Evaluating the Infectivity, Safety, and Immunogenicity of a Single Dose of a Recombinant Live-Attenuated Respiratory Syncytial Virus Vaccine (D46/NS2/N/ΔM2-2-HindIII) in RSV-Seronegative Infants 6 to 24 Months of Age

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT03102034
• Collaborator: (none)
• Enrollment: 32
• Locations: 10
• Arms: 2
• Actual Duration (Months): 13.6
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the safety, infectivity, and immunogenicity of a single dose of a recombinant live-attenuated respiratory syncytial virus (RSV) vaccine in RSV-seronegative infants and children 6 to 24 months of age.

This study was a companion study to CIR 313.

Condition or Disease	Intervention/Treatment	Phase
Respiratory Syncytial Virus Infections	Biological: D46/NS2/N/ΔM2-2-HindIII; Biological: Placebo	Phase 1

Detailed Description

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. This study evaluated the safety, infectivity, and immunogenicity of a single dose of RSV D46/NS2/N/ΔM2-2-HindIII, a recombinant live-attenuated RSV vaccine, in RSV-seronegative infants and children 6 to 24 months of age.

Participants were randomly assigned to receive a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine or placebo (administered as nose drops) at study entry (Day 0).

Participants could be enrolled in the study outside of RSV season (between April 1 and 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 Manual Of Procedures). All participants remained on study until they completed the post-RSV season visit between April 1 and April 30 in the calendar year following enrollment. Participants' total study duration was between 6 and 13 months, depending on when they enrolled in the study. Participants attended several study visits throughout the study, which included physical examinations, blood collection, and nasal washes. Participants' parents or guardians were contacted by study staff at various times during the study to monitor participants' health.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Phase I Placebo-Controlled Study of the Infectivity, Safety and Immunogenicity of a Single Dose of a Recombinant Live-Attenuated Respiratory Syncytial Virus Vaccine, D46/NS2/N/ΔM2-2-HindIII, Lot RSV#011B, Delivered as Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age
• Actual Study Start Date: Apr 6, 2017
• Actual Primary Completion Date: May 25, 2018
• Actual Study Completion Date: May 25, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RSV D46/NS2/N/ΔM2-2-HindIII Vaccine Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0).	Biological: D46/NS2/N/ΔM2-2-HindIII; 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops
Placebo Comparator: Placebo Participants received a single dose of placebo at study entry (Day 0).	Biological: Placebo; Isotonic diluent; administered as nose drops

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Solicited Adverse Events (AEs) by Grade [Measured from Day 0 through Day 28]

   Solicited adverse events included fever; otitis media; upper respiratory illness (URI); lower respiratory illness (LRI) and cough (without LRI). The number of participants who experienced solicited adverse events was presented. A participant was only counted once in each solicited AE category, and that was in the line corresponding to the highest grade adverse event they had in that category. These events were graded (Grade 1-mild to Grade 4-life-threatening) following protocol-defined grading system outlined in Table 3 and Table 4 in the protocol document.

2. Number of Participants With Unsolicited AEs by Grade [Measured from Day 0 through Day 28]

   Unsolicited adverse events were other events, not included in the solicited AEs. The number of participants who experienced solicited adverse events was presented. A participant was only counted once in each unsolicited AE category, and that was in the line corresponding to the highest grade adverse event they had in that category. AE grading (Grade 1- mild to Grade 4-life-threatening) was done by DAIDS AE Grading table v2.0 (see References).

3. Number of Participants With Serious Adverse Events (SAEs) [Measured from Day 0 through Day 56]

   A Serious Adverse Event (SAE) was an AE, whether considered related to the study product or not, that: Resulted in death during the period of protocol-defined surveillance Was life threatening: defined as an event in which the patient was at immediate risk of death at the time of the event; it did not refer to an event that hypothetically might have caused death were it more severe Required 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 Resulted in a persistent or significant disability/incapacity Was a congenital anomaly or birth defect Was an important medical event that might not be immediately life threatening or result in death or hospitalization but might jeopardize the patient or might require intervention to prevent one of the outcomes listed above.

4. Number of Participants Infected With RSV Vaccine Virus [Measured at Days 0, 3, 5, 7, 10, 12, 14, 17, and 28 for nasal washes, and at Days 0, 56 for serum RSV-neutralizing antibodies]

   Defined as 1) vaccine virus identified in a nasal wash from Study Day 0-28 (a binary outcome based on nasal washes) and/or 2) greater than or equal to 4-fold rise in RSV-neutralizing antibody titer from Study Day 0 and 56.

