Newborns are severely affected by infection. Immunization is one of the most effective strategies to prevent infection but many vaccines do not work optimally in early life. Our understanding of the mechanisms leading to vaccine-induced protection is early life is very limited. This relates in part to the small sample volumes obtainable, and the fact that the host response to vaccination in the newborn is complicated by a rapidly shifting developmental program and presence of maternal antibodies (MatAbs). Our Human Immunology Project Consortium (HIPC) team has developed a robust protocol that allows the full force of systems vaccinology (transcriptomics, proteomics, immune profiling; collectively called OMIC) to be applied with < 2ml of blood. We also have developed the informatics tools to decipher the impact of rapidly changing host immune status as well as MatAbs. Lastly, we developed in vitro platforms that enable assessment of cause-effect relationships. We have proven the feasibility of this comprehensive approach in a pilot (Expanded Program on Immunization Consortium; EPIC) study. We are now proposing to employ our state-of-the-art experimental and informatics pipeline to characterize vaccine-induced molecular pathways in newborns correlating with hepatitis B vaccine (HBV) immunogenicity. HBV was chosen as the model, because it is the only newborn vaccine with a clearly established, quantifiable correlate of protection (CoP). The goal of the Clinical Core (CC) is to define the impact on HBV responses of both basal characteristics (immune status, MatAbs, etc) and of co-administration of Bacille Calmette-Gurin (BCG) vaccine. Enrollment of newborns for a training- and test-set of samples at the Medical Research Council (MRC)-Gambia (CC-Site 1) will be followed by validation of key signatures in a cohort in Papua New Guinea (PNG; CC-Site 2). Given their longstanding and proven track records, both CC-Sites are particularly well suited to conduct these studies. Across both CCs, we will use identical vaccines, clinical and laboratory protocols and reagents. We approach this via 4 Specific Aims: 1) Enroll well-defined cohorts of Gambian newborns for in vivo OMIC profiling and in vitro responses following immunization with HBV BCG; 2) Measure adaptive immune responses to HBV, enabling correlation of in vivo OMIC signatures and in vitro vaccine modeling assays with established CoP; 3) Measure MatAbs in relation to vaccine-induced neonatal and infant OMIC vaccine signatures and adaptive responses; 4) Validate key signatures identified in a distinct independent PNG newborn cohort. Overall, the proposed CC will enable characterization and validation of vaccine-induced OMIC signatures and assessment of their potential to predict CoP. These studies will ultimately define mechanisms that will inform development of vaccine formulations optimized for early life immunization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI118608-04
Application #
9822172
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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