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

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate 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, and RSV 276, in RSV-seronegative children 6 to 24 months of age.

Detailed Description
-----------------
This study will evaluate 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, and RSV 276, in RSV-seronegative children 6 to 24 months of age. Participants will be randomly assigned to receive a single dose of RSV ΔNS2/Δ1313/I1314L vaccine, RSV 6120/ΔNS2/1030s vaccine, RSV 276 vaccine, or placebo intranasally at study entry. Participants will be enrolled in the study outside of RSV season. All participants will remain on study until they complete the post-RSV season visit between April 1 and April 30 in the calendar year following enrollment. Participants' total study duration will be between 6 and 13 months, depending on when they enroll in the study. Participants will attend several study visits throughout the study, which may include physical examinations, blood collection, and nasal washes. Participants' parents or guardians will be contacted by study staff at various times during the study to monitor participants' health.

Official Title
-----------------
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

Conditions
-----------------
Respiratory Syncytial Virus (RSV)

Intervention / Treatment
-----------------
* Biological: RSV ΔNS2/Δ1313/I1314L Vaccine
* Biological: RSV 6120/ΔNS2/1030s Vaccine
* Biological: RSV 276 Vaccine
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Greater than or equal to 6 months (defined as greater than or equal to 180 days) of age at the time of screening and less than 25 months (defined as less than 750 days) of age at the time of enrollment. In good health based on review of the medical record, history, and physical examination, without evidence of chronic disease. Parent/guardian is willing and able to provide written informed consent as described in the study 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 study product administration. Note: results from specimens collected during screening for any study of an RSV vaccine developed by the Laboratory of Infectious Diseases (LID) (National Institute of Allergy and Infectious Diseases [NIAID], National Institutes of Health [NIH]) are acceptable. If study product will not be administered the same day as randomization (see the study protocol), it must be administered no more than 42 days after the screening sample is collected. Growing normally for age in the opinion of the site clinician in the six months prior to enrollment AND has a current height and weight above the 3rd percentile for age and sex per Centers for Disease Control and Prevention (CDC) World Health Organization (WHO) growth standards. Has received routine immunizations appropriate for age (as per national Center for Disease Control Advisory Committee on Immunization Practices [ACIP]). Note: COVID-19 vaccination will not be required unless fully licensed for this age group and ACIP-recommended. See study-specific Manual of Procedures for further guidance Is expected to be available for the duration of the study. If born to an HIV-infected woman, potential participant must have 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. If potential participant was breastfed by an HIV-infected woman, each of the sampling times noted above must be measured in weeks after the last exposure to breast milk, rather than weeks of age. Exclusion Criteria: Prior laboratory-confirmed RSV infection. Known or suspected HIV infection or impairment of immunological functions. Receipt of immunosuppressive therapy, including any systemic, nasal, or inhaled corticosteroids within 28 days of enrollment. Note: Cutaneous (topical) steroid treatment is not an exclusion. Any receipt of bone marrow/solid organ transplant. Major congenital malformations (such as congenital cleft palate) or cytogenetic abnormalities. Previous enrollment in this trial, previous pediatric receipt of a licensed or investigational RSV vaccine, or previous maternal or pediatric receipt of or planned administration of any other anti-RSV product (such as ribavirin or RSV IG or RSV monoclonal antibody [mAb]) within 4 months of screening or planned administration of an anti-RSV product between screening and day 56 after enrollment. Any previous anaphylactic reaction. Any known hypersensitivity to any study product component. Heart disease. Note: Potential 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 contains a person with chronic lung disease, including but not limited to chronic obstructive pulmonary disease (COPD), emphysema, or home oxygen use, reactive airway disease or asthma. Note: Asthma or reactive airway disease in a household member is not exclusionary unless the household member has taken oral steroids for asthma management in the past month and/or has been hospitalized for asthma in the past month. Member of a household that contains, or will contain, an infant who is less than 4 months of age at the enrollment date through Day 14. Member of a household that contains another child/other children who is/are enrolled or is/are scheduled to be enrolled in IMPAACT 2021 on a different date and has/have not completed the Day 56 visit in the same calendar year (i.e., all eligible children from the same household must be enrolled/receive study product on the same date or additional children in the household may be screened, enrolled, and randomized independently after other children in the household complete the Day 56 Visit). 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 Day 0 to 14 of that other child's participation in the study. Member of a household that contains an immunocompromised individual, including, but not limited to: a person who has been diagnosed with cancer and who has received chemotherapy within the 12 months prior to enrollment; or a person living with a solid organ, cord blood, or bone marrow transplant. Shares a daycare room with infants less than 4 months of age, and parent/guardian is unable or unwilling to suspend daycare for 14 days following study product administration. 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 (including but not limited to rhinorrhea, cough, or pharyngitis) or nasal congestion significant enough to interfere with successful study product administration, or otitis media. Note: if participant is randomized and subsequently noted to have any of the above, study product administration must be deferred per the study protocol. Receipt of the following prior to enrollment (start counting backwards with '1' as the day of planned study product administration): 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. Note: if COVID-19 vaccine has EUA approval and ACIP recommendation for this age group, it is not considered investigational Scheduled administration of the following after planned study product administration (start counting with '1' as the day of planned study product administration): 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. Note: if COVID-19 vaccine has EUA approval and ACIP recommendation for this age group, it is not considered investigational. Receipt of immunoglobulin, any antibody products, or any blood products within the past 6 months prior to enrollment 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. Born at less than 34 weeks gestation. Born between 34 weeks gestation and 36 weeks and 6 days gestation and less than 1 year of age at the time of enrollment. Current suspected or documented developmental disorder, delay, or other developmental problem. Any previous receipt of supplemental oxygen therapy in a home setting. Known or suspected SARS-CoV-2 exposure within the 14 days prior to enrollment. Note: known or suspected SARS-CoV-2 includes a known asymptomatic household member under quarantine for SARS-CoV-2 exposure but without a positive SARS-CoV-2 test.