5. Peak Titer of Vaccine Virus Shed [Measured at Days 0, 3, 5, 7, 10, 12, 14, 17, and 28]

   This is the highest value per participant of the titer of vaccine virus shed. It was measured by culture. Only participants who met the definition of infection with vaccine virus were included.

6. Duration of Vaccine Virus Shedding in Nasal Washes [Measured at Days 0, 3, 5, 7, 10, 12, 14, 17, and 28. Last day positive is reported.]

   Determined separately by a) culture and b) reverse transcription polymerase chain reaction (RT-PCR)

7. Number of Participants With a Greater Than or Equal to 4-fold Rise in Serum RSV-neutralizing Antibody Titer [Measured at Day 0 and Day 56]

   Immunogenicity was assessed pre-inoculation, and at approximately 2 months post-inoculation (Study Day 56). Antibody responses were defined as a greater than or equal to 4-fold increase in titer in paired specimens, between pre-inoculation and post-inoculation time points.

8. Serum Antibody Responses to RSV F Glycoprotein as Assessed by Enzyme-linked Immunosorbent Assay (ELISA) [Measured at Day 56]

   Immunogenicity was assessed at approximately 2 months post-inoculation (Study Day 56).

Secondary Outcome Measures

1. Number of Participants Who Had Symptomatic, Medically Attended Respiratory and Febrile Illness, Among Those Who Experienced Natural Infection With wt RSV During the Subsequent RSV Season [Measured from November 1st through participant's post-RSV season surveillance visit]

   The number of participants who had RSV-associated, medically attended, acute respiratory illness (RSV-MAARI) or RSV-associated, medically attended, acute lower respiratory illness (RSV-MAALRI) among those who had RSV detected in nasal washes or greater than or equal to 4 fold rise in serum antibodies during the subsequent RSV season were presented.

2. Magnitude of Serum RSV-neutralizing Antibody Responses in the Vaccine and Placebo Recipients Who Experienced Natural Infection With wt RSV During the Subsequent RSV Season. [Measured through participant's last study visit, up to a total of 6 to 13 months depending on when participants enrolled in the study]

   Only participants who had RSV detected in nasal washes or a greater than or equal to 4-fold rise in serum antibodies during the subsequent RSV season were included. RSV-neutralizing antibody titers were measured pre- and post-RSV surveillance season.

3. Number of Participants With B Cell Responses to Vaccine [Measured at day 0 and Day 56]

   A B cell response to vaccine is indicated by a greater than or equal to 4-fold change in serum antibody titers to RSV F glycoprotein between the pre- and post-inoculation time points.

Other Outcome Measures

1. Frequency of Mucosal Antibody Responses to Vaccine [Measured at Day 0, 28 and 56]

   Determined from nasal wash samples. This outcome has been changed from a secondary outcome measure to an 'other pre-specified' outcome measure. Since this outcome measure relies on previously untested assays to reliably quantify RSV specific mucosal antibodies from nasal wash samples, it was changed to other pre-specified to fit with its intended analysis type.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 24 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Good health based on review of the medical record, history, and physical examination, without evidence of chronic disease.

• Parents/guardians willing and able to provide written informed consent as described in the protocol.

• Seronegative for RSV antibody, defined as a serum RSV-neutralizing antibody titer less than 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 Laboratory of Infectious Diseases (LID) (NIAID, NIH) were acceptable as long as within the 42-day window.

• Growing at a normal velocity for age (as demonstrated on a standard growth chart) AND

• If less than 1 year of age: current height and weight above the 5th percentile

• If 1 year of age or older: current height and weight above the 3rd percentile for age.

• 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 was indicated only if the participant was age-eligible per ACIP.

• Expected to be available for the duration of the study.

• If born to an HIV-infected woman, participant must not have been breastfed and must have had documentation of 2 negative HIV nucleic acid (RNA or DNA) test results from samples collected on different dates with both collected when greater than or equal to 4 weeks of age and at least one collected when greater than or equal to 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 greater than or equal to 24 weeks of age.

Exclusion Criteria:

• Known or suspected HIV infection or impairment of immunological functions.

• Receipt of immunosuppressive therapy, including any systemic, including either nasal or inhaled, corticosteroids within 28 days of enrollment. Note: Cutaneous (topical) steroid treatment was not an exclusion.

