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

Phase I Placebo-Controlled Study of the Infectivity, Safety and Immunogenicity of a Single Dose of a Recombinant Live-Attenuated Respiratory Syncytial Virus Vaccine, D46/NS2/N/ΔM2-2-HindIII, Lot RSV#011B, Delivered as Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age

The purpose of this study was to evaluate the safety, infectivity, and immunogenicity of a single dose of a recombinant live-attenuated respiratory syncytial virus (RSV) vaccine in RSV-seronegative infants and children 6 to 24 months of age.

This study was a companion study to CIR 313.

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 evaluated 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 were randomly assigned to receive a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine or placebo (administered as nose drops) at study entry (Day 0).

Participants could be enrolled in the study outside of RSV season (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 Manual Of Procedures). All participants remained on study until they completed the post-RSV season visit between April 1 and April 30 in the calendar year following enrollment. Participants' total study duration was between 6 and 13 months, depending on when they enrolled in the study. Participants attended several study visits throughout the study, which included physical examinations, blood collection, and nasal washes. Participants' parents or guardians were contacted by study staff at various times during the study to monitor participants' health.

Inclusion Criteria:

• Good health based on review of the medical record, history, and physical examination, without evidence of chronic disease.

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

• Growing at a normal velocity for age (as demonstrated on a standard growth chart) AND

  • If less than 1 year of age: current height and weight above the 5th percentile
  • If 1 year of age or older: current height and weight above the 3rd percentile for age.

• 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 was indicated only if the participant was age-eligible per ACIP.

• 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 had 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 was 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 contained, or would contain, an infant who was less than 6 months of age at the enrollment date through Day 28.

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

  • a person who was 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 had 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 was sufficient documentation if the parent/guardian was confident of history.

• Attended a daycare facility and shared a room with infants less than 6 months of age, and parent/guardian was 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.