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 25 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RSV ΔNS2/Δ1313/I1314L Vaccine<br>Participants will receive a single dose of the RSV ΔNS2/Δ1313/I1314L vaccine at study entry (Day 0). | Biological: RSV ΔNS2/Δ1313/I1314L Vaccine<br>* 10^6 plaque-forming units (PFU); administered as nose drops<br>|
| Experimental: RSV 6120/ΔNS2/1030s Vaccine<br>Participants will receive a single dose of the RSV 6120/ΔNS2/1030s vaccine at study entry (Day 0). | Biological: RSV 6120/ΔNS2/1030s Vaccine<br>* 10^5 plaque-forming units (PFU); administered as nose drops<br>|
| Experimental: RSV 276 Vaccine<br>Participants will receive a single dose of the RSV 276 vaccine at study entry (Day 0). | Biological: RSV 276 Vaccine<br>* 10^5 plaque-forming units (PFU); administered as nose drops<br>|
| Placebo Comparator: Placebo<br>Participants will receive a single dose of placebo at study entry (Day 0). | Biological: Placebo<br>* Administered as nose drops<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Grade 1 or higher solicited adverse events (AEs) | Solicited adverse events include fever; otitis media; upper respiratory illness (URI); lower respiratory illness (LRI) and are graded following a protocol-defined grading system for solicited events. | Measured through Day 28 | 
| Frequency of Grade 2 or higher lower respiratory illnesses (LRIs) | Graded following a protocol-defined grading system for solicited events | Measured through Day 28 | 
| Frequency of serious AEs | Serious adverse events are defined according to Version 2.0 of the DAIDS EAE Manual. | Measured through Day 56 | 
| Frequency of a greater than or equal to 4-fold rise in serum RSV-neutralizing antibody titer | Determined from immunologic assays | Measured through Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of a greater than or equal to 4-fold rise in serum RSV F immunoglobulin G (IgG) | Determined from immunologic assays | Measured through Day 56 | 
| Titer of serum RSV F IgG | Determined from immunologic assays | Measured at the Day 56 Visit | 
| Titer of serum RSV-neutralizing antibodies | Determined from immunologic assays | Measured at the Day 56 Visit | 
| Frequency of RSV-associated medically attended acute respiratory illness (RSV-MAARI) | Graded following a protocol-defined grading system for solicited events | Measured through the last day of the RSV season, which will occur between 5 and 12 months after study entry, depending on when the participant enrolls in the study | 
| Maximum grade (if more than one illness within a participant) of RSV-MAARI | Graded following a protocol-defined grading system for solicited events | Measured through the last day of the RSV season, which will occur between 5 and 12 months after study entry, depending on when the participant enrolls in the study | 
| Frequency of RSV-associated medically attended acute lower respiratory illness (RSV-MAALRI) | Graded following a protocol-defined grading system for solicited events | Measured through the last day of the RSV season, which will occur between 5 and 12 months after study entry, depending on when the participant enrolls in the study | 
| Maximum grade (if more than one illness within a participant) of RSV-MAALRI | Graded following a protocol-defined grading system for solicited events | Measured through the last day of the RSV season, which will occur between 5 and 12 months after study entry, depending on when the participant enrolls in the study |