Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity

Conditions
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Newborn Vaccine Immunogenicity

Intervention / Treatment
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* Biological: Hepatitis B vaccine (HBV)
* Biological: Bacillus Calmette-Guérin (BCG)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 0 Days
Maximum Age: 1 Day

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Newborn infants will have delayed immunization, with catch-up immunization at day of life 7 (DOL7), or immunization at birth with hepatitis B vaccine (HBV), Bacille Calmette-Guérin (BCG) or (HBV +BCG). All participants will have peripheral blood collected at birth (DOL0) and each group will be divided into sub-groups with follow-up peripheral blood collection at DOL1, DOL3, or DOL7.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: NO VACCINES AT BIRTH<br>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<br>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)<br>* Licensed pediatric HBV vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.<br>|
| Other: BCG VACCINE AT BIRTH<br>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)<br>* Licensed BCG vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.<br>|
| Other: (HBV + BCG) VACCINES AT BIRTH<br>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)<br>* Licensed pediatric HBV vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.<br>Biological: Bacillus Calmette-Guérin (BCG)<br>* Licensed BCG vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.<br>|

What is the study measuring?
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Primary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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newborn vaccine responses