Infectivity, Safety and Immunogenicity of a Recombinant Live-Attenuated Respiratory Syncytial Virus Vaccine (D46/NS2/N/ΔM2-2-HindIII) in RSV-Seronegative Infants and Children 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 and Children 6 to 24 Months of Age

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 and children 6 to 24 months of age.

This study is a companion study to IMPAACT 2013.

Study Overview

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

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 will evaluate whether D46/NS2/N/ΔM2-2-HindIII vaccine is attenuated and immunogenic in children 6 to 24 months of age.

Participants will be randomly assigned to receive a single dose of the RSV D46/NS2/N/ΔM2-2-HindIII vaccine or placebo at study entry (Day 0).

Participants will be enrolled in the study between April 1 and October 31 (outside of 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. Participants' total study duration will be between 6 and 13 months, depending on when they enroll in the study. Participants will be evaluated in study visits that may include physical examinations, blood collection, and nasal washes. Additionally, participants' parents or guardians will be contacted by study staff at various times during the study to monitor participants' health.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health
    • Baltimore, Maryland, United States, 21224
      • Center for Immunization Research East, Johns Hopkins Bayview Medical Center Campus
    • Laurel, Maryland, United States, 20708
      • Center for Immunization Research South

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 2 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 any IMPAACT RSV study or previous receipt of or planned administration of any anti-RSV product (such as ribavirin or RSV Ig or RSV 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 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 (temporal or rectal temperature of greater than or equal to 100.4°F), 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
• 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
Experimental: RSV D46/NS2/N/ΔM2-2-HindIII Vaccine; Participants will receive a single dose of the RSV D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0).	Biological: RSV D46/NS2/N/ΔM2-2-HindIII Vaccine; 10^5 plaque-forming units (PFUs); administered as nose drops
Placebo Comparator: Placebo; Participants will receive a single dose of placebo at study entry (Day 0).	Biological: Placebo; Administered as nose drops

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grades of study product-related solicited adverse events (AEs)	May include fever, upper respiratory illness (URI), otitis media, or lower respiratory illness (LRI)	Measured through Day 28
Grades of study product-related unsolicited AEs	Defined as all other AEs that are not solicited AEs	Measured through Day 28
Grades of study product-related serious adverse events (SAEs)	SAEs as defined in the protocol	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) and/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	Determined from virologic assays	Measured through Day 28
Duration of vaccine virus shedding in nasal washes	Determined by a) culture and b) RT-PCR from Study Day 0-28	Measured through Day 28
Frequency of a greater than or equal to 4-fold rise in RSV-neutralizing antibody titer	Determined from virologic and immunologic assays	Measured through Day 56
Antibody responses to RSV F glycoprotein	As assessed by enzyme-linked immunosorbent assay (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 wild-type 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 study completion, an average of 12 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 through study completion, an average of 13 months
Frequency of B cell responses to vaccine	Will be measured at the post-RSV season visit (between April 1 and April 30 in the calendar year following study entry)	Measured through study completion, an average of 13 months

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Ruth Karron, MD, Center for Immunization Research (CIR), Johns Hopkins Bloomberg School of Public Health (JHSPH)

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.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2017
• Primary Completion (Actual): April 30, 2018
• Study Completion (Actual): April 30, 2018

Study Registration Dates

• First Submitted: March 28, 2017
• First Submitted That Met QC Criteria: March 28, 2017
• First Posted (Actual): April 4, 2017

Study Record Updates

• Last Update Posted (Actual): August 31, 2018
• Last Update Submitted That Met QC Criteria: August 30, 2018
• Last Verified: August 1, 2018

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: CIR 313

Drug and device information, study documents

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