Evaluating the Infectivity, Safety, and Immunogenicity of Recombinant Live-Attenuated RSV Vaccines RSV ΔNS2/Δ1313/I1314L or RSV 276 in RSV-Seronegative Infants 6 to 24 Months of Age

NCT ID: NCT03227029

Last Updated: 2022-04-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 65 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-22
• Study Completion Date: 2020-10-01

Brief Summary

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.

Detailed Description

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.

Conditions

Respiratory Syncytial Virus Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

RSV ΔNS2/Δ1313/I1314L vaccine

Participants received a single dose of the RSV ΔNS2/Δ1313/I1314L vaccine at study entry (Day 0).

Group Type: EXPERIMENTAL

RSV ΔNS2/Δ1313/I1314L

Intervention Type: BIOLOGICAL

10\^6 plaque-forming units (PFU); administered as nose drops

RSV 276 vaccine

Participants received a single dose of the RSV 276 vaccine at study entry (Day 0).

Group Type: EXPERIMENTAL

RSV 276

Intervention Type: BIOLOGICAL

10\^5 PFU; administered as nose drops

Placebo

Participants received a single dose of placebo at study entry (Day 0).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: BIOLOGICAL

Isotonic diluent, administered as nose drops

Interventions

RSV ΔNS2/Δ1313/I1314L

10\^6 plaque-forming units (PFU); administered as nose drops

Intervention Type: BIOLOGICAL

RSV 276

10\^5 PFU; administered as nose drops

Intervention Type: BIOLOGICAL

Placebo

Isotonic diluent, administered as nose drops

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

• In good health based on review of the medical record, history, and physical examination, without evidence of chronic disease.
• Parent/guardian 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.
• Growing normally for age (i.e., not downwardly crossing two major centiles on a standard growth chart) in the six months prior to enrollment 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).
• 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.
• Any receipt of bone marrow/solid organ transplant.
• Major congenital malformations (such as congenital cleft palate) or cytogenetic abnormalities.
• Previous receipt of a licensed or investigational RSV vaccine (or placebo in any International Maternal Pediatric Adolescent AIDS Clinical Trials Network RSV study) or previous receipt of or planned administration of any anti-RSV product (such as ribavirin or RSV IG or RSV mAb).
• Any previous anaphylactic reaction.
• Any previous vaccine-associated adverse reaction that was Grade 3 or above. Note: if grading is not possible, determine if the reaction was considered severe or life threatening; if so, it is exclusionary.
• Any 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 is less than 6 months of age at the enrollment date through Day 28.
• Member of a household that contained another child/other children who was/were, or was/were scheduled to be, enrolled in IMPAACT 2018 AND the date of enrollment to IMPAACT 2018 would not be concurrent with the other participant(s) living in the household (i.e., all eligible children from the same household must be enrolled on the same date).
• Member of a household that contained another child who was, or was scheduled to be, enrolled in another study evaluating an intranasal live-attenuated RSV vaccine, AND there has 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 for individuals with detectable virus or within 12 months prior to enrollment for individuals with undetectable virus, 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. Documenting the verbal report of CD4 T cell lymphocyte count was sufficient if the parent/guardian was confident of history. Individually identifiable information (e.g., name) pertaining to members of the household were not collected or recorded. Confirmatory laboratory tests for members of the household were not ordered or collected.
• 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 prior to enrollment.
• Receipt of any of the following medications within 3 days prior to 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.
• Current suspected or documented developmental disorder, delay, or other developmental problem.
• Any previous receipt of supplemental oxygen therapy in a home setting.

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 24 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Coleen Cunningham, MD

Role: STUDY_CHAIR

Children's Health Center, DUMC

Locations

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

St. Jude Children's Research Hospital CRS

Memphis, Tennessee, United States

Texas Children's Hospital CRS

Houston, Texas, United States

Countries

United States

References

Cunningham CK, Karron RA, Muresan P, Kelly MS, McFarland EJ, Perlowski C, Libous J, Oliva J, Jean-Philippe P, Moye J, Schappell E, Barr E, Rexroad V, Johnston B, Chadwick EG, Cielo M, Paul M, Deville JG, Aziz M, Yang L, Luongo C, Collins PL, Buchholz UJ; International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 2018 Study Team. Evaluation of Recombinant Live-Attenuated Respiratory Syncytial Virus (RSV) Vaccines RSV/DeltaNS2/Delta1313/I1314L and RSV/276 in RSV-Seronegative Children. J Infect Dis. 2022 Dec 13;226(12):2069-2078. doi: 10.1093/infdis/jiac253.

Reference Type: DERIVED

PMID: 35732186 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Related Links

http://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf

Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Corrected Version 2.1 - July 2017)

http://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-adverse-events-daids

Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

Other Identifiers

38405

Identifier Type: REGISTRY

Identifier Source: secondary_id

IMPAACT 2018

Identifier Type: -

Identifier Source: org_study_id

NCT03422237

Identifier Type: -

Identifier Source: nct_alias