• Bone marrow/solid organ transplant recipient.

• Major congenital malformations (such as congenital cleft palate) or cytogenetic abnormalities.

• 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 immunoglobulin [IG] or RSV monoclonal antibody [mAb]).

• Previous anaphylactic reaction.

• Previous vaccine-associated adverse reaction that was Grade 3 or above.

• Known hypersensitivity to any study product component.

• Heart disease. Note: Participants with cardiac abnormalities documented to be clinically insignificant and requiring no treatment may be enrolled.

• Lung disease, including any history of reactive airway disease or medically diagnosed wheezing.

• Member of a household that contained, or would contain, an infant who was less than 6 months of age at the enrollment date through Day 28.

• Member of a household that contains another child who was, or was scheduled to be, enrolled in IMPAACT 2011, 2012 or 2013 or another study evaluating an intranasal live-attenuated RSV vaccine, AND there had been or would be an overlap in residency during that other child's participation in the study's Acute Phase (Days 0 to 28).

• Member of a household that contained an immunocompromised individual, including, but not limited to:

• a person who was greater than or equal to 6 years of age with HIV-related immunodeficiency, defined as having a most recent CD4 T lymphocyte cell count less than 300 cells/mm^3. CD4 T lymphocyte count must have been measured within 6 months prior to enrollment, 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 less than 25 or CD4 T lymphocyte count less than 750 cells/mm^3 (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 less than 30 or CD4 T lymphocyte count less than 1000 cells/mm^3 (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 had 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.

Verbal report of CD4 T cell lymphocyte was sufficient documentation if the parent/guardian was confident of history.

• Attended a daycare facility and shared a room with infants less than 6 months of age, and parent/guardian was unable or unwilling to suspend daycare for 28 days following inoculation.

• Any of the following events at the time of enrollment:

• fever (rectal temperature of greater than or equal to 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.

• 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

• 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

• Receipt of immunoglobulin, any antibody products, or any blood products within the past 6 months

• Receipt of any of the following medications within 3 days of 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.

• Receipt of salicylate (aspirin) or salicylate-containing products within the 28 days prior to enrollment.

• Born at less than 34 weeks gestation.

• Born at less than 37 weeks gestation and less than 1 year of age at the time of enrollment.

• Suspected or documented developmental disorder, delay, or other developmental problem.

• Previous receipt of supplemental oxygen therapy in a home setting.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Usc La Nichd Crs	Los Angeles	California	United States	90089
2	David Geffen School of Medicine at UCLA NICHD CRS	Los Angeles	California	United States	90095-1752
3	Univ. of Colorado Denver NICHD CRS	Aurora	Colorado	United States	80045
4	Emory University School of Medicine NICHD CRS	Atlanta	Georgia	United States	30322
5	Rush Univ. Cook County Hosp. Chicago NICHD CRS	Chicago	Illinois	United States	60612
6	Lurie Children's Hospital of Chicago (LCH) CRS	Chicago	Illinois	United States	60614-3393
7	Johns Hopkins University Center for Immunization Research	Baltimore	Maryland	United States	21205
8	Jacobi Med. Ctr. Bronx NICHD CRS	Bronx	New York	United States	10461
9	SUNY Stony Brook NICHD CRS	Stony Brook	New York	United States	11794
10	St. Jude Children's Research Hospital CRS	Memphis	Tennessee	United States	38105-3678

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: Elizabeth (Betsy) J. McFarland, MD, University of Colorado School of Medicine and Children's Hospital Colorado, Pediatric Infectious Diseases

Study Documents (Full-Text)

• Study Protocol - Feb 14, 2017
• Statistical Analysis Plan: Statistical Analysis Plan, Version 1.0 - May 31, 2017
• Statistical Analysis Plan: Statistical Analysis Plan, Version 3.1 - Jan 11, 2022

More Information

Additional Information:

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT03102034
• Other Study ID Numbers: IMPAACT 2013; 30074
• First Posted: Apr 5, 2017
• Last Update Posted: Feb 8, 2022
• Last Verified: Jan 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Respiratory Syncytial Virus Infections

Study Results

Participant Flow

Recruitment Details	Recruitment period was from April to October 2017. Participants were recruited from medical clinics.

