Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity
Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity
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.
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.
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