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.

Study Overview

• Status: Completed
• Conditions: Respiratory Syncytial Virus Infections
• Intervention / Treatment: Biological: D46/NS2/N/ΔM2-2-HindIII; Biological: Placebo

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 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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90089
      • Usc La Nichd Crs
    • Los Angeles, California, United States, 90095-1752
      • David Geffen School of Medicine at UCLA NICHD CRS
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Univ. of Colorado Denver NICHD CRS
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine NICHD CRS
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush Univ. Cook County Hosp. Chicago NICHD CRS
    • Chicago, Illinois, United States, 60614-3393
      • Lurie Children's Hospital of Chicago (LCH) CRS
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University Center for Immunization Research
  • New York
    • Bronx, New York, United States, 10461
      • Jacobi Med. Ctr. Bronx NICHD CRS
    • Stony Brook, New York, United States, 11794
      • SUNY Stony Brook NICHD CRS
  • Tennessee
    • Memphis, Tennessee, United States, 38105-3678
      • St. Jude Children's Research Hospital CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 2 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants received a single dose of placebo at study entry (Day 0).	Biological: Placebo; Isotonic diluent; administered as nose drops
Experimental: RSV D46/NS2/N/ΔM2-2-HindIII Vaccine; Participants received a single dose of the D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0).	Biological: D46/NS2/N/ΔM2-2-HindIII; 10^5 plaque-forming units (PFU) per 0.5ml vaccine; administered as nose drops

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Measured at Days 0, 3, 5, 7, 10, 12, 14, 17, and 28
Number of Participants With a Greater Than or Equal to 4-fold Rise in Serum RSV-neutralizing Antibody Titer	Immunogenicity was assessed pre-inoculation, and at approximately 2 months post-inoculation (Study Day 56). 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.	Measured at Day 0 and Day 56
Serum Antibody Responses to RSV F Glycoprotein as Assessed by Enzyme-linked Immunosorbent Assay (ELISA)	Immunogenicity was assessed at approximately 2 months post-inoculation (Study Day 56).	Measured at Day 56
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 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 3 and Table 4 in the protocol document.	Measured from Day 0 through Day 28
Number of Participants With Unsolicited AEs by Grade	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 was 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 DAIDS AE Grading table v2.0 (see References).	Measured from Day 0 through Day 28
Number of Participants With Serious Adverse Events (SAEs)	A Serious Adverse Event (SAE) was an AE, whether considered related to the study product or not, that: Resulted in death during the period of protocol-defined surveillance; Was life threatening: defined as an event in which the patient was at immediate risk of death at the time of the event; it did not refer to an event that hypothetically might have caused death were it more severe; Required 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; Resulted in a persistent or significant disability/incapacity; Was a congenital anomaly or birth defect; Was an important medical event that might not be immediately life threatening or result in death or hospitalization but might jeopardize the patient or might require intervention to prevent one of the outcomes listed above.	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-neutralizing antibody titer from Study Day 0 and 56.	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
Duration of Vaccine Virus Shedding in Nasal Washes	Determined separately by a) culture and b) reverse transcription polymerase chain reaction (RT-PCR)	Measured at Days 0, 3, 5, 7, 10, 12, 14, 17, and 28. Last day positive is reported.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Had Symptomatic, Medically Attended Respiratory and Febrile Illness, Among Those Who Experienced Natural Infection With wt RSV During the Subsequent RSV Season	The number of participants who had RSV-associated, medically attended, acute respiratory illness (RSV-MAARI) or RSV-associated, medically attended, acute lower respiratory illness (RSV-MAALRI) among those who had RSV detected in nasal washes or greater than or equal to 4 fold rise in serum antibodies during the subsequent RSV season were presented.	Measured from November 1st through participant's post-RSV season surveillance visit
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.	Measured through participant's last study visit, up to a total of 6 to 13 months depending on when participants enrolled in the study
Number of Participants With B Cell Responses to Vaccine	A B cell response to vaccine is indicated by a greater than or equal to 4-fold change in serum antibody titers to RSV F glycoprotein between the pre- and post-inoculation time points.	Measured at day 0 and Day 56

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Mucosal Antibody Responses to Vaccine	Determined from nasal wash samples. This outcome has been changed from a secondary outcome measure to an 'other pre-specified' outcome measure. Since this outcome measure relies on previously untested assays to reliably quantify RSV specific mucosal antibodies from nasal wash samples, it was changed to other pre-specified to fit with its intended analysis type.	Measured at Day 0, 28 and 56

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Elizabeth (Betsy) J. McFarland, MD, University of Colorado School of Medicine and Children's Hospital Colorado, Pediatric Infectious Diseases

Publications and helpful links

General Publications

• McFarland EJ, Karron RA, Muresan P, Cunningham CK, Perlowski C, Libous J, Oliva J, Jean-Philippe P, Moye J, Schappell E, Barr E, Rexroad V, Fearn L, Cielo M, Wiznia A, Deville JG, Yang L, Luongo C, Collins PL, Buchholz UJ. Live-Attenuated Respiratory Syncytial Virus Vaccine With M2-2 Deletion and With Small Hydrophobic Noncoding Region Is Highly Immunogenic in Children. J Infect Dis. 2020 Jun 11;221(12):2050-2059. doi: 10.1093/infdis/jiaa049.

Helpful Links

• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010
• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014

Study record dates

Study Major Dates

• Study Start (Actual): April 6, 2017
• Primary Completion (Actual): May 25, 2018
• Study Completion (Actual): May 25, 2018

Study Registration Dates

• First Submitted: March 23, 2017
• First Submitted That Met QC Criteria: March 29, 2017
• First Posted (Actual): April 5, 2017

Study Record Updates

• Last Update Posted (Actual): February 8, 2022
• Last Update Submitted That Met QC Criteria: January 13, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Paramyxoviridae Infections; Mononegavirales Infections; Pneumovirus Infections; Respiratory Syncytial Virus Infections
• Other Study ID Numbers: IMPAACT 2013; 30074 (DAIDS-ES Registry Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No