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops
Period Title: Overall Study
STARTED	21	11
COMPLETED	20	11
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo	Total
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops	Total of all reporting groups
Overall Participants	21	11	32
Age (months) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [months]	9	9	9
Sex: Female, Male (Count of Participants)
Female	13 61.9%	8 72.7%	21 65.6%
Male	8 38.1%	3 27.3%	11 34.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 57.1%	6 54.5%	18 56.3%
Not Hispanic or Latino	9 42.9%	5 45.5%	14 43.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 28.6%	4 36.4%	10 31.3%
White	14 66.7%	6 54.5%	20 62.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 4.8%	1 9.1%	2 6.3%
Region of Enrollment (participants) [Number]
United States	21 100%	11 100%	32 100%
Serum RSV-neutralizing antibody titers (log 2 titers) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [log 2 titers]	2.3	2.3	2.3

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Solicited Adverse Events (AEs) by Grade
Description	Solicited adverse events included fever; otitis media; upper respiratory illness (URI); lower respiratory illness (LRI) and cough (without LRI). The number of participants who experienced solicited adverse events was presented. A participant was only counted once in each solicited AE category, and that was in the line corresponding to the highest grade adverse event they had in that category. These events were graded (Grade 1-mild to Grade 4-life-threatening) following protocol-defined grading system outlined in Table 3 and Table 4 in the protocol document.
Time Frame	Measured from Day 0 through Day 28

Outcome Measure Data

Analysis Population Description

Study participants who received inoculation were included.

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops
Measure Participants	21	11
Did not have this AE	17 81%	9 81.8%
Grade 1	3 14.3%	1 9.1%
Grade 2	1 4.8%	1 9.1%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Did not have this AE	21 100%	11 100%
Grade 1	0 0%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Did not have this AE	6 28.6%	10 90.9%
Grade 1	15 71.4%	1 9.1%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Did not have this AE	21 100%	11 100%
Grade 1	0 0%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Did not have this AE	9 42.9%	11 100%
Grade 1	12 57.1%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% vaccine recipients with solicited AEs
	Estimated Value	76
	Confidence Interval	(2-Sided) 90%; 56 to 90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence intervals were Exact Clopper-Pearson.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% placebo recipients with solicited AEs
	Estimated Value	18
	Confidence Interval	(2-Sided) 90%; 3 to 47
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence intervals were Exact Clopper-Pearson.

2. Primary Outcome

Title	Number of Participants With Unsolicited AEs by Grade
Description	Unsolicited adverse events were other events, not included in the solicited AEs. The number of participants who experienced solicited adverse events was presented. A participant was only counted once in each unsolicited AE category, and that was in the line corresponding to the highest grade adverse event they had in that category. AE grading (Grade 1- mild to Grade 4-life-threatening) was done by DAIDS AE Grading table v2.0 (see References).
Time Frame	Measured from Day 0 through Day 28

Outcome Measure Data

Analysis Population Description

Study participants who received inoculation were included.

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops
Measure Participants	21	11
Did not have this AE	17 81%	11 100%
Grade 1	4 19%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Did not have this AE	20 95.2%	10 90.9%
Grade 1	1 4.8%	1 9.1%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Did not have this AE	20 95.2%	11 100%
Grade 1	1 4.8%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Did not have this AE	20 95.2%	11 100%
Grade 1	1 4.8%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Did not have this AE	19 90.5%	11 100%
Grade 1	2 9.5%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Did not have this AE	20 95.2%	11 100%
Grade 1	1 4.8%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Did not have this AE	20 95.2%	11 100%
Grade 1	1 4.8%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Did not have this AE	20 95.2%	11 100%
Grade 1	1 4.8%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% vaccinees with unsolicited AEs
	Estimated Value	24
	Confidence Interval	(2-Sided) 90%; 10 to 44
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence intervals were Exact Clopper-Pearson.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% placebo with unsolicited AEs
	Estimated Value	9
	Confidence Interval	(2-Sided) 90%; 0 to 36
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence intervals were Exact Clopper-Pearson.

3. Primary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs)
Description	A Serious Adverse Event (SAE) was an AE, whether considered related to the study product or not, that: Resulted in death during the period of protocol-defined surveillance Was life threatening: defined as an event in which the patient was at immediate risk of death at the time of the event; it did not refer to an event that hypothetically might have caused death were it more severe Required 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 Resulted in a persistent or significant disability/incapacity Was a congenital anomaly or birth defect Was an important medical event that might not be immediately life threatening or result in death or hospitalization but might jeopardize the patient or might require intervention to prevent one of the outcomes listed above.
Time Frame	Measured from Day 0 through Day 56

Outcome Measure Data

Analysis Population Description

Study participants who received inoculation were included.

