Evaluating the Infectivity, Safety, and Immunogenicity of a Recombinant Live-Attenuated Respiratory Syncytial Virus Vaccine in RSV-Seronegative Infants and Children 6 to 24 Months of Age

Study Overview
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Brief Summary
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The purpose of this study is 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 6 to 24 months of age. This study is a companion study to IMPAACT 2011.

Detailed Description
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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. The purpose of this study is to evaluate the safety, infectivity, and immunogenicity of a single dose of a recombinant live-attenuated RSV vaccine, RSV LID ΔM2-2 1030s, in RSV-seronegative infants 6 to 24 months of age. Participants will be randomly assigned to receive a single dose of the RSV LID ΔM2-2 1030s vaccine or placebo (administered as nose drops) at study entry (Day 0). Participants will be enrolled in the study between April 1 and October 31, outside of the RSV season, and will remain on study until they complete the post-RSV season visit between April 1 and April 30 in the calendar year following enrollment. Total study duration is between 6 to 13 months, depending on when participants enroll in the study. Participants will attend several study visits throughout the study, and the visits may include blood collection, nasal washes, and physical examinations. Participants' parents or guardians will be contacted by study staff at various times during the study to monitor participants' health.

Official Title
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Phase I Placebo-Controlled Study of the Infectivity, Safety and Immunogenicity of a Single Dose of a Recombinant Live-attenuated Respiratory Syncytial Virus Vaccine, LID ΔM2-2 1030s, Lot RSV#010A, Delivered as Nose Drops to 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: RSV LID ΔM2-2 1030s vaccine
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Greater than or equal to 6 months (greater than or equal to 180 days) of age at the time of screening and less than 25 months (less than 750 days) of age 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 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 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 Center for Disease Control Advisory Committee on Immunization Practices [ACIP]) Participant is expected to be available for the duration of the study 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 receipt of placebo in this study or previous receipt of or planned administration of any anti-RSV product (such as ribavirin or RSV IG) 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 documented 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 CIR 311, 312 or 313 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 HIV infected a person who has received chemotherapy within the 12 months prior to enrollment a person receiving immunosuppressant agents a person living with a solid organ or bone marrow transplant 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 killed 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: killed 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 Receipt of salicylate (aspirin) or salicylate-containing products within the past 28 days 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 Meets criteria for failure to thrive within the six months prior to enrollment: a decline in height or weight growth that has crossed two major growth percentiles (e.g., from above the 75th to below the 25th) in an interval of less than 6 months Suspected or documented developmental disorder, delay, or other developmental problem Previous receipt of supplemental oxygen therapy in a home setting

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 24 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: RSV LID ΔM2-2 1030s vaccine<br>Participants will receive a single dose of the RSV LID ΔM2-2 1030s vaccine at Day 0. | Biological: RSV LID ΔM2-2 1030s vaccine<br>* 10^5.0 PFU; administered as nose drops<br>|
| Placebo Comparator: Placebo<br>Participants will receive a single dose of placebo vaccine at Day 0. | Biological: Placebo<br>* Administered as nose drops<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grades of study product-related solicited adverse events (AEs) as defined in the protocol |  | Measured through Day 28 | 
| Grades of study product-related unsolicited AEs |  | Measured through Day 28 | 
| Grades of study product-related serious adverse events (SAEs) |  | Measured through Day 56 | 
| Number of participants with infection with vaccine virus | Defined as 1) vaccine virus identified in a nasal wash from Study Day 0-28 (a binary outcome based on nasal washes done throughout the study period; Day 0 nasal wash will be counted as baseline) or 2) greater than or equal to 4-fold rise in RSV neutralizing antibody titer from Study Day 0-56 | Measured through Day 56 | 
| Peak titer of vaccine virus shed |  | Measured through Day 28 | 
| Duration of vaccine virus shedding in nasal washes measured by culture |  | Measured through Day 28 | 
| Duration of vaccine virus shedding in nasal washes measured by RT-PCR |  | Measured through Day 28 | 
| Greater than or equal to 4-fold rise in RSV-neutralizing antibody titer |  | Measured through Day 56 | 
| Antibody responses to RSV F glycoprotein as assessed by ELISA |  | Measured through Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of symptomatic, medically attended respiratory and febrile illness in the vaccine and placebo recipients who experience natural infection with wt RSV during the subsequent RSV season | Will be measured through the subsequent RSV season (November 1 in the calendar year of study entry to March 31 in the calendar year following study entry) | Measured through 5 months | 
| Measurement of antibody responses in the vaccine and placebo recipients who experience natural infection with wt RSV during the subsequent RSV season | Will be measured at the post-RSV season visit (between April 1 and April 30 in the calendar year following study entry) | Measured at the participant's last study visit, up to a total of 6 to 13 months after study entry depending on when participants enroll in the study | 
| Changes from baseline in the B cell responses to RSV | Will be measured at the post-RSV season visit (between April 1 and April 30 in the calendar year following study entry) | Measured through participant's last study visit, up to a total of 6 to 13 months after study entry depending on when participants enroll in the study |