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

Clarification Memorandum #1       
Page 1 of 5 
18 January 2023 
IMPAACT 2021 Protocol Version 3.0 
Clarification Memorandum # 1 for: 
 
IMPAACT 2021 
Randomized Phase I/II Study of the Safety and Immunogenicity of a Single Dose 
of the Recombinant Live-Attenuated Respiratory Syncytial Virus (RSV) Vaccines 
RSV ΔNS2/Δ1313/I1314L, RSV 6120/ΔNS2/1030s, RSV 276 or Placebo, Delivered 
as Nose Drops to RSV-Seronegative Children 6 to 24 Months of Age 
 
Version 3.0, dated 28 April 2022 
 
 DAIDS Study ID 38530 
IND # 018943 Held By DAIDS 
 
Clarification Memorandum Date: 18 January 2023  
 
 
Summary of Clarifications 
 
This Clarification Memorandum (CM) updates the Protocol Team roster, clarifies the type of data 
included in Data and Safety Monitoring Board (DSMB) post-accrual season study reviews, and clarifies 
the listing of solicited adverse events (AEs) to note that wheezing may include a diagnosis of 
bronchiolitis.  
 
 
Implementation 
 
Single Institutional Review Board (sIRB) approval of this CM is not required by the study sponsor prior 
to implementation. However, the CM will be submitted to the sIRB (Advarra) centrally by the IMPAACT 
Operations Center for their information. In addition, sites may submit this CM to other site regulatory 
entities for their information or, if required by the regulatory entities, 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 2021.  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 2021 protocol. 
 
The modifications included in this CM are listed below in order of appearance within a specified 
clarification in the protocol and will be incorporated into the next protocol amendment as specified below.  
Additions to the text are indicated in bold; deletions are indicated by strike-through.   
 
1. Protocol Roster Update 
 
To reflect current Protocol Team membership, Jared Kneebone, Sam Yi, and Marcus Bolton are 
removed from the roster and Azizza Davis, John Binkowski, Carly Hoffmann, and Michelle Haber 
are added:  

Clarification Memorandum #1       
Page 2 of 5 
18 January 2023 
IMPAACT 2021 Protocol Version 3.0 
 
Protocol Pharmacists 
Kelly Colsh, PharmD  
DAIDS/NIAID/NIH  
5601 Fishers Lane, Room 9D38  
Rockville, MD 20852  
Phone: 240-669-5721  
Email: kelly.colsh@nih.gov 
 
Azizza Davis, PharmD 
DAIDS/NIAID/NIH 
5601 Fishers Lane, Room 9E14 
Rockville, MD 20852 
Phone: 301-792-7962 
Email: azizza.davis@nih.gov 
 
Protocol Data Managers 
Benjamin Johnston, BS  
Frontier Science Foundation  
4033 Maple Rd.  
Amherst, NY 14226-1056  
Phone: 716-834-0900 x7407  
Email: johnston@frontierscience.org 
 
Jared Kneebone, PhD 
Frontier Science Foundation 
4033 Maple Rd. 
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7263 
Email: kneebone@frontierscience.org 
 
John Binkowski, MA 
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 ext. 7371 
Email: binkowski@frontierscience.org 
 
Carly Hoffmann, BA 
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 ext. 7396 
Email: hoffmann@frontierscience.org 
 
Laboratory Center Representatives 
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 310-889-4786 
Email: ntobin@milabcentral.org 
 
Sam Yi 
IMPAACT Laboratory Center 
University of California Los Angeles 
10990 Wilshire Blvd., Suite 260 
Los Angeles, CA 90024 
Phone: 323-806-8836 
Email: syi@milabcentral.org 
 
IMPAACT Community Program Associate 
Marcus Bolton, MEd 
IMPAACT Operations Center 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701 
Phone: (919) 544-7040 x11678 
Email: mbolton@fhi360.org 
 
Michelle Haber, CMSW  
IMPAACT Operations Center 
FHI 360  
359 Blackwell Street, Suite 200 
Durham, NC 22701  
Phone: 919-321-3472 
Email: mhaber@fhi360.org 
 
 

 
Clarification Memorandum #1       
Page 3 of 5 
18 January 2023 
IMPAACT 2021 Protocol Version 3.0 
2. Clarification of Data Included in DSMB Post-Accrual Season Study Reviews 
 
a) Section 1.4, Rationale, Evaluation of Study Products subsection, Page 32:  
 
Table 1: Post-Accrual Season Study Review Criteria 
 
Yes 
No 
1. Is there a statistically significant (p<0.05) difference in the 
percentage with immune response (e.g., ≥4-fold rise in serum 
RSV-neutralizing antibodies IgG antibody to RSV F protein) to 
the candidate vaccines such that one or two products can be 
identified to be immunologically superior to the remaining 
product or products, with the absence of a safety signal among 
the higher performing product(s)? 
  
