Clinical Protocol for a Longitudinal Cohort Study Employing Systems Biology to Identify Markers of Vaccine Immunogenicity in Newborn Infants in The Gambia and Papua New Guinea

Abstract

Background: Infection contributes to significant morbidity and mortality particularly in the very young and in low- and middle-income countries. While vaccines are a highly cost-effective tool against infectious disease little is known regarding the cellular and molecular pathways by which vaccines induce protection at an early age. Immunity is distinct in early life and greater precision is required in our understanding of mechanisms of early life protection to inform development of new pediatric vaccines. Methods and Analysis: We will apply transcriptomic, proteomic, metabolomic, multiplex cytokine/chemokine, adenosine deaminase, and flow cytometry immune cell phenotyping to delineate early cellular and molecular signatures that correspond to vaccine immunogenicity. This approach will be applied to a neonatal cohort in The Gambia (N ~ 720) receiving at birth: (1) Hepatitis B (HepB) vaccine alone, (2) Bacille Calmette Guerin (BCG) vaccine alone, or (3) HepB and BCG vaccines, (4) HepB and BCG vaccines delayed till day 10 at the latest. Each study participant will have a baseline peripheral blood sample drawn at DOL0 and a second blood sample at DOL1,-3, or-7 as well as late timepoints to assess HepB vaccine immunogenicity. Blood will be fractionated via a "small sample big data" standard operating procedure that enables multiple downstream systems biology assays. We will apply both univariate and multivariate frameworks and multi-OMIC data integration to identify features associated with anti-Hepatitis B (anti-HB) titer, an established correlate of protection. Cord blood sample collection from a subset of participants will enable human in vitro modeling to test mechanistic hypotheses identified in silico regarding vaccine action. Maternal anti-HB titer and the infant microbiome will also be correlated with our findings which will be validated in a smaller cohort in Papua New Guinea (N ~ 80). Ethics and Dissemination: The study has been approved by The Gambia Government/MRCG Joint Ethics Committee and The Boston Children's Hospital Institutional Review Board. Ethics review is ongoing with the Papua New Guinea Medical Research Advisory Committee. All de-identified data will be uploaded to public repositories following submission of study output for publication. Feedback meetings will be organized to disseminate output to the study communities. Clinical Trial Registration: Clinicaltrials.gov Registration Number: NCT03246230.

Keywords: OMICS; immunogenicity; markers; newborn; systems biology; vaccine.

Copyright © 2020 Idoko, Smolen, Wariri, Imam, Shannon, Dibassey, Diray-Arce, Darboe, Strandmark, Ben-Othman, Odumade, McEnaney, Amenyogbe, Pomat, van Haren, Sanchez-Schmitz, Brinkman, Steen, Hancock, Tebbutt, Richmond, van den Biggelaar, Kollmann, Levy, Ozonoff and Kampmann.

Figures

Figure 1

Geographical distribution of partnering sites for the EPIC-002 study. An overarching administrative core, clinical core (CC), data management core (DMC), as well as an in vitro vaccine modeling project are based at Boston Children's Hospital (Boston, MA). Clinical Core Sites are located in The Gambia (West Africa) and Papua New Guinea (Australasia). End-point assays are conducted in The Gambia (whole blood assay and cell mediated immunity), PNG (whole blood assay), University of British Columbia (flow cytometry and RNASeq), BCH (multiplex cytokines/chemokines, plasma proteomics, in vitro modeling including WBA and tissue constructs) as well as the Center for Vaccinology (CEVAC; Ghent, Belgium; anti-hepatitis B surface antigen titres).

Figure 2

Field algorithm for management of intercurrent illness during the EPIC-002 study. Green, amber and red signs are as defined in Supplementary Table 2. FW, Field worker.