytoplasm, and 
virions form by budding from the apical plasma membrane of respiratory epithelial cells.  
 
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. Although passive 
immunoprophylaxis with the monoclonal RSV-neutralizing antibody palivizumab (Synagis®; 
MedImmune) is available for high-risk infants, this approach is not feasible for general use. A 
formalin-inactivated vaccine against RSV was evaluated clinically in the 1960s and did not 
confer protection; instead, disease enhancement occurred at a high rate following natural 
infection of vaccinees with wt RSV (10). Studies in experimental animals established that disease 
enhancement was specific to non-replicating RSV vaccines and not seen with infectious RSV or 
replicating vaccine vectors (11, 12).   
 
Following the failure of the formalin-inactivated RSV vaccine, attempts at developing RSV 
vaccines at National Institute of Allergy and Infectious Diseases (NIAID) have focused largely on 
live-attenuated approaches (3). Importantly, over a period of over 20 years, a number of live-
attenuated investigational RSV vaccines have been evaluated in RSV-naïve infants and children, 
and enhanced disease following wt RSV infection of vaccinees has not been observed (2). Apart 
from the absence of enhanced disease, live-attenuated RSV vaccines have a number of known 
advantages over non-replicating RSV vaccines. They can be administered intranasally, induce 
protective mucosal immunity in the respiratory tract (as well as systemic immunity), infect in the 
presence of maternally-derived RSV serum antibody, and have been well tolerated and 
immunogenic when administered to infants as young as four weeks of age (13).  
 
Human RSV has a single serotype with two antigenic subgroups, A and B. The two subgroups 
exhibit a 3- to 4-fold reciprocal difference in neutralization by polyclonal convalescent serum. 
Analysis of glycoprotein-specific responses in infants by enzyme-linked immunosorbent assay 
(ELISA) with purified F and G glycoproteins showed that the fusion proteins (F proteins) were 
50% related antigenically, and the G proteins were 7% related (14). Consistent with this level of 

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antigenic relatedness, F protein expressed by a recombinant vaccinia virus was equally protective 
in cotton rats against challenge with either subgroup A or B, whereas the G protein was 13-fold 
less effective against the heterologous subgroup (15). Thus, the F protein is responsible for most 
of the observed cross-subgroup neutralization and protection, and a subgroup A vaccine virus is 
likely to induce a broad immune response against wt RSV of either subgroup. Antibodies to the F 
protein are one of the endpoints evaluated in this study. 
 
The RSV vaccines to be evaluated in this study were derived using a recombinant 
deoxyribonucleic acid (DNA)-based technique called reverse genetics (16).  The technique of 
reverse genetics has been used to produce a number of licensed vaccines; among them is 
FluMist® (MedImmune). This technique allows de novo recovery of infectious virus entirely 
from complementary DNA (cDNA) in a qualified cell substrate under defined conditions. 
Reverse genetics provides a means to introduce predetermined mutations into the RSV genome 
via the cDNA intermediate. Derivation of vaccine virus from cDNA minimizes the risk of 
contamination with adventitious agents and helps to keep the passage history brief and well 
documented. Once recovered, the vaccine virus is propagated in the same manner as a 
biologically derived virus. As a result of repeated passage and amplification, the drug substance 
(clinical trials material) does not contain any recombinant DNA. Both RSV vaccine candidates to 
be tested under this protocol are derivatives of strain A2, subgroup A. 
 
Vaccine Description 
 
In previous Phase I studies in RSV-seronegative infants and children, 6 to 24 months of age, the 
live-attenuated RSV strains RSV ∆NS2/∆1313/I1314L and the close facsimile of RSV 276, 
MEDI/∆M2-2, have emerged as the most promising candidates.  
 
RSV ΔNS2/Δ1313/I1314L contains two independent attenuating elements: (i) a 523 nt deletion of 
the viral interferon/apoptosis antagonist NS2 gene, and (ii) an amino acid deletion in the L protein 
(Δ1313; deletion of S1313). In addition, RSV ΔNS2/Δ1313/I1314L contains the genetically 
stabilizing mutation I1314L (17). This stabilizing mutation was included to prevent the de-
attenuating second site mutation I1314T (18). RSV with NS2 deletion is attenuated in animal 
models, including in chimpanzees (19). As shown in the bovine RSV/calf model (20), the 
deletion of an RSV interferon/apoptosis antagonist may increase immunogenicity. To study the 
attenuating effect of 1313 alone, a recombinant RSV with deletion of codon 1313 of the L gene 
was evaluated (RSV 1313). On its own, the deletion of codon 1313 of the polymerase gene had 
a substantial attenuating effect on RSV. 1313 rendered RSV temperature sensitive (ts), with a 
shutoff temperature (TSH) of 37°C, and was strongly attenuating in mice.   
 
MEDI/∆M2-2 is not available for further study. RSV 276 was designed to be essentially identical 
to MEDI/∆M2-2, differing only by two nucleotides in the 5’ noncoding region of the M2 gene (nt 
8198/99; GC in MEDI/∆M2-2; CG in RSV 276). Like MEDI/∆M2-2, RSV 276 contains a 
deletion of the RSV RNA-regulatory M2-2 protein, resulting in increased mRNA production and 
reduced RNA replication (4). The RSV M2-2 protein is a small protein (90 amino acids in RSV 
strain A2) encoded by the second, downstream ORF in the M2 mRNA, which slightly overlaps 
the 5'-proximal, upstream M2-1 ORF (21). M2-2 is expressed intracellularly at a low level (22), 
and it is not known whether it is packaged into the virion. Recombinant RSV with M2-2 deletion 
grows more slowly in vitro than wt RSV (4, 23). Deletion of M2-2 results in increased 
accumulation of intracellular viral mRNA and decreased accumulation of genome and 
antigenome. This finding suggests that, during infection by wt RSV, M2-2 plays a role in shifting 
the balance of RNA synthesis from transcription to RNA replication (4). The increase in mRNA 
accumulation in cells infected with an M2-2-deleted RSV (∆M2-2) was accompanied by an 

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increase in the expression of RSV proteins, including expression of the F and G glycoproteins, 
suggesting that M2-2 deletion mutants might be more immunogenic than wt RSV. The decreased 
RNA replication results in the delayed assembly of new virus particles, resulting in attenuation. 
Indeed, M2-2 deletion mutants were highly attenuated in pre-clinical and clinical studies (5, 23, 
24).  
 
As indicated above, RSV 276 was designed to be a close facsimile to MEDI/∆M2-2, a vaccine 
candidate that was very highly restricted, well tolerated, safe, and immunogenic in a previous 
study in RSV-seronegative children and infants (5). RSV 276 contains the same 234 nt deletion of 
the M2-2 open reading frame as MEDI/∆M2-2, and it is identical to MEDI/∆M2-2, except for 
two marker nucleotides in the 5’ noncoding region of the M2 gene (nt 8198/99; GC in 
MEDI/∆M2-2; CG in RSV 276, CC in wt RSV). It is anticipated that these two nucleotide 
differences between MEDI/∆M2-2 and RSV 276 will not have any effect on the replication, 
attenuation, safety, and immunogenicity in humans because they are in a non-coding region 
adjacent to the deletion in M2-2. 
 
RSV ∆NS2/∆1313/I1314L and RSV 276 are cDNA derived live-attenuated RSV vaccine 
candidates. The seed viruses were generated at the Laboratory of Infectious Diseases (LID), 
NIAID (non-GMP), and transferred to Charles River Laboratories [CRL; Malvern, PA; operated 
under cGMP (current Good Manufacturing Practice)]. The seed viruses passed pre-production 
testing (Sterility, Mycoplasma, Bacteriostasis/Fungistasis, and testing for porcine circovirus types 
1 and 2; testing performed at CRL under cGMP), and were accepted for manufacturing of the 
Drug Product under cGMP. For the production of the Drug Products at CRL, Vero cells (MF 
11702) were grown in OptiPRO™ serum-free medium. On day 3 post-infection, OptiPro™ 
medium was removed, and replaced with fresh medium (Dulbecco’s modified Eagle medium 
(DMEM) in case of RSV 276; OptiPro serum-free medium (SFM) in case of RSV 
ΔNS2/Δ1313/I1314L). Antibiotics were not used in any stage of cell passage, virus growth, or 
vaccine development. The virus-containing supernatant was harvested on day 7 (RSV 
ΔNS2/Δ1313/I1314L) or on day 5 (RSV 276), and clarified by centrifugation. Any residual intact 
cells were removed by filtration. 
 
Clarified supernatant in 1X SPG (sucrose, 0.218 M; KH2PO4, 0.0038 M; K2HPO4, 0.0072 M; L-
Glutamic Acid, 0.0054 M) was dispensed in 0.6 mL aliquots into labeled 2.0 mL cryogenic vials. 
Vials are snap-frozen and stored at -80ºC ± 15ºC.  
 
The RSV ΔNS2/Δ1313/I1314L Drug Product is a concentrate of live recombinant RSV 
ΔNS2/Δ1313/I1314L Vero Grown Virus Vaccine (Lot RSV#006A) in OptiPro SFM with 
1X SPG (sucrose, 0.218 M; KH2PO4, 0.0038 M; K2HPO4, 0.0072 M; L-Glutamic Acid, 0.0054 
M). The Drug Product has a potency of about 7.3 log10 PFU/mL and is diluted to dose on site 
 
The RSV 276 Drug Product is a concentrate of live recombinant RSV 276 Vero Grown Virus 
Vaccine (Lot RSV#014A) in DMEM without phenol red with 1X SPG (sucrose, 0.218 M; 
KH2PO4, 0.0038 M; K2HPO4, 0.0072 M; L-Glutamic Acid, 0.0054 M). The Drug Product has a 
potency of about 6.2 log10 PFU/mL and is diluted to dose on site. 
 

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The Final Drug Products, RSV ΔNS2/Δ1313/I1314L, Lot RSV#006A and RSV 276, Lot 
RSV#014A, passed all in-vitro and in-vivo testing required for viral vaccines (Detection of 
Inapparent Viruses in a Viral Vaccine Product, in vitro Tuberculosis Testing, PCR-based Reverse 
Transcriptase Testing, Porcine Circovirus Testing, Sterility, Mycoplasma, 
Bacteriostasis/Fungistasis, Residual DNA testing, DNA Sizing, Endotoxin, Determination of the 
Sucrose Level, pH Determination, Intact Cell Assay, Potency/Infectivity, Identity, Purity, 
Toxicology and Pharmacology testing).  Sequence analysis confirmed that the genomic sequences 
of the Drug Products, Lots RSV#006A and Lot RSV#014A, were identical to the cDNA that each 
was derived from. RSV ΔNS2/Δ1313/I1314L, Lot RSV#006A, and RSV 276, Lot RSV#014A, 
were released by CRL for use as investigational vaccines. 
 
1.3 
Prior Research 
 
1.3.1 
Experimental Vaccines against Respiratory Syncytial Virus 
 
Efforts have been directed toward the development of a live-attenuated RSV vaccine because of 
the advantages of live-attenuated vaccines over inactivated or subunit vaccines. These advantages 
include the ability to (i) induce the full spectrum of protective immune responses including serum 
and local antibodies as well as CD4+ and CD8+ T cells and innate immunity, (ii) infect and 
replicate in the presence of maternal antibody permitting immunization of young infants, and (iii) 
produce an acute, self-limited, attenuated infection that is well tolerated and readily eliminated 
from the respiratory tract. Another important advantage is the absence of vaccine-related 
enhanced disease, as has been confirmed in clinical studies (2). 
 
Several live-attenuated RSV vaccines have been evaluated in clinical trials in adult and pediatric 
populations as part of NIAID's ongoing RSV vaccine development program (5, 13, 25-27). RSV 
∆NS2/∆1313/I1314L and RSV 276 represent the lead vaccine candidates from these two 
attenuation strategies. Prior to RSV ΔNS2/Δ1313/I1314L, three RSV vaccine viruses with NS2 
deletion (rA2cpΔNS2, rA2cp248/404ΔNS2, and rA2cp530/1009ΔNS2) had been evaluated in 
clinical studies (28). Prior to evaluation of RSV 276 under the present protocol, several RSV 
candidates with M2-2 deletion have been evaluated. RSV 276 differs from the lead ∆M2-2 
candidate, MEDI/∆M2-2, only by two marker nucleotides in a noncoding region. A short 
summary of preclinical studies involving these vaccine candidates is included below, and a 
description of the previous human experience with the prior candidates that are most closely 
related to the candidates of the present protocol can be found in Section 1.3.3.  
 
1.3.2 
Preclinical Studies 
 
1.3.2.1 Genetic Stability of RSV ΔNS2/Δ1313/I1314L 
 
RSV ΔNS2/Δ1313/I1314L is temperature sensitive, with a shut-off temperature for virus 
replication of 38ºC-39°C. This phenotype is associated with the deletion of a single codon of the 
polymerase ORF, codon 1313 (17, 18). To prevent a de-attenuating second-site mutation that had 
been observed in an in-vitro genetic stability stress test, the neighboring codon I1314 was 
genetically stabilized by changing it to I1314L. In further in-vitro stability stress tests, this 
I1314L change indeed stabilized the 1313 site of the RSV polymerase ORF. The genetic stability 
of RSV ΔNS2/Δ1313/I1314L was confirmed by sequence analysis of RSV ΔNS2/Δ1313/I1314L 
isolates from a previous Phase 1 study. This recent pediatric vaccine study showed that RSV 
ΔNS2/Δ1313/I1314L is a genetically stable RSV vaccine candidate.  
 

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1.3.2.2 Evaluation of the Attenuation Phenotype of RSV ΔNS2/Δ1313/I1314L and RSV 276 in 
Experimental Animals 
 
Recombinant RSV with deletion of ΔNS2 and codon 1313 of the polymerase ORF was evaluated 
for its ability to replicate in the upper and lower respiratory tract (URT and LRT, respectively) of 
mice. While wt RSV rA2 replicated to about 4.0 log10 PFU and 4.5 log10 PFU per g of tissue in 
the upper and lower respiratory tract of mice, replication of the deletion ΔNS2/Δ1313 mutant was 
reduced to below the level of detection, a surrogate for attenuation. 
 
Replication and immunogenicity of RSV ΔNS2/Δ1313/I1314L was evaluated in nonhuman 
primates (African green monkeys, AGM). AGMs are semi-permissive for RSV. AGMs which 
were seronegative for RSV were inoculated intranasally and intratracheally with RSV 
ΔNS2/Δ1313/I1314L; a dose of 1 x 106 PFU of vaccine in a 1 mL volume was administered per 
site to sedated juvenile male and female AGMs (total dose per animal: 2 x 106 PFU). 
Nasopharyngeal (NP) swabs were collected daily on Days 0 through 10 and Day 14, tracheal 
lavage (TL) samples were collected every other day from Day 2 through Day 10 and on Day 14, 
and virus shedding was analyzed by plaque assay. Serum RSV neutralizing antibody titers were 
determined by a complement-enhanced 60% plaque reduction neutralization assay. Results from 
studies following the same protocol, performed in animals from the same group and origin, 
inoculated with recombinant wtRSV A2 at the same dose, were included for comparison 
(Appendix I, Table 11, Table 12, and Table 13). Studies were approved by the Animal Care and 
Use Committee of NIAID, NIH. Virus shedding was analyzed by immunoplaque assay. 
Substantial shedding from the upper and lower respiratory tract over several days of the RSV A2 
control virus was detected by plaque assay, with mean peak titers of 3.5 log10 PFU per mL in the 
URT and in the LRT (Appendix I, Table 11, Table 12). Compared to RSV A2, mean peak titers 
of RSV ΔNS2/Δ1313/I1314L were slightly reduced in the URT (3.2 log10 PFU per mL), and 
greatly reduced in the LRT (1.4 log10 PFU per mL), with detectable shedding in TL samples of 
only three of four animals. The sum of daily titers (area under the curve) of shedding of RSV 
ΔNS2/Δ1313/I1314L from the upper and lower respiratory tract was substantially lower than that 
of RSV A2. Despite the lower level of shedding, RSV ΔNS2/Δ1313/I1314L was immunogenic in 
AGMs (Table 13). 
 
RSV 276 also was evaluated for its ability to replicate in AGMs in two independent non-GLP 
studies. The first NHP study was done to evaluate an Experimental Lot of RSV 276 (total dose 
administered: 2 x 106 PFU per animal), and the second study (total dose administered: 2 x 106 
PFU per animal) was done to test the clinical safety of the clinical trial material (CTM) RSV 276 
in nonhuman primates (Appendix I, Table 14, Table 15, and Table 16). As described above, 
AGMs, seronegative for RSV, were inoculated intranasally and intratracheally with 1 x 106 PFU 
of RSV 276 in a 1 mL volume per site (total dose per animal: 2 x 106 PFU). NP and TL samples 
were collected as described above, and virus shedding was analyzed by plaque assay. Serum RSV 
neutralizing antibody titers were determined by a complement-enhanced 60% plaque reduction 
neutralization assay (PRNT60). Results from studies following the same protocol, performed in 
animals from the same group and origin, inoculated with MEDI/ΔM2-2 and recombinant wt RSV 
A2 at the same dose, were included for comparison (Appendix I, Table 14, Table 15, and Table 
16). Substantial shedding from the upper and lower respiratory tract over several days of the RSV 
A2 control virus was detected by plaque assay, with mean peak titers of 4.2 log10 PFU per mL in 
the URT, and 4.1 log10 PFU per mL in the LRT (Appendix I, Table 14, Table 15). RSV 276 was 
infectious for AGMs, and except for a single animal with undetectable shedding from the upper 
respiratory tract, all animals from two independent studies shed RSV 276 over several days from 
the upper and lower respiratory tract. However, compared to RSV A2, shedding of RSV 276 was 
reduced in the upper and lower respiratory tract. Mean peak titers of the experimental lot and of 

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the CTM of RSV 276 were not significantly different from those of MEDI/ΔM2-2 in a previous 
study. Both lots of RSV 276 induced serum neutralizing antibody titers that were higher than 
those to MEDI/ΔM2-2, and comparable to those to the RSV A2 control virus (Table 16). These 
results show that at a total dose of 2 x 106 PFU, administered intranasally and intratracheally, 
RSV 276 is attenuated to a similar degree as MEDI/ΔM2-2, and very immunogenic in AGMs. 
 
These study results indicate that both RSV ΔNS2/Δ1313/I1314L and RSV 276 are restricted for 
replication in AGMs, the most permissive RSV nonhuman primate model that is currently 
available. At the dose of 1 x 106 PFU per site, shedding of both vaccine candidates was detectable 
from the URT and LRT, but was substantially reduced compared to recombinant wt RSV A2. 
Despite the low level of shedding, both candidates were very immunogenic in AGMs. Overall, 
replication and immunogenicity of RSV 276 were comparable to MEDI/ΔM2-2. In summary, it is 
anticipated that these investigational RSV ΔNS2/Δ1313/I1314L and RSV 276 live vaccine 
candidates will be attenuated, immunogenic, and safe upon intranasal application in RSV-
seronegative children and infants. It is expected that RSV 276 will be as attenuated and 
immunogenic as the previous RSV vaccine candidate MEDI/ΔM2-2. 
 
1.3.3 
Previous Clinical Experience 
 
RSV ΔNS2/Δ1313/I1314L has recently been evaluated in a first-in-human Phase I study. The 
live-attenuated recombinant RSV 276 vaccine virus is being evaluated for the first time in 
humans in the present study. The RSV 276 vaccine is a close facsimile of the live-attenuated 
recombinant RSV MEDI M2-2 vaccine virus, which has been studied in RSV-seropositive 
cohorts, and in RSV-seronegative children. 
 
1.3.3.1 RSV Vaccine Candidates with NS2 Deletion 
 
Prior to RSV ΔNS2/Δ1313/I1314L, three RSV vaccine viruses with NS2 deletion (rA2cpΔNS2, 
rA2cp248/404ΔNS2, and rA2cp530/1009ΔNS2) had been evaluated in clinical studies (28). 
 
rA2cpΔNS2 contains the NS2 deletion as well as a set of 5 amino acid substitutions in the N, F, 
and L proteins that were identified in a cold-passaged (cp) RSV [V267I in N; E218A and T523I 
in F; and C319Y and H1690Y in L (29, 30)]. rA2cp248/404ΔNS2 contains all of the mutations in 
rA2cpΔNS2 as well as two additional point mutations: "248," an amino acid substitution in the L 
protein (Q831L) (29, 31, 32), and "404," a nucleotide substitution in the M2 gene start signal (31, 
33). rA2cp530/1009ΔNS2 also contains all of the mutations in rA2cpΔNS2 as well as two 
additional point mutations in L: “530” (F521L) and “1009” (M1169V) (34, 35).  
 
rA2cpΔNS2, which had the fewest attenuating mutations, was evaluated in a dose-escalating 
study (105.0 PFU, 106.0 PFU, or 107.0 PFU) administered to a total of 45 adults, and was also 
evaluated at a dose of 105.0 PFU in eight 15- to 59-month-old RSV-seropositive children.  
Shedding of rA2cpΔNS2 was not detected in any of the adults and only 2 of 16 adults who 
received 107.0 PFU had an antibody response. In contrast, at the dose of 105.0 PFU, rA2cpΔNS2 
was shed by 3 of 8 vaccinated seropositive children with mean peak titers of 103.4 PFU/mL of 
nasal wash. Two additional children had detectable virus by PCR. Based on these results, 
rA2cpΔNS2 was deemed under-attenuated, and was not further evaluated in seronegative 
children.  
 
rA2cp248/404ΔNS2 was evaluated in adults (n=16 vaccinees), 15- to 59-month-old RSV-
seropositive children (n=16 vaccinees), and 6- to 24-month-old RSV-seronegative children (n=10 

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vaccinees). rA2cp248/404ΔNS2 was not shed by adults. Only one seropositive child shed vaccine 
virus (peak titer of 100.4 PFU/mL of nasal wash), and four seronegative children shed vaccine 
virus (mean peak titer of 102.3 PFU/mL of nasal wash). 
  
rA2cp530/1009ΔNS2 was also evaluated in adults (n=19 vaccinees), 15-to-59-month-old RSV-
seropositive children (n=14 vaccinees), and 6- to 24-month-old RSV-seronegative children (n=15 
vaccinees). rA2cp530/1009ΔNS2 was shed by one adult (peak titer of 100.4 PFU/mL of nasal 
wash), none of the seropositive children, and three seronegative children (mean peak titer of 101.3 
PFU/mL of nasal wash). In summary, deletion of the NS2 gene attenuates RSV. rA2cpΔNS2 was 
over-attenuated for adults but under-attenuated for use in young children, whereas both 
rA2cp248/404ΔNS2 and rA2cp530/1009ΔNS2 were over-attenuated and insufficiently 
immunogenic for seronegative children (28). 
 
Based on these results, RSV∆NS2/∆1313/I1314L was developed. In a recent Phase I trial 
(NCT01893554), this candidate vaccine was evaluated in RSV-seropositive children 12-59 
months of age at a dose of 106 PFU (10V, 5P), and no shedding or immune response was 
detected, indicative of attenuation. Next, it was evaluated in seronegative children 6-24 months of 
age at two sequential dose levels. At the lower dose of 105 PFU (15V, 7P), the vaccine was poorly 
infectious (7% and 80% of recipients shed virus detected by culture and RT-qPCR, respectively) 
and immunogenicity was low. At the higher dose of 106 PFU (20V, 10P), 80% and 90% of 
recipients shed virus detected by culture and RT-qPCR, respectively, and 94% had an F-ELISA 
serum antibody response defined by at least a 4-fold rise in titer. Assessment of neutralizing 
antibodies for this study will occur when the samples after RSV surveillance have been collected. 
 
1.3.3.2 RSV MEDI/ΔM2-2 
 
Two versions of RSV vaccine candidates with M2-2 deletion have recently been evaluated. The 
first vaccine candidate, designated RSV MEDI/ΔM2-2, was sequentially evaluated in adults, 
RSV-seropositive children, and RSV-seronegative infants and children (5). Fifteen healthy adults 
received a 106 PFU dose of this vaccine in an open-label study. The vaccine was generally well 
tolerated, and vaccine virus was not detected in nasal washes collected from any of the vaccine 
recipients. Serum antibody responses were not detected in any of these adult vaccinees. Thus, 
there was no evidence of replication of RSV MEDI/ΔM2-2 in adult vaccinees. A 106 PFU dose of 
RSV MEDI/ΔM2-2 was subsequently evaluated in RSV-seropositive children ages 12-59 months 
(double-blind, placebo-controlled). Ten children in this RSV-seropositive cohort received a 106 
PFU dose of vaccine, and five received placebo. Among the vaccinees, five children had 
rhinorrhea or nasal congestion, which was associated in all cases with shedding of rhinovirus and 
with shedding of adenovirus (1 child) or enterovirus (1 child). All illnesses were mild in severity. 
None of the vaccinees shed vaccine virus, indicating that there was also no evidence of 
replication of RSV MEDI/ΔM2-2, evaluated at a dose of 106 PFU in RSV-seropositive children. 
 
RSV MEDI/∆M2-2 was subsequently evaluated at a 105 PFU dose in RSV-seronegative children. 
RSV MEDI/∆M2-2 replicated at low titers yet induced substantial RSV neutralizing antibody 
responses in RSV-seronegative children. Vaccine virus was detected by culture in only 60% (12 
of 20) RSV-seronegative vaccinees, at a low mean peak titer of 1.5 log10 PFU/ml. 17 of 20 had 
vaccine virus detected by qRT-PCR. Four-fold or greater increases in RSV neutralizing antibody 
occurred in 19 of 20 children, with mean log2 titers of 2.7 ± 0.9 before vaccination and 6.6 ± 1.1 
following vaccination. Thus, while the levels of infectivity and replication of RSV MEDI/∆M2-2 
were similar to what might be seen with an over-attenuated vaccine virus, the levels of RSV-
specific serum antibodies, indicated that this virus was surprisingly immunogenic. Respiratory 
illnesses were observed in 85% of vaccinees and 70% of placebo recipients, including fever (20% 

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vs. 30%), rhinorrhea (85% vs. 50%), cough (35% vs. 30%), and otitis media (5% vs. 0%). Lower 
respiratory tract illness (LRI) was not detected in any participant. Transmission of vaccine virus 
occurred in a set of 13-month-old twin study participants; both were minimally symptomatic and 
vaccine virus shed retained the M2-2 deletion and remained very highly restricted in the 
secondary infection. When data on vaccine virus infectivity and immunogenicity in RSV-
seronegative children were compared to those achieved with rA2 cp248/404/1030/ΔSH, a live-
attenuated RSV vaccine candidate that was well tolerated and immunogenic in previous pediatric 
Phase I studies (13), it was found that the MEDI/∆M2-2 shedding was significantly more 
restricted. However, the post-vaccination RSV-neutralizing serum antibody achieved (GMT = 
1:97) was significantly greater with RSV MEDI/∆M2-2 than with rA2 cp248/404/1030/ΔSH. 
Surveillance during the subsequent RSV season showed that several RSV-seronegative RSV 
MEDI/∆M2-2 recipients had substantial antibody rises without reported medically attended 
illness, suggesting that the vaccine was protective yet primed for strong anamnestic responses to 
RSV. The M2-2 deletion was stable in all shed vaccine virus samples that were tested (5).  
 
