Safety and Immunogenicity of the RSV D46cpΔM2-2 Vaccine in RSV-Seropositive Children and RSV-Seronegative Infants and Children

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and immunogenicity of the RSV D46cpΔM2-2 vaccine in RSV-seropositive children and RSV-seronegative infants and children.

Detailed Description
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Human 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 will evaluate the safety and immunogenicity of the RSV D46cpΔM2-2 vaccine in RSV-seropositive children and RSV-seronegative infants and children. The vaccine will be evaluated in a stepwise fashion beginning in RSV-seropositive children (Group 1), and then in RSV-seronegative infants and children (Group 2). In each group, participants will be randomly assigned to receive a single dose of D46cpΔM2-2 vaccine or placebo at study entry (day 0). Participants will be enrolled in the study between April 1 and October 31, outside of the RSV season. Group 1 (RSV-seropositive children) will attend several study visits and will be followed for 28 days. Group 2 (RSV-seronegative infants and children) 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 in Group 2 will also attend several study visits during the time they are enrolled in the study. Study visits for all participants may include clinical assessments, blood collection, and nasal washes.

Official Title
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A Phase I Study of the Safety and Immunogenicity of a Single Dose of the Live Recombinant RSV D46cpΔM2-2 Vero Grown Virus Vaccine (Lot RSV #008A), Delivered as Nose Drops to RSV-Seropositive Children 12 to 59 Months of Age and RSV-Seronegative Infants and Children 6 to 24 Months of Age

Conditions
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Respiratory Syncytial Virus Infections

Intervention / Treatment
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* Biological: D46cpΔM2-2 vaccine
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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RSV-Seropositive Children: Inclusion Criteria: Greater than or equal to 12 months of age and less than 60 months of age Received routine immunizations appropriate for age Serum RSV neutralizing antibody titer greater than or equal to 1:40 Serum RSV neutralizing antibody result obtained this calendar year Pre-inoculation serum RSV neutralizing antibody specimen obtained less than or equal to 56 days prior to inoculation Parent/guardian has completed the study comprehension assessment Parent/guardian has signed the study informed consent document (ICD) Subject is expected to be available for the duration of the study Exclusion Criteria: Evidence of chronic disease Within the past 6 months had a decline in height or weight growth that crosses two major growth percentiles (e.g., from above the 75th to below the 25th) Known or suspected impairment of immune function Maternal history of positive HIV test Bone marrow/solid organ transplant recipient Major congenital malformations, including congenital cleft palate or cytogenetic abnormalities Current or unresolved suspected or documented developmental disorder, delay, or other developmental problem Cardiac abnormality requiring treatment Lung disease or reactive airway disease More than one episode of wheezing in the first year of life Wheezing episode or received bronchodilator therapy within the past 12 months Previous immunization with an experimental RSV vaccine Previous receipt or planned administration of anti-RSV antibody product Previous serious vaccine-associated AE or anaphylactic reaction Known hypersensitivity to any vaccine component Previous receipt of immunoglobulin or any antibody products Previous receipt of any other blood products within the past 6 months Member of a household that contains an infant who is less than 12 months of age during study days 0 to 10 Member of a household that includes an immunocompromised individual Member of a household that includes a person who has received chemotherapy within the past 12 months Will attend a daycare facility that does not separate children by age and contains an infant who is greater than 12 months of age during study days 0 to 10 RSV-Seronegative Infants and Children: Inclusion Criteria: Greater than or equal to 6 months of age and less than 25 months of age Received routine immunizations appropriate for age Serum RSV neutralizing antibody titer is less than 1:40 Screening and pre-inoculation serum RSV neutralizing antibody specimen obtained less than or equal to 42 days prior to inoculation Parent/guardian has completed the study comprehension assessment Parent/guardian has signed the study ICD Subject is expected to be available for the duration of the study Born at greater than or equal to 37 weeks gestation or is currently greater than 1 year of age Exclusion Criteria: Evidence of chronic disease Within the past 6 months had a decline in height or weight growth that crosses two major growth percentiles (e.g., from above the 75th to below the 25th) Known or suspected impairment of immune function Maternal history of positive HIV test Bone marrow/solid organ transplant recipient Major congenital malformations, including congenital cleft palate or cytogenetic abnormalities Current or unresolved suspected or documented developmental disorder, delay, or other developmental problem Cardiac abnormality requiring treatment Lung disease or reactive airway disease More than one episode of wheezing in the first year of life Wheezing episode or received bronchodilator therapy within the past 12 months Previous immunization with an experimental RSV vaccine Previous receipt or planned administration of anti-RSV antibody product Previous receipt of immunoglobulin or any antibody products Previous receipt of any other blood products within the past 6 months Previous serious vaccine-associated AE or anaphylactic reaction Known hypersensitivity to any vaccine component Member of a household which contains an infant who is less than 6 months of age during study days 0 to 28 Member of a household that includes an immunocompromised individual Member of a household that includes a person who has received chemotherapy within the past 12 months Will attend a daycare facility that does not separate children by age and contains an infant who is less than 6 months of age during study days 0 to 28 Temporary Exclusion Criteria for RSV-Seropositive and RSV-Seronegative Children: To be eligible to participate, RSV-seropositive and RSV-seronegative infants and children must satisfy none of the temporary exclusion criteria. The following conditions are temporary or self-limiting. Once the condition is resolved and the subject is otherwise eligible, the subject may be enrolled or rescreened, if necessary. Any of the following events at the time of inoculation: fever (rectal temperature of greater than or equal to 100.4°F), upper respiratory signs or symptoms (rhinorrhea, cough, or pharyngitis) nasal congestion significant enough to interfere with successful inoculation otitis media Receipt of any killed vaccine or live-attenuated rotavirus vaccine less than 14 days prior to inoculation Receipt of the following medications less than 28 days prior to inoculation: any live vaccine other than rotavirus another investigational vaccine or investigational drug, systemic corticosteroids administered for greater than 14 days at a dosage equivalent to prednisone at greater than 2 mg/kg or 20 mg daily salicylate (aspirin) or salicylate-containing products Receipt of a non-permitted concomitant medication or any of the following medications less than 3 days prior to inoculation: systemic antibacterial, antiviral, antifungal, anti-parasitic, or antituberculous agents, whether for treatment or prophylaxis, intranasal medications Scheduled administration of the following in relation to planned inoculation: killed vaccine within the 14 days following, any live vaccine other than rotavirus within the 28 days following, another investigational vaccine or drug within the 28 days following for RSV-seropositive children and the 56 days following for RSV-seronegative infants and children

