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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

Primary Purpose

Respiratory Syncytial Virus Infections

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
RSV D46/NS2/N/ΔM2-2-HindIII Vaccine
Placebo
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Respiratory Syncytial Virus Infections

Eligibility Criteria

6 Months - 24 Months (Child)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health
  • Center for Immunization Research East, Johns Hopkins Bayview Medical Center Campus
  • Center for Immunization Research South

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

RSV D46/NS2/N/ΔM2-2-HindIII Vaccine

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

Grades of study product-related solicited adverse events (AEs)
May include fever, upper respiratory illness (URI), otitis media, or lower respiratory illness (LRI)
Grades of study product-related unsolicited AEs
Defined as all other AEs that are not solicited AEs
Grades of study product-related serious adverse events (SAEs)
SAEs as defined in the protocol
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
Peak titer of vaccine virus shed
Determined from virologic assays
Duration of vaccine virus shedding in nasal washes
Determined by a) culture and b) RT-PCR from Study Day 0-28
Frequency of a greater than or equal to 4-fold rise in RSV-neutralizing antibody titer
Determined from virologic and immunologic assays
Antibody responses to RSV F glycoprotein
As assessed by enzyme-linked immunosorbent assay (ELISA)

Secondary Outcome Measures

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)
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)
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)

Full Information

First Posted
March 28, 2017
Last Updated
August 30, 2018
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT03099291
Brief Title
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
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
April 1, 2017 (Actual)
Primary Completion Date
April 30, 2018 (Actual)
Study Completion Date
April 30, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Respiratory Syncytial Virus Infections

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Double Blind
Allocation
Randomized
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
RSV D46/NS2/N/ΔM2-2-HindIII Vaccine
Arm Type
Experimental
Arm Description
Participants will receive a single dose of the RSV D46/NS2/N/ΔM2-2-HindIII vaccine at study entry (Day 0).
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will receive a single dose of placebo at study entry (Day 0).
Intervention Type
Biological
Intervention Name(s)
RSV D46/NS2/N/ΔM2-2-HindIII Vaccine
Intervention Description
10^5 plaque-forming units (PFUs); administered as nose drops
Intervention Type
Biological
Intervention Name(s)
Placebo
Intervention Description
Administered as nose drops
Primary Outcome Measure Information:
Title
Grades of study product-related solicited adverse events (AEs)
Description
May include fever, upper respiratory illness (URI), otitis media, or lower respiratory illness (LRI)
Time Frame
Measured through Day 28
Title
Grades of study product-related unsolicited AEs
Description
Defined as all other AEs that are not solicited AEs
Time Frame
Measured through Day 28
Title
Grades of study product-related serious adverse events (SAEs)
Description
SAEs as defined in the protocol
Time Frame
Measured through Day 56
Title
Number of participants with infection with vaccine virus
Description
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
Time Frame
Measured through Day 56
Title
Peak titer of vaccine virus shed
Description
Determined from virologic assays
Time Frame
Measured through Day 28
Title
Duration of vaccine virus shedding in nasal washes
Description
Determined by a) culture and b) RT-PCR from Study Day 0-28
Time Frame
Measured through Day 28
Title
Frequency of a greater than or equal to 4-fold rise in RSV-neutralizing antibody titer
Description
Determined from virologic and immunologic assays
Time Frame
Measured through Day 56
Title
Antibody responses to RSV F glycoprotein
Description
As assessed by enzyme-linked immunosorbent assay (ELISA)
Time Frame
Measured through Day 56
Secondary Outcome Measure Information:
Title
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
Description
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)
Time Frame
Measured through study completion, an average of 12 months
Title
Measurement of antibody responses in the vaccine and placebo recipients who experience natural infection with wt RSV during the subsequent RSV season
Description
Will be measured at the post-RSV season visit (between April 1 and April 30 in the calendar year following study entry)
Time Frame
Measured through study completion, an average of 13 months
Title
Frequency of B cell responses to vaccine
Description
Will be measured at the post-RSV season visit (between April 1 and April 30 in the calendar year following study entry)
Time Frame
Measured through study completion, an average of 13 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
24 Months
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ruth Karron, MD
Organizational Affiliation
Center for Immunization Research (CIR), Johns Hopkins Bloomberg School of Public Health (JHSPH)
Official's Role
Principal Investigator
Facility Information:
Facility Name
Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
Center for Immunization Research East, Johns Hopkins Bayview Medical Center Campus
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21224
Country
United States
Facility Name
Center for Immunization Research South
City
Laurel
State/Province
Maryland
ZIP/Postal Code
20708
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
32006006
Citation
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.
Results Reference
derived

Learn more about this trial

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

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