Thus, MEDI/∆M2-2 phenotype appears to be very promising for an RSV vaccine. However, 
because of the overall low titer of shedding, and the lack of shedding in a number of vaccinees, it 
was possible that a virus that replicates somewhat more efficiently might be more immunogenic, 
provided it is suitably attenuated. Therefore, several other ∆M2-2 candidates with differences 
affecting replication and temperature sensitivity were also evaluated.  
 
1.3.3.3 RSV LID M2-2  
 
A closely genetically related ∆M2-2 vaccine virus, called RSV LID M2-2, has been developed. 
RSV LID ΔM2-2 was evaluated in RSV-seronegative children (IMPAACT 2000/CIR 291, 
ClinicalTrials.gov identifiers NCT02237209, NCT02040831), 20 of whom received vaccine and 
nine of whom received placebo. RSV LID ΔM2-2 was found to be highly infectious; 95% of 
vaccinees shed vaccine virus, with a mean peak titer of 103.4 PFU/mL by viral culture and a mean 
peak titer of 105.9 log10 copies/mL by qRT-PCR. Overall, the level of replication of RSV LID 
ΔM2-2 in seronegative children was greater than expected based on previous study of 
MEDI/∆M2-2. Respiratory or febrile illnesses occurred frequently in both recipients of RSV LID 
ΔM2-2 (95%) and placebo (78%). One vaccinee experienced a mild LRI (rhonchi) accompanied 
by shedding of vaccine virus and rhinovirus. It was not possible to determine whether the vaccine 
virus played a causal role in this participant's LRI, since an additional respiratory pathogen was 
also present.  However, based upon the overall high level of vaccine virus replication and the 
concern that this might be a marker for under-attenuation, a decision was made to stop accrual to 
the study at 29 rather the targeted 51 participants.  
 
Compared to RSV MEDI/∆M2-2, LID M2-2 replicated to higher viral titers, as measured in nasal 
washes from RSV-seronegative vaccinees. MEDI/M2-2 and LID M2-2 differ in three general 
ways: (i) they were derived from two different laboratory lineages of strain A2 and have 19 point 
mutations scattered through the genome that result in two amino acids coding changes; (ii) they 
have differences in the construction of the ∆M2-2 deletion that result in 24 nucleotide differences, 
and (iii) the LID/∆M2-2 virus has a 112 nt deletion and five coding changes in the 5' noncoding 
region in the LID M2-2 SH gene. This latter mutation in particular may confer increased 
replication of LID M2-2 in vivo.  
 
Thus, a vaccine candidate was desirable with a slightly lower level of replication, similar to that 
of MEDI/∆M2-2. As described above, RSV 276 was designed to be similar to MEDI/∆M2-2. In 
pre-clinical nonhuman primate studies in AGMs, the most permissive RSV animal model 

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currently available, the level of replication of RSV 276 was similar to MEDI/ΔM2-2. Based on 
the non-clinical testing results, it is anticipated that the investigational RSV 276 live vaccine 
candidate will be similar to the previously studied RSV vaccine candidate MEDI/ΔM2-2, and will 
be safe and immunogenic upon intranasal application in RSV-seronegative children and infants.  
 
RSV 276 differs from MEDI/ΔM2-2 only by two nucleotides in the 5’ noncoding region of the 
M2 gene, and therefore it is reasonable to expect that these two viruses will have similar levels of 
replication and attenuation in humans, and likely will be phenotypically indistinguishable. 
MEDI/ΔM2-2 was evaluated in RSV-seropositive adults and RSV-seropositive infants and 
children at a dose of 106 PFU, and virus shedding was undetectable at this dose by culture or RT-
qPCR. The results showed that RSV MEDI/M2-2 is highly attenuated and does not infect RSV-
experienced individuals. At a dose of 105 PFU, vaccine shedding in RSV-seronegative infants and 
children also was very low, showing that this vaccine virus is very highly attenuated in 
seronegative children. Since RSV MEDI/M2-2 did not infect RSV-seropositive individuals at 
the dose level of 106 PFU, testing RSV 276 in RSV-seropositive individuals would not be 
expected to yield any relevant safety information.  
 
1.4 
Rationale 
 
In previous Phase I studies in RSV-seronegative infants and children, 6 to 24 months of age, the 
two live-attenuated RSV strains RSV ∆NS2/∆1313/I1314L and RSV MEDI/M2-2, based on 
two different attenuation strategies, have emerged as the most promising candidates. Based on 
infectivity, safety, and immunogenicity data, these two candidate vaccines appear to be the 
strongest candidates to move into expanded Phase IB trials. However, before the Phase IB trials 
can be designed, there are some remaining unanswered questions about these candidates that 
require a Phase I study. The gaps in data necessitating the proposed trial include: 
 
• 
The initial ∆M2-2 vaccine candidate, MEDI/∆M2-2, is not available for further study. A 
close facsimile of this virus, called RSV 276, has now been prepared. RSV 276 differs from 
MEDI/∆M2-2 only by two marker nucleotides in the 5’ noncoding region of the M2 gene (nt 
8198/99; GC in MEDI/∆M2-2; CG in RSV 276). A first-in-human study of RSV 276 is 
needed to confirm its safety and immunogenicity. 
• 
Additional safety data are needed regarding RSV∆NS2/∆1313/I1314L prior to the larger 
Phase IB study, due to the small number of infants who have received this product to date. 
• 
This study will monitor vaccine shedding at several time points during the acute phase. The 
detailed virus shedding data obtained under this protocol will be used to refine the design and 
the most suitable evaluation time points for a Phase IB study with a less intensive sampling 
schedule. 
 
This protocol monitors safety, infectivity, replication, and immunogenicity of both candidates, 
with particular attention to vaccine virus infectivity and replication (i.e., percentage of 
participants shedding virus, peak vaccine virus titer in nasal washes, as well as duration of 
shedding), which are the most quantifiable metrics for the level of attenuation. Based on results 
from this study, a comparison of infectivity and immunogenicity of these candidates will be 
possible. It is anticipated that the two lead candidate from the different attenuation strategies will 
move forward to an expanded Phase IB study in 2018 to further evaluate safety and 
immunogenicity.   
 
Rationale for first in human testing of RSV 276 in RSV-seronegative infants. MEDI/∆M2-2, a 
candidate vaccine that differs from RSV 276 by only two marker nucleotides in the 5’ noncoding 

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region of the M2 gene, has been studied in seronegative infants and found to be very highly 
restricted and well tolerated. Given that the only difference in the two vaccines is in a non-coding 
region, it is expected that RSV 276 will have identical attenuation compared to MEDI/∆M2-2. 
 
The primary immunogenicity endpoints to be evaluated in this study are serum RSV neutralizing 
antibody titers, and serum antibody titers to the RSV F protein (by ELISA). Neutralizing antibody 
is a well-established and important surrogate marker of protection from RSV disease. Antibodies 
to the F protein are also associated with cross-subgroup neutralization and protection (15). These 
assays will be performed at a central laboratory at the CIR at JHU that has performed the assays 
for the preceding clinical trials.      
 
As a secondary objective, additional details of the B cell response to RSV will be studied. RSV 
neutralizing serum antibody levels represent the most reliable correlate of protection from RSV 
LRI; the protective role of antibody has been established in infants over years of preventive use of 
palivizumab (36). Recent findings suggest that antibodies to the pre-fusion form of the F protein 
may be most effective in neutralizing RSV. However, new experimental approaches to discern 
antibody specificities to epitopes present on the pre- and post-fusion forms of the fusion protein 
have become available. The team plans to study the epitope specificity and the quality (affinity 
and avidity) of the primary immune response to RSV vaccines. The induction of memory B cells 
is essential for long-term protection from severe RSV disease. RSV F protein specific B cells will 
be isolated, and studies on class switching, antibody maturation, and induction of B cell memory 
will be performed. 
 
1.5 
Hypotheses 
 
RSV ΔNS2/Δ1313/I1314L and RSV 276 will be safe, infectious, and immunogenic in RSV-
seronegative infants 6 to 24 months of age. The vaccines will be good candidates to move 
forward in a Phase IB study by meeting the following criteria: 
 
• 
>90% of vaccinees should be infected with vaccine virus as defined by shedding vaccine 
virus, detected by infectivity assay and/or RT-qPCR and/or ≥4-fold rise in RSV-specific 
serum antibodies, detected by ELISA against the RSV F protein and/or an RSV plaque 
reduction neutralization assay (RSV-PRNT);  
• 
The vaccines will be safe;  
• 
The mean peak titer of shed virus in nasal washes should be approximately 2.5 log10 PFU;  
• 
RSV-neutralizing serum antibody titers (measured 56 days post inoculation) should be similar 
to or better than MEDI/∆M2-2 (geometric mean titer of >1:97); and   
• 
Post-vaccination surveillance during the RSV season following vaccination should reveal 
substantial rises in RSV-neutralizing serum antibodies in a subset of vaccine recipients in the 
absence of RSV-associated medically attended acute respiratory illness (RSV-MAARI), 
which would be indicative of exposure to wt RSV without illness. 
 
 

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2 
OBJECTIVES  
 
2.1 
Primary Objective 
 
The primary objectives of this study are the following:  
 
2.1.1 
Safety: To assess the frequency and severity of study product-related solicited and 
unsolicited adverse events (AEs) from Study Day 0 through midnight of the 28th day 
following inoculation 
 
2.1.2 
Safety: To assess the frequency of study product-related serious adverse events (SAEs) 
from Study Day 0 through midnight on the 56th day following inoculation  
 
2.1.3 
Infectivity: To determine the peak titer of vaccine virus shed and duration of virus 
shedding by each participant, where the primary aim is to check if the mean peak titer of 
shed virus in nasal washes is approximately 2.5 log10 
 
2.1.4 
Infectivity: To assess the proportion of vaccinated participants infected* with study 
vaccine, where the primary aim is to check whether >90% of vaccinees are infected with 
vaccine virus 
 
2.1.5 
Immunogenicity: To characterize antibody responses (Day 56) to the study product in 
each treatment group, where the primary aim is to check if the RSV-neutralizing antibody 
titers in the vaccine groups are similar to or better than MEDI/∆M2-2 (geometric mean 
titer of 1:97) 
 
* Infected with vaccine virus as defined by shedding vaccine virus, detected by infectivity assay 
and/or RT-qPCR, and/or ≥4-fold rise in RSV-specific serum antibodies, detected by ELISA against 
the RSV F protein and/or an RSV plaque reduction neutralization assay (RSV-PRNT) 
 
2.2 
Secondary Objectives 
 
The secondary objectives of this study are to:  
 
2.2.1 
To characterize clinical outcomes (frequency and severity of symptomatic, medically 
attended respiratory and febrile illness) in the vaccine and placebo recipients who 
experience natural infection with wt RSV during the subsequent RSV season  
 
2.2.2 
To characterize antibody responses in the vaccine and placebo recipients who experience 
natural infection to wt RSV during the subsequent RSV season, where the primary aim is 
to check if substantial rises in RSV-neutralizing serum antibodies are present in a subset 
of vaccine recipients in the absence of RSV-associated medically attended acute 
respiratory illness (RSV-MAARI), which would be indicative of exposure to wt RSV 
without illness 
 
2.2.3 
To characterize the B cell response to vaccine and to characterize these responses in the 
vaccine and placebo recipients who experience natural infection to wt RSV during the 
subsequent RSV season 
 

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2.2.4 
To characterize the mucosal antibody response to vaccine 
 
2.2.5 
To identify differences in infectivity and immunogenicity between the vaccines. 
 
2.3 
Exploratory  Objective 
 
2.3.1 
Study samples may be used to compare to samples from other RSV vaccine studies 
initiated by the Laboratory of Infectious Diseases, NIAID, NIH or to evaluate other 
questions related to respiratory viral infections 
 
3 
STUDY DESIGN 
 
IMPAACT 2018 is a companion study to the Johns Hopkins University (JHU) Center for 
Immunization Research (CIR) protocol 321. The CIR 321 and IMPAACT 2018 protocols have 
identical primary and secondary objectives, investigational agents, inoculation schedules, 
evaluation assays and schedules, and safety monitoring and reporting. Because the CIR site does 
not enroll HIV-exposed infants, the eligibility criteria pertaining to that population are not 
included in CIR 321. 
 
The study will be conducted in infants at the JHU CIR and selected IMPAACT sites in the United 
States. The vaccines will be evaluated in RSV-seronegative (i.e., RSV-naïve) infants ≥6 months 
(180 days) to <25 months (750 days) of age. For the purpose of this study, RSV-seronegative is 
defined as having a serum neutralizing antibody titer of <1:40. This definition has been used in 
previous evaluations of live-attenuated RSV vaccines (13, 26, 37). In these previous studies, live-
attenuated RSV vaccines were highly restricted in replication and poorly immunogenic in 
children with titers ≥1:40 but were far less restricted in replication and highly immunogenic in 
children with titers <1:40. These data suggest that this neutralizing antibody cutoff can 
distinguish effectively between RSV-experienced and RSV-naïve children. 
 
The study will be double-blind, randomized, and placebo-controlled. Approximately 80 RSV-
seronegative participants will be randomized at a ratio of 2:2:1 to the three arms of the study; two 
active vaccine arms and one placebo arm. Placebo recipients are needed in pediatric studies to 
distinguish the background respiratory and febrile illnesses that occur in infants and children from 
those attributable to study vaccine. These numbers were chosen based upon experience with 
Phase I evaluation of other live-attenuated respiratory virus candidate vaccines (25-27) and 
statistical considerations (see Section 9).   
 
Enrollment will occur between April 1st and October 14th for most sites or—for sites with local 
RSV seasons that start earlier—as specified on a site-by-site basis in the MOP to avoid the time 
during which wt RSV typically circulates in the community. Specific study phases are described 
in the paragraphs that follow. 
 
Duration of participation in the initial phase of the study is 56 days, which consists of an Acute 
and a Post-Acute Phase. During the Acute Phase (Study Day 0 to midnight on the 28th day 
following inoculation), participants will be contacted daily. These contacts will consist either of: 
1) in-person evaluation of interim medical history, clinical assessment, and nasal wash or 2) 
interim medical history conducted by phone, text, or email. During the Post-Acute Phase (Study 
Day 29 to midnight on the 56th day following inoculation), study participants will have a 
scheduled visit on Day 56. The schedule of evaluations during the Acute Phase and Post-Acute 
Phase is shown in Appendix II. 

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The study has a third phase that assesses the incidence and severity of illness suggestive of RSV 
occurring during the RSV season following inoculation. During the RSV Season Surveillance 
Period, encompassing November 1st to March 31st for most sites or—for sites with local RSV 
seasons that start earlier—as specified on a site-by-site basis in the MOP, site study staff will 
make weekly contact with the participants to identify medically attended episodes of fever, URI 
or LRI, or otitis media. Participants who have such an episode will have a study visit to perform a 
nasal wash to evaluate for RSV and other respiratory pathogens (adventitious agents) (see 
Appendix III).  
 
Participants will also have a study visit during the pre-RSV season (between October 1st and 31st 
for most sites or—for sites with local RSV seasons that start earlier—as specified on a site-by-site 
basis in the MOP) to collect a blood sample for immunological assays, which will be used to 
assess the durability of the vaccine response and to serve as a pre-RSV season specimen. All 
participants will have a post-RSV season visit (April 1st to April 30th) to collect blood for 
measurement of RSV immune response to further assess the durability of the vaccine response 
and to assess the immune response to naturally occurring wt RSV infection. Thus, the maximum 
duration of participation will be up to 395 days, depending upon the time of enrollment relative to 
the RSV season. 
 
Figure 2 summarizes the study phases and periods of evaluation. There may be overlap in these 
various phases and periods. Accrual will stop effective on October 14th for most sites or—for sites 
with local RSV seasons that start earlier—as specified on a site-by-site basis in the MOP. 
 
Figure 2: Study Phases and Periods of Evaluation 
  

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4 
STUDY POPULATION 
 
The vaccines will be evaluated in RSV-seronegative infants ≥6 months (180 days) to <25 months 
(750 days) of age. Approximately 80 participants will be enrolled (32 per vaccine arm, 16 in the 
placebo arm) from US sites only. Infants will be selected for participation according to the criteria 
in Sections 4.1 and 4.2. The sections that follow describe study-specific co-enrollment 
considerations; the recruitment, screening, and enrollment process; and participant retention and 
withdrawal or termination. Sites are expected to obtain the participant's medical records from the 
participant's primary care provider to review for eligibility. The criteria related to the health status 
and age of household members, day care attendance, scheduled vaccine administration in relation 
to inoculation of study product, and use of salicylates (except as noted in the medical record) may 
rely on parent report.  
 
Any questions regarding interpretation of the inclusion/exclusion criteria or other considerations 
described in this section should be forwarded to the Protocol Team. 
 
4.1 
Inclusion Criteria 
 
Potential participants must meet all of the following criteria in order to be included in this study: 
 
 
4.1.1 
≥6 months (defined as ≥180 days) of age at the time of screening and <25 months 
(defined as < 750 days) of age at the time of enrollment 
 
4.1.2 
In good health based on review of the medical record, history, and physical examination, 
without evidence of chronic disease.  
 
4.1.3 
Parent/guardian is willing and able to provide written informed consent as described in 
protocol Section 12.3.  
 
4.1.4 
Seronegative for RSV antibody, defined as a serum RSV-neutralizing antibody titer 
<1:40 at screening from a sample collected no more than 42 days prior to inoculation. 
Note: results from specimens collected during screening for any study of an RSV vaccine 
developed by the LID (NIAID, NIH) are acceptable as long as within the 42-day window.  
 
4.1.5 
Growing normally for age (i.e., not downwardly crossing two major centiles on a 
standard growth chart) in the six months prior to enrollment AND 
• 
If less than 1 year of age: has a current height and weight above the 5th percentile  
• 
If 1 year of age or older: has a current height and weight above the 3rd percentile 
for age. 
 
4.1.6 
Has received routine immunizations appropriate for age (as per national Center for 
Disease Control Advisory Committee on Immunization Practices [ACIP]).  
Note: if rotavirus immunization was delayed, “catch-up” rotavirus immunization is 
indicated only if the participant is age-eligible per ACIP.  
 
4.1.7 
Is expected to be available for the duration of the study. 
 
4.1.8 
If born to an HIV-infected woman, participant must not have been breastfed and must 
have documentation of 2 negative HIV nucleic acid (RNA or DNA) test results from 
samples collected on different dates with both collected when ≥4 weeks of age and at 

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least one collected when ≥16 weeks of age, and no positive HIV nucleic acid (RNA or 
DNA) test; or 2 negative HIV antibody tests, both from samples collected at ≥24 weeks 
of age.    
 
4.2 
Exclusion Criteria 
 
Potential participants who meet any of the following criteria will be excluded from this study: 
 
4.2.1 
Known or suspected HIV infection or impairment of immunological functions. 
 
4.2.2 
Receipt of immunosuppressive therapy, including any systemic, including either nasal or 
inhaled, corticosteroids within 28 days of enrollment.  Note: Cutaneous (topical) steroid 
treatment is not an exclusion. 
 
4.2.3 
Any receipt of bone marrow/solid organ transplant. 
 
4.2.4 
Major congenital malformations (such as congenital cleft palate) or cytogenetic 
abnormalities. 
 
4.2.5 
Previous receipt of a licensed or investigational RSV vaccine (or placebo in any 
IMPAACT RSV study) or previous receipt of or planned administration of any anti-RSV 
product (such as ribavirin or RSV IG or RSV mAb). 
 
4.2.6 
Any previous anaphylactic reaction.  
 
4.2.7 
Any previous vaccine-associated adverse reaction that was Grade 3 or above. Note: if 
grading is not possible, determine if the reaction was considered severe or life 
threatening; if so, it is exclusionary. 
 
4.2.8 
Any known hypersensitivity to any study product component. 
 
4.2.9 
Heart disease. Note: Participants with cardiac abnormalities documented to be clinically 
insignificant and requiring no treatment may be enrolled. 
 
4.2.10 Lung disease, including any history of reactive airway disease or medically diagnosed 
wheezing.   
 
4.2.11 Member of a household that contains, or will contain, an infant who is less than 6 months 
of age at the enrollment date through Day 28. 
 
4.2.12 Member of a household that contains another child/other children who is/are, or is/are 
scheduled to be, enrolled in IMPAACT 2018 AND the date of enrollment to IMPAACT 
2018 will not be concurrent with the other participant(s) living in the household (i.e., all 
eligible children from the same household must be enrolled on the same date).  
 
4.2.13 Member of a household that contains another child who is, or is scheduled to be, enrolled 
in another study evaluating an intranasal live-attenuated RSV vaccine, AND there has 
been or will be an overlap in residency during that other child’s participation in the 
study’s Acute Phase (Days 0 to 28). 
 

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4.2.14 Member of a household that contains an immunocompromised individual, including, but 
not limited to: 
• 
a person who is greater than or equal to 6 years of age with HIV-related 
immunodeficiency, defined as having a most recent CD4 T lymphocyte cell count 
<300 cells/mm3. CD4 T lymphocyte count must have been measured within 6 
months prior to enrollment for individuals with detectable virus or within 12 
months prior to enrollment for individuals with undetectable virus, or 
• 
a person age 1 year up to less than 6 years with HIV-related immunodeficiency, 
defined as having a most recent CD4 T lymphocyte cell percentage <25 or CD4 T 
lymphocyte count <750 cells/mm3 (if both values are available, use the lower of the 
two). CD4 T lymphocyte parameter must have been measured within the 6 months 
prior to enrollment; or 
• 
a person age less than 1 year with HIV-related immunodeficiency, defined as 
having a most recent CD4 T lymphocyte cell percentage <30 or CD4 T lymphocyte 
count <1000 cells/mm3 (if both values are available, use the lower of the two). CD4 
T lymphocyte parameter must have been measured within the 6 months prior to 
enrollment; or  
• 
a person who has received chemotherapy within the 12 months prior to enrollment; 
or 
• 
a person receiving immunosuppressant agents; or 
• 
a person living with a solid organ or bone marrow transplant. 
 
Documenting the verbal report of CD4 T cell lymphocyte count is sufficient if the 
parent/guardian is confident of history. Individually identifiable information (e.g., name) 
pertaining to members of the household will not be collected or recorded. Confirmatory 
laboratory tests for members of the household will not be ordered or collected. 
 
4.2.15 Attends a daycare facility and shares a room with infants less than 6 months of age, and 
parent/guardian is unable or unwilling to suspend daycare for 28 days following 
inoculation.  
 
4.2.16 Any of the following events at the time of enrollment: 
• 
fever (rectal temperature of ≥100.4°F (38°C)), or  
• 
upper respiratory signs or symptoms (rhinorrhea, cough, or pharyngitis) or 
• 
nasal congestion significant enough to interfere with successful inoculation, or  
• 
otitis media. 
 
4.2.17 Receipt of the following prior to enrollment: 
• 
any inactivated vaccine or live-attenuated rotavirus vaccine within the 14 days 
prior, or  
• 
any live vaccine, other than rotavirus vaccine, within the 28 days prior, or 
• 
another investigational vaccine or investigational drug within 28 days prior 
 
4.2.18 Scheduled administration of the following after planned inoculation: 
• 
inactivated vaccine or live-attenuated rotavirus vaccine within the 14 days after, or 
• 
any live vaccine other than rotavirus in the 28 days after, or 
• 
another investigational vaccine or investigational drug in the 56 days after 
 

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4.2.19 Receipt of immunoglobulin, any antibody products, or any blood products within the past 
6 months prior to enrollment 
 
4.2.20 Receipt of any of the following medications within 3 days prior to study enrollment: 
• 
systemic antibacterial, antiviral, antifungal, anti-parasitic, or antituberculous 
agents, whether for treatment or prophylaxis, or 
• 
intranasal medications, or 
• 
other prescription medication except as listed below 
 
Permitted concomitant medications (prescription or non-prescription) include nutritional 
supplements, medications for gastroesophageal reflux, eye drops, and topical 
medications, including (but not limited to) cutaneous (topical) steroids, topical 
antibiotics, and topical antifungal agents. 
 
4.2.21 Receipt of salicylate (aspirin) or salicylate-containing products within the 28 days prior to 
enrollment. 
 
4.2.22 Born at less than 34 weeks gestation. 
 
4.2.23 Born at less than 37 weeks gestation and less than 1 year of age at the time of enrollment. 
 
4.2.24 Current suspected or documented developmental disorder, delay, or other developmental 
problem. 
 
4.2.25 Any previous receipt of supplemental oxygen therapy in a home setting. 
 
 
4.3 
Co-Enrollment Considerations 
 
Co-enrollment to any interventional study is not allowed during the Acute Phase or Post-Acute 
Phase.  After the Post-Acute Phase, co-enrollment may be considered if both protocol teams 
agree. 
 
Note: co-enrollment into IMPAACT 2018 is allowable for participants already enrolled in 
IMPAACT P1112, provided all eligibility criteria above are met; in particular, per criterion 
4.2.19, the participant must not have received P1112 study product in the past 6 months. The 
P1112 and IMPAACT 2018 teams should be queried in each case to confirm. 
 
4.4 
Recruitment, Screening, and Enrollment Process 
 
Recruitment will take place at IMPAACT sites selected on the ability to recruit and enroll both 
HIV-exposed, uninfected and HIV-unexposed infants in RSV vaccine studies. Each site will 
identify the specific clinics (e.g., hospital, community, and private pediatric clinics) where 
recruitment will occur as part of the site selection process, which will be reviewed and approved 
by the Protocol Team. All recruitment materials must be reviewed and approved by site IRBs. 
 
The IMPAACT Operations Center will monitor screening and enrollment through close contact 
with sites. These data will be provided to the team during regular team calls. Screening may occur 
no more than 42 days prior to enrollment during the dates specified in Section 6.2. 
 

