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Author Notes:

To whom correspondence may be addressed. Email: bpulend@emory.edu or rahmed@emory.edu.

Author contributions: D.K., R.v.d.M., R.A.v.d.B., W.R.B., E.J., U.W.-R., C.O., A.A., J.S., J.H., R.A., and B.P. designed research

D.K., H.I.N., E.K.L., M.J.J., and J.W. performed research

J.S. and J.H. contributed new reagents/analytic tools

D.K., H.I.N., A.A., D.E.Z., R.A., and B.P. analyzed data

R.v.d.M. and R.A.v.d.B. contributed to the development of the clinical study

R.A.v.d.B. contributed to the analysis plan

D.K., H.I.N., and B.P. wrote the paper.

The clinical study was performed at the Walter Reed Army Institute of Research Malaria Vaccine Branch, which provided the PBMCs for this study.

We thank Dr. Matthew Woodruff for critically reading the manuscript.

Conflict of interest statement: R.v.d.M., R.A.v.d.B., W.R.B., and E.J. are employees of the GSK group of companies.

They report ownership of GSK shares and/or restricted GSK shares.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • malaria
  • vaccine
  • systems vaccinology
  • systems biology
  • immune
  • YELLOW-FEVER VACCINE
  • CIRCUMSPOROZOITE-PROTEIN
  • CELL RESPONSES
  • IMMUNOGENICITY
  • BIOLOGY
  • EXPRESSION
  • CANDIDATE
  • CHILDREN
  • EFFICACY
  • SAFETY

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

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Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 114, Number 9

Publisher:

, Pages 2425-2430

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2017, National Academy of Sciences. All rights reserved.

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