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

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
will evaluate 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 will be randomly assigned to receive a single dose of the
D46/NS2/N/ΔM2-2-HindIII vaccine or placebo at study entry (Day 0).

Participants will be enrolled in the study outside of RSV season, i.e., 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 MOP. 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.

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

- The participant is in good health based on review of the medical record, history, and
physical examination, without evidence of chronic disease.

- Parents/guardians are 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)
are acceptable as long as within the 42-day window.

- Is growing at a normal velocity for age (as demonstrated on a standard growth chart)
AND

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

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

- Participant has 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 is indicated
only if the participant is age-eligible per ACIP.

- Participant is 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 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 is 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 contains, or will contain, an infant who is less than 6
months of age at the enrollment date through Day 28.

- Member of a household that contains another child who is, or is scheduled to be,
enrolled in IMPAACT 2011, 2012 or 2013 or another study evaluating an intranasal
live-attenuated RSV vaccine, AND there has been or will 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 contains an immunocompromised individual, including, but
not limited to:

- a person who is 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 has 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 is sufficient documentation if the
parent/guardian is confident of history.

- Attends a daycare facility and shares a room with infants less than 6 months of age,
and parent/guardian is 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.