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The IMPAACT Data Management Center (DMC) Subject Enrollment System (SES) will be used 
to track enrollment. When informed consent is obtained, a participant identification number (PID) 
will be assigned to the infant by the study staff. For infants found to be eligible, randomization 
and enrollment will occur upon successful entry of required eligibility data into the SES. 
Successful entry into the SES will generate a study identification number (SID) and blinded 
prescribing information for the study product arm to which the infant has been randomly 
assigned; this represents the effective point of enrollment. Note that any eligible children living in 
the same household will be randomized to the same arm per Section 9.1 and must be 
randomized/enrolled on the same date. Refer to Section 9.4 for more information on monitoring 
participant accrual in this study.  
 
4.5 
Participant Retention 
 
Once an infant is enrolled in this study, study staff will make every effort to retain him or her in 
follow-up for the protocol-specified duration of follow-up, i.e., through the Post-RSV Season 
Study Visit, thereby minimizing potential biases associated with loss to follow-up.   
 
4.6 
Participant Withdrawal or Termination from the Study 
 
Regardless of the participant retention procedures referenced above, parents/guardians of infants 
participating in this study may voluntarily withdraw their infants from the study at any time. Any 
participant who has received study product will be encouraged to remain in study follow-up for 
the duration of the study even if sample collection is refused.  
 
A participant may withdraw or be terminated from the study early for any of the following 
reasons: 
 
• 
Withdrawal of consent – applies to a parent/guardian who verbally or in writing 
withdraws consent to participate in the study for any reason. 
• 
Noncompliant with protocol – applies to a parent/guardian who does not comply with 
protocol-specific visits or evaluations on a consistent basis, such that adequate follow-up 
is not possible and the participant’s safety would be compromised by continuing in the 
study. 
• 
Participant re-locates away from the study site or is otherwise determined to be lost-to-
follow-up. 
• 
Investigator or designee determines that continued participation in the study would be 
unsafe or otherwise not in the best interest of the participant, after consultation with the 
protocol team. 
• 
Other – a category used when previous categories do not apply; requires an explanation. 
 
The entire study may be stopped or canceled by the study investigators, sponsors, IMPAACT, 
government or regulatory authorities, or site IRBs/IBCs for any reason.  
 
For any participant who withdraws or is terminated from the study prior to scheduled completion 
of follow-up, study staff will document the reason for the withdrawal or termination in detail and 
will make every effort to complete final evaluations as described in Section 6.11.  In the event 
that the circumstances that led to a participant’s withdrawal or termination change (e.g., he or she 
returns to the study site area after having re-located previously), the site investigator or designee 
should contact the protocol team to discuss options for resumption of follow-up. 
 

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5 
STUDY PRODUCT CONSIDERATIONS 
 
Site pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS Clinical 
Trials Networks for standard pharmacy operations. Refer to  for an overview of the study design 
and to the Investigator’s Brochures (IBs) for further information about the study product. 
 
 
5.1 
Study Products 
 
The products that will be administered in this study are: 
• 
Live Recombinant Respiratory Syncytial Virus (RSV) ΔNS2/Δ1313/I1314L 106 PFU per 
0.5ml vaccine 
• 
Live Recombinant Respiratory Syncytial Virus RSV 276 105 PFU per 0.5ml vaccine 
• 
Placebo for RSV vaccine will be 1X L-15 Leibovitz medium (1X L-15) 0.5ml 
 
5.2 
Study Product Regimens 
 
Enrolled study participants will receive a single dose of the indicated vaccine or placebo, 
administered as nose drops within 3 days of randomization. Ideally, the date of randomization 
will be the same as the date of inoculation (see Section 6.2).  
 
5.3 
Study Product Formulation  
 
5.3.1 
Vaccines 
 
The RSV ΔNS2/Δ1313/I1314L vaccine is provided in a sterile 2.0 mL cryovial, each containing 
0.6 mL of Vaccine (Lot RSV #006A), with a titer of approximately 107.3 PFU/mL. The vaccine 
virus concentrate is diluted to an appropriate dose by designated licensed pharmacy personnel to 
prepare a dose of 106 PFU in a 0.5 mL volume. The vaccine vial is labeled as shown below in 
Figure 3. 
 
The RSV 276 vaccine is provided in a sterile 2.0 mL cryovial, each containing 0.6 mL of Vaccine 
(Lot RSV #014A), with a titer of approximately 106.2 PFU/mL. The vaccine virus concentrate is 
diluted to an appropriate dose by designated licensed pharmacy personnel to prepare a dose of 105 
PFU in a 0.5 mL volume. The vaccine vial is labeled as shown below in Figure 3. 
 
  

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15 June 2017 
Figure 3: Investigational Product Label (Enlarged Sample) 
 
RSV ΔNS2/Δ1313/I1314L Vaccine: 
 
Live Recombinant Respiratory Syncytial Virus 
RSV ΔNS2 Δ1313 I1314L  
VERO GROWN VIRUS VACCINE 
Date: 17OCT2016 
Vial#:XXX 
Lot: RSV #006A 
CAUTION: NEW DRUG LIMITED 
 BY FEDERAL (USA) LAW 
TO INVESTIGATIONAL USE 
Store at –80C ± 15C 
Charles River Laboratories, Malvern, PA 
 
RSV 276 Vaccine: 
 
Live recombinant Respiratory Syncytial Virus   
RSV 276 
VERO GROWN VIRUS VACCINE 
Date: 24OCT2016 
Vial#:XXX 
Lot: RSV#014A 
CAUTION: NEW DRUG LIMITED 
 BY FEDERAL (USA) LAW 
TO INVESTIGATIONAL USE 
Store at –80C ± 15C 
Charles River Laboratories, Malvern, PA 
 
 
5.3.2 
Diluent for RSV ΔNS2/Δ1313/I1314L and RSV 276 
 
The diluent for RSV ΔNS2/Δ1313/I1314L and RSV 276 is 1X Leibovitz L-15 medium.  
 
Sterile Water For Injection, USP (SWFI) and 2X Leibovitz L-15 medium are required to prepare 
the diluent for the vaccine. 2X Leibovitz L-15 medium is a specific lot of Leibovitz L-15 
medium. It is a solution of amino acids, sugar, and salt that has been safety tested as described in 
a Master File (MF 12959), which has been submitted to the FDA.  
 
5.3.3 
Placebo for RSV ΔNS2/Δ1313/I1314L and RSV 276 
 
The placebo for RSV ΔNS2/Δ1313/I1314L and RSV 276 is 1X Leibovitz L-15 medium.  
 
Sterile Water For Injection, USP (SWFI) and 2X Leibovitz L-15 medium are required to prepare 
the Placebo for the vaccine.  
 
5.4 
Study Product Storage 
 
Vaccine will be stored in a secure freezer -80°C ±15°C. It must remain frozen until time of use. 
Once the vaccine is thawed, it should never be refrozen for reuse. Vaccine will be prepared from 
new, unopened containers for each use.  
 
Leibovitz L-15 medium will be stored in a secure refrigerator at 2°C to 8°C. Vaccine 
diluent/placebo will be prepared from new, unopened containers for each use. 
Sterile Water for Injection, USP (SWFI) must also be stored in the refrigerator at 2°C to 8°C.  
 

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Procedures for managing the vaccine and diluent/placebo shipment are in the Manual of 
Procedures (MOP). 
 
5.5 
Study Product Preparation 
 
The diluent for the vaccines, the placebo for the vaccines, and the RSV vaccines must be prepared 
by following the detailed instruction in the MOP. 
 
Prior to inoculation, an authorized prescriber will supply a prescription to the pharmacy. The 
prescription must include the information outlined in the MOP. Designated licensed pharmacy 
personnel will prepare the correct dose of vaccine for each participant in a Biological Safety 
Cabinet (BSC) or Compounding Aseptic Containment Isolator (CACI) using aseptic technique.  
To preserve blinding, yellow overlays will be applied to all prepared syringes. 
 
5.5.1 
Preparation of Diluent for RSV ΔNS2/Δ1313/I1314L and RSV 276 
 
The diluent is prepared by mixing concentrated 2X Leibovitz L-15 medium with sterile water for 
injection in 1:1 ratio. The prepared vaccine diluent will be 1X Leibovitz L-15 medium.  
 
Please follow the MOP for detailed instructions on diluent preparation. 
 
5.5.2 
Preparation of Placebo for RSV ΔNS2/Δ1313/I1314L and RSV 276 
 
Placebo for RSV ΔNS2/Δ1313/I1314L and RSV 276 will be prepared by mixing the concentrated 
2X Leibovitz L-15 medium with sterile water for injection in 1:1 ratio. The prepared product will 
be 1X Leibovitz L-15 medium.  
 
Placebo will be drawn up to a volume of 0.5 mL in a sterile 1 mL oral syringe and labeled per 
instructions in MOP. An auxiliary label stating “FOR INTRANASAL ADMINISTRATION 
ONLY” will be affixed to the syringe or outside bag. The labeled, filled syringe(s) will be 
transported in a cooler monitored and maintained at 2ºC to 8ºC with ice or cold packs to the 
clinical site for administration. Placebo must be administered within 4 hours of concentrated 2X 
Leibovitz L-15 being removed from the refrigerator.  
 
Please follow the MOP for detailed instructions on preparation of placebo. 
 
5.5.3 
Preparation of Live Recombinant Respiratory Syncytial Virus RSV ΔNS2/Δ1313/I1314L and 
RSV 276 
 
Diluent must be prepared prior to removal of the RSV vaccine from the freezer.  
 
If the -80°C freezer where the RSV vaccines are stored is not in close proximity to where the 
preparation is being done, the vaccine vials should be transported on dry ice from the freezer 
to the biologic safety cabinet/isolator. Do not thaw this product on the bench top or allow the 
vial to thaw completely before putting onto wet ice. RSV is extremely sensitive to 
temperature fluctuations. Please follow the MOP for proper handling of the study product.  
 
At least two vials of undiluted vaccine are needed to prepare the vaccine dose. When 
manipulating the undiluted vaccine, use as small a gauge needle as possible to avoid loss of 
vaccine in the needle and syringe hub. The frozen vaccine will be thawed and diluted with 1X L-

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15 to the indicated dose of either 106 (RSV ΔNS2/Δ1313/I1314L) or 105 PFU (RSV 276) in 0.5 
mL prior to administration.  
 
The diluted vaccine will be drawn up to a volume of 0.5 mL in a sterile 1 mL oral syringe and 
labeled per instructions in MOP. An auxiliary label stating “FOR INTRANASAL 
ADMINISTRATION ONLY” will be affixed to the syringe or outside bag. The labeled, filled 
syringe(s) will be transported in a cooler monitored and maintained at 2ºC to 8ºC with ice or 
cold packs to the clinical site for administration. Vaccine must be prepared and administered 
within 4 hours of being removed from the freezer and thawing. However, the expiration time 
is assigned based on the time the concentrated 2X Leibovitz L-15 is removed from the 
refrigerator in order to maintain the blind. 
 
Samples of undiluted (if available) and diluted vaccine will be aliquoted from the vaccine 
remaining after vaccine has been prepared and delivered to the clinical staff. The samples will 
be snap frozen as per the MOP and stored at -80°C ±15°C separate from the study product in 
the investigational pharmacy until they are shipped to the central laboratory for titration.   
Titration of vaccine is done to confirm the titer of the vaccine administered to the participants. 
To “snap freeze” diluted and undiluted vaccine aliquots, follow CoolBox procedures described 
in the MOP. 
 
Please follow the MOP for detailed instructions on vaccine storage, handling, preparation, 
labelling and transport to the clinic. 
 
5.6 
Study Product Administration/ Inoculation Procedure 
 
All study participants will receive a single dose of study product, administered as nose drops. 
There is no nasal preparation prior to administration. While the participant is supine, a volume of 
0.5 mL of study product will be delivered as nose drops (approximately 0.25 mL per nostril) 
using a sterile, needle-less 1 mL oral syringe. Participant will remain supine for approximately 60 
seconds following inoculation. 
 
5.7 
Study Product Acquisition 
 
The clinical lots of RSV ΔNS2/Δ1313/I1314L and RSV 276 were generated by Charles River 
Laboratories using the seed virus provided by the National Institutes of Health (NIH).  
 
A specific lot concentrated 2X L-15 Leibovitz Medium that will be used to prepare the Diluent and 
Placebo is provided by the National Institutes of Health (NIH). 
 
Sterile Water for Injection, USP (SWFI) must be obtained by each site.  
 
Upon successful completion of protocol registration procedures, the clinical research site (CRS) 
pharmacists can order the vaccine, the 2X L-15 Leibovitz Medium (which is used to make the 
diluent and placebo), sterile oral 1ml syringes (commercially available, individually packaged), 
sterile syringe caps and yellow overlays from the CRPMC by following the instructions in 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks.  
 
Please refer to the MOP for details on shipment of the vaccines and diluent/placebo. 
 

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5.8 
Study Product Accountability 
 
The site pharmacist is responsible for maintaining an accurate inventory and accountability record 
of vaccine and Leibovitz L-15 medium supplies for this study. The vaccines will be prepared as 
instructed with the site pharmacist serving as the unblinded dispenser. A copy of the 
randomization code will be retained by the site pharmacist. On a case-by-case basis, the 
randomization code may only be released at the written request of the Protocol Chair(s) and only 
after discussion with the senior protocol statistician and the MO. Additional information is 
available in the IMPAACT Network Manual of Procedures (MOP) Appendix I: Unblinding 
Procedures. The site pharmacist will be responsible for maintaining the blind, and pharmacy 
records will be maintained in the pharmacy only. Partially used vials of vaccine and Leibovitz L-
15 medium components may not be saved and reused at a later time. 
 
5.9 
Disposition of Used/Unused Study Product 
 
After the designated licensed pharmacy personnel dilutes the vaccine and draws up the vaccine 
into a syringe for administration, he/she will remove the label from all vaccine vials and place it 
in the accountability log. Please see the IMPAACT 2018 MOP Appendix VI for the study 
preparation and accountability documents. In this manner, monitoring personnel will be able to 
verify the accountability of all vaccine vials used for the study. If there is any vaccine left after 
the syringes have been drawn up and aliquots have been removed for titering, it will be destroyed 
by pharmacy personnel as per the MOP.  
 
5.10 
Final Disposition of Study Products 
 
All unused study products must be returned to the CRPMC after the study is completed or 
terminated, unless otherwise instructed by the Protocol Team. Procedures and relevant forms are 
provided in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. 
 
5.11 
Concomitant Medications 
 
5.11.1 Prohibited Concomitant Medications 
 
The use of prophylactic antipyretics, decongestants, or antihistamines is not permitted during the 
Acute Phase (28 days following inoculation); however, use of these medications for treatment of 
symptoms is allowed.  
 
5.11.2 Precautionary Concomitant Medications  
 
 
Due to their potentially confounding effect on immunogenicity results, the following treatments 
should be avoided after inoculation unless urgently clinically indicated or after consultation with 
the Protocol Safety Review Team (PSRT) via email at impaact.psrt2018@fstrf.org:  
• 
Use of an investigational drug or investigational vaccine other than the study product 
within 56 days after receiving study product 
• 
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  
• 
Licensed inactivated vaccine or live-attenuated rotavirus vaccine within 14 days after 
receiving study product  
• 
Immunoglobulins and/or any blood products  
• 
Licensed live virus vaccine, other than rotavirus vaccine, within 28 days after receiving 

IMPAACT 2018, Version 1.0 
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15 June 2017 
study product 
 
6 
STUDY VISITS AND PROCEDURES 
 
Study visits, except inoculation, may be conducted at one of the clinical sites or as home visits. 
Inoculation must be conducted at one of the clinical sites. 
 
An overview of the study visits, evaluation schedule, and specimen collection and volumes are 
provided in Appendices II and III. Presented in this section is additional information on visit-
specific study procedures.  Study phases and periods of evaluation are summarized in Figure 2 of 
Section 3. 
 
Unless otherwise specified, visits may be split, with required procedures conducted on more than 
one day within the allowable visit window, if necessary. All visits and procedures must be 
documented in accordance with the NIAID Division of AIDS (DAIDS) policies for source 
documentation; refer to Section 10 for more information on documentation requirements and 
completion of eCRFs. Refer to Section 7 for information on expedited adverse event (EAE) 
reporting, which is required at specified times during follow-up.   
 
In addition to the protocol-specified procedures listed in this section, study staff may complete 
other tasks consistent with site SOPs, including but not limited to collecting, reviewing, and 
updating demographic and locator information; reviewing elements of informed consent; 
scheduling telephone contacts and visits; providing instructions for contacting study staff between 
visits; providing visit reminders; and following up on missed visits. All such tasks should be 
documented consistent with site SOPs. Clinical evaluations must be performed by a medical 
professional. Study staff should inform participant parents/guardians of clinically meaningful 
physical exam findings and laboratory test results when available. 
 
6.1 
Screening Visit 
 
Screening may begin 14 days prior to the start of the spring enrollment period (i.e., screening may 
begin on March 18 and proceed through early October with results received by October 14 for 
most sites or—for sites with local RSV seasons that start earlier—as specified on a site-by-site 
basis in the MOP). As sites consider scheduling for the screening visit, it is important to also 
consider potential dates of randomization, given that inoculation cannot occur 42 days or more 
after the screening evaluation. Sites should schedule randomization and inoculation to be as soon 
as feasible after screening, allowing for the turnaround time for the RSV serology testing. 
 
iron works The parent/guardian must complete the informed consent process and sign the 
informed consent form before any study-related procedures are performed. Parents/guardians will 
also be offered a signed copy of the informed consent form (see Section 12.3). 
 
As in previous Phase I trials of other live-attenuated RSV vaccines (13, 25-27), screening 
laboratory tests other than the RSV antibody will not be performed on participants. Such tests are 
not routinely performed as part of well-child care, given that the risk of undiagnosed hepatic, 
metabolic, and renal diseases is much lower in children than in adults (38).  
 

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Screening Visit Procedures*  
Administrative 
and Regulatory 
• Obtain written informed consent 
• Confirm parent/guardian’s informed consent comprehension using 
the template quiz provided in the MOP or other, site-specific 
method.  
• Assign participant identification number (PID) 
• Assess eligibility 
Clinical 
• Obtain available medical records, including immunization record.  
If necessary, obtain release of medical records from 
parent/guardian to review the participant’s medical record as 
required per Health Insurance Portability and Accountability Act 
(HIPAA). 
• Obtain medical history, which should include demographics, prior 
diagnoses, current medications, signs and symptoms, and 
developmental status. 
• Perform complete infant physical examination including 
temperature, heart rate, respiratory rate, weight, length and 
assessment of HEENT [Head, Ears, Eyes, Nose, Throat], lungs, 
heart, abdomen, musculoskeletal, age-appropriate neurological and 
skin exam. 
Laboratory 
Blood  
Collect blood for: 
• Screening and pre-study inoculation for RSV serum antibody 
testing.  Note: if the potential participant had been screened but not 
enrolled into any study of an RSV vaccine developed by the LID 
(NIAID, NIH), the results from the sample collected for that study 
may be used if the sample was collected within the 42-day 
enrollment window for IMPAACT 2018; it is not necessary to 
collect another sample. 
• Only from participants who are at sites with capacity for 
processing viable PBMCs: Cryopreservation of PBMCs to 
characterize the B cell response.  Remaining plasma to be stored. If 
the potential participant had been screened but not enrolled into 
any study of an RSV vaccine developed by the LID (NIAID, NIH), 
the stored blood collected for that study at screening may be used 
for IMPAACT 2018, if it was collected within the 42-day 
enrollment window for IMPAACT 2018. 
Study Product 
Not applicable 
Schedule Enrollment Visit 
Note that Enrollment must be no more than 42 days after screening 
and within 3 days of randomization.  
*No more than 42 days prior to enrollment; not prior to March 18 and through early October with 
results received by October 14 for most sites or—for sites with local RSV seasons that start 
earlier—as specified on a site-by-site basis in the MOP. 
 
6.2 
Enrollment Visit 
 
Study enrollment and inoculation must occur outside of the RSV season, i.e., between April 1st 
and October 14th inclusive for most sites or—for sites with local RSV seasons that start earlier—
as specified on a site-by-site basis in the MOP,  and after: 
• 
the screening sample confirms that the infant is RSV-seronegative, and 
• 
he/she meets all other inclusion/exclusion criteria.  
 
Day 0 will correspond to the day of inoculation with study product. Whenever possible, 
inoculation is to occur on the same day as randomization. Although sites are allowed up to 3 days 

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after randomization to conduct the enrollment visit and administer study product, sites should not 
proceed to randomization until a) final eligibility determination has been confirmed and b) it has 
been confirmed that study product can be administered within this window. If these 2 conditions 
cannot be met, randomization should be postponed. 
 
If participant is randomized and subsequently noted to have any of the following, inoculation 
must be deferred: 
• 
fever (rectal temperature of ≥100.4°F (38°C)), or  
• 
upper or lower respiratory symptoms or signs (including but not limited to rhinorrhea, 
cough, or pharyngitis), or 
• 
nasal congestion significant enough to interfere with successful inoculation, or  
• 
otitis media 
Note: if the inoculation will not occur within 3 days of randomization, the site MUST contact the 
Protocol Safety Review Team (PSRT) via email at impaact.psrt2018@fstrf.org to explain the 
circumstances and obtain permission to inoculate after the 3-day window period.   
 
If the 42-day window from screening to inoculation is exceeded during the deferral and the infant 
has already been randomized, the team may grant permission for the infant to be rescreened. If 
found to still be eligible, the infant will be taken off study, re-enrolled and randomized again 
(possibly to a different arm than the original randomization). Sites are advised to avoid this 
situation by scheduling the enrollment visit early in the screening window. 
 

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Enrollment Visit Procedures   
Must be no more than 42 days from screening and within 3 days of randomization  
Administrative 
and Regulatory 
• Complete eligibility determination and confirmation*  
• Complete paper-based eligibility checklist*, enter checklist data 
into SES to enroll/randomize the infant, print and file a copy of the 
confirmation file 
Clinical 
• Obtain interim history  
• Clinical examination: 
o Perform focused clinical examination including temperature, 
heart rate, respiratory rate, EENT, lung, heart, and lymph 
nodes. 
o Record temperature, pulse, and respirations 
 
Note: Confirm eligibility including clinical examination prior to 
administering study product. 
Laboratory 
 
Blood  
If insufficient volume collected at screening, collect blood: 
• To ensure that back-up aliquot is available for comparing pre- and 
post sera.  
Nasosorption 
SAM Strip  
Collect nasosorption strip for RSV antibody assays 
 
Note: The nasosorption must be performed prior to the nasal wash. 
Nasal Wash 
Collect nasal wash for: 
• RSV antibody assays 
• RSV viral detection and quantification  
 
Note: The nasal wash must be performed prior to administering the 
study product. 
Study Product 
• Prescribe and prepare/dispense study product 
• Administer study product and maintain participant in a supine 
position for 1 minute. 
• Observe for at least 30 minutes after inoculation to evaluate for 
immediate hypersensitivity reactions. 
Prepare for follow-up 
• Provide the following: temperature card with explanation, temporal 
and rectal thermometers with instructions for use, illness criteria 
explanation, and study personnel contact information.  Schedule 
non-visit day contact for Days 1 and 2 and schedule an in-person 
visit for Day 3. 
*Perform prior to enrollment/randomization 
 
Following the Entry Visit, the parent/guardian will record the infant’s temperatures and signs of 
illness on the temperature card and provide these to study personnel during an in-person visit or 
non-visit day phone, email, or text contact. New rectal thermometers will be given, and temporal 
artery thermometers will be provided, to parents/guardians for use during the study. For 
temperature measurements, parents/guardians will be instructed to use the study-provided 
temporal artery thermometer to screen for elevated temporal artery temperatures. This device is 
used to minimize the number of rectal temperature measurements and has been shown to be an 
effective screening tool for rectal fever (39). The parent/guardian will measure temporal artery 
temperatures following the manufacturer’s directions.  If any temporal artery temperature is 
≥100.0°F, parents/guardians will be asked to measure a rectal temperature within 20 minutes (39). 
For study-specific management and grading of temperatures, see Section 8.1.1 and Table 6. 
 

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6.3 
Acute Phase Visits and Contacts  
 
Refer to  for a timeline of study visits. The Acute Phase begins with inoculation and ends at 
midnight on the 28th day after inoculation. During the Acute Phase of the study, a study 
physician, physician assistant, nurse practitioner, or study nurse will be available by telephone 24 
hours a day for consultation with parents/guardians regarding any illnesses that may occur during 
this period. 
 
Study personnel will have daily contact with participant’ parents/guardians for the first 28 days 
after inoculation. This 28-day period is consistent with the duration of shedding of live-attenuated 
respiratory virus vaccines in RSV-seronegative infants and children (29, 39-41). A clinical 
assessment will be completed during visits on Days 3, 5, 7, 10, 12, 14, 17, and 28 (each visit ±1 
day) after inoculation. This clinical assessment must be performed by a medical professional. 
 
On non-visit days, study staff will contact the parent/guardian and will record the 
parent/guardian-provided temperatures and signs of illness. Participants with illness may have 
additional visits to assess the severity of the illness (see Section 6.10 for Illness Visits).   
 
There will be a final non-visit contact on Day 29 to obtain interim history through midnight on 
the 28th day following inoculation. 
 
Certain events may trigger study pause or stop during the first 56 days following inoculation, 
review Section 8.2 for details associated with pausing and stopping rules. 
 
6.3.1 
Acute Phase Visits: Study Days 3, 5, 7, 10, 12, 14, 17, and 28 (all are ±1 day) 
 
Study visits during the Acute Phase are scheduled to be conducted at the frequency noted above 
with a visit window of ± 1 day.  If an in-person visit is moved by ± 1 day, then telephone contact 
is conducted in place of the original interim visit date.   
 
Events that took place through midnight of Day 28 are considered to have occurred during the 
Acute Phase and will be reported on the non-visit contact conducted on Day 29.  Note that it is 
not necessary to also have a “Day 29” contact (Section 6.4) if the Day 28 Visit is conducted on 
this day. 
 

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Days 3, 5, 7, 10, 12, 14, 17, and 28 Visit Procedures (each visit from day of inoculation ± 1 day) 
Clinical 
• Obtain interim history 
• Perform focused clinical examination including temperature, heart 
rate, respiratory rate, EENT, lung, heart, and lymph nodes. 
• Record temperature, pulse, and respirations.   
Laboratory 
 
Nasosorption 
SAM strip  
Day 28 visit only: Collect nasosorption strip for RSV antibody assays 
 
Note: The nasosorption must be performed prior to the nasal wash. 
Nasal Wash 
Collect nasal wash for: 
• RSV viral detection and quantification  
Day 28 visit only: Collect nasal wash for: 
• RSV antibody assays 
• RSV viral detection and quantification  
Prepare for follow-up 
• Schedule non-visit day contact and follow-up in-person visits.  
• Day 28 only: review SAE criteria with participants and how to 
contact study personnel during Post-Acute Phase (Study Day 30 to 
the Day 56 Visit). 
 