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops
Measure Participants	21	11
Count of Participants [Participants]	0 0%	0 0%

4. Primary Outcome

Title	Number of Participants Infected With RSV Vaccine Virus
Description	Defined as 1) vaccine virus identified in a nasal wash from Study Day 0-28 (a binary outcome based on nasal washes) and/or 2) greater than or equal to 4-fold rise in RSV-neutralizing antibody titer from Study Day 0 and 56.
Time Frame	Measured at Days 0, 3, 5, 7, 10, 12, 14, 17, and 28 for nasal washes, and at Days 0, 56 for serum RSV-neutralizing antibodies

Outcome Measure Data

Analysis Population Description

Study participants who received inoculation were included.

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops
Measure Participants	21	11
Count of Participants [Participants]	21 100%	0 0%

5. Primary Outcome

Title	Peak Titer of Vaccine Virus Shed
Description	This is the highest value per participant of the titer of vaccine virus shed. It was measured by culture. Only participants who met the definition of infection with vaccine virus were included.
Time Frame	Measured at Days 0, 3, 5, 7, 10, 12, 14, 17, and 28

Outcome Measure Data

Analysis Population Description

Only participants who met the definition of infection with vaccine virus were included.

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops
Measure Participants	21	0
Median (Inter-Quartile Range) [log10 PFU/mL]	3.5

6. Primary Outcome

Title	Duration of Vaccine Virus Shedding in Nasal Washes
Description	Determined separately by a) culture and b) reverse transcription polymerase chain reaction (RT-PCR)
Time Frame	Measured at Days 0, 3, 5, 7, 10, 12, 14, 17, and 28. Last day positive is reported.

Outcome Measure Data

Analysis Population Description

Only participants who met the definition of infection with vaccine virus were included.

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops
Measure Participants	21	0
Culture positive	10
RT-PCR positive	14

7. Primary Outcome

Title	Number of Participants With a Greater Than or Equal to 4-fold Rise in Serum RSV-neutralizing Antibody Titer
Description	Immunogenicity was assessed pre-inoculation, and at approximately 2 months post-inoculation (Study Day 56). Antibody responses were defined as a greater than or equal to 4-fold increase in titer in paired specimens, between pre-inoculation and post-inoculation time points.
Time Frame	Measured at Day 0 and Day 56

Outcome Measure Data

Analysis Population Description

Study participants who received inoculation were included.

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops
Measure Participants	21	11
Count of Participants [Participants]	20 95.2%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Due to unequal sample sizes, a 1-sided Fisher's exact test was used to test the hypothesis that proportions of greater than or equal to 4-fold rises were higher in the vaccinated than in the placebo group. Statistical significance level was 0.05.
	Method	Fisher Exact
	Comments

8. Primary Outcome

Title	Serum Antibody Responses to RSV F Glycoprotein as Assessed by Enzyme-linked Immunosorbent Assay (ELISA)
Description	Immunogenicity was assessed at approximately 2 months post-inoculation (Study Day 56).
Time Frame	Measured at Day 56

Outcome Measure Data

Analysis Population Description

Study participants who received inoculation were included.

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops
Measure Participants	21	11
Median (Inter-Quartile Range) [log 2 titers]	15.7	8.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The threshold for statistical significance is 0.05.
	Method	Log Rank
	Comments

9. Secondary Outcome

Title	Number of Participants Who Had Symptomatic, Medically Attended Respiratory and Febrile Illness, Among Those Who Experienced Natural Infection With wt RSV During the Subsequent RSV Season
Description	The number of participants who had RSV-associated, medically attended, acute respiratory illness (RSV-MAARI) or RSV-associated, medically attended, acute lower respiratory illness (RSV-MAALRI) among those who had RSV detected in nasal washes or greater than or equal to 4 fold rise in serum antibodies during the subsequent RSV season were presented.
Time Frame	Measured from November 1st through participant's post-RSV season surveillance visit

Outcome Measure Data

Analysis Population Description

Only participants who had RSV detected in nasal washes or greater than or equal to 4 fold rise in serum antibodies during the subsequent RSV season were included.

