Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity
Condition: Newborn Vaccine Immunogenicity
Study type: Interventional

Summary: 
      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: 
      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.
    

Intervention name(s): Hepatitis B vaccine (HBV); Bacillus Calmette-Guérin (BCG)
Intervention type(s): Biological; Biological
Intervention description(s): Licensed pediatric HBV vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.; Licensed BCG vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.
Intervention MeSH terms: BCG Vaccine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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)
Primary purpose: Basic Science
Keywords: newborn vaccine responses