If the infant is diagnosed as having an LRI or otitis media, fever or URI (per Appendix IV) during 
the Acute Phase, evaluations required for the Illness Visit need to be performed and processed. If 
illness criteria are met or suspected (see Section 6.10 and Appendix IV), also request that an 
Adventitious Agent Assay be performed on the nasal wash (see MOP and LPC).    
 
6.3.2 
Acute Phase Contacts: Study Days 1, 2, 4, 6, 8, 9, 11, 13, 15,16, 18, 19, 20, 21, 22, 23, 24, 25, 
26, and 27 (±1 day)  
 
The non-visit contacts during the Acute Phase will be conducted via phone or email.   
 
If the parent reports symptoms suspicious for an LRI, otitis media, fever or URI (per Appendix 
IV), then an Illness Visit should be scheduled (see Section 6.10). 
 
Days 1, 2, 4, 6, 8, 9, 11, 13, 15, 16, 18,19, 20, 21, 22, 23, 24, 25, 26 and 27 Contact Procedures (each 
visit from day of inoculation ± 1 day) 
Interim History 
• Obtain and document from parent/guardian the participant’s 
previous days’ interim history, including any changes in 
medications and/or immunizations.   
• Document highest temperature (temporal or rectal) 
Prepare for follow-up 
• Address any concerns and schedule appointment if necessary. 
 
 
6.4 
Day 29 Contact (+ 1 day) 
 
There will be a non-visit contact on Day 29 to obtain interim history through midnight on the 28th 
day following inoculation. If the Day 28 Visit is conducted on Day 29, it is not necessary to have 
an additional telephone or email contact with the family on Day 29. 
 

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Day 29 Contact Procedures (+ 1 day) 
Interim History 
• Obtain interim history through midnight of the 28th day following 
inoculation 
• Document highest temperature (temporal or rectal) 
Prepare for follow-up 
• Address any concerns. 
• Review SAE criteria with participants and how to contact study 
personnel during Post-Acute Phase (Day 30 to the Day 56 Visit). 
 
6.5 
Post-Acute Phase (Days 30 to 56) 
 
The Post-Acute Phase begins at 12:01 am on the 29th day after inoculation and ends at midnight 
on the 56th day after inoculation. During the Post-Acute Phase, parents/guardians will be 
instructed to monitor for and contact the study site if their infant has symptoms that are 
suggestive a Serious Adverse Event (SAE). If the parent reports an SAE that may meet the study 
pause or stop criteria (Section 8.2) then an Illness Visit should be scheduled (see Section 6.10). 
 
Certain events may trigger study pause or stop during the first 56 days following inoculation; 
review Section 8.2 for details associated with pausing and stopping rules. 
 
6.5.1 
Day 56 Visit (+7 Days) 
 
The Day 56 Visit should be conducted between 56 and 63 days following inoculation. Because 
the Post-Acute Phase ends as of midnight on the 56h day following inoculation, only events 
through that time should be evaluated as having occurred during the Post-Acute Phase. If the Day 
56 visit is conducted on the 56th day after inoculation, sites should arrange a non-visit contact the 
next day to confirm that there were no events between the time of the study visit and midnight of 
the 56th day after inoculation. The evaluations expected at this visit are outlined below.  
 
Day 56 Visit (from day of inoculation +7 Days) 
Clinical 
• Obtain interim history since last contact  
• Record temperature, pulse, and respirations.  
Laboratory 
 
Blood 
Collect blood for: 
• Serum antibodies to RSV 
• Only from participants who are at sites with capacity for 
processing viable PBMCs: Cryopreservation of PBMCs to 
characterize the B cell response. Remaining plasma to be stored. 
Nasosorption 
SAM strip  
Collect nasosorption strip for RSV antibody assays 
Prepare for follow-up 
Follow-up depends on when, during the calendar year, the Day 56 
visit is conducted. If the Day 56 Visit is conducted: 
• Prior to October 1st*, schedule for Pre-RSV Season Visit (Section 
6.7) 
• On or after October 1st*, the Day 56 Visit will also be the Pre-RSV 
Season Visit. Therefore, review plans for weekly contact during 
the RSV Season Surveillance Period (see Section 6.8). 
*This date applies to most sites but may differ for those with local RSV seasons that start earlier. 
 

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6.6 
Period after Day 56 Visit until October 31st or as specified in the MOP 
 
During this period, contact with the participant is not required except for the Pre-RSV Season 
Study Visit described in Section 6.7. No clinical data will be recorded on eCRFs or reported 
under this protocol except for data as outlined in Table 3 in Section 7.2. 
 
6.7 
Pre-RSV Season Study Visit (October 1st to 31st or as specifiedin the MOP)  
 
The Pre-RSV Season Study Visit is not required if the Day 56 Visit is conducted on or after 
October 1st for most sites or—for sites with local RSV seasons that start earlier—as specified on a 
site-by-site basis in the MOP (i.e., the samples collected at the Day 56 Visit are sufficient for the 
Pre-RSV Season Study Visit). Otherwise, an in-person visit is expected of participants during the 
Pre-RSV Season for collection of a blood sample and nasosorption strip for RSV antibody assays.  
 
Pre-RSV Season Study Visit (October 1st* to 31st*)  
Laboratory 
 
Blood 
Collect blood for: 
• Serum antibodies to RSV  
• Only from participants who are at sites with capacity for 
processing viable PBMCs: Cryopreservation of PBMCs to 
characterize the B cell response. Remaining plasma to be stored. 
Nasosorption 
SAM strip  
Collect nasosorption strip for RSV antibody assays 
Prepare for follow-up 
• Review plans for weekly contact during the RSV Season 
Surveillance Period (see Section 6.8). 
*These dates apply to most sites but may differ for those with local RSV seasons that start earlier. 
 
6.8 
RSV Season Surveillance (November 1st through March 31st following inoculation or as 
specified in the MOP) 
 
Based on previous data regarding the seasonality of RSV in the Baltimore, MD area (Appendix 
V), surveillance for RSV-associated disease will be conducted between November 1st and March 
31st for most sites or—for sites with local RSV seasons that start earlier—as specified on a site-
by-site basis in the MOP. Note, RSV Season Surveillance may overlap with the Study Acute and 
Post-Acute Phase. In this case, evaluations required for each of the relevant phases of the study 
will be conducted. During the RSV season following receipt of study product, participants 
enrolled in this study will be monitored for symptomatic, medically attended, RSV-like illnesses 
listed below. These contacts may be by weekly telephone, email, or an in-person visit. 
Information about these illnesses will be obtained during the RSV Season Surveillance Period 
by weekly communication between study personnel and the participant’s parent/guardian. For 
this period, determine if any of the following medically attended events occurred.  Please note 
that the symptoms below do not need to meet the Appendix IV criteria. 
o Medically attended fever 
o Medically attended upper respiratory illness  
o Medically attended otitis media 
o Medically attended lower respiratory illness  
 
An Illness Visit should be scheduled within 3 days of a site’s study staff notification of any of 
these events (see Section 6.10).   
 

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RSV Season Surveillance (November 1st* through March 31st following inoculation) 
Clinical 
• Obtain interim history 
Prepare for follow-up 
• Continue with weekly contacts through March 31st  
• Schedule an Illness Visit if warranted  
• Schedule Post-RSV Season Study Visit to take place between April 
1st and 30th 
*This date applies to most sites but may differ for those with local RSV seasons that start earlier. 
 
6.9 
Post-RSV Season Study Visit (April 1st to 30th) 
 
There will be a single in-person visit between April 1st and 30th. This window applies to all sites.  
 
Post-RSV Season Study Visit (April 1st to 30th) 
Administrative 
and Regulatory 
• Inform participant’s parent/guardian of study randomization, if 
known. 
Laboratory 
 
Blood 
Collect blood for: 
• Serum antibodies to RSV. 
• Only from participants who are at sites with capacity for 
processing viable PBMCs: Cryopreservation of PBMCs to 
characterize the B cell response. Remaining plasma to be stored. 
Nasosorption 
SAM strip  
Collect nasosorption strip for RSV antibody assays 
 
6.10  Illness Visit 
 
The timeframe after site notification in which the Illness Visit must occur depends on grading of 
the fever and respiratory symptoms per Section 7.4 and Appendix IV and the phase of the study. 
If the Illness Visit occurs on a day concurrent with a routine Study Visit, a single nasal wash 
collection is required, however, an Adventitious Agent request form should be completed. 
Following an Illness Visit, sites should continue to follow participants until resolution of 
symptoms. Illness visits may occur during any of the following phases of the study.  
  
• 
Acute Phase: For fever, otitis media, or URI, the Illness Visit must be conducted within 3 
days if Grade 1 and within 2 days if Grade ≥ 2. 
• 
Acute Phase: For a possible LRI, with any grade, the assessment will occur within 1 day. 
• 
Post-Acute Phase: For an SAE that may meet the study pause or stop criteria (Section 
8.2), an Illness Visit must be conducted within 3 days of site notification. 
• 
RSV Season Surveillance Period (between November 1st and March 31st for most sites 
or—for sites with local RSV seasons that start earlier—as specified on a site-by-site basis 
in the MOP): The Illness Visit should be scheduled within 3 days of site notification of a 
medically-attended illness of the following types: fever, URI, LRI or otitis media. 
However, if this phase overlaps with the Acute or Post-Acute Phases, the time frames 
specified for the relevant Acute or Post-Acute phase should be used. 
 

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Illness Visit Procedures 
Clinical 
• Obtain interim history 
• Perform focused clinical examination including temperature, heart 
rate, respiratory rate, EENT, lung, heart, and lymph nodes. 
• Record temperature, pulse, and respirations.   
Laboratory 
 
Nasal Wash 
Collect nasal wash for: 
• Viral detection and quantification 
• Complete Adventitious Agent Assay Request for rRT/PCR on 
nasal wash for adventitious agents (see MOP and LPC). 
Prepare for follow-up 
• Schedule follow-up as appropriate 
 
 
6.11 Early Discontinuation Study Visit 
 
In the event that a participant is unable to continue participation in the study, every effort should 
be made to schedule a final Early Discontinuation Visit. 
 
Early Discontinuation 
Clinical 
• Obtain interim history   
Laboratory 
 
Blood 
Collect blood for: 
• Serum antibodies to RSV 
• Only from participants who are at sites with capacity for 
processing viable PBMCs: Cryopreservation of PBMCs to 
characterize the B cell response. Remaining plasma to be stored. 
Nasosorption 
SAM strip  
If Early Discontinuation Visit is conducted within 56 Days of 
inoculation (Appendix II), collect nasosorption strip for RSV 
antibody assays 
 
• Note: The nasosorption must be performed prior to the nasal wash. 
Nasal Wash 
If Early Discontinuation Visit is conducted within 56 Days of 
inoculation (Appendix II), collect nasal wash for: 
• Viral detection and quantification 
• RSV antibody assays 
 
6.12 Additional Considerations for Laboratory Procedures 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy on 
Requirements for DAIDS Funded and/or Sponsored Laboratories in Clinical Trials Policy, which 
is available at: 
https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf  
 
6.12.1 Specimen Collection 
 
Specimens will be collected for this study as indicated in the Schedule of Evaluations and per 
detailed guidance provided in the Laboratory Processing Chart (LPC), which will be available on 
the IMPAACT web site: www.impaactnetwork.org. Further information on collection of blood 
and nasal wash specimens will also be provided in the MOP. 
 
In accordance with US National Institutes of Health (NIH) recommendations, pediatric blood 
collection will not exceed 5 mL/kg in a single day or 9.5 mL/kg in any eight-week period.   
 

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Virus Detection 
 
Specimens for viral culture and quantification of vaccine virus shedding will be collected by nasal 
wash with approximately 20 mL of Ringer’s lactate solution once before and approximately 8 
times after inoculation as shown in Appendix II. These specimens may also be tested for 
adventitious agents if the participant is ill. Additional nasal wash specimens for detection of RSV 
and adventitious respiratory viruses by culture and rRT-PCR will also be collected from 
participants who meet illness criteria during the initial phase (Day 0 to the Day 56 Visit) and RSV 
Season Surveillance Period (November 1st – March 31st for most sites or—for sites with local 
RSV seasons that start earlier—as specified on a site-by-site basis in the MOP). Laboratory 
testing will be performed by personnel that are not involved with clinical assessment to maintain 
the blinding of the study. 
 
6.12.2 Specimen Preparation, Testing, Storage, and Shipping 
 
All specimens collected for this study will be labeled, transported, processed, tested, stored and/or 
shipped in accordance with the DAIDS policy referenced in Section 6.12, site and local 
laboratory SOPs, and the LPC. The frequency of specimen collection and testing will be directed 
by the Schedule of Evaluations (Appendices II and III). The Laboratory Data Management 
System (LDMS) will be used to document specimen collection, testing, storage, and shipping as 
specified in LPC.  
 
Virologic and Immunologic Assays 
 
Serum specimens will be collected up to 42 days prior to inoculation for the screening and the 
study pre-inoculation, and at the Day 56 Visit for measurement of post-inoculation serum 
antibodies to RSV. In addition, pre-RSV season and post-RSV season serum specimens will be 
collected. These samples will be used to determine whether a fourfold or greater rise in antibody 
titer has occurred during the RSV season, which would signify infection with wt RSV. This 
will allow comparison of the rate and severity of significant RSV illness following infection 
with wt virus, as well as comparison of the antibody responses, in vaccine and placebo 
recipients. Screening serum samples will be shipped real time to JHU for RSV serology. All 
other serum will be shipped to JHU within approximately two weeks of obtaining the sample. 
 
Blood specimens for cryo-preservation of PBMCs will be collected up to 42 days prior to 
inoculation and at the Day 56 Visit to analyze the B cell response to the vaccine. In addition, pre-
RSV season and post-RSV season PBMCs will be collected. These samples will be used to 
analyze the B cell response to vaccination, and to wt RSV infection during the surveillance 
season. Plasma leftover from the processing of the PBMCs will be saved. Analysis of the B cell 
response may include sequencing of participant genes related to their immune response to the 
vaccine or RSV if the parent/guardian consents to limited genetic testing. 
 
Nasal adsorption (nasosorption) specimens for measurement of secretory immunity will be 
collected from participants before inoculation, at the Day 28 and 56 Visits after inoculation, and 
at the Pre-RSV Season and Post-RSV Season Visits. Synthetic adsorptive matrix (SAM) strips 
will be applied to the mucosa of the lower turbinate for 30 seconds. Mucosal antibody assays will 
be performed at LID, NIAID.  
 
Quantitation of the amount of vaccine virus shed, assays to measure immune responses before 
and after inoculation, and assessment of nasal washes for the presence of adventitious viral agents 
will be performed at the JHU CIR. Cytokine/chemokine assays may also be performed on nasal 

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washes from participants infected with vaccine virus if sufficient material is available. Selected 
specimens may be sent to LID, NIAID for confirmatory testing.  PBMC analyses will be 
performed at LID, NIAID.  
 
Nasal wash samples for viral detection will be shipped within two weeks after the Acute Phase 
(Day 28) to JHU. Nasal adsorption specimens and nasal wash samples for antibody detection will 
be shipped within two weeks after the Post-Acute Phase (Day 56) to LID, NAID. If a participant 
experiences an illness meeting protocol-specified Pausing/Stopping Rules, nasal wash specimens 
for adventitious PCR from the Illness Visit will be shipped real time to JHU. Plasma and PBMC 
samples will be held on-site until the end of the study and then shipped to LID, NIAID. 
 
Plan for Future Use and Storage of Biological Samples 
 
All specimens collected as part of this study may, with the parent/guardian’s permission, be 
stored for future research as part of JHU CIR’s approved biospecimen repository for vaccine 
research or at the LID, NIAID. These samples may be used for future screening for respiratory 
virus vaccine studies and to learn more about RSV infection and other diseases. These samples 
will not be sold or used to make commercial products. With permission, limited human genetic 
tests may be performed on these samples. Samples will be stored only with the parent/guardian’s 
permission.  
 
All samples stored in the repository will be labeled with the participant identification (PID) 
numbers of the participants that, by themselves, cannot identify study participants but are linkable 
to the study databases generated by the main study. The repository database will contain only the 
study participants’ PID numbers. A master log linking the study participants’ PID numbers is 
maintained at the individual enrolling site and will not be shared with the Protocol Team or the 
laboratory at CIR. Study participants, or their parents/guardians, may withdraw consent for future 
testing of their specimens at any time. 
 
In the future, other investigators (both at NIH and outside) may wish to study these samples 
and/or data. In that case, IRB approval must be sought prior to any sharing of samples and/or 
data. Any clinical information shared about the sample would similarly require prior IRB 
approval. 
 
6.12.3 Biohazard Containment 
 
As the transmission of 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 Centers for Disease Control and Prevention and the 
National Institutes of Health. Additional specimen collection and processing precautions are 
included in the MOP. All infectious specimens will be transported using packaging mandated in 
Title 42 of the Code of Federal Regulations, Part 72 (42 CFR 72) and in accordance with 
individual carrier guidelines (e.g., Federal Express, Airborne Express). 
 
7 
SAFETY ASSESSMENT, MONITORING, AND REPORTING 
 
Participant safety will be carefully assessed, monitored, and reported at multiple levels 
throughout this study. Sections 7.1-7.3 describe safety-related roles, responsibilities, and 
procedures for site investigators. The safety monitoring roles of the Protocol Safety Review Team 
(PSRT) and the Data Safety and Monitoring Board (DSMB) are briefly referenced in Section 7.1 

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and described in detail in Sections 9.4.1 and 9.4.2. 
 
7.1 
Safety-Related Roles and Responsibilities 
 
7.1.1 
Site Investigators 
 
Site investigators are responsible for continuous monitoring of all study participants and for 
alerting the Protocol Team if unexpected concerns arise. Site investigators will record safety-
related data on eCRFs as indicated in Section 7.2 and complete expedited adverse event (EAE) 
reporting as indicated in Section 7.3.  Site investigators are also responsible for prompt reporting 
to their IRBs/IBCs and other applicable review bodies of any unanticipated problems involving 
risks to participants or others. 
 
7.1.2 
Protocol Safety Review Team 
 
A Protocol Safety Review Team (PSRT) will routinely review clinical and laboratory safety data 
reports prepared by the SDMC. Designees for PSRT members will be allowed in the event of 
their non-availability for a review. To meet minimum quorum for a safety data review the PSRT 
must include (but is not limited to): 
• 
the Protocol Chair or Vice Chair 
• 
Data Manager 
• 
DAIDS or NICHD Medical Officer 
• 
the Protocol Statistician 
 
The content, format and frequency of safety monitoring will be agreed upon in advance by the 
PSRT. Representatives of the product developer may also be included on PSRT discussions, but 
not in decisions. 
 
The PSRT will convene via teleconference or other means routinely throughout the study to 
review data relevant to safety monitoring and discuss any safety concerns – at least twice per 
month during the active immunization phases – and at least once a month thereafter, as well as on 
an ad hoc (as needed) basis outside of regularly scheduled calls. The PSRT will also provide 
rapid consultation to site clinicians regarding toxicity management as needed. 
 
On behalf of the full Protocol Team, the PSRT will monitor participant safety through routine 
review of study data reports as described in Section 9.4.1.  
 
7.1.3 
Data Safety Monitoring Board 
 
An independent DSMB will monitor participant safety through routine and as needed reviews of 
study data.  Refer to Section 9.4.2 for more information on the composition and role of the 
DSMB in monitoring of this study.   
 
7.1.4 
Sponsor Reporting  
 
Serious and unexpected suspected adverse reactions (SUSAR) as defined in 21 CFR 312.32 will 
be determined by the IND Sponsor and reported to the FDA and all participating investigators as 
IND Safety Reports. The sponsor will also submit a brief report of the progress of the 
investigation to the FDA on an annual basis as defined in 21 CFR 312.33  
 

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7.2 
Safety-Related Recording on Case Report Forms 
 
Any event that occurs during protocol-specified AE reporting periods (see Table 3), following 
inoculation with study product, is to be considered an AE and should be evaluated as a potential 
Expedited AE (per DAIDS). The current section outlines which events should be collected on 
source documents and which should be recorded on eCRFs for inclusion in the database. 
 
AEs may be observed by the site investigator, elicited from the parent/guardian or participant, 
captured on participant’s temperature cards, or volunteered by the parent/guardian. Assessment of 
safety will include clinical observation and monitoring of hematological, chemical, and 
immunologic parameters as necessary. Follow-up such as history, physical examination, and 
laboratory testing and/or treatment may be necessary if a participant experiences an AE. Details 
of AEs will be properly collected on the source documents, recorded on eCRFs, and provided to 
PSRT and the DSMB in separate semi-annual and annual reports. AEs will be provided to the 
IRB as defined by the individual IRB policy. 
 
This study has several periods of AE surveillance that have different AE eCRF recording 
requirements. In addition, there may be a period when no AEs are recorded on eCRFs if the Day 
56 Visit is conducted in advance of the start of the RSV Season Surveillance Period (November 
1st for most sites or—for sites with local RSV seasons that start earlier—as specified on a site-by-
site basis in the MOP). The adverse events (solicited and unsolicited; and SAEs) to be recorded 
on eCRFs and the study phase and the calendar dates during which they are to be reported are 
defined in Table 5. 
 
Adverse events identified in this study will be recorded on eCRFs as signs, symptoms, laboratory 
test results, and diagnoses, as described in Table 3. Expectations regarding the recording of 
Concomitant Medications are also detailed in this table. 

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Table 3: AE eCRF Recording Requirements 
Study Phase at the 
time of event onset 
Calendar Date 
AEs to record on eCRFs 
Concomitant Medications to 
record on eCRFs 
Days 0 through 
midnight of 28th 
day following 
inoculation 
(Acute Phase) 
ANY 
• All SAEs 
• All solicited AEs that meet Appendix 
IV criteria  
• All unsolicited AEs (Grades 1 to 4), 
with the exception of the following 
conditions if not treated with 
prescription medication or OTC 
medications with antipyretic 
properties: diaper rashes, teething 
pain, and spitting up. 
 
Note: SAEs and LRIs must be reported 
via DAIDS Adverse Experience 
Reporting System (DAERS; see Section 
7.3.33). If randomization and Day 0 do 
not occur on the same day and AEs 
occur in the interim, record these AEs. 
Record these medications on 
eCRFs regardless of whether 
the related event is recorded on 
eCRFs: 
• All cough and cold remedies 
including decongestants, 
cough suppressants, 
expectorants 
• All nasal sprays (except 
saline spray) 
• All antihistamines 
• All antipyretics 
• All prescription medications 
 
For SAE and LRIs: 
• All concomitant medications 
related to the recorded event 
From 12:01 am on 
29th day after 
inoculation to 
midnight of the 
56th day following 
inoculation 
(Post-Acute Phase) 
ANY 
• All SAEs 
 
Note: SAEs must be reported via 
DAERS (see Section 7.3.3). 
• All concomitant medications 
related to the recorded event 
After Day 56 Visit 
and until RSV 
Season 
Surveillance Period 
Up to October 
31st* in year of 
inoculation 
• Grade ≥3 AE or SAE that is deemed 
related to Pre-RSV Season Study Visit 
procedures. 
• All concomitant medications 
related to the recorded event 
RSV Season 
Surveillance Period 
November 1st* 
to March 31st 
following 
inoculation 
• Fever, LRI, URI, and/or otitis media 
that are medically attended  
• All SAEs  
 
Note: these events do not need to meet 
the Appendix IV criteria. SAEs and 
Grade ≥3 LRIs must be reported via 
DAERS (see Section 7.3.3). 
For SAE and LRIs (all grades): 
• All concomitant medications 
related to the recorded event 
 
Medications related to 
recorded medically attended 
illness should be documented 
in source notes. 
Post-RSV Season 
April 1st-April 
30th in the year 
after the 
inoculation 
• Grade ≥3 AE or SAE that is deemed 
related to Post-RSV Season Study 
Visit procedures. 
 
• All concomitant medications 
related to the recorded event 
Throughout study 
ANY 
• Unresolved AE or SAE with onset 
date during Day 0 to midnight on the 
28th day after inoculation 
• Unresolved SAE with onset date prior 
to midnight on the 56th day following 
inoculation 
• Unresolved SAE with onset date 
during RSV Surveillance Period or 
related to the Pre- or Post-RSV Season 
Study Visit 
• All concomitant medications 
related to the recorded event 
*These dates apply to most sites but may differ for those with local RSV seasons that start earlier. 

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7.3 
Expedited Adverse Event (EAE) Reporting 
 
7.3.1 
Adverse Event Reporting 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 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system, must be used for expedited AE reporting to DAIDS. In the event of system outages or 
technical difficulties, expedited AEs may be submitted via the DAIDS EAE Form. For questions 
about DAERS, please contact NIAID CRMS at CRMSsupport@niaid.nih.gov. Site queries may 
also be sent from within the DAERS application itself. 
 
Where DAERS has not been implemented, sites will submit expedited AEs by documenting the 
information on the current DAIDS EAE Form. This form is available on the RSC website: 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids/paper-eae-reporting. For 
questions about expedited reporting, please contact DAIDS RSC 
(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 by this study. 
• 
In addition to the SAE Reporting Category identified above, other AEs that must be 
reported in an expedited manner are LRIs occurring during the periods specified in Table 
4. 
• 
The study agents for which expedited reporting is required are recombinant live-
attenuated respiratory syncytial virus vaccines RSV ΔNS2/Δ1313/I1314L and RSV 276 
and placebo. 
• 
After the protocol-defined AE reporting period, unless otherwise noted, only SUSARs as 
defined in Version 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). 
 
7.3.3 
Expedited AE Reporting Period 
 
Table 4 details the events that must be reported in an expedited fashion via DAERS during 
specific periods of the study. 
 
