Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity (EPIC-HIPC)

November 30, 2023 updated by: Ofer Levy, Boston Children's Hospital
Infection is the most common cause of death in early life, especially for newborns and can be reduced by immunization but insufficient knowledge of how vaccines protect the very young limits their optimal use. To gain insight into how vaccines induce protection of the most vulnerable, this National Institutes of Health (NIH)/National Institute of Allergy & Infectious Diseases (NIAID)-funded Human Immunology Project Consortium (HIPC) study, based at Boston Children's Hospital and conducted by the Expanded Program on Immunization Consortium (EPIC), employs two novel approaches studying newborn responses to hepatitis B vaccine (HBV): (a) systems biology that uses technologies which comprehensively measure global changes in molecules such as transcriptomics (RNA) and proteomics (proteins), as well as cell composition of the blood and (b) use of human newborn blood components, collected prior to immunization, to model vaccine responses in vitro (outside the body). Characterizing vaccine-induced molecular patterns ("signatures") that correspond to vaccine-mediated protection will accelerate development and optimization of vaccines against early life infections of major global health importance.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

While the greatest number of vaccines is administered to the very young, vaccine preventable infections remain a major cause of morbidity and mortality, especially for the newborn. To improve vaccine-mediated protection early in life, the investigators will identify biomarkers that predict protective efficacy and garner insight into the underlying mechanisms of vaccine-mediated protection. Systems biology approaches ("OMICs") applied to vaccinology, i.e., systems vaccinology, has revolutionized the field with an unbiased identification of pathways relevant to vaccine-induced immune responses. However, thus far systems vaccinology has focused primarily on adults, with few studies conducted in children and infants, and none in newborns. This study will bridge this gap by conducting a comprehensive systems vaccinology study in newborns. Specifically, the investigators will determine the molecular pathways that are associated with successful neonatal immunization with hepatitis B virus vaccine (HBV). HBV is the ideal model because i) it is highly (>90%) effective; ii) it has a well-established correlate of protection (CoP; anti-hepatitis surface antigen antibody (anti-HBs)); iii) there is substantial variation in anti-HBs titers and quantifiable inter-subject variability is essential for systems biological approaches; iv) it is highly relevant as HBV is given at birth in the U.S. and most developing countries; v) it is amenable to in vivo manipulation with another regularly administered neonatal vaccine, Bacille Calmette-Guérin (BCG), which will greatly enhance detection of relevant signatures. As complex networks of functional interactions among genes and proteins drive the response to immunization, the investigators will integrate transcriptomic, proteomic and immune phenotyping approaches. Importantly, the investigators have successfully adapted these experimental platforms to be fully operational within the small blood volumes obtainable in newborns. The investigators have also developed in vitro systems amenable to experimental manipulation on the cellular and molecular level to identify cause-effect relationships. Pilot data prove feasibility of collecting the relevant high-quality samples according to stringent standard operating procedures, processing them and delivering cogent OMIC data suggesting vaccine-specific 'signatures' in the human newborn. This HIPC will identify biomarkers of neonatal HBV immunogenicity by pursuing the following Overall Specific Aims:

  • Aim 1. Characterize pre-vaccine OMIC and immune signatures in vivo that predict immunogenicity of HBV in human newborns. In adult systems vaccinology studies, baseline immune status of vaccine recipients predicted vaccine immunogenicity at least as well or even better than changes induced by the vaccine. For Aim 1 the investigators will determine the pre-vaccine (Day 0) characteristics of whole blood gene expression, plasma proteome as well as the composition of the white blood cell compartment and their functional status in correlation with the HBV-induced neonatal antibody response.
  • Aim 2. Characterize the post-vaccine impact of HBV on OMIC and immune signatures in vivo that predict immunogenicity of HBV in human newborns. In adults, analysis of vaccine-induced signatures (i.e. post-vaccine) has provided new insights for several vaccines, including HBV. The investigators will for the first time apply this approach to newborns and expand it by manipulating the neonatal response to HBV in vivo by co-administering BCG, as it substantially changes immunogenicity of HBV thereby testing cause-effect relationships in vivo. For Aim 2 the investigators will characterize whole blood gene expression and the plasma and leukocyte proteome as well as white blood cell composition and functional status at Days 1, -3 and -7 postvaccine contrasting infants that received nothing (delayed vaccines to 7 days of age), HBV, BCG or (HBV + BCG) at birth and correlate this with anti-HBs titers.
  • Aim 3. Interrogate functional correlations identified in silico via novel human in vitro platforms that accurately model age-specific vaccine responses and are amenable to a wide range of experimental manipulation allowing mechanistic cause-effect relationships to be probed on the molecular level.