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops
Measure Participants	6	4
RSV-MAARI	2 9.5%	3 27.3%
RSV-MAALRI	0 0%	1 9.1%

10. Secondary Outcome

Title	Magnitude of Serum RSV-neutralizing Antibody Responses in the Vaccine and Placebo Recipients Who Experienced Natural Infection With wt RSV During the Subsequent RSV Season.
Description	Only participants who had RSV detected in nasal washes or a greater than or equal to 4-fold rise in serum antibodies during the subsequent RSV season were included. RSV-neutralizing antibody titers were measured pre- and post-RSV surveillance season.
Time Frame	Measured through participant's last study visit, up to a total of 6 to 13 months depending on when participants enrolled in the study

Outcome Measure Data

Analysis Population Description

Only participants who had RSV detected in nasal washes or a greater than or equal to 4-fold rise in serum antibodies during the subsequent RSV season were included.

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops
Measure Participants	6	4
Pre-RSV surveillance	6.3	2.3
Post-RSV Surveillance	10.4	7.1

11. Secondary Outcome

Title	Number of Participants With B Cell Responses to Vaccine
Description	A B cell response to vaccine is indicated by a greater than or equal to 4-fold change in serum antibody titers to RSV F glycoprotein between the pre- and post-inoculation time points.
Time Frame	Measured at day 0 and Day 56

Outcome Measure Data

Analysis Population Description

All participants who received inoculation were included.

Arm/Group Title	RSV D46/NS2/N/ΔM2-2-HindIII Vaccine	Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops	Participants received a single dose of placebo at study entry (Day 0). Placebo: Isotonic diluent; administered as nose drops
Measure Participants	21	11
Count of Participants [Participants]	21 100%	0 0%

12. Other Pre-specified Outcome

Title	Frequency of Mucosal Antibody Responses to Vaccine
Description	Determined from nasal wash samples. This outcome has been changed from a secondary outcome measure to an 'other pre-specified' outcome measure. Since this outcome measure relies on previously untested assays to reliably quantify RSV specific mucosal antibodies from nasal wash samples, it was changed to other pre-specified to fit with its intended analysis type.
Time Frame	Measured at Day 0, 28 and 56

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From study entry to end of study. The duration of follow-up for a given participant was between 6 and 13 months depending on time of enrollment.
Adverse Event Reporting Description	From day 0-28, all SAEs, solicited AEs, and unsolicited AEs, with the exception of the following if not treated with prescription medication or over the counter medications with antipyretic properties: diaper rashes, teething pain, and spitting up. SAEs and LRIs were reported according to DAIDS EAE Manual V2.0 (see References). From day 29-56, SAEs were collected. After day 56, from November 1 - March 31 of the following year, medically attended fever, LRI, URI and otitis media were collected.
Arm/Group Title	Vaccine		Placebo
Arm/Group Description	Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0). D46/NS2/N/ΔM2-2-HindIII: 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops		Participants received a single dose of placebo study entry (Day 0). Placebo: Isotonic diluent, administered as nose drops
All Cause Mortality
	Vaccine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/11 (0%)
Serious Adverse Events
	Vaccine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Vaccine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/21 (81%)		10/11 (90.9%)
Blood and lymphatic system disorders
Lymphadenopathy	1/21 (4.8%)		1/11 (9.1%)
Gastrointestinal disorders
Diarrhoea	5/21 (23.8%)		0/11 (0%)
Infantile vomiting	2/21 (9.5%)		0/11 (0%)
General disorders
Pyrexia	10/21 (47.6%)		6/11 (54.5%)
Infections and infestations
Conjunctivitis viral	0/21 (0%)		1/11 (9.1%)
Otitis media acute	5/21 (23.8%)		2/11 (18.2%)
Respiratory syncytial virus bronchiolitis	0/21 (0%)		1/11 (9.1%)
Upper respiratory tract infection	5/21 (23.8%)		2/11 (18.2%)
Metabolism and nutrition disorders
Decreased appetite	4/21 (19%)		2/11 (18.2%)
Respiratory, thoracic and mediastinal disorders
Cough	14/21 (66.7%)		4/11 (36.4%)
Epistaxis	1/21 (4.8%)		1/11 (9.1%)
Nasal congestion	4/21 (19%)		3/11 (27.3%)
Rhinorrhoea	16/21 (76.2%)		4/11 (36.4%)
Wheezing	1/21 (4.8%)		1/11 (9.1%)
Skin and subcutaneous tissue disorders
Rash	0/21 (0%)		1/11 (9.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.