 

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Table 4: EAE Reporting 
 
Study Phase at the time of 
event onset 
Calendar Date 
Events to Report via 
DAERS 
Days 0 through midnight of 28th day 
following inoculation 
(Acute Phase) 
ANY 
• SAEs  
• LRIs 
From 12:01 am on 29th day after 
inoculation to midnight of the 56th day 
following inoculation 
(Post-Acute Phase) 
ANY 
• SAEs 
 
After Day 56 Visit and until RSV 
Season Surveillance Period 
 
Up to October 31st* in year of 
inoculation 
• Follow-up related to 
SAEs/LRIs already 
reported 
Pre-RSV Season 
October 1st* to October 31st* in the 
year of inoculation 
• SAEs related to Pre-
RSV Season Study Visit 
procedures 
 
RSV Season Surveillance Period 
November 1st* to March 31st 
following inoculation 
 
• SAEs 
• Grade ≥3 LRIs 
 
Post-RSV Season 
April 1st to April 30th in the year 
after the inoculation 
• SAEs related to Post-
RSV Season Study Visit 
procedures  
 
 
*These dates apply to most sites but may differ for those with local RSV seasons that start earlier. 
 
7.4 
Grading Severity of Events 
 
All solicited AEs and fever will be graded following protocol-defined grading system outlined in 
Table 5 and Table 6. Other AEs (i.e., excluding solicited AEs and fever) will be assessed for 
severity by the site investigator using the Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events (DAIDS AE Grading Table): Version 2.1, dated March 2017. 
In the event that this table is updated following protocol implementation, events will continue to 
be evaluated per this version of the DAIDS AE Grading Table.  The DAIDS AE Grading Table is 
available on the RSC website at http://rsc.tech-res.com/docs/default-source/safety/daids-ae-
grading-table-mar2017.pdf?sfvrsn=6. 
 

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Solicited AE Grading 
 
Table 5: Grading Table for Solicited AEs 
 
Severity 
Defined 
Grade (0) None 
Not applicable 
Grade (1) Mild 
No medical intervention required; may include use of over-the-counter 
medications managed by the caregiver for treatment of symptoms 
Grade (2) Moderate 
Outpatient medical intervention by a health care provider required; may 
include use of over-the-counter and/or prescription medications 
Grade (3) Severe 
Prolonged medical intervention and/or hospitalization required 
Grade (4) Life 
threatening 
Illness requiring hospitalization with intensive care  
Grade (5) Death 
Event resulting in fatal outcome to the participant 
 
Fever Grading: Temperature Measurement 
Table 6: Fever Grading* 
 
 
 
 
 
Severity 
Defined 
Grade (0) 
≥100.0ºF but <100.4ºF (≥37.8ºC but <38ºC) 
Grade (1) 
≥100.4ºF but ≤101.4ºF (≥38ºC but <38.6ºC) 
Grade (2) 
≥101.5ºF but ≤102.4ºF (≥38.6ºC but ≤39.1ºC) 
Grade (3) 
≥102.5ºF but ≤104.8ºF (≥39.2ºC but ≤40.4ºC) 
Grade (4) 
≥104.9ºF (≥40.5ºC)  
*Applies to any modality of temperature measurement  
 
The expedited AE reporting period for this study is defined in Section 7.3.33. 
 
 

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8 
PARTICIPANT MANAGEMENT 
 
8.1 
Management of Adverse Events 
 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
participant administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this product. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. This includes exacerbation of pre-existing conditions and intercurrent 
illnesses. This definition of “adverse event” will be applied to all enrolled infants beginning at the 
time of randomization.  
 
All adverse events identified in this study will be source documented in infant research records, 
consistent with the policies and procedures referenced in Section 10.  Among other details, source 
documentation will include the severity of each event (graded as described in Section 7.4) and its 
relationship to study product, assessed by the site clinician (see below).  Further standardized 
guidance on determining whether there is a reasonable possibility of a relationship is available in 
the DAIDS EAE Manual, referenced in Section 7.3.1. 
 
Relationship categories for Adverse Events are as follows: 
 
Related 
There is a reasonable possibility that the adverse event may be related to 
the study drug. 
 
Not related 
There is not a reasonable possibility that the adverse event may be 
related to the study drug.  
 
There are two categories of AEs specific to IMPAACT 2018: solicited and unsolicited.  Solicited 
AEs are described in Section 8.1.1. Unsolicited AEs are all other AEs. 
 
Serious Adverse Events (SAEs) are described in Section 8.1.2. 
 
8.1.1 
Solicited Adverse Events 
 
Solicited AEs are predefined AEs that can occur after inoculation with study product, may be 
expected to occur if the study product is insufficiently attenuated, and have protocol-specific 
criteria for reporting.  
 
Solicited AEs, whether identified by a parent/guardian or clinician, are only recorded on eCRFs if 
they met the definitions per Appendix IV. Individual symptoms listed in the “events” column that 
fail to meet the criteria in the “definition” column in Appendix IV are recorded in source 
documents but are not recorded on the eCRFs.  During the Acute Phase of this study, Days 0 to 
28, solicited AEs meeting the criteria for reporting will be recorded on eCRFs, assigned a severity 
grade (Section 7.4 and Table 5 and Table 6), and assessed for relationship to study product (see 
Section 8.1).  For this study, the solicited AEs are defined in Appendix IV and include the 
following:  
 
1. Fever 
2. Upper respiratory illness (URI) 

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a. Rhinorrhea, 
b. Pharyngitis,  
c. Cough without LRI, or 
d. Hoarseness. 
3. Otitis Media 
4. Lower respiratory illness (LRI) 
a. Wheezing, 
b. Pneumonia, 
c. Laryngotracheobronchitis (croup), 
d. Rhonchi, or 
e. Rales. 
 
Solicited Adverse Events Elicited by History Unconfirmed by Clinical Assessment 
 
With the exception of fever, solicited AEs reported by parents/guardians are NOT recorded on 
eCRFs if a clinical assessment done on the day of the event(s) does/did not confirm their 
presence. For example, if a parent/guardian reports rhinorrhea on the day of visit, and there is/was 
no rhinorrhea upon exam, then the participant is considered to not have rhinorrhea that day. 
 
If the parent/guardian report of a fever meets the “definition” column criteria in Appendix IV on a 
day on which there was a clinical assessment, the fever will be recorded on eCRFs regardless of 
whether the clinical assessment confirmed its presence. 
 
Events elicited by parent/guardian history for days on which there was no clinical exam will be: 
 
• 
Recorded on the eCRFs as AEs if the parent/guardian description meets the “definition” 
column criteria in Appendix IV. 
• 
Recorded only on the source document, and NOT on the eCRF, if the parent/guardian 
description fails to meet the “definition” column criteria in Appendix IV. For example, both 
rhinorrhea and cough must each occur on 2 consecutive days to meet the definition required 
for reporting per Appendix IV. 
 
8.1.2 
Serious Adverse Event 
 
A Serious Adverse Event (SAE) is an AE, whether considered related to the study product or not, 
that: 
1. Results in death during the period of protocol-defined surveillance 
2. Is life threatening: defined as an event in which the participant was at immediate risk 
of death at the time of the event; it does not refer to an event that hypothetically 
might have caused death were it more severe 
3. Requires inpatient hospitalization (or prolongation of existing hospitalization): 
defined as at least an overnight stay in the hospital or emergency ward for treatment 
that would have been inappropriate if administered in the outpatient setting 
4. Results in a persistent or significant disability/incapacity 
5. Is a congenital anomaly or birth defect 
6. 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 outcomes listed above. 
 

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8.2 
Pausing and Stopping Rules 
 
If any of the following occur in a participant during the specified period after he/she receives 
study product, additional inoculations and continued enrollment will be temporarily suspended at 
all sites: 
 
• 
Through midnight of the 56th day following inoculation: 
o An SAE that cannot be attributed to an etiology or cannot be attributed to a cause 
unrelated to the study product, OR 
• 
Through midnight of the 28th day following inoculation: 
o An LRI per Appendix IV, OR 
o A fever of Grade 4 OR  
o Any Grade 3 or above solicited AE (other than fever)  
 
If any of these events occur: 
• 
The site will report the event (as outlined in Sections 7.3) AND will notify the PSRT of 
the event (including a description of the event) via email at impaact.psrt2018@fstrf.org 
within 24 hours of site notification.  
• 
The Protocol Team will notify all sites to suspend enrollment and inoculation.  
• 
The site reporting the event will complete the event assessment including the collection 
of viral samples.  
• 
Respiratory viral samples collected from the participant up to that point will be shipped to 
the Johns Hopkins University laboratory as soon as possible (see MOP). Note that this 
procedure will be performed every time such a pause is triggered in order to maintain the 
blind. The virology studies will determine if there is shedding of RSV and/or adventitious 
viral agent(s) at the time of the event.  
• 
Study accrual will remain suspended while the virology studies are performed.  
• 
The DSMB and the study sponsor will be informed of the event. 
• 
The DSMB will receive an e-mail from the unblinded study statistician (while the rest of 
the team remains blinded) containing the following: 
o  Pertinent, blinded, clinical description of the event, prepared by the clinical trials 
specialists in consultation with site staff and approved by the Protocol Chair. 
o Results of virology studies, prepared by the testing lab. 
o Study product assignment (vaccine vs. placebo), from the unblinded study 
statistician.  
• 
Follow-up visits for participants already inoculated will continue as outlined in Appendix 
II. 
 
The event will be reviewed by the DSMB prior to resuming enrollment. The DSMB will review 
the information provided, including whether the event can be attributed to an etiology, a cause or 
a diagnosis unrelated to the study vaccine or if it is associated with shedding of vaccine virus at 
the time of the event (even if another pathogen is identified).   
 
The DSMB will notify the Protocol Chair (via the study sponsor) of their recommendations, and 
the sponsor and PSRT will determine if enrollment can resume, or if the study needs to be 
stopped. In the event of an SAE, the study may be resumed if it can be demonstrated to the 
DSMB that there is no proven causal relationship with the vaccine. In all cases, once a pause 
occurs, the sites cannot resume enrollment or inoculation until notified to do so by the Protocol 
Team. 
 

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9 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
The goal of this Phase I, blinded, randomized, placebo-controlled vaccine trial is to assess the 
safety, infectivity, and immunogenicity of the RSV ΔNS2/Δ1313/I1314L and RSV 276 vaccine 
candidates in RSV-seronegative pediatric participants and to assess whether these two vaccines 
are good candidates to move forward into a Phase IB study (by meeting the criteria listed in the 
Schema). Approximately 80 participants will be randomized in a 2:2:1 ratio to receive either of 
the candidate vaccines or placebo. The Protocol Team is interested in only whether the vaccines 
are better than placebo with respect to infectivity and immunogenicity; thus, the statistical 
comparisons between vaccine and placebo groups will consist of one-tailed tests. The study will 
not be powered for the modest difference expected between the two vaccines; thus, the groups 
receiving vaccine will be compared by means of descriptive analyses. Both vaccines may be used 
in a subsequent trial aimed at assessing efficacy, provided that this is not counter indicated by 
safety results.   
 
In an effort to promote rapid enrollment, eligible children living in the same household (including 
twins, siblings, or other non-related children) will be allowed to enroll and will be randomized to 
the same study product arm. The potential bias introduced by correlations among such children 
will be addressed by means of sensitivity analyses, as described in Section 9.5.1.  
 
Data from this study and from a companion study of these vaccines conducted at the Center for 
Immunization Research (CIR), Johns Hopkins Bloomberg School of Public Health, will be 
maintained in the same database and will be analyzed together. A subset of the study team will be 
unblinded to study results prior to completion of the study follow-up (see Section 9.4.1 for 
details).  
  
9.2 
Outcome Measures 
 
9.2.1 
Primary Outcome Measures 
 
o Safety: types and grades of study product-related: 
▪ 
solicited AEs as defined in Appendix IV from Study Day 0-28 
▪ 
unsolicited AEs from Study Day 0-28 
▪ 
SAE (as defined in Section 8.1.2) from Study Day 0-56 
o Infectivity: 
▪ 
infection with RSV defined as 1) vaccine virus identified in a nasal wash from Study 
Day 0-28 (a binary outcome based on nasal washes done throughout this time period; 
Day 0 nasal wash will be counted as baseline) and/or 2) ≥4-fold rise in RSV serum 
neutralizing antibody titer and/or serum ELISA titer to the RSV F protein from study 
entry to Study Day 56 
▪ 
peak titer of vaccine virus shed from Study Day 0-28 
▪ 
duration of virus shedding in nasal washes as determined by a) culture and b) RT-
PCR from Study Day 0-28 
 
o Immunogenicity: 
▪ 
≥4-fold rise in RSV serum neutralizing antibody titer from study entry to Study Day 
56 

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▪ 
RSV serum neutralizing antibody titers assessed by 60% RSV plaque reduction 
neutralization assay at study entry and Study Day 56 
▪ 
≥4-fold rise in serum antibody titers to RSV F glycoprotein as assessed by ELISA 
from study entry to Study Day 56 
▪ 
serum antibody titers to RSV F glycoprotein as assessed by ELISA at study entry and 
Study Day 56 
 
9.2.2 
Secondary Outcome Measures 
 
• 
Types and grades of symptomatic, medically attended respiratory and febrile illness adverse 
events in the vaccine and placebo recipients who experience natural infection with wt RSV during 
the subsequent RSV season. 
• 
Antibody titers in the vaccine and placebo recipients who experience natural infection with wt 
RSV during the subsequent RSV season. 
• 
Frequency of B cell response to vaccine  
• 
Mucosal antibody titers to vaccine, in nasal wash or nasosorption samples 
 
9.3 
Sample Size and Accrual 
 
 
 
9.3.1 
Sample Size and Randomization 
 
Approximately 80 RSV-seronegative infants will be enrolled in the study (IMPAACT 2018 and 
CIR 321 combined) and will receive RSV ΔNS2/Δ1313/I1314L (106 PFU), RSV 276 (105 PFU), 
or placebo in a 2:2:1 ratio (32:32:16). Assuming an attrition rate of about 6%, approximately 30 
vaccine recipients per vaccine arm and 15 placebo recipients will provide data for the primary 
objectives. In the case of children from the same household, all eligible children will be assigned 
to the same study product regimen. This will be done to reduce the potential cross-contamination 
that could result if children living together were to receive different study products. Permuted 
block randomization will be used to ensure that the 2:2:1 ratio of treated to control participants 
will be maintained across time.  
 
The sample size was chosen based upon past experience with Phase I evaluation of other live-
attenuated respiratory virus candidate vaccines (5, 26, 27) and on the number of participants 
feasible to enroll in the 2017 fall prior to RSV season. No formal power calculations have been 
used. The following paragraphs show the limitations of the sample sizes being used.  
 
All enrolled infants will be included in safety analyses. 
 
9.3.2 
Sample Size Limitations with Respect to Safety 
 
Given the small sample size, the study will have limitations with respect to detecting AEs and in 
estimating the rates of such events in the population represented by the study sample. 
 
The following calculations focus on the assessment of the safety of the vaccines and in particular, 
occurrence of LRI, which occurs very infrequently in children who participate in these types of 
studies but which would be considered a sentinel safety event if observed in participants infected 
with vaccine virus.   
 

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Table 7 shows the probability of observing 0 events of LRI within the sample of 30 vaccinees 
receiving either vaccine, as well as the probability of observing 1 or more events, or 2 or more 
events, under a range of assumptions concerning the true rate of such events in the participant 
population represented by this sample. From this table, it can be seen that if the true proportion of 
LRI (or other AE) is at least 10%, there is an 82% chance of observing 2 or more events in a 
group of size 30, and a 96% chance of observing at least a single event in a sample of this size. 
 
 
Table 7: The Probability of Observing LRI events in Vaccinees 
 
 
N=30 
True underlying probability of LRI 
or AEs 
Pr  
(0 events) 
Pr  
(1+ events) 
Pr 
(2+ events) 
.01 
.74 
.26 
.04 
.03 
.40 
.60 
.23 
.05 
.21 
.79 
.45 
.1 
.04 
.96 
.82 
.15 
.01 
.99 
.95 
 
Table 8 presents 90% CIs around potential rates of AEs that might be observed in the sample of 
30 vaccinees. The CIs around similar rates in a sample of 15 placebo recipients are also 
presented. Note that if no AEs are detected among either group of 30 vaccinees, there is 90% 
confidence that the true probability of AEs in the population from which the sample is drawn is 
between 0 and 10%. 
 
Table 8: Percent of Participants Experiencing AEs with Exact 90% Confidence 
Intervals 
 
N 
% LRI or AEs 
90% CI 
15 
0% 
0% -- 18% 
30 
0% 
0% -- 10% 
15 
10% 
1% -- 32% 
30 
10% 
3% -- 24% 
15 
20% 
6% -- 44% 
30 
20% 
9% -- 36% 
15 
30% 
12% -- 55% 
30 
30% 
17% -- 47% 
 
9.3.3 
Sample Size Limitations with Respect to Infectivity and Immunogenicity 
 
Criterion “The mean peak titer of shed virus in nasal washes should be approximately 2.5 log10 
PFU”  
 
With a sample size of 30 vaccinees, the 90% CI around a targeted sample mean peak titer of shed 
virus of 2.5 log10, assuming a SD of 1.5 (derived from IMPAACT 2000) is (2.04, 2.97). This 
ensures with 90% confidence that the true population mean peak titer of shed virus is between 
2.04 and 2.97 log10, and with 95% confidence that the true population mean of shed virus is not 
lower than 2.04 log10. 

IMPAACT 2018, Version 1.0 
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With respect to infectivity and immunogenicity, group sample sizes of 30 in either of the 
vaccinated groups and 15 in the placebo group would achieve 80% power to detect a difference 
between the vaccine and placebo groups proportions of at least 0.34. The test statistic used is the 
one-sided Fisher's Exact test, in the direction that either vaccinated group will have a higher 
proportion than the placebo group. The alpha level of the test was targeted at 0.05. Table 9 
presents examples of true group differences that can be detected with 80% power, and Figure 4 
displays graphically power curves for 90% power, 80% power, and 70% power given the sample 
sizes. 
 
 
Table 9: Magnitude of Difference in Responses Detectable with 80% Power 
 
Response Proportion 
in the Placebo 
Group 
Response Proportion in 
Either Vaccinated Group 
Difference 
0.05 
0.40 
0.34 
0.1 
0.49 
0.39 
0.15 
0.56 
0.41 
0.2 
0.63 
0.43 
0.5 
0.89 
0.39 
 

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Response proportion in the Vaccine Group 
Response proportion in the Placebo Group 
Response proportion in the Placebo Group 
Figure 4: Power curves for comparisons between responses to either vaccine to 
responses to placebo 
 
 
 
(Alpha=.05; N Vaccine=30; N Placebo=15; 1-Sided Exact Test) 
 
Criterion “>90% of vaccinees should be infected with vaccine virus” 
   
Table 10 presents 90% confidence intervals (CIs) around potential rates of infection with vaccine 
virus that might be observed in the sample of 30 vaccinees. For the target proportion of 93% (i.e. 
>90%), this ensures with 90% confidence that the true proportion of vaccinees who shed virus is 
between 80% and 98.7% and with 95% confidence that the true proportion of vaccinees who shed 
vaccine virus is not lower than 80%. 
 

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Table 10: Percent of Vaccinees who are Infected with Vaccine Virus with Exact 
90% Confidence Intervals 
 
N 
% of vaccinees 
infected with 
vaccine virus 
90% CI 
30 
90% (27/30) 
76% -- 97% 
30 
93% (28/30) 
80% -- 98.7% 
30 
97% (29/30) 
86% -- 99.9% 
 
 
9.4 
Monitoring 
 
Accrual to this study will be monitored by the IMPAACT leadership in accordance with standard 
operating procedures. The team will monitor feasibility monthly, first based on site activation and 
then on accrual. Initially, the team will monitor site activation weekly to ensure that an adequate 
number of sites have been activated to participate in the study.  If relatively few of the eligible 
sites have been activated after the study has been approved for 1 month, the team will re-assess 
the feasibility of the study and the reasons why sites have not been activated, and may amend the 
protocol accordingly.   
 
9.4.1 
Monitoring by the Protocol Team 
 
Study Progress and Quality of Study Conduct 
 
The Protocol Team is responsible for continuous monitoring of study progress, including timely 
achievement of key milestones, and quality of study conduct.   
 
The team will closely monitor participant accrual and retention based on reports that will be 
generated at least monthly by the Statistical and Data Management Center (SDMC). The team has 
developed a study accrual plan that includes site-specific and total enrollment projections over the 
course of the accrual period, and actual accrual will be monitored relative to these projections. 
The team will monitor the timing of site-specific study activation, which will determine when 
each site will begin accruing participants, and actual accrual following activation. Accrual 
performance will be reported by the DMC, by site and across sites, and the team will review and 
discuss study progress at least monthly.  For any site that is delayed in completing the study 
activation process, or that falls short of its accrual projections, the team will communicate with 
the site to identify the barriers the site has encountered and the operational strategies and action 
plans to address these. 
 
The Protocol Team will similarly review participant retention and other key indicators of the 
quality of study conduct (e.g., data quality, and data and specimen completeness) based on reports 
generated by the SDMC and take action with study sites as needed to ensure high quality study 
conduct throughout the period of study implementation.  
 

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Participant Safety 
 
The Protocol Team and the PSRT will closely monitor participant safety through routine review 
of safety data reports generated by the SDMC. These reports will provide tabulations of adverse 
events (defined in Section 8.1) identified in enrolled infants, including abnormal laboratory test 
results, signs, symptoms, and diagnoses, pooled across arms (with the vaccine and placebo arms 
presented together). The PSRT will review these reports via conference call or other meeting at 
least twice a month during the first 56 days post inoculation and at least monthly thereafter. At 
the time of each call, the DAIDS Medical Officer will also review any EAEs (defined in Section 
7.3) reported to the DAIDS Safety Office that are not yet reflected in the data reports. The PSRT 
will continually evaluate the pattern and frequency of reported events and assess for any 
individual occurrences or trends of concern.    
 
If there is a report of any event that meets the pause/stop criteria, procedures as per 8.2 will be 
followed. 
 
Blinding/Unblinding 
 
At the end of the RSV Season Surveillance Period, each site will receive a list of the assignments 
so that each participant’s parent/guardian may be informed of their infant’s assignment at the 
final visit (between April 1st and 30th following inoculation). 
 
If the need arises to unblind a specific participant’s assignment in the event of a serious illness 
prior to completion of the RSV Season Surveillance Period, IMPAACT procedures for 
unblinding will be followed. In the event that unblinding is required, only that specific 
participant’s assignment will be unblinded. Whenever possible, the Protocol Chair will make a 
decision regarding early unblinding in collaboration with the Data and Safety Monitoring Board 
(DSMB). The sponsor and the DSMB Executive Secretary will also be notified of the event in 
real time. 
 
A subset of protocol team members limited to the Protocol Statistician, Protocol Vice Chair, and 
the two Scientific Investigators of the Laboratory of Infectious Diseases will be unblinded to all 
data at the completion of the Post-Acute Phase of follow-up (Day 56) for the last participant 
enrolled in each calendar year to enable more efficient and timely study evaluation and planning 
for appropriate next steps with respect to RSV candidate vaccine development. Unblinding will 
occur after all the relevant data that are needed to make decisions have been entered into the 
database and analyzed. 
 
9.4.2 
Monitoring by the NIAID Intramural Data and Safety Monitoring Board 
 
The NIAID Intramural DSMB is constituted to review the safety data of Intramural NIAID 
clinical studies that require DSMB oversight. The NIAID Intramural DSMB includes independent 
experts in infectious diseases, biostatistics, and clinical research that do not have direct 
involvement in the conduct of the study and have no significant conflicts of interests as defined 
by NIAID policy. The DSMB will review the protocol prior to opening the study to enrollment. 
The DSMB will meet at least twice a year or on a schedule specified by the DSMB to review the 
completeness of the study data, the adherence to the protocol, and AE data. Cumulative safety 
data will be submitted to the DSMB Executive Secretary for DSMB review. Two reports will be 
prepared: one that will preserve the blind and will include data pooled across arms (with the 
vaccine and placebo arms presented together) and a second one,  in which the data will be broken 
down by masked treatment arm, and the codes identifying the arms will be provided to the 

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DSMB. The DSMB may choose not to unblind themselves if no events of major concern are 
observed. The DSMB will be consulted in the event that pausing or halting criteria are met. The 
DSMB Executive Secretary will provide the Protocol Chair with DSMB recommendations 
promptly, and the official DSMB Report will then be provided in a timely fashion through the 
office of the NIAID Clinical Director. The Protocol Chair will submit the written DSMB 
recommendations to the sites’ IRBs upon receipt. All SAEs, LRIs, and all IND Safety Reports as 
specified in Section 7.2 will be reported by the Protocol Chair to the DSMB at the same time they 
are submitted to the IND sponsor or FDA. The Protocol Chair will notify the DSMB of any cases 
of intentional or unintentional unblinding as soon as possible. The Protocol Chair will notify the 
Board at the time pausing or halting criteria are met and obtain a recommendation concerning 
continuation, modification, or termination of the study. 
 
 
9.5 
Analyses 
 
A detailed statistical analysis plan will be developed and finalized before the first distribution of 
safety data for DSMB review.  
 
Where appropriate, a 1-tailed Wilcoxon rank sum test will be used to test the hypothesis that a 
vaccinated group will exhibit greater peak viral titers and antibody titers following vaccination 
compared to the placebo group. A 1-tailed Fisher’s exact test will be used to test the hypothesis 
that a vaccinated group will exhibit a greater proportion of participants who develop fourfold or 
greater rises in RSV-neutralizing antibody titer following vaccination compared to the placebo 
group. The statistical tests will be one-sided with a nominal significance level of 0.05. Statistical 
analyses will be based on the as-treated approach, unless otherwise specified. For safety, 
infectivity and immunogenicity analyses, the time starts at inoculation (Study Day 0). 
  
 
In the event that twins or siblings are enrolled in the study, both siblings will be included in the 
safety analyses, to ensure that any serious adverse events is obeserved. In the infectivity and 
immunogenicity analyses, one of the siblings will be randomly selected to be included in the 
analyses. Sensitivity analyses will be performed in which the selected child will be replaced by 
the other sibling(s) to ensure that any choice would support the same overall results. Line listings 
will provide individual data from all children. 
 
 
9.5.1 
Assessment of Primary Objectives  
 
The safety, infectivity and immunogenicity data will be summarized for each study product 
group. In addition, the criteria listed in Section 1.1 will be used to determine if these vaccines are 
promising candidates for further evaluation in a Phase IB study. The analyses for these criteria are 
described below.  
 
Safety Analyses, addressing the criterion “The vaccines will be safe” 
 
All enrolled infants will be included in safety analyses. 
 
The frequency of study-product related solicited AEs and unsolicited AEs, along with 90% 
confidence intervals, during Study Days 0 to 28 and of study product-related SAE during Study 
Day 0 to the Day 56 will be summarized. A similar summary will include all AEs, regardless of 
relationship to study product. In addition, line listings of individual clinical solicited AEs and 

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unsolicited AEs during Study Days 0 to 28 and vaccine-related SAE during Study Day 0 to the 
Day 56 Visit, graded by severity, will be prepared.  
 
Infectivity and Immunogenicity Analyses 
 
The primary infectivity and immunogenicity analyses will be based on the as-treated approach, 
including the study participants who have been inoculated. In an additional analysis, those who 
do not provide data for the Study Day 28 or 56 (due to early discontinuation or missed visit) will 
be treated as “failures” in an intent-to-treat analysis. Sensitivity analyses will be performed to 
check whether the results are consistent with those observed when these participants are 
excluded. Participants who receive any of the disallowed treatments listed in Section 5.11 after 
inoculation may be excluded from the infectivity and immunogenicity evaluations after the time 
of the treatment.  
 
Criterion “>90% of vaccinees should be infected with vaccine virus” 
 
The proportion of participants infected with vaccine virus along with 90% confidence intervals, 
will be summarized. Infection with vaccine virus is defined by shedding vaccine virus, detected 
by infectivity assay and/or RT-qPCR, and/or fourfold or greater rise in RSV-specific serum 
antibodies, detected by ELISA against the RSV F protein  and/or an RSV plaque reduction 
neutralization assay (RSV-PNRT). 
  
Criterion “The mean peak titer of shed virus in nasal washes should be approximately 2.5 log10 
PFU” 
 
The mean peak titer and mean duration of virus shed with 90% confidence intervals will be 
provided, for each study product group. In addition, line listing of the individual peak titer of 
vaccine virus shed and duration of virus shedding in nasal washes by each individual will also be 
prepared. 
 
Criterion “RSV-neutralizing serum antibody titers (measured 56 days post inoculation) should be 
similar to or better than MEDI/∆M2-2 (geometric mean titer of >1:97)” 
 
The proportion of participants that develop fourfold or greater rises in RSV-neutralizing antibody 
titer following vaccination will be summarized. A line listing of the individual RSV antibody titer 
pre- and post-vaccination will be prepared. In addition, the geometric mean and median antibody 
titers will be provided for each study product group. Line listings of individual RSV-neutralizing 
antibody responses as well as of antibody responses to the RSV F glycoprotein will be prepared 
as well.  
 
9.5.2 Assessment of Secondary Objectives  
 
Summaries of the frequency and severity of symptomatic, medically attended respiratory and 
febrile illness in the vaccine and placebo recipients who experience natural infection with wt RSV 
during the subsequent RSV season will be presented.  
 
A line listing of the individual RSV antibody titer pre- and post-RSV Season Surveillance Period 
will be prepared. In addition, the geometric mean and median antibody titers will be provided for 
each study product group. To address the criterion “Post-vaccination surveillance during the RSV 
season following vaccination should reveal substantial rises in RSV-neutralizing serum antibodies 
in a subset of vaccine recipients in the absence of RSV associated medically attended acute 

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respiratory illness (RSV-MAARI), which would be indicative of exposure to wt RSV without 
illness,” the changes in median antibody titers between day 56 and the post RSV surveillance 
time point will be summarized in the subset of vaccine recipients who do not experience RSV-
MAARI.   
 
The B cell responses to vaccine will be summarized for each study product group. A line listing 
of the mucosal antibody response detected in nasal wash specimens will be prepared. 
 
The two vaccine groups will be compared descriptively with respect to peak viral titers and 
antibody titers following vaccination. 
 
10 
DATA HANDLING AND RECORD KEEPING 
 
10.1 
Data Management Responsibilities 
 
As described in Section 4.4, data on enrollment in this study will be collected using the DMC 
Subject Enrollment System.   
 
Study sites must maintain adequate and accurate research records containing all information 
pertinent to the study for all screened and enrolled participants, including eCRFs and supporting 
source data. In maintaining these records, sites must comply with the standards of source 
documentation specified in the DAIDS policy on Requirements for Source Documentation in 
DAIDS Funded and/or Sponsored Clinical Trials.  
All DAIDS policies referenced in this section are available at: 
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures  
 
eCRFs are completed by study site staff and, following quality control and quality assurance 
reviews, are entered using a remote data entry system and transferred electronically to the DMC. 
Selected laboratory data are transferred electronically to the DMC through the LDMS.   
 
At the DMC, computerized checks are applied to the transferred data and, when required, data 
queries are issued for resolution by study site staff. All data must be transferred to the DMC 
within timeframes specified in the forms instructions; queries must also be resolved in a timely 
manner.  
 
Further information on the study eCRFs and IMPAACT data management procedures, including 
a Forms Manual: Policies and Procedures for Forms Completion for DAIDS-Sponsored Clinical 
Trials, a comprehensive Computing Manual, and a User Manual for the Subject Enrollment 
System, are available on the DMC portal at www.fstrf.org.   
 
10.2 
Essential and Source Documents and Access to Source Data 
 
All DAIDS policies referenced in this section are available at: 
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures  
 

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Study-related documentation will be completed as required by the IRB, the sponsor, and 
regulatory authorities. Continuing review documentation will be submitted by the site investigator 
to the IRB as specified by the IRB. An annual report will be submitted by the sponsor to the FDA 
based on the anniversary date that the IND for the RSV ΔNS2/Δ1313/I1314L and RSV 276 
vaccines went into effect. These reports will provide a brief description of the progress of the 
investigation as outlined in 21 CFR 312.33 and will include any revisions of the protocol not 
previously submitted to the FDA. 
 
Study-related documents will be maintained by the site investigator for a period of at least 2 years 
after final marketing approval of the vaccine, or at least 2 years after the formal discontinuation 
of clinical development of the product (or longer based upon local laws). The sponsor is required 
to inform the site investigator as to when such documents need no longer be retained. No study 
document should be destroyed without prior written agreement between the sponsor and the 
Protocol Chair. Storage of all study-related documents will be such that confidentiality will be 
strictly maintained. These records are also to be maintained in compliance with IRB, state, and 
federal medical records retention requirements, whichever are longest. Should the site 
investigator wish to assign the study records to another party and/or move them to another 
location, the site investigator must provide written notification of such intent to the sponsor with 
the name of the person who will accept responsibility for the transferred records and/or their new 
location. The sponsor must be notified in writing, and written permission must be received by the 
site from the sponsor prior to destruction or relocation of research records. 
 
All study records must be accessible for inspection, monitoring, and/or auditing during and after 
the conduct of the study by authorized representatives of the study sponsors and their contracted 
monitors, IMPAACT, the US Food and Drug Administration, site drug regulatory authorities, site 
IRBs/IBCs, OHRP, and other applicable regulatory entities.  Records must be kept on-site 
throughout the period of study implementation; thereafter, instructions for off-site storage may be 
provided by NIH.  No study records may be removed to an off-site location or destroyed prior to 
receiving approval from NIH.  
 
10.3 
Clinical Investigator’s Brochure 
 
Investigators will receive the current version of the Clinical Investigator’s Brochure (IB) that 
comprehensively describes all the available preclinical experience with the experimental 
vaccines. If relevant new information becomes available during the course of the trial, the 
investigators will receive a revised IB or an amendment to the current version. 
 
10.4 
Quality Control and Quality Assurance 
 
Study sites must ensure that essential documents and participant research records are subject to 
continuous quality control and quality assurance procedures consistent with the DAIDS policy on 
Requirements for Clinical Quality Management Plans, which is available at: 
https://www.niaid.nih.gov/sites/default/files/qmppolicy.pdf  
 

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11 
CLINICAL SITE MONITORING 
 
Site monitors under contract to NIAID or NICHD will visit study sites to inspect study facilities 
and review participant study records including consent forms, eCRFs, medical records, laboratory 
records, and pharmacy records, to ensure protection of study participants, compliance with the 
IRB/IBC-approved protocol, and accuracy and completeness of records. The monitors also will 
review essential document files to ensure compliance with all applicable regulatory requirements.  
Site investigators will make study facilities and documents available for inspection by the 
monitors.   
 
The trial will be conducted in compliance with this protocol, ICH GCP guidelines, and any 
applicable regulatory requirement(s). The study site monitoring will be conducted according to 
the “NIAID/DAIDS and NICHD Clinical Research Site Monitoring Guidelines”.   
 
The site investigator or designee will make study documents (e.g., consent forms, eCRFs) and 
pertinent medical or clinical records readily available for inspection by the local IRB, the FDA, 
the site monitors, and the NIAID staff for confirmation of study data. The sponsor will retain 
originals of the Form FDA 1572 and copies of other study documents as deemed necessary. 
 
12 
HUMAN SUBJECTS PROTECTIONS 
 
12.1 
Institutional Review Board/Ethics Committee Review and Approval  
 
Prior to study initiation, site investigators must obtain IRB/IBC review and approval of this 
protocol and site-specific ICFs in accordance with 45 CFR 46; subsequent to initial review and 
approval, IRBs/IBCs must review the study at least annually. Site investigators must also 
promptly report to the IRB/IBC any changes in the study and any unanticipated problems 
involving risks to participants or others. 
 
All IRB/IBC policies and procedures must be followed and complete documentation of all 
correspondence to and from the IRBs/IBCs must be maintained in site essential document files.  
Sites must submit documentation of both initial review and approval and continuing review to the 
DAIDS Protocol Registration Office (PRO) in accordance with the DAIDS Protocol Registration 
Manual (Section 13.2). 
 
A copy of the study approval (including approval of the informed consent form) is to be 
maintained in the site investigator’s study document binder, and a copy will be supplied to the 
sponsor.  
 
During the study, the site investigator is responsible for providing the IRB with all documents 
subject to review (i.e., protocol amendments, informed consent form updates, advertisements, and 
any written information that may be provided to the participant’s parents/guardians). Study 
progress reports will be made to the IRB by the investigator in accordance with IRB guidelines 
and government regulations. 
 

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12.2 
Vulnerable Participants 
 
The NIH is mandated by law to ensure that children be included in clinical research when 
appropriate (42, 43). This study responds to that mandate and will provide clinical research data 
to inform RSV vaccine infectivity, safety and immunogenicity in children. Nonetheless, the 
infants who take part in this study are considered vulnerable participants per the US Code of 
Federal Regulations, and site IRBs/IBCs must consider the potential risks and benefits to child 
participants as described in 45 CFR 46 Subpart D (for children). 
 
With respect to 45 CFR 46 Subpart D, IRBs/IBCs must determine the level of risk to children in 
the categories specified in 45 CFR 46.404-407. Documentation of this determination is required 
to complete the DAIDS protocol registration process described in Section 13.2, and the risk 
category assigned by the IRB/IBC further determines the parental informed consent requirements 
for the study at each site.  Per 45 CFR 46.408 (b), the IRB/IBC may find that the consent of one 
parent is sufficient for research to be conducted under 46.404 or 46.405. If the IRB/IBC finds that 
the research is covered by 46.406 or 46.407, both parents must give their consent, unless one 
parent is deceased, unknown, incompetent, or not reasonably available or when only one parent 
has legal responsibility for the care and custody of the child (as determined locally). IRBs/IBCs 
must document their risk determination, and study sites should adapt the signature pages of their 
site-specific ICFs as needed to accommodate the parental consent requirements associated with 
the IRB/IBC determination. 
 
Study sites must comply with the requirements of the DAIDS policy on Enrolling Children 
(including Adolescents) in Clinical Research, which is available at: 
https://www.niaid.nih.gov/sites/default/files/enrollingchildrenrequirements.pdf  
 
12.3 
Informed Consent 
 
In obtaining and documenting informed consent, the site investigator must comply with the 
applicable regulatory requirements, ICH GCP guidelines, and ethical principles. The written 
informed consent form must be approved by the IRB prior to its use. 
 
Written informed consent for infant study participation will be obtained before any study-specific 
procedures are performed. The informed consent process will include information exchange, 
detailed discussion, and assessment of understanding of all required elements of informed 
consent, including the potential risks, benefits, and alternatives to study participation.  The 
process will emphasize the unproven efficacy of the study vaccine products. 
  
As part of the informed consent process, parents/guardians will also be asked whether they agree 
to storage and future research testing of biological specimens remaining after all protocol-
specified testing has been completed.  Future research testing of residual specimens may be 
declined with no impact on other aspects of infant study participation. Parents/guardians will also 
be asked whether they agree to limited genetic testing, including future limited genetic testing; 
this testing may be declined with no impact on other aspects of infant study participation.   
 
Parental consenting requirements at each site will depend on the IRB/IBC risk determination 
described in Section 12.2; all IRB/IBC requirements will be followed.   
 

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12.4 
Potential Benefits 
 
Participants may not receive direct study product-related benefit from enrollment in this 
study. However, based on prior studies, there is the possibility of a reduced risk of disease from 
RSV for vaccine recipients. Placebo recipients will not receive any direct benefit from enrollment 
in this study. It is hoped that information gained in this study will contribute to the development 
of a safe and effective vaccine for the prevention of illness associated with RSV infection. 
 
12.5 
Potential Risks  
 
12.5.1 Venipuncture 
 
Risks occasionally associated with venipuncture include pain and bruising at the site of 
venipuncture, lightheadedness, infection, and syncope (rarely). 
 
12.5.2 Nasal Wash 
 
Risks occasionally associated with nasal wash include pain or discomfort and occasionally 
epistaxis. Nasal washes are not standard care in well children and are not usually performed on ill 
children, although many parents/guardians are advised to use saline nose drops and nasal bulb 
suction (the 2 components of the nasal wash procedure used in this study) to clear a young child’s 
congested nostrils during a URI. 
 
12.5.3 Receipt of Study Product 
 
If a vaccine (RSV ΔNS2/Δ1313/I1314L or RSV 276) is insufficiently attenuated, participants 
could experience rhinorrhea, cough, fever, hoarseness, otitis media, or LRI. Immediate 
hypersensitivity reactions—which could be life threatening—including urticaria, anaphylaxis, or 
other Immunoglobulin E (IgE)-mediated responses are possible, as with any vaccine. There is a 
theoretical possibility, as with any investigational vaccine, of risks about which there is no 
present knowledge. Parents/guardians will be informed of any such risks should further data 
become available. A previous vaccine candidate, RSV MEDI/∆M2-2, that is nearly identical to 
RSV 276, was previously evaluated in 20 RSV-seronegative children 6 to 24 months of age at a 
dose of 105 PFU and was very highly attenuated and appeared to be well tolerated. 
 
12.6 
Reimbursement/Compensation 
 
Compensation will be provided to the participant’s parent/guardian based on each site’s standard. 
The amount must be reviewed and approved by each sites’ IRB. Compensation will be in 
accordance with each institution’s IRB policies and will be specified in site-specific ICFs or other 
materials if applicable per IRC/EC policies and procedures. 
 
12.7 
Privacy and Confidentiality 
 
All study procedures will be conducted in private and every effort will be made to protect 
participant privacy and confidentiality to the extent possible. Participant information will not be 
released without written permission to do so except as necessary for review, monitoring, and/or 
auditing as described in Section 10.2. 
 

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All study-related information will be stored securely. Participant research records will be stored 
in locked areas with access limited to study staff. All laboratory specimens, eCRFs, and other 
documents that may be transmitted off-site (e.g., EAE report forms, photographs of observed 
reactions) will be identified by PID only. Likewise, communications between study staff and 
Protocol Team members regarding individual participants will identify participants by PID only.   
 
Study sites are encouraged but not required by DAIDS policies to store study records that bear 
participant names or other personal identifiers separately from records identified by PID. All local 
databases must be secured with password protected access systems. Lists, logbooks, appointment 
books, and any other documents that link PID numbers to personal identifying information should 
be stored in a separate, locked location in an area with limited access.   
 
In addition to the above, a Certificate of Confidentiality has been obtained for this study from the 
US Department of Health and Human Services. This certificate protects study staff from being 
compelled to disclose study-related information by any US Federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings.  It thus serves to protect the identity and privacy 
of study participants. Because the certificate cannot be enforced outside of the US, however, it 
applies only to US sites and participants. 
 
12.8 
Management of Incidental Findings 
 
Site clinicians will inform parents (or other authorized guardians if applicable) of all clinically 
meaningful physical exam findings and laboratory tests. When applicable, site clinicians will 
provide referrals to non-study sources of medical care for further evaluation and/or treatment of 
these findings.  
 
13 
ADMINISTRATIVE PROCEDURES 
 
13.1 
Regulatory Oversight 
 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), 
Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), and 
National Institute of Mental Health (NIMH), which are part of the United States National 
Institutes of Health (NIH).   
 
The Division of AIDS (DAIDS) within the NIAID is responsible for regulatory oversight of this 
study and holds the Investigational New Drug (IND) application under which the study will be 
conducted. DAIDS will distribute safety-related information pertaining to the study product prior 
to and during the conduct of the study, in accordance with its sponsor obligations.  
 
NIAID and NICHD provide funding to the clinical research sites at which this study will be 
conducted.  Each institute contracts with independent clinical site monitors who will perform 
monitoring visits as described in Section 11.  As part of these visits, monitors will inspect study-
related documentation to ensure compliance with all applicable US and local regulatory 
requirements. 
 
13.2 
Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol ICFs approved, as appropriate, by their local IRB/IBC, 

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local IBC, and any other applicable regulatory entity.  Upon receiving final approval, sites will 
submit all required protocol registration documents to the DAIDS PRO at the RSC.  The DAIDS 
PRO will review the submitted protocol registration packet to ensure that all of the required 
documents have been received.   
 
Site-specific 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. 
 
For any future protocol amendments, upon receiving final IRB/IBC and any other applicable 
regulatory entity approvals, 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 the required 
documents have been received. Site-specific ICFs will not be reviewed and approved by the 
DAIDS PRO and sites will receive an Amendment Registration Notification when the DAIDS 
PRO receives a complete 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, which is available on the RSC website:  
http://rsc.tech-res.com/clinical-research-sites/protocol-registration 
 
 
13.3 
Study Implementation 
 
This study will be conducted in accordance with the protocol, international good clinical practice 
guidelines, and all applicable US and local regulations. Study implementation will also be guided 
by the IMPAACT Network MOP, study-specific MOP, LPC, and other study implementation 
materials, which will be available on the IMPAACT website: www.impaactnetwork.org. 
 
13.4 
Protocol Deviation Reporting 
 
Per the policy for Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials, all protocol deviations must be documented in participant research records. 
Reasons for the deviations and corrective and preventive actions taken in response to the 
deviations should also be documented. 
 
Deviations should be reported to site IRBs/IBCs and other applicable review bodies in 
accordance with the policies and procedures of these review bodies. Serious deviations that are 
associated with increased risk to one or more study participants and/or significant impacts on the 
integrity of study data must also be reported within IMPAACT, following procedures specified in 
Section 12 of the IMPAACT Manual of Procedures. 
 

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13.5 
ClinicalTrials.gov 
 
This protocol is not subject to the United States Food and Drug Administration Amendments Act 
of 2007 (FDAAA). However, it will be registered in ClinicalTrials.gov to meet International 
Committee of Medical Journal Editors requirements. 
 
 
14 
PUBLICATIONS 
 
All presentations and publications of data collected in this study are governed by IMPAACT 
policies, which are available in the IMPAACT Network MOP, and NIAID policies. Any 
presentation, abstract, or manuscript will be made available for review by the pharmaceutical and 
NIAID sponsors prior to submission. Publication or presentation approval will conform to any 
CRADA or other collaborative agreement in place. 
 
 

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15 
REFERENCES 
 
1. 
Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, et al. Global 
burden of acute lower respiratory infections due to respiratory syncytial virus in young 
children: a systematic review and meta-analysis. Lancet. 2010;375(9725):1545-55. 
2. 
Wright PF, Karron RA, Belshe RB, Shi JR, Randolph VB, Collins PL, et al. The absence 
of enhanced disease with wild type respiratory syncytial virus infection occurring after 
receipt of live, attenuated, respiratory syncytial virus vaccines. Vaccine. 
2007;25(42):7372-8. 
3. 
Collins PL, Murphy BR. New generation live vaccines against human respiratory 
syncytial virus designed by reverse genetics. ProcAm ThoracSoc. 2005;2(2):166-73. 
4. 
Bermingham A, Collins PL. The M2-2 protein of human respiratory syncytial virus is a 
regulatory factor involved in the balance between RNA replication and transcription. 
ProcNatlAcadSciUSA. 1999;96(20):11259-64. 
5. 
Karron RA, Luongo C, Thumar B, Loehr KM, Englund JA, Collins PL, et al. A gene 
deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with 
improved antibody responses in children. Science translational medicine. 
2015;7(312):312ra175. 
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. The New England 
journal of medicine. 2009;360(6):588-98. 
7. 
Hall CB. Respiratory syncytial virus and parainfluenza virus. The New England journal 
of medicine. 2001;344(25):1917-28. 
8. 
Martinez FD. Respiratory syncytial virus bronchiolitis and the pathogenesis of childhood 
asthma. PediatrInfect DisJ. 2003;22(2 Suppl):S76-S82. 
9. 
Collins PL, Karron RA. Respiratory syncytial virus and metapneumovirus. In: Knipe 
DM, Howley PM, Cohen JI, Griffin DE, Lamb RA, Martin MA, et al., editors. Fields 
Virology, Sixth Edition. 1. Sixth ed. Philadelphia: Lippincott Williams & Wilkins; 2013. 
p. 1086-123. 
10. 
Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, et al. Respiratory 
syncytial virus disease in infants despite prior administration of antigenic inactivated 
vaccine. Am J Epidemiol. 1969;89(4):422-34. 
11. 
Collins PL, Murphy BR. Vaccines against Human Respiratory Syncytial Virus. 
Respiratory Syncytial Virus. 2007;14:233-78. 
12. 
Acosta PL, Caballero MT, Polack FP. Brief history and characterization of enhanced 
respiratory syncytial virus disease. Clinical and Vaccine Immunology. 2015;23(3):189-
95. 
13. 
Karron RA, Wright PF, Belshe RB, Thumar B, Casey R, Newman F, et al. Identification 
of a recombinant live attenuated respiratory syncytial virus vaccine candidate that is 
highly attenuated in infants. J Infect Dis. 2005;191(7):1093-104. 
14. 
Hendry RM, Burns JC, Walsh EE, Graham BS, Wright PF, Hemming VG, et al. Strain-
specific serum antibody responses in infants undergoing primary infection with 
respiratory syncytial virus. J Infect Dis. 1988;157(4):640-7. 
15. 
Johnson PR, Jr., Olmsted RA, Prince GA, Murphy BR, Alling DW, Walsh EE, et al. 
Antigenic relatedness between glycoproteins of human respiratory syncytial virus 
subgroups A and B: evaluation of the contributions of F and G glycoproteins to 
immunity. J Virol. 1987;61(10):3163-6. 