  
If yes, the DSMB may recommend that the study close to accrual 
If no, the DSMB will consider the following questions for each specific product: 
2. Is the upper limit of the 95% confidence interval for the 
percentage of participants exhibiting immune response (e.g., a 
≥4-fold rise in serum RSV-neutralizing antibodies IgG antibody 
to RSV F protein) at the Day 56 Visit less than 70%? 
  
  
3. Have more than two participants receiving the specific product 
experienced LRI of ≥ Grade 2 in the 28 days following study 
product administration for which vaccine virus was isolated 
without other potential explanation? 
  
  
4. Were there two or more participants who experienced vaccine-
associated Grade 4 events of similar type (as listed below) after 
study product administration with presence of vaccine virus 
without other potential explanation? 
                Otitis media within 28 days of study product administration 
                Pharyngitis within 28 days of study product administration 
  
  
 
 
b) Section 9.4.3, Rationale, Monitoring by the NIAID Data and Safety Monitoring Board, Page 76, 
fourth paragraph:  
 
The DSMB might consider halting enrollment to a vaccine arm: 
 
1. For clear differences in immunogenicity: if there is a statistically significant difference in the 
percentage with immune response (e.g., ≥4-fold rise in serum RSV-neutralizing antibodies 
IgG antibody to RSV F protein) to the candidate vaccines such that one or two products can 
be identified to be immunologically superior to the remaining product or products, with the 
absence of a safety signal among the higher performing product(s) 
2. For inadequate immunogenicity: the upper limit of a 95% CI around the response rate (e.g., 
≥4-fold rise in RSV-neutralizing antibody titer serum IgG antibody to RSV F protein) for a 
vaccine arm is less than 70%.  [With a sample size of 10 (15, 20, 25, 30, 38), this would 
occur if the observed response rate was <30% (<40%, <45%, <48%, <50%, <53%)] 
3. for safety concerns (also considering vaccine virus shedding and adventitious data): 

 
Clarification Memorandum #1       
Page 4 of 5 
18 January 2023 
IMPAACT 2021 Protocol Version 3.0 
a. if >2 participants receiving the specific product experience LRIs of ≥Grade 2 in the 
28 days following study product administration for which vaccine virus is isolated 
without other potential explanation 
b. if there are ≥2 participants with vaccine-associated Grade 4 events of similar type 
(otitis media or pharyngitis within 28 days of study product administration) with 
presence of vaccine virus without other potential explanation. 
 
 
3. Inclusion of Bronchiolitis in Listing of Solicited AEs 
 
a) Section 7.2, Safety-Related Data Collection, Adverse Events subsection, Page 60, 2nd paragraph:  
 
[…]For this study, the solicited AEs are defined in Appendix III and include the following:  
1. Fever 
2. Upper respiratory illness (URI) 
a. Rhinorrhea 
b. Pharyngitis,  
c. Cough without LRI, or 
d. Hoarseness. 
3. Otitis Media 
4. Lower respiratory illness (LRI) 
a. Wheezing (may include bronchiolitis), 
b. Pneumonia, 
c. Laryngotracheobronchitis (croup), 
d. Rhonchi, or 
e. Rales. 
 
b) Appendix III: Definitions of Solicited Adverse Events, Page 91: 
 
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 (may include 
bronchiolitis5) 
Sustained, high pitched, musical breath sounds, especially during the 
expiratory phase, which do not clear with cough. 

 
Clarification Memorandum #1       
Page 5 of 5 
18 January 2023 
IMPAACT 2021 Protocol Version 3.0 
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) 1,2,4 
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. 
4 It is not necessary for medical professional(s) to witness inspiratory stridor as long as parent or guardian report is consistent 
with stridor and a medical professional judges the symptoms in total to be consistent with croup. 
5 Bronchiolitis should be recorded as a solicited AE whether wheezing is detected or not.  
 
NOTE: Solicited AEs will only be entered into eCRFs according to guidance outlined in Section 7.2