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 60 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: D46cpΔM2-2 Vaccine<br>RSV-seropositive children will receive a single dose of 10^6 PFU D46cpΔM2-2 vaccine at study entry (day 0). | Biological: D46cpΔM2-2 vaccine<br>* Delivered as nose drops<br>|
| Placebo Comparator: Group 1: Placebo<br>RSV-seropositive children will receive a single dose of placebo at study entry (day 0). | Biological: Placebo<br>* Delivered as nose drops<br>|
| Experimental: Group 2: D46cpΔM2-2 Vaccine<br>RSV-seronegative infants and children will receive a single dose of 10^5 PFU D46cpΔM2-2 vaccine at study entry (day 0). | Biological: D46cpΔM2-2 vaccine<br>* Delivered as nose drops<br>|
| Placebo Comparator: Group 2: Placebo<br>RSV-seronegative infants and children will receive a single dose of placebo at study entry (day 0). | Biological: Placebo<br>* Delivered as nose drops<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of vaccine-related solicited adverse events (AEs) that occur during the acute monitoring phase of the study |  | Measured at days 0-10 for seropositive and days 0-28 for seronegative | 
| Severity of vaccine-related solicited AEs that occur during the acute monitoring phase of the study |  | Measured at days 0-10 for seropositive and days 0-28 for seronegative | 
| Frequency of vaccine-related lower respiratory illness |  | Measured during study days 0-28 for seropositive subjects and study days 0-56 for seronegative subjects | 
| Proportion of subjects shedding vaccine virus |  | Measured during study days 0-28 for seropositive subjects and study days 0-56 for seronegative subjects | 
| Proportion of subjects that develop 4-fold or greater increases in RSV neutralizing antibody titer following vaccination |  | Measured during study days 0-28 for seropositive subjects and study days 0-56 for seronegative subjects |