IMPAACT 2018, Version 1.0 
Page 83 of 106 
15 June 2017 
16. 
Collins PL, Hill MG, Camargo E, Grosfeld H, Chanock RM, Murphy BR. Production of 
infectious human respiratory syncytial virus from cloned cDNA confirms an essential 
role for the transcription elongation factor from the 5' proximal open reading frame of the 
M2 mRNA in gene expression and provides a capability for vaccine development. 
ProcNatlAcadSciUSA. 1995;92(25):11563-7. 
17. 
Luongo C, Winter CC, Collins PL, Buchholz UJ. Increased genetic and phenotypic 
stability of a promising live-attenuated respiratory syncytial virus vaccine candidate by 
reverse genetics. J Virol. 2012;86(19):10792-804. 
18. 
Luongo C, Winter CC, Collins PL, Buchholz UJ. Respiratory syncytial virus modified by 
deletions of the NS2 gene and amino acid S1313 of the L polymerase protein is a 
temperature-sensitive, live-attenuated vaccine candidate that is phenotypically stable at 
physiological temperature. J Virol. 2013;87(4):1985-96. 
19. 
Whitehead SS, Bukreyev A, Teng MN, Firestone CY, St Claire M, Elkins WR, et al. 
Recombinant respiratory syncytial virus bearing a deletion of either the NS2 or SH gene 
is attenuated in chimpanzees. J Virol. 1999;73(4):3438-42. 
20. 
Valarcher JF, Furze J, Wyld S, Cook R, Conzelmann KK, Taylor G. Role of alpha/beta 
interferons in the attenuation and immunogenicity of recombinant bovine respiratory 
syncytial viruses lacking NS proteins. J Virol. 2003;77(15):8426-39. 
21. 
Collins PL, Hill MG, Johnson PR. The two open reading frames of the 22K mRNA of 
human respiratory syncytial virus: sequence comparison of antigenic subgroups A and B 
and expression in vitro. J GenVirol. 1990;71 ( Pt 12):3015-20. 
22. 
Ahmadian G, Randhawa JS, Easton AJ. Expression of the ORF-2 protein of the human 
respiratory syncytial virus M2 gene is initiated by a ribosomal termination-dependent 
reinitiation mechanism. EMBO J. 2000;19(11):2681-9. 
23. 
Jin H, Cheng X, Zhou HZ, Li S, Seddiqui A. Respiratory syncytial virus that lacks open 
reading frame 2 of the M2 gene (M2-2) has altered growth characteristics and is 
attenuated in rodents. J Virol. 2000;74(1):74-82. 
24. 
Teng MN, Whitehead SS, Bermingham A, St CM, Elkins WR, Murphy BR, et al. 
Recombinant respiratory syncytial virus that does not express the NS1 or M2-2 protein is 
highly attenuated and immunogenic in chimpanzees. J Virol. 2000;74(19):9317-21. 
25. 
Karron RA, Wright PF, Crowe JE, Jr., Clements-Mann ML, Thompson J, Makhene M, et 
al. Evaluation of two live, cold-passaged, temperature-sensitive respiratory syncytial 
virus vaccines in chimpanzees and in human adults, infants, and children. J Infect Dis. 
1997;176(6):1428-36. 
26. 
Wright PF, Karron RA, Belshe RB, Thompson J, Crowe JE, Jr., Boyce TG, et al. 
Evaluation of a live, cold-passaged, temperature-sensitive, respiratory syncytial virus 
vaccine candidate in infancy. J Infect Dis. 2000;182(5):1331-42. 
27. 
Wright PF, Karron RA, Madhi SA, Treanor JJ, King JC, O'Shea A, et al. The interferon 
antagonist NS2 protein of respiratory syncytial virus is an important virulence 
determinant for humans. J Infect Dis. 2006;193(4):573-81. 
28. 
Wright PF, Karron RA, Madhi SA, Treanor JJ, King JC, O'Shea A, et al. The interferon 
antagonist NS2 protein of respiratory syncytial virus is an important virulence 
determinant for humans. J Infect Dis. 2006;193(4):573-81. 
29. 
Crowe JE, Jr., Bui PT, London WT, Davis AR, Hung PP, Chanock RM, et al. 
Satisfactorily attenuated and protective mutants derived from a partially attenuated cold-

IMPAACT 2018, Version 1.0 
Page 84 of 106 
15 June 2017 
passaged respiratory syncytial virus mutant by introduction of additional attenuating 
mutations during chemical mutagenesis. Vaccine. 1994;12(8):691-9. 
30. 
Whitehead SS, Juhasz K, Firestone CY, Collins PL, Murphy BR. Recombinant 
respiratory syncytial virus (RSV) bearing a set of mutations from cold-passaged RSV is 
attenuated in chimpanzees. J Virol. 1998;72(5):4467-71. 
31. 
Crowe JE, Jr., Bui PT, Davis AR, Chanock RM, Murphy BR. A further attenuated 
derivative of a cold-passaged temperature-sensitive mutant of human respiratory 
syncytial virus retains immunogenicity and protective efficacy against wild-type 
challenge in seronegative chimpanzees. Vaccine. 1994;12(9):783-90. 
32. 
Crowe JE, Jr., Firestone CY, Whitehead SS, Collins PL, Murphy BR. Acquisition of the 
ts phenotype by a chemically mutagenized cold-passaged human respiratory syncytial 
virus vaccine candidate results from the acquisition of a single mutation in the 
polymerase (L) gene. Virus Genes. 1996;13(3):269-73. 
33. 
Whitehead SS, Firestone CY, Collins PL, Murphy BR. A single nucleotide substitution in 
the transcription start signal of the M2 gene of respiratory syncytial virus vaccine 
candidate cpts248/404 is the major determinant of the temperature-sensitive and 
attenuation phenotypes. Virology. 1998;247(2):232-9. 
34. 
Juhasz K, Whitehead SS, Boulanger CA, Firestone CY, Collins PL, Murphy BR. The two 
amino acid substitutions in the L protein of cpts530/1009, a live-attenuated respiratory 
syncytial virus candidate vaccine, are independent temperature-sensitive and attenuation 
mutations. Vaccine. 1999;17(11-12):1416-24. 
35. 
Juhasz K, Whitehead SS, Bui PT, Biggs JM, Crowe JE, Boulanger CA, et al. The 
temperature-sensitive (ts) phenotype of a cold-passaged (cp) live attenuated respiratory 
syncytial virus vaccine candidate, designated cpts530, results from a single amino acid 
substitution in the L protein. J Virol. 1997;71(8):5814-9. 
36. 
Palivizumab, a Humanized Respiratory Syncytial Virus Monoclonal Antibody, Reduces 
Hospitalization From Respiratory Syncytial Virus Infection in High-risk Infants. 
Pediatrics. 1998;102(3):531-7. 
37. 
McFarland EJ, Buchholz UJ, Muresan P, Cunningham CK, Luongo C, Thumar B, et al., 
editors. High Infectivity of recombinant live-attenuated respiratory syncytial virus 
vaccine RSV LID ΔM2-2 in RSV-seronegativeinfants and children. ID Week Advancing 
Science, Improving Care; 2015; San Diego, CA. 
38. 
American Academy of Pediatrics, Committee on Practice and Ambulatory Medicine. 
Recommendations for Preventive Pediatric Health Care. Pediatrics. 2007;120(6):1376. 
39. 
Siberry GK, ener-West M, Schappell E, Karron RA. Comparison of temple temperatures 
with rectal temperatures in children under two years of age. ClinPediatr(Phila). 
2002;41(6):405-14. 
40. 
Whitehead SS, Juhasz K, Firestone CY, Collins PL, Murphy BR. Recombinant 
respiratory syncytial virus (RSV) bearing a set of mutations from cold-passaged RSV is 
attenuated in chimpanzees. J Virol. 1998;72(5):4467-71. 
41. 
Gharpure MA, Wright PF, Chanock RM. Temperature-sensitive mutants of respiratory 
syncytial virus. J Virol. 1969;3(4):414-21. 
42. 
National Institutes of Health. Guidelines for the Inclusion of Women and Minorities as 
Subjects in Clinical Research. Federal Register. 1994 March 18. Report No. 
43. 
National Institutes of Health. NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects. 1998 March 6. Report No. 
 

 
IMPAACT 2018, Version 1.0 
Page 85 of 106 
15 June 2017 
APPENDICES 
 
Appendix I: Tables Referenced in the Background Section 
 
Table 11: Viral Titers of Nasopharyngeal Swab Samples from African Green Monkeys Inoculated with the CTM 
RSV ΔNS2/Δ1313/I1314L, Lot#006A, or with recombinant wt RSV rA2 
 
Group Virus Test Articlea 
AGM  ID 
NP virus titer (log10 PFU/mL) on indicated daysb 
Peak 
virus  
titer 
Sum of 
daily 
titers c 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
14 
TM1 
RSV ΔNS2/Δ1313 
I1314L 
CTM RSV#006A d 
7648 
- 
- 
1.7 
1.2 
1.8 
2.9 
2.2 
4.0 
3.7 
3.4 
- 
4.0 
22.0 
7692 
- 
- 
- 
- 
1.9 
- 
- 
3.3 
1.0 
1.5 
- 
3.3 
10.2 
7714 
- 
- 
0.7 
- 
1.3 
- 
- 
1.4 
2.4 
2.8 
- 
2.8 
10.7 
7764 
- 
- 
- 
0.7 
0.7 
1.0 
- 
2.3 
1.2 
2.9 
- 
2.9 
10.5 
 
 
Mean: 
 
 
 
 
 
 
 
 
 
 
 
3.2 
13.3 
TM2 
RSV rA2e 
wt RSV 
7638f 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
0.7 
3.9 
7744 
- 
0.7 
2.1 
3.3 
3.4 
3.4 
2.5 
3.4 
2.4 
1.2 
- 
3.4 
23.1 
7781 
1.0 
- 
1.0 
2.1 
2.6 
1.8 
3.4 
2.9 
1.6 
0.7 
- 
3.4 
17.1 
7799 
- 
1.5 
3.7 
3.3 
2.5 
3.0 
3.3 
2.9 
2.6 
1.2 
- 
3.7 
24.7 
 
 
Mean: 
 
 
 
 
 
 
 
 
 
 
 
3.5 
21.7 
a Monkeys were inoculated intranasally and intratracheally. with 106 PFU of the indicated virus in a 1 mL inoculum per site (total dose =2x106 PFU/AGM). 
b Virus titrations were performed on Vero cells at 32°C. The lower limit of detection was 1.0 log10 PFU/mL. Samples with no detectable virus are represented as “-“. Peak titers 
for each animal are underlined. The results show that RSV ΔNS2/Δ1313/I1314L is strongly restricted in the URT of AGMs compared to RSV rA2. 
c The sum of daily titers is used as an estimate for the magnitude of shedding (area under the curve). A value of 0.35 was used for samples with no detectable virus.  
d CTM vial numbers 0004, 1377, 2505. 
e wt RSV, rA2 D53#51(4), 8/13/07 
f This AGM reacted to each anaesthesia by emesis. It is likely that the emesis interfered with the efficacy of the intranasal inoculation. Based on this assumption, NP shedding 
results from this animal were excluded from calculations of means and from statistical analysis. 
 
 
 
 
 
 

 
IMPAACT 2018, Version 1.0 
Page 86 of 106 
15 June 2017 
 
 
 
Table 12: Viral Titer of Tracheal Lavage samples from African Green Monkeys Inoculated with the CTM RSV 
ΔNS2/Δ1313/I1314L, Lot RSV#006A, or with recombinant wt RSV rA2a 
 
 
Group 
Virus Test Articlea 
AGM  ID 
TL virus titer (log10 PFU/mL) on indicated dayb 
Peak virus 
titer 
Sum of daily  
titers c 
2 
4 
6 
8 
10 
14 
 
 
TM1 
RSV ΔNS2/Δ1313/I1314L 
CTM RSV#006A d 
7648 
- 
- 
- 
1.5 
- 
- 
1.5 
5.0 
7692 
- 
- 
- 
1.0 
1.7 
- 
1.7 
5.5 
7714 
- 
- 
- 
- 
- 
- 
- 
4.2 
7764 
- 
- 
- 
1.3 
- 
- 
1.3 
4.8 
Mean: 
 
 
 
 
 
 
1.4 
4.9 
TM2 
RSV rA2 e 
wt RSV 
7638 
2.3 
3.1 
3.6 
3.0 
- 
- 
3.6 
13.3 
7744 
2.3 
2.7 
2.3 
2.4 
1.0 
- 
2.7 
11.4 
7781 
3.0 
3.2 
1.9 
2.7 
- 
- 
3.2 
12.2 
7799 
3.7 
4.1 
4.7 
3.3 
2.1 
- 
4.7 
18.5 
Mean: 
 
 
 
 
 
 
3.5 
13.9 
a Monkeys were inoculated intranasally and intratracheally with 106 PFU of the indicated virus in a 1 mL inoculum per site (total dose =2x106 PFU/AGM). 
b Virus titrations were performed on Vero cells at 32°C. The lower limit of detection was 1.0 log10 PFU/mL. Samples with no detectable virus are represented as “-“. Underlined 
value indicates maximum titer for each animal. As expected, the highly temperature sensitive virus RSV ΔNS2/Δ1313/I1314L did not replicate in the lower respiratory tract of 
AGMs (body temperature: 39°C). 
c The sum of daily titers is used as an estimate for the magnitude of shedding (area under the curve). Values of 0.7 are used for samples with no detectable virus.  
d CTM vial numbers 0004, 1377, 2505 
e wt RSV, rA2 D53#51(4), 8/13/07 
 
 

 
  
 
IMPAACT 2018, Version 1.0 
Page 87 of 106 
15 June 2017 
Table 13:  Neutralizing antibody titers of AGMs inoculated with CTM RSV ΔNS2/Δ1313/I1314L, Lot RSV#006Aa, or 
with recombinant wt RSV rA2b 
Group 
Virus Test Article 
AGM  ID 
RSV Neutralization Titer      
 (Log2 of reciprocal) on days 
0 
21 
28 
TM1 
RSV ΔNS2 Δ1313 I1314L 
Lot RSV #006Aa  
7648 
<3.3 
6.4 
6.8 
7692 
<3.3 
6.6 
6.4 
7714 
<3.3 
4.4 
6.1 
7764 
<3.3 
5.5 
6.0 
 
 
Mean: 
<3.3 
5.8 
6.3 
TM2 
RSV rA2b 
wt RSV  
7638 
<3.3 
7.0 
6.6 
7744 
<3.3 
6.5 
7.9 
7781 
<3.3 
8.0 
8.6 
7799 
<3.3 
7.6 
7.8 
 
 
Mean: 
<3.3 
7.3 
7.8 
a Lot RSV#006A, vial numbers 0004, 1377, 2505 
b  wt RSV, rA2 D53#51(4), 8/13/07. The lower limit of detection of the 60% Plaque Reduction assay is 3.3 (Log2 of the dilution reciprocal). Samples below the lower limit of 
detection are recorded as “-“.  
 
 

 
  
 
IMPAACT 2018, Version 1.0 
Page 88 of 106 
15 June 2017 
Table 14:  Viral titers of nasopharyngeal swab samples from African green monkeys (AGMs) inoculated with 
recombinant wildtype RSV A2, MEDI/M2-2, or RSV 276a 
RSV Vaccine 
candidate 
AGM ID 
NP virus titer (log10 PFU/mL) on indicated daysb   
Duration of 
sheddingc 
Peak 
virus  
titer 
Sum of 
daily titers 
c 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
12/14 
RSV A2 
CTM 
RSV#004A 
7209 
- 
- 
3.1 
4.4 
4.4 5.2 3.6 4.1 3.4 
2.0 
- 
8 
5.2 
31.1 
7467 
- 
0.7 
2.8 
3.8 
2.1 3.9 3.4 3.2 1.9 
2.0 
- 
9 
3.9 
24.4 
7468 
- 
1.7 
2.6 
4.0 
3.9 3.7 3.6 2.7 3.6 
2.6 
- 
9 
4.0 
29.0 
7492 
0.7 1.2 
2.3 
3.9 
2.9 3.9 3.9 2.4 1.7 
1.0 
- 
10 
3.9 
24.2 
 
Mean: 
 
 
 
 
 
 
 
 
 
 
 
9 
4.2 
27.2 
RSV MEDI/M2-2
CTM 
RSV#002A  
Y655 
- 
- 
- 
2.1 
1.2 1.2 1.5 1.5 1.2 
- 
- 
6 
2.1 
10.3 
Y684 
- 
- 
0.7 
0.7 
1.0 
- 
1.6 
- 
- 
- 
- 
5 
1.6 
6.5 
Y609 
- 
- 
- 
0.7 
2.2 1.6 2.2 2.1 1.0 
- 
- 
6 
2.2 
11.1 
Y658 
- 
- 
- 
1.4 
- 
- 
- 
- 
- 
- 
- 
1 
1.4 
4.9 
 
Mean: 
 
 
 
 
 
 
 
 
 
 
 
5 
1.8 
8.3 
RSV 276 
Exp. Lot 
8918 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
0 
- 
3.9 
8902 
- 
1.5 
2.0 
2.9 
2.5 3.0 3.1 2.5 1.4 
1.3 
- 
9 
3.1 
21.0 
8913 
- 
- 
- 
- 
- 
0.7 1.4 1.0 
- 
- 
- 
3 
1.4 
6.0 
8952 
- 
- 
- 
- 
0.7 0.7 1.5 
- 
- 
1.2 
- 
6 
1.5 
6.5 
 
Mean: 
 
 
 
 
 
 
 
 
 
 
 
5 
1.6 
9.3 
RSV 276 
CTM 
RSV#014A 
8903 
- 
- 
- 
0.7 
- 
1.3 
- 
- 
- 
- 
- 
3 
1.3 
5.2 
8900 
- 
- 
0.7 
- 
1.0 1.0 1.3 1.0 1.0 
1.0 
- 
8 
1.3 
8.4 
9025 
- 
- 
- 
- 
- 
- 
1.2 
- 
0.7 
- 
- 
3 
1.2 
5.0 
8986 
- 
- 
- 
2.3 
1.0 1.0 1.2 
- 
0.7 
- 
- 
6 
2.3 
8.3 
 
Mean: 
 
 
 
 
 
 
 
 
 
 
 
5 
1.5 
6.7 
a AGMs were inoculated by the combined intranasal and intratracheal routes with 106 PFU of the indicated virus in a 1 mL inoculum per site (total dose: 2x106 
PFU per animal). Results from four individual studies are shown side-by-side. Results from a study of recombinant wildtype challenge virus lot (RSV A2 
RSV#004A) are included for comparison. Studies were performed in AGMs from the same origin, following the same general sampling schedule for all studies. 
The AGM studies were approved by the Animal Care and Use Committee of NIAID, NIH. CTM, Clinical Trial Material; Exp. Lot, Experimental Lot. CTM RSV 
275, RSV# 014A, vial numbers 0019-0022, 1269, 1271-1274, 2483-2487. 
b Combined nasopharyngeal (NP) swabs were placed in 2 mL of L-15 medium with sucrose phosphate buffer as stabilizer. Virus titrations were performed on 
Vero cells at 37°C.  The lower limit of detection was 0.7 log10 PFU/mL. Samples with no detectable virus are represented as “-“.  Peak titers for each animal 
are underlined. Results of MEDI/M2-2 and RSV 276 are not significantly different (ANOVA, Tukey post-hoc analysis). 
c The period of days from the first to the last day on which virus was detected, including negative days (if any) in between.  
d The sum of daily titers is used as an estimate for the magnitude of shedding (area under the curve).  A value of 0.35 was used for samples with no detectable 
virus. 

 
  
 
IMPAACT 2018, Version 1.0 
Page 89 of 106 
15 June 2017 
Table 15: Viral titers of tracheal lavage samples from AGMs inoculated with recombinant wildtype RSV A2,  
MEDI/M2-2, or RSV 276a 
RSV vaccine 
candidatea 
AGM ID 
Tracheal lavage virus titer (log10 PFU/mL) on 
indicated daysb 
Duration of 
shedding c 
Peak 
virus  
titer 
Sum of 
daily  
titers c 
 
2 
4 
6 
8 
10 
12/14 
 
 
 
RSV A2 
CTM 
RSV#004A 
7209 
3.0 
3.8 
4.3 
4.5 
2.6 
- 
11 
4.5 
18.9 
7467 
3.0 
3.0 
4.3 
3.4 
2.8 
- 
11 
4.3 
17.2 
7468 
2.5 
1.7 
2.9 
3.0 
2.9 
- 
11 
3.0 
13.6 
7492 
1.9 
3.5 
4.7 
3.3 
- 
- 
9 
4.7 
14.8 
 
Mean: 
 
 
 
 
 
 
11 
4.1 
16.1 
RSV MEDI/M2-2 
CTM 
RSV#002A  
Y655 
- 
0.7 
1.0 
2.0 
- 
- 
7 
2.0 
5.8 
Y684 
0.7 
- 
2.3 
- 
- 
- 
7 
2.3 
5.8 
Y609 
- 
2.3 
3.3 
1.3 
- 
- 
7 
3.3 
9.1 
Y658 
1.2 
1.0 
2.9 
0.7 
- 
- 
9 
2.9 
7.2 
 
Mean: 
 
 
 
 
 
 
8 
2.6 
7.0 
RSV 276 
Exp. Lot 
8918 
- 
1.7 
2.3 
1.6 
1.0 
- 
9 
2.3 
8.0 
8902 
2.2 
1.6 
2.9 
2.1 
- 
- 
9 
2.9 
10.3 
8913 
- 
- 
3.2 
1.3 
- 
- 
5 
3.2 
7.3 
8952 
1.8 
2.1 
1.6 
1.8 
- 
- 
9 
2.1 
8.8 
 
Mean: 
 
 
 
 
 
 
8 
2.6 
8.6 
RSV 276 
CTM 
RSV#014A 
8903 
- 
2.6 
3.8 
1.3 
- 
- 
7 
3.8 
9.9 
8900 
1.8 
- 
2.4 
- 
- 
- 
7 
2.4 
7.0 
9025 
2.6 
- 
1.3 
- 
1.0 
- 
11 
2.6 
7.0 
8986 
2.3 
1.7 
3.9 
- 
- 
- 
7 
3.9 
10.0 
 
Mean: 
 
 
 
 
 
 
8 
3.2 
8.5 
 
a AGMs were inoculated by the combined intranasal and intratracheal routes with 106 PFU of the indicated virus in a 1 mL inoculum per site (total dose: 2 x 106 
PFU per animal). Results from four individual studies are shown side-by-side. Results from a study of recombinant wildtype challenge virus lot (RSV A2 
RSV#004A) are included for comparison.  Studies were performed in AGMs from the same origin, following the same general sampling schedule for all studies. 
The AGM studies were approved by the Animal Care and Use Committee of NIAID, NIH. CTM, Clinical Trial Material; Exp. Lot, Experimental Lot. CTM RSV 
275, RSV# 014A, vial numbers 0019-0022, 1269, 1271-1274, 2483-2487.  
b On days 2, 4, 6, 8, 10, and 12 or 14, tracheal lavage was performed with 3 mL of PBS. Virus titrations were performed on Vero cells at 37°C.  The lower limit 
of detection was 1.0 log10 PFU/mL of lavage solution, or log10 PFU/mL for the MEDIM2-2 study.  Samples with no detectable virus are represented as “-“.  
Peak titers for each animal are underlined. Results of MEDI/M2-2 and RSV 276 are not significantly different (ANOVA, Tukey post-hoc analysis). 
c The period of days from the first to the last day on which virus was detected, including negative days (if any) in between. 
d The sum of daily titers is used as an estimate for the magnitude of shedding (area under the curve).  A value of 0.7 was used for samples with no detectable 
virus. 

 
  
 
IMPAACT 2018, Version 1.0 
Page 90 of 106 
15 June 2017 
Table 16: Neutralizing antibody titers of AGMs inoculated with recombinant wildtype RSV A2, MEDI/M2-2, or 
RSV 276a 
RSV Vaccine candidate 
AGM ID 
Neutralizing antibody titers  
(PRNT60, reciprocal log2) on indicated daysb 
0 
21/22 
28 
RSV A2 
CTM 
RSV#004A 
7209 
<3.3 
7.1 
6.7 
7467 
<3.3 
8.1 
8.7 
7468 
<3.3 
5.9 
5.9 
7492 
<3.3 
7.7 
8.8 
 
Mean: 
<3.3 
7.2 
7.5 
RSV MEDI/M2-2 
CTM 
RSV#002A  
Y655 
<3.3 
5.2 
5.1 
Y684 
<3.3 
6.5 
5.5 
Y609 
<3.3 
5.4 
5.2 
Y658 
<3.3 
5.7 
5.7 
 
Mean: 
<3.3 
5.7 
5.4 
RSV 276 
Exp. Lot 
8918 
<3.3 
6.1 
6.2 
8902 
<3.3 
8.4 
8.8 
8913 
<3.3 
8.8 
8.9 
8952 
<3.3 
9.7 
9.9 
 
Mean: 
<3.3 
8.3 
8.5 
RSV 276 
CTM 
RSV#014A 
8903 
<3.3 
9.0 
10.1 
8900 
<3.3 
8.7 
9.6 
9025 
<3.3 
6.4 
6.9 
8986 
<3.3 
6.3 
6.3 
 
Mean: 
<3.3 
7.6 
8.2 
a  AGMs were inoculated intranasally and intratracheally with 106 PFU of the indicated virus in a 1 mL inoculum per site (total dose = 106.3 
PFU per animal). 
b On days 0, 21 or 22, and 28 p.i., serum was obtained. Neutralizing antibody titers were determined in a 60% plaque reduction neutralization 
assay. The lower limit of detection was 3.3 (1:10).

 
  
 
IMPAACT 2018, Version 1.0 
Page 91 of 106 
15 June 2017 
Appendix II: Schedule of Events: Screening, Acute Phase, and Post-Acute Phase  
 
 
 
 
ACUTE PHASE 
 
 
 
POST-ACUTE 
PHASE 
 
 
Screening 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Day 15 
Day 16 
Day 17 
Day 18-27 
(contact 
each day) 
Day 28 
Day 29 
Day 30-55 
Day 56  
Illness 
Visit  
Early DC 
In person visit 
X 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
Non-visit contact 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
Per 6.5 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim History 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Per 6.5 
X 
X 
X 
Physical exam (full) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment 
(focused PE) 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
Administer study 
product 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for: 
immunologic assays 
5mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5mL 
 
5mL 
Blood for: cellular 
immune assay 
(viable PBMCs) 
3mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3mL 
 
3mL 
Nasosorption SAM 
strip for antibody 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Nasal wash for: 
 RSV antibody 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Nasal wash for: 
viral detection & 
quantification 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
Request 
adventitious agent 
assay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Total blood volume 
8mL 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
8mL 
-- 
8mL 

IMPAACT 2018, Version 1.0 
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15 June 2017 
Appendix III: Schedule of Events: RSV Pre-season Sampling, seasonal 
surveillance, and Post-season Sampling 
 
 
 
Pre-RSV season 
Weekly contact 
Post-RSV season 
Illness 
Visit 
Early 
DC 
Visit Period 
Oct 1st* to Oct 31st*  
Nov 1st* to Mar 31st 
Apr 1st to Apr 30th 
 
 
Clinical assessment 
(focused PE) 
 
 
 
X 
 
Interim history 
 
X 
 
X 
X 
LABORATORY EVALUATIONS 
Blood for: 
immunologic assays 
5 mL 
 
5 mL 
 
5 mL 
Blood for: cellular 
immune assay (viable 
PBMCs) 
3 mL 
 
3 mL 
 
3 mL 
Nasosorption SAM 
strip for antibody 
X 
 
X 
 
X 
Nasal wash for: 
viral detection & 
quantification 
 
 
 
X 
 
Request adventitious 
agent assay  
 
 
 
X 
 
TOTAL BLOOD 
VOLUME 
8 mL 
-- 
8 mL 
-- 
8 mL 
*These dates apply to most sites but may differ for those with local RSV seasons that start earlier. 
 

IMPAACT 2018, Version 1.0 
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Appendix IV: Definitions of Solicited Adverse Events 
 
Event 
Defined 
Fever 
Temporal temperatures ≥100.0oF unconfirmed by rectal temp -or-  
Rectal temperature of ≥100.4oF. 
Acute Otitis Media1 
Loss of tympanic membrane landmarks, accompanied by erythema and loss 
of mobility. May or may not be associated with fever or other respiratory 
symptoms. Confirmed with tympanometry if possible. 
Upper Respiratory Tract Illness (URI) 
Rhinorrhea 
Two or more consecutive days of clear or purulent discharge from the 
nares.  
Note: Not associated with crying, change of room temperature, or eating 
and drinking. 
Pharyngitis1 
Pharyngeal erythema accompanied by exudate or pharyngeal erythema with 
enlarged tender lymph nodes.   
Note: May be associated with sore throat, or painful or difficult swallowing. 
Cough without LRI  
Two or more consecutive days of 3 or more episodes of cough during a 15-
minute timed observation period, or cough awakens child from sleep.  
Note: Not associated with eating, drinking or choking. 
Hoarseness 
An unnaturally deep or rough quality of voice. 
Lower Respiratory Tract Illness (LRI) 
Wheezing2,3 
Sustained, high pitched, musical breath sounds, especially during the 
expiratory phase, which do not clear with cough. 
Pneumonia1,2,3 
Rales and crackles, originating in the lower respiratory tract, usually 
accompanied by tachypnea, which do not clear with cough. May be 
confirmed by x-ray showing areas of consolidation. 
Laryngotracheobronchitis 
(croup) 1,2,3 
Barking cough, hoarseness, and inspiratory stridor 
Rhonchi2,3 
Coarse breath sounds which are not transmitted noises from the upper 
airway and do not clear with cough. 
Rales2,3 
Abnormal lung sound heard through a stethoscope. Rales may be sibilant 
(whistling), dry (crackling) or wet (more sloshy) depending on the amount 
and density of fluid refluxing back and forth in the air passages. 
1 Diagnosis must be made by a medical professional 
2 Must be sustained over 20 minutes. 
3 Clinical assessment must be made by a medical professional and confirmed by a second medical professional, if possible. 
 
