Systems analysis of protective immune responses to RTS, S malaria vaccination in humans

• Type of Material: Article
• Authors: Dmitri Kazmin, Emory University; Helder Nakaya, Emory University; Eva K. Lee, Georgia Institute of Technology; Matthew J. Johnson, University of Minnesota; Robbert van der Most, GSK Vaccines; Robert A. van den Berg, GSK Vaccines; W. Ripley Ballou, GSK Vaccines; Erik Jongert, GSK Vaccines; Ulrike Wille-Reece, Program for Appropriate Technology in Health-Malaria Vaccine Initiative; Christian Ockenhouse, Program for Appropriate Technology in Health-Malaria Vaccine Initiative; Alan Aderem, Center for Infectious Disease Research; Daniel E. Zak, Center for Infectious Disease Research; Jerald Sadoff, Crucell; Jenny Hendriks, Crucell; Jens Wrammert, Emory University; Rafi Ahmed, Emory University; Bali Pulendran, Emory University
• Language: English
• Date: 2017-02-28
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2017, National Academy of Sciences. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1621489114
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 114
• Issue: 9
• Start Page: 2425
• End Page: 2430
• Grant/Funding Information: This work was supported by a research grant from MVI-Path (to B.P.), National Institutes of Health Grants U19AI090023 (to B.P.) and U19AI057266 (to R.A.), and National Science Foundation Grants NSF-1516074 and NSF-1361532 (to E.K.L.).
• Keywords: CANDIDATE; systems biology; IMMUNOGENICITY; YELLOW-FEVER VACCINE; SAFETY; Multidisciplinary Sciences; Science & Technology - Other Topics; systems vaccinology; EFFICACY; immune; CIRCUMSPOROZOITE-PROTEIN; vaccine; CELL RESPONSES; CHILDREN; EXPRESSION; Science & Technology; BIOLOGY; malaria
• Research Categories: Health Sciences, Pathology; Chemistry, Pharmaceutical

Abstract

RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in ∼50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4 + T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination.