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

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.

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