NOTE: Solicited AEs will only be recorded on eCRFs according to criteria defined in Section 7.2

IMPAACT 2018, Version 1.0 
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Appendix V: RSV Seasonality in Baltimore 
 
 
 
 
 
 
 
 
All specimens collected and tested at Johns Hopkins Hospital through 10 March 2016 
 
 

IMPAACT 2018, Version 1.0 
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Appendix VI: Sample Informed Consent Form 
 
DIVISION OF AIDS  
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS 
(IMPAACT) NETWORK  
 
For protocol: 2018 
Randomized Phase I Study of the Infectivity, Safety, and Immunogenicity of a Single Dose of the 
Recombinant Live-Attenuated Respiratory Syncytial Virus (RSV) Vaccines RSV ΔNS2/Δ1313/I1314L or 
RSV 276 or Placebo, Delivered as Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age 
 
 Version 1.0, dated 15 June 2017 
 
SHORT TITLE FOR IMPAACT 2018: Safety and Immunogenicity of a Single Dose of the RSV 
ΔNS2/Δ1313/I1314L or RSV 276 Vaccine 
 
INTRODUCTION 
 
You are being asked to allow your baby to take part in this research study to test vaccines to prevent 
Respiratory Syncytial Virus (RSV) illness in infants. This study is sponsored by the National Institutes of 
Health (NIH). The doctor in charge of this study at this site is: [Site: insert name of site investigator].  
Before you decide if you want your baby 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 clinical research staff will talk with 
you about this information. You are free to ask questions about this study at any time. If you agree to 
allow your baby to take part in this study, you will be asked to sign this consent form. You will get a copy 
to keep. 
 
WHY IS THIS STUDY BEING DONE? 
 
The study is being done to look at the safety (side effects) and antibody (germ fighters) response of 
infants to a single dose of one of two vaccines against a virus called respiratory syncytial virus, or RSV. 
The study will look at the amount of vaccine virus that is in your child’s nose over time. It will tell us 
how stable and strong the vaccine was during the study. This research study is testing two experimental 
vaccines. These vaccines have not been licensed by the U.S. Food and Drug Administration (FDA). Your 
baby was chosen to be in this study because your baby is at least 6 months (180 days) old and less than 25 
months (750 days) old, has not had RSV, and is healthy.  
 
 
RSV is a virus (germ) that can cause breathing problems in infants and children. Symptoms of infection 
with RSV may include: 
• 
Fever 
• 
Runny nose 
• 
Sore throat 
• 
Ear infection 
• 
Cough  
• 
Croup (barky cough with hoarseness) 
 
RSV can cause serious lung infections such as pneumonia and wheezing. At this time, there is no 
approved vaccine to prevent RSV illness. 
 
 
 

 
  
 
IMPAACT 2018, Version 1.0 
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Doctors who develop vaccines at the NIH have made live virus vaccines that may help prevent RSV 
illness in babies and children. A live virus vaccine contains a weakened, live virus that is made to help 
your body respond in a way that will protect you from getting sick from the virus. This is called an 
“immune response.” The investigational RSV vaccines in this study contain a live, weakened form of 
RSV and are given as nose drops. One of thevaccines has not been tested in humans. However, other RSV 
vaccines very similar to this one have been tested in both adults and children. The other vaccine has been 
tested in humans in one other research study. There were not many side effects, and there was an immune 
response. 
  
We are asking you to allow your baby to participate in this study. If you agree, we will give your baby 
either 1 dose of one of the vaccines or 1 dose of placebo. The placebo has no vaccine in it. The placebo is 
made of water, salt, vitamins, and sugar that is gentle on the inside of the nose. It is sterile and approved 
for use on people. Approximately 80 babies who have not already had an illness caused by RSV virus will 
take part in the study.  
 
WHAT DOES MY BABY HAVE TO DO IF HE/SHE IS IN THIS STUDY? 
 
The next few paragraphs provide an overview of the study procedures. After that, there are lists of the 
specific procedures that will be completed at different visits during the study.  
 
At the first visit, your baby’s blood will be tested to see if your baby has had RSV in the past. You will be 
told the result of the test. If your baby goes on the study, you will be told whether he/she got vaccine or 
placebo after the end of the study in the spring. You will not receive information about your baby’s 
response to the vaccine, but you will receive a summary of the overall response to the vaccine for 
everyone in the study. 
 
If you agree to allow your baby to take part in this study, you will be asked some questions to be sure 
he/she can be in this study.   
 
Your baby cannot take part in this study if he/she already has antibodies against RSV, which means 
he/she already had the RSV illness, lives with people who have weak immune systems, or is not well. 
Your baby cannot take part in this study if he/she lives with or is in a daycare room with babies younger 
than 6 months of age, unless you are able to keep your baby out of daycare for 28 days after he/she 
receives vaccine or placebo. Your baby should not get any vaccines, including rotavirus vaccine for at 
least 14 days and other live vaccines for at least 28 days after getting the study vaccine or placebo. We 
ask that you talk with the study staff before your baby gets any routine vaccines for the 28 days after the 
study vaccine or placebo. We ask that your baby does not take part in any other experimental vaccine or 
drug studies for 8 weeks after they receive vaccine or placebo. We will ask you to review and sign this 
study consent prior to administering the vaccine/placebo to your baby. At that time, we will ask you to 
answer questions to see how well you understand the study. 
 
The vaccine/placebo will be given to your baby by gently squirting it inside his/her nose like nose drops. 
The amount is very small (a few drops). Your baby will need to lie down on his/her back for one minute 
after getting the vaccine/placebo. About 2 of each 5 enrolled babies will get one of the RSV vaccines, and 
about 2 of each 5 enrolled babies will get the other RSV vaccine. Approximately 1 of each 5 enrolled 
babies will get nose drops without vaccine (placebo). Whether your baby gets one of the vaccines or nose 
drops without vaccine (placebo) will be decided randomly by computer, like flipping a coin. Neither you 
nor the study doctors or study nurses will know whether your baby got one of the vaccines or placebo 
until the study ends, but this information can be made available to the study doctor if needed. 
 

 
  
 
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Your baby will be in this study until April of the year after he/she started the study. For the first 8 weeks 
after getting vaccine or placebo, your baby will be followed closely. During this part of the study, there 
will be about 9 days when your baby is seen by the clinical research staff and 21 days when your baby 
will not be seen but you will be contacted by telephone or email by the clinical research staff. Your baby 
will also be followed from [site: insert November 1st until March 31st unless other dates are specified in 
the MOP for your site] (the winter season after your baby gets the vaccine or placebo). During this winter 
time, we will contact you [site: insert the methods of contact] each week to ask about your baby's health 
and arrange for follow-up visits if needed.  
 
Study visits will last about 30 minutes, except on the day when your baby is screened and on the day 
he/she is given the vaccine or placebo; those 2 visits may take about 1 to 2 hours each. 
 
• 
If your baby has RSV symptoms, such as runny nose, sore throat, cough, fever or difficulty 
breathing, he/she might need to be seen for an evaluation, sometimes as soon as within 24 hours. 
• 
Study visits, except the visit where your baby gets the vaccine or placebo, may take place at your 
home or at one of the research sites/clinics. The visit where your baby receives vaccine or 
placebo must take place at one of the research sites/clinics where emergency equipment is 
available. 
• 
For temperature measurements, you will be asked to use a temporal thermometer, which is used 
on your baby’s forehead. You will measure forehead temperatures 3 times in a row, following the 
directions. The highest of the 3 readings will be recorded on a chart we will give to you. If your 
baby has a forehead temperature ≥100.0oF, you will be asked to check your baby’s rectal 
temperature within 20 minutes. Forehead and rectal thermometers will be given to you for use 
during the study. 
 
Screening Visit 
 
The purpose of the screening visit is to find out if your baby may enter the study. It will take about 1 to 2 
hours and will include: 
• 
the study staff telling you about the study and asking you questions to be sure you understand the 
study. 
• 
going over and signing the consent form.   
• 
going over your baby's medical history and doing a physical examination. The physical 
examination will include checking your baby’s temperature, pulse (heart rate), weight, length, and 
how fast your baby is breathing. If the physical examination results are not normal, the clinical 
research staff will tell you and refer your baby for follow-up care with your baby's primary 
medical provider. 
• 
answering questions about the health of your baby and people living in your house. 
• 
collecting a small amount of blood (about 2 teaspoons) to test for antibodies (germ fighters) 
against RSV and how your baby’s cells are reacting to RSV. If your baby had been screened for 
any study of an RSV vaccine developed by the NIH doctors, we may not need to collect this 
sample, because we may be able to use the results and blood from the other study.  
• 
if requested, giving written permission to review your baby’s medical records. 
• 
if we think your baby may be eligible for the study, your baby will be asked to return for a series 
of study visits, beginning with the visit when we will confirm that he/she is eligible and then give 
your baby the vaccine or placebo. 
 
Day Vaccine/Placebo is Given 
• 
We will confirm that your baby has not been ill recently and will check your baby’s temperature, 
pulse (heart rate), and how fast your baby is breathing. 

 
  
 
IMPAACT 2018, Version 1.0 
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15 June 2017 
• 
Your baby will have a nasal wash. To do this, we will gently squirt less than 2 tablespoons of salt 
water inside your baby’s nose and then collect it when it comes back out of the other side of the 
nose. This is done before the vaccine or placebo is given to check for other viruses and to check 
for antibodies in the nose. We will also use an absorbent strip to check for antibodies in the nose. 
The strip will be placed in your baby’s nose for about 30 seconds and then removed.  
• 
Your baby will receive 1 dose of vaccine or placebo given as nose drops using a small medicine 
dropper. Your baby will be lying on his/her back while we give the nose drops and will remain 
lying down for about 1 minute afterwards. Your baby can be in your lap during this time. 
• 
After the nose drops are given, we will watch your baby in the clinic for 30 minutes.  
• 
We will provide you with the dates of the rest of the visits and telephone/email contact days.  
• 
You will be given a forehead thermometer, a rectal thermometer, and a temperature chart to 
record your baby's temperature daily for 29 days (including the day the vaccine/placebo is given 
to your baby), and at any other time you are concerned about fever. 
 
Monitoring for 56 Days after Vaccine/Placebo is Given 
• 
Your baby will have study visits on Days 3, 5, 7, 10, 12, 14, 17, and 28  
(each ± 1 day), after the vaccine or placebo is given. Each visit will take about 30 minutes, and 
we will: 
o Check your baby's temperature, pulse, and breathing rate. 
o Do a brief clinical assessment. 
o Ask about your baby's health since the last visit. 
o Give your baby a nasal wash using less than 2 tablespoons of salt water, as described 
above, to check for the virus that’s in the study vaccine and other viruses. On Day 28 
only, the nasal wash will also be used to check for antibodies in the nose, and we will 
also use an absorbent strip to check for antibodies in the nose. The strip will be placed in 
your baby’s nose for about 30 seconds and then removed. 
o Because study visits will be less frequent after the first month, on Day 28, we will review 
when you should contact the study staff in the event your baby becomes ill during the 
following month. 
• 
The study nurse will contact you on Days 1, 2, 4, 6, 8, 9, 11, 13, 15, 16, and daily from Days 18 
to 27, and on Day 29. The study staff will ask you to report your baby’s temperatures and any 
illness your baby has had since the last visit or contact. The contact may be by telephone, text, or 
email, whichever you prefer.   
• 
Your baby will have a follow-up visit about 56 days after the study nose drops were given. At this 
visit, we will ask about your baby’s health since the last visit and take a small amount of blood 
(about 2 teaspoons) from your baby to measure antibodies (germ fighters) against RSV and how 
your baby’s blood cells are making antibodies. We will check your baby's temperature, pulse, and 
breathing rate. We will also use an absorbent strip to check for antibodies in the nose. The strip 
will be placed in your baby’s nose for about 30 seconds and then removed. 
• 
We also ask you to call us right away to tell us about any illness that your baby has from the day 
he/she receives the nose drops up to the follow-up visit (8 weeks). 
• 
A study nurse or study doctor will be available by telephone to answer your questions 24 hours a 
day during the 28 days after your baby receives the vaccine or placebo. 
• 
If your baby becomes ill, you may be asked to bring him/her to the clinic for an examination, 
sometimes as quickly as within 24 hours. We may do a nasal wash at that time to look for the 
RSV vaccine virus or any other virus that may be in your baby's nose. 
 
Monitoring Before, During, and After RSV Season 
• 
Your baby will also be followed during the winter RSV season [site: insert (November 1st until 
March 31st) unless other dates are specified in the MOP for your site] after getting the study nose 

 
  
 
IMPAACT 2018, Version 1.0 
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15 June 2017 
drops. We will be in contact with you each week to inquire about your baby's health. If your baby 
has a fever, a respiratory illness (a cold), or an ear infection that requires medical care, we will 
work with you to schedule a visit so that we can perform a nasal wash and clinical assessment. 
• 
We will collect a small amount of blood (about 2 teaspoons) once in [site: insert October unless 
another month is specified in the MOP for your site] before the winter RSV season and once in 
April after the winter RSV season to look at the antibodies (germ fighters) against natural RSV 
infection and how your baby’s blood cells are making antibodies. We will also use an absorbent 
strip to check for antibodies in the nose. The strip will be placed in your baby’s nose for about 30 
seconds and then removed. If your baby’s Day 56 Visit occurred on or after [site: insert October 
1 unless another date is specified in the MOP for your site], a separate visit in [site: insert 
October unless another month is specified in the MOP for your site] will not be required.  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
There will be approximately 80 babies taking part in this study. 
HOW LONG WILL MY BABY BE IN THIS STUDY? 
Your baby will be in this study through next April, which is between 7 and 13 months from now, 
depending on which month of the year he/she started the study.    
WHAT ARE THE RISKS OF THE STUDY? 
Risks of the Vaccines 
• 
If the vaccines are not weakened enough, they may cause a runny nose, sore throat, cough, or 
other signs of a cold. It is also possible that they may cause a sinus infection, croup, ear infection, 
fever, wheezing, or pneumonia (infection of the lungs). In another study with a similar vaccine, 
mild respiratory illnesses or colds were observed frequently in babies who received either vaccine 
or placebo. Runny nose occurred more often in babies who got the vaccine than those who got the 
placebo. 
• 
Study investigators have used the same placebo for studies of RSV, parainfluenza, and influenza 
vaccines in several hundred babies and children over the past 20 years.  They have not noticed 
side effects with this placebo.   
• 
There is no specific medicine to treat RSV illness. If any symptoms of RSV occur, such as runny 
nose, sore throat, cough, or difficulty breathing, your baby will receive prompt medical care. 
• 
The vaccines were made in a way that was designed to minimize the possibility of other 
ingredients. However, as with all biological products, there is a small chance that they contain 
unidentified material. There is a very small chance that such material may cause illness, including 
possibly serious illness. 
• 
There may be other side effects of the vaccines that are not yet known. If new information about 
possible side effects of the vaccines becomes available, we will let you know. 
• 
It is possible that the vaccine virus could be spread from your baby to other people in the home or 
daycare and may make them sick. It could be spread to young babies and people with weakened 
immune systems. We have not seen this type of spread when other vaccines like this one have 
been studied.  
• 
The vaccines could cause a severe allergic reaction. A severe reaction can cause hives, throat 
swelling, rapid heart rate, weakness, difficulty breathing, or death. These reactions are rare. 
 

 
  
 
IMPAACT 2018, Version 1.0 
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Risks of Nasal Washes 
Nasal washes may cause brief discomfort or pain that is like the feeling of getting salt water in the nose 
and may rarely cause a nosebleed. 
 
Risks of Having Blood Drawn 
Blood drawing can cause bleeding, pain, bruising, or infection at the place where the blood is taken. 
Sometimes, blood drawing can cause your baby to feel lightheaded or to faint. It sometimes takes more 
than 1 try to get blood from a small baby. 
WHY WOULD THE DOCTOR TAKE MY BABY OFF THIS STUDY EARLY? 
The study doctors or the sponsor have the right to end your baby's participation in the study at any time 
without your consent for any of the following reasons: 
• 
For your baby’s safety; 
• 
You do not follow study procedures as directed by the study doctors;  
• 
New information becomes available regarding the safety of the vaccine; 
• 
If it is in your baby's best interest; 
• 
You do not consent to continue in the study after being told of changes in the research that may 
affect your baby; 
• 
The study sponsor, the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
(IMPAACT), the Institutional Review Board (IRB), the Office for Human Research Protections 
(OHRP), the National Institute of Allergy and Infectious Diseases (NIAID), or the United States 
Food and Drug Administration (FDA) decide to end the study. (An IRB is a committee that 
watches over the safety and rights of research participants.) 
 
WHAT HAPPENS IF MY BABY IS INJURED? 
 
If your baby suffers physical injury from this study, the study doctor will provide or will refer your baby 
for immediate medical treatment.  The study doctor will also provide referrals to appropriate health care 
facilities. 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 National Institutes of Health (NIH). No 
financial compensation by the doctors that gave your baby the vaccine or placebo will be made for any 
discomfort suffered because of participation in this study. You will not be giving up any of your legal 
rights by signing this consent form. 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
• 
Your baby may not receive any direct benefit from being in the study. 
• 
Being in the study may help find a vaccine that works well to prevent serious RSV illness. Such a 
vaccine may be of future benefit to babies and children in this country and in the rest of the 
world. 
WHAT OTHER CHOICES DO I/DOES MY BABY HAVE BESIDES THIS STUDY? 
There are no licensed vaccines to protect against RSV illness at this time. There is no other similar study 
or licensed vaccine that we can offer your baby. You may choose to not allow your baby to take part in 
this study. 

 
  
 
IMPAACT 2018, Version 1.0 
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WHAT ABOUT CONFIDENTIALITY? 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health.  With this Certificate, the researchers cannot be forced to disclose information that 
may identify you, even by a court subpoena, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings.  The researchers will use the Certificate to resist any demands for 
information that would identify you, except as explained below.  The Certificate cannot be used to resist a 
demand for information from personnel of the United States Government that is used for auditing or 
evaluation of federally funded projects or for information that must be disclosed in order to meet the 
requirements of the federal Food and Drug Administration (FDA).   
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your 
family from voluntarily releasing information about you or your baby’s participation in this research.  If 
an insurer, employer, or other person obtains your written consent to receive research information, then 
the researchers may not use the Certificate of Confidentiality to withhold that information. 
 
The Certificate of Confidentiality does not prevent the researchers from disclosing voluntarily, without 
your consent, information that would identify you as a participant in the research project under certain 
circumstances such as child abuse.  
 
Your baby’s name, birth date, and Social Security number are not routinely given to anyone unless required by 
law. All of the information you give us during this study will be put in locked file cabinets and/or in 
password-protected computer files. The only people who will have access to this information will be those 
who are involved in the study. 
 
There will be people involved in the study who need to see your baby’s health information. These people 
may include the researchers, study and laboratory personnel, and other clinical research staff. Others who may 
see your baby’s information are the groups of people who make sure that the study is being done as it 
should be: Hospital Institutional Review Boards (IRBs), the Center for Immunization Research (CIR), 
the National Institute of Allergy and Infectious Diseases (NIAID; NIH) Intramural Data and Safety 
Monitoring Board and others who need to see your baby’s information to make sure that the study is going 
as planned.  
 
Other groups of people who may be involved in the study and may need to see your baby’s 
information are: 
• 
The government agency “Office for Human Research Protections,” that makes sure that we are 
conducting the research as planned, and the U.S. FDA 
• 
The sponsor of the study and people with whom the sponsor may contract for the study, such as 
study monitors. 
 
At the end of the study, whatever we learn from the research may be used in a medical journal or used for 
teaching. Your baby’s name or other details about his/her health will not be used in a manner such that 
anyone can personally identify your baby. 
WHAT ARE THE COSTS TO ME? 
There are no costs to you or your baby for him/her being in the study. The costs for vaccine/placebo, 
study visits, or study procedures are covered by the sponsor (NIH/NIAID).  However, taking part in this 
study may lead to added costs to you or your baby and your/your baby’s insurance company if medical 
complications arise or if your baby’s doctor decides extra tests are needed.  In some cases, it is possible 

 
  
 
IMPAACT 2018, Version 1.0 
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that your/your baby’s insurance company will not pay for these costs, because your baby is taking part in 
a research study.   
WILL MY BABY RECEIVE ANY COMPENSATION? 
You will be paid for your baby's participation in this study at the following rate [Site: insert payment 
schedule and amount.] 
 
You will also be paid during the winter RSV surveillance period as follows [Site: insert payment schedule 
and amount.] 
 
[Optional, depending on site: If you stop your baby from taking part in the study early, you will only be 
paid for the days of the study that your baby completed. Your baby may also receive age-appropriate 
books or small toys. If needed, bus tokens or parking passes will be given to you.] 
 
You may be required to provide your Social Security number to be paid. If your payment for study 
participation exceeds $600 per year, this information must be reported to the Internal Revenue Service. 
WHAT ARE MY BABY’S RIGHTS AS A RESEARCH PARTICIPANT? 
Taking part in this study is completely voluntary.  You may choose not to have your baby take part in this 
study or leave this study at any time.  Your decision will not have any impact on your baby’s participation 
in other studies and will not result in any penalty or loss of benefits to which you or your baby are 
otherwise entitled. 
 
A study physician, physician assistant, nurse practitioner, or study nurse will inform you of any 
significant abnormal physical findings and will make appropriate referrals back to your baby’s primary 
care giver, if necessary. 
 
We will tell you about new information from this or other studies that may affect your baby’s health, 
welfare, or willingness to stay in this study. You may be asked to sign a revised consent form if this 
occurs. If you want the results of the study, let the clinical research staff know. 
 
At the end of the study, you will be told in writing whether your baby was given one of the vaccines or 
the placebo. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This website will 
not include information that can identify your baby. At most, the website will include a summary of the 
results. You can search this website at any time. 
WHAT ARE MY RESPONSIBILITIES? 
• 
If you decide to withdraw your baby from the study early, we ask that you notify the study nurse 
or study doctor. 
• 
If your baby comes off the study early, we will ask you to bring him/her into the clinic for an 
early discontinuation visit. At that visit, we will do a final blood draw (about 1 teaspoon) and 
collect a nasal wash and/or use an absorbent strip to check for antibodies in the nose. The strip 
will be placed in your baby’s nose for about 30 seconds and then removed. 
• 
Any baby who has received the study product will be encouraged to remain in the study so that 
safety information can be collected. 

 
  
 
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• 
It is important that you do not enroll your baby in other studies where your baby receives 
vaccines or medications for 8 weeks after he/she receives vaccine/placebo. 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about this study or a research-related injury, contact: 
• 
[Site: Insert name of the investigator or other study staff] 
• 
[Site: insert telephone number of above] 
 
For questions about your baby’s rights as a research participant, contact:  
• 
[Site: insert name or title of person on the Institutional Review Board (IRB) or other organization] 
• 
[Site: insert telephone number of above]   
 

 
  
 
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15 June 2017 
GENETIC TESTING 
 
Some of the blood tests done for this study will look at how your baby’s genes (DNA) affect his or her 
response to RSV. Genes are the basic “instruction book” for the cells that make up our bodies. The 
differences in people’s genes can help explain why some people get a disease while others do not. 
Researchers may use your baby’s samples for limited genetic testing.  For example, researchers may do 
“genetic variations” research. They may look at genes that affect how your baby fights infections.  Our 
genes are passed to us from our birth parents. The researchers will not contact you or your baby’s regular 
health care provider with the results of these tests.  This is because these tests are often done with 
experimental procedures and the results should not be used to make decisions about your baby’s health 
care.  However, if the researchers decide that a result is important information for your baby’s health care, 
the study doctor will be notified.  If you would like to be contacted with this sort of information, you must 
notify the study staff of any changes of your address and phone number. Your baby’s name will not be 
available to the laboratory or to the scientists who may be doing limited genetic testing. 
 
You may decide that you do not want your baby’s blood used for limited genetic testing. Your baby can 
still be in this study even if you make this decision. Please read the following statement carefully and then 
mark your initials in the appropriate space provided. 
 
I allow my baby’s blood to be used for limited genetic testing, including future limited genetic testing, as 
part of this study. 
 
Yes:  
Initials _________ 
Date ____________ 
 
No:  
Initials _________ 
Date ____________ 
 
 
STORAGE AND FUTURE USE OF UNUSED SPECIMENS  
 
If you agree, any unused blood or nasal wash samples taken from your baby will be stored indefinitely 
(with protectors of identity) once this study is complete. These unused blood and nasal wash samples may 
be used for future laboratory studies to learn more about RSV and other viruses. This information may 
lead to other new virus vaccines in the future. 
 
• 
Your baby’s unused blood or nasal wash samples, if any, will be used only for laboratory studies 
and will not be sold or used directly to make products that will be for sale. 
• 
The samples will be coded so that your baby’s name cannot be easily identified. 
• 
Reports about studies done with your baby’s unused samples will not be put in your baby’s health 
or study records.  
• 
There will be no direct benefit to your baby in using the samples as noted above, but from 
studying the unused samples of babies taking part in the studies, we may learn more about the 
RSV germ or other viruses that cause illness in babies and children. 
• 
Results from future studies using your baby’s unused samples may be included in medical papers 
and meeting reports, but your baby’s name will not be used. 
 
You can change your mind at any time about allowing your baby’s unused samples to be used for future 
laboratory studies. If you do change your mind, contact the study doctor or study nurse and let him/her 
know. Then the samples will no longer be used for laboratory studies and will be destroyed. 
 
 

 
  
 
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PERMISSION FOR STORAGE AND FUTURE USE OF UNUSED SPECIMENS 
Your choice will not have any effect on your baby’s taking part in this study. 
 
I will allow the use of my baby’s unused blood or nasal wash samples to be stored indefinitely and to be 
used in future laboratory studies for the purposes described above. Your baby’s name will not be 
available to the laboratory or to the scientists who may be doing any future tests. (Please check one and 
initial below) 
 
Yes:  
Initials _________ 
Date ____________ 
 
No:  
Initials _________ 
Date ____________ 
 
 
If NO, your baby’s study samples will only be used for the testing described in this study.  
 
 
 

 
  
 
IMPAACT 2018, Version 1.0 
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15 June 2017 
SIGNATURE  
 
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. 
 
 
____________________________                 
Study Participant’s Name (print) 
 
 
 
 
 
_____________________________              ____________________________________ 
Participant’s Legal Guardian (print) 
 
Legal Guardian’s Signature and Date 
 
 
 
 
____________________________                ____________________________________ 
Clinical Research Staff Conducting 
 
Clinical Research Staff Signature and Date 
 
 
Consent Discussion (print)  
 
 
____________________________                ____________________________________ 
Witness’ Name (print)  
 
            Witness’ Signature and Date 
 
 
 
(As appropriate) 
 
 
____________________________ 
 
__________________________________ 
Second Parent/Guardian’s Name 
 
Signature and Date 
(As appropriate)