Overall, these integrated studies will identify vaccine-induced molecular pathways correlating with protective immune responses in newborns and will generate and test new mechanistic hypotheses regarding vaccine action in vivo and in vitro. This study will ultimately inform, accelerate and optimize early life immunization resulting in major public health benefit.

Study Type

Interventional

Enrollment (Actual)

911

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Gambia
      • Fajara, Gambia, 000273
        • Medical Research Council Unit, The Gambia
  • Papua New Guinea
    • Eastern Highlands
      • Goroka, Eastern Highlands, Papua New Guinea
        • Institute for Medical Research

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 second to 1 day (Child)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • <24 hours of age
  • >37 weeks gestational age
  • HIV unexposed
  • Healthy (no malformations, normal temperature range and vital signs for age)

Exclusion Criteria:

  • Premature (<37 weeks gestational age)
  • Hepatitis B antigen-positive mother
  • HIV-positive or HIV-exposed
  • Febrile, unstable vital signs

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: NO VACCINES AT BIRTH
These will be newborns who will not receive any vaccines at birth and will have delayed immunization with catch-up (i.e., HBV, BCG and polio vaccine) by Day of Life 7.
Other: HBV VACCINE AT BIRTH
Participants in this arm will receive licensed hepatitis B vaccine (HBV) at birth (Day of Life (DOL)-0) with catch up immunization (i.e., BCG and polio vaccine) at DOL-1, -3, or -7.
Biological: Hepatitis B vaccine (HBV)
Licensed pediatric HBV vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.
Other: BCG VACCINE AT BIRTH
Participants in this arm will receive licensed Bacillus Calmette-Guérin (BCG) vaccine at birth (Day of Life(DOL)-0) with catch up immunization (i.e., HBV and polio vaccine) at DOL-1, -3 or- 7.
Biological: Bacillus Calmette-Guérin (BCG)
Licensed BCG vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.
Other: (HBV + BCG) VACCINES AT BIRTH
Participants in this arm will receive licensed hepatitis B vaccine (HBV) and licensed Bacillus Calmette-Guérin (BCG) vaccine at birth (Day of Life (DOL- 0) with catch up immunization (i.e., polio vaccine) at DOL-1, -3, or -7.
Biological: Hepatitis B vaccine (HBV)
Licensed pediatric HBV vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.
Biological: Bacillus Calmette-Guérin (BCG)
Licensed BCG vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Molecular signature correlating with anti-hepatitis B vaccine antibody response
Time Frame: 1 month of age
We will employ bioinformatics to define molecular signatures correlating with anti-HBV responses
1 month of age

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Boston Children's Hospital

Collaborators

University of British Columbia
Medical Research Council Unit, The Gambia
The University of Western Australia
Institute for Medical Research, Papua New Guinea

Investigators

  • Principal Investigator: Ofer Levy, MD, PhD, Boston Children's Hospital
  • Study Director: Tobias R Kollmann, MD, PhD, The University of Western Australia
  • Study Chair: Beate Kampmann, MD, PhD, Medical Research Council (MRC) Gambia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 6, 2017

Primary Completion (Actual)

August 29, 2022

Study Completion (Actual)

August 29, 2022

Study Registration Dates

First Submitted

August 4, 2017

First Submitted That Met QC Criteria

August 8, 2017

First Posted (Actual)

August 11, 2017

Study Record Updates

Last Update Posted (Estimated)

December 6, 2023

Last Update Submitted That Met QC Criteria

November 30, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB-P00024239

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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