The purpose of this study was to evaluate the infectivity, safety, and immunogenicity of the recombinant live-attenuated respiratory syncytial virus (RSV) vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 when delivered as nose drops to RSV-seronegative infants 6 to 24 months of age. This study was a companion study to Center for Immunization Research (CIR) 321.
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 infectivity, safety, and immunogenicity of two recombinant live-attenuated RSV vaccines: RSV ΔNS2/Δ1313/I1314L and RSV 276. The vaccines were delivered as nose drops to RSV-seronegative infants 6 to 24 months of age. Participants were randomly assigned to receive a single dose of the RSV ΔNS2/Δ1313/I1314L vaccine, the RSV 276 vaccine, or placebo at study entry (Day 0). Participants could 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 manual of procedures. 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, nasal washes, and/or nasal adsorption (nasosorption) specimen collection. Participants' parents or guardians were contacted by study staff at various times during the study to monitor participants' health.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
65
10\^6 plaque-forming units (PFU); administered as nose drops
10\^5 PFU; administered as nose drops
Isotonic diluent, administered as nose drops
University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program
La Jolla, California, United States
Usc La Nichd Crs
Los Angeles, California, United States
David Geffen School of Medicine at UCLA NICHD CRS
Los Angeles, California, United States
Univ. of Colorado Denver NICHD CRS
Aurora, Colorado, United States
Rush Univ. Cook County Hosp. Chicago NICHD CRS
Chicago, Illinois, United States
Lurie Children's Hospital of Chicago (LCH) CRS
Chicago, Illinois, United States
Johns Hopkins University Center for Immunization Research
Baltimore, Maryland, United States
Boston Medical Center Ped. HIV Program NICHD CRS
Boston, Massachusetts, United States
SUNY Stony Brook NICHD CRS
Stony Brook, New York, United States
Jacobi Med. Ctr. Bronx NICHD CRS
The Bronx, New York, United States
...and 2 more locations
Number of Participants With Solicited Adverse Events (AEs) by Grade
Solicited adverse events included fever; otitis media; upper respiratory illness (URI); lower respiratory illness (LRI) and cough (without LRI). The number of participants who experienced solicited adverse events was presented. A participant was only counted once in each solicited AE category, and that is in the line corresponding to the highest grade adverse event they had in that category. These events were graded (Grade 1-mild to Grade 4-life-threatening) following protocol-defined grading system outlined in Table 5 and Table 6 in the protocol document.
Time frame: Measured from Day 0 through Day 28
Number of Participants With Unsolicited AEs
Unsolicited adverse events were other events, not included in the solicited AEs. The number of participants who experienced solicited adverse events was presented. A participant was only counted once in each unsolicited AE category, and that is in the line corresponding to the highest grade adverse event they had in that category. AE grading (Grade 1- mild to Grade 4-life-threatening) was done by Division of AIDS (DAIDS) AE Grading table v2.0 (see References).
Time frame: Measured from Day 0 through Day 28
Number of Participants With Serious Adverse Events (SAEs)
A Serious Adverse Event (SAE) is an AE, whether considered related to the study product or not, that: * Results in death during the period of protocol-defined surveillance; * Is life threatening: defined as an event in which the patient was at immediate risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death were it more severe; * Requires inpatient hospitalization (or prolongation of existing hospitalization): defined as at least an overnight stay in the hospital or emergency ward for treatment that would have been inappropriate if administered in the outpatient setting; * Results in a persistent or significant disability/incapacity; * Is a congenital anomaly or birth defect, OR * Is an important medical event that may not be immediately life threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the outcomes listed above.
Time frame: Measured from Day 0 through Day 56
Number of Participants Infected With RSV Vaccine Virus
Defined as 1) vaccine virus identified in a nasal wash from Study Day 0-28 (a binary outcome based on nasal washes); and/or 2) greater than or equal to 4-fold rise in RSV serum neutralizing antibody titer and/or serum enzyme-linked immunosorbent assay (ELISA) titer to the RSV F protein from study entry to Study Day 56
Time frame: Measured at Days 0, 3, 5, 7, 10, 12, 14, 17, and 28 for nasal washes, and at Days 0, 56 for serum RSV-neutralizing antibodies
Peak Titer of Vaccine Virus Shed
This is the highest value per participant of the titer of vaccine virus shed. It was measured by culture. Only participants who met the definition of infection with vaccine virus were included.
Time frame: Measured at Days 0, 3, 5, 7, 10, 12, 14, 17, and 28
Duration of Virus Shedding in Nasal Washes
Determined separately by a) culture and b) reverse transcription polymerase chain reaction (RT-PCR)
Time frame: Measured at Days 0, 3, 5, 7, 10, 12, 14, 17, and 28. Last day positive is reported.
Number of Participants With a Greater Than or Equal to 4-fold Rise in Serum RSV-neutralizing Antibody Titers
Antibody responses were defined as a greater than or equal to 4-fold increase in titer in paired specimens, between pre-inoculation and post-inoculation time points.
Time frame: Measured at Day 0 and Day 56
Serum RSV-neutralizing Antibody Titers
Serum RSV-neutralizing antibody titers were assessed by 60% RSV-plaque reduction neutralization titer (RSV-PRNT) assay.
Time frame: Measured at Day 56
Number of Participants With a Greater Than or Equal to 4-fold Rise in Serum Antibody Titers to RSV F Glycoprotein
Antibodies were assessed by Enzyme-linked Immunosorbent Assay (ELISA). A response was defined as a greater than or equal to 4-fold increase in titer in paired specimens, between pre-inoculation and post-inoculation time points.
Time frame: Measured at Day 0 and Day 56
Serum Antibody Responses to RSV F Glycoprotein
Serum antibody titers to RSV F glycoprotein were assessed by ELISA.
Time frame: Measured at Day 56
Number of Participants Who Had RSV-associated Symptomatic, Medically Attended Respiratory and Febrile Illness, by Grade, Among Those Who Experienced Natural Infection With wt RSV During the Subsequent RSV Season
The number of participants who had RSV-associated, symptomatic, medically attended respiratory and febrile illness (MAARI) among those who had indicators of natural infection with wt RSV were presented. Natural infection with wt RSV during the RSV season surveillance was defined as having either RSV detected in nasal washes collected during illness visits for MAARI events or a \> 4-fold rise in serum antibodies from pre- to post-RSV season in the absence of RSV-associated medical events. A participant was only counted once in each MAARI category, and that was in the line corresponding to the highest grade adverse event they had in that category. These events were graded (Grade 1-mild to Grade 4-life-threatening) following protocol-defined grading system outlined in Table 5 and Table 6 in the protocol document.
Time frame: Measured through participant's last study visit, up to a total of 6 to 10 months depending on when participants enrolled in the study
Magnitude of Serum RSV-neutralizing Antibody Responses in the Vaccine and Placebo Recipients Who Experienced Natural Infection With wt RSV During the Subsequent RSV Season.
Only participants who had RSV detected in nasal washes or a greater than or equal to 4-fold rise in serum antibodies during the subsequent RSV season were included. RSV-neutralizing antibody titers were measured pre- and post-RSV surveillance season subsequent to the time of the inoculation.
Time frame: Measured through participant's last study visit, up to a total of 6 to 10 months depending on when participants enrolled in the study
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