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