Mapping functional humoral correlates of protection against malaria challenge following RTS,S/AS01 vaccination

Todd J. Suscovich, Jonathan K. Fallon, Jishnu Das, Allison R. Demas, Jonathan Crain, Caitlyn H. Linde, Ashlin Michell, Harini Natarajan, Claudia Arevalo, Thomas Broge, Thomas Linnekin, Viraj Kulkarni, Richard Lu, Matthew D. Slein, Corinne Luedemann, Meghan Marquette, Sandra March, Joshua Weiner, Scott Gregory, Margherita CocciaYevel Flores-Garcia, Fidel Zavala, Margaret E. Ackerman, Elke Bergmann-Leitner, Jenny Hendriks, Jerald Sadoff, Sheetij Dutta, Sangeeta N. Bhatia, Douglas A. Lauffenburger, Erik Jongert, Ulrike Wille-Reece, Galit Alter

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Vaccine development has the potential to be accelerated by coupling tools such as systems immunology analyses and controlled human infection models to define the protective efficacy of prospective immunogens without expensive and slow phase 2b/3 vaccine studies. Among human challenge models, controlled human malaria infection trials have long been used to evaluate candidate vaccines, and RTS,S/AS01 is the most advanced malaria vaccine candidate, reproducibly demonstrating 40 to 80% protection in human challenge studies in malaria-naive individuals. Although antibodies are critical for protection after RTS,S/AS01 vaccination, antibody concentrations are inconsistently associated with protection across studies, and the precise mechanism(s) by which vaccine-induced antibodies provide protection remains enigmatic. Using a comprehensive systems serological profiling platform, the humoral correlates of protection against malaria were identified and validated across multiple challenge studies. Rather than antibody concentration, qualitative functional humoral features robustly predicted protection from infection across vaccine regimens. Despite the functional diversity of vaccine-induced immune responses across additional RTS,S/AS01 vaccine studies, the same antibody features, antibody-mediated phagocytosis and engagement of Fc gamma receptor 3A (FCGR3A), were able to predict protection across two additional human challenge studies. Functional validation using monoclonal antibodies confirmed the protective role of Fc-mediated antibody functions in restricting parasite infection both in vitro and in vivo, suggesting that these correlates may mechanistically contribute to parasite restriction and can be used to guide the rational design of an improved vaccine against malaria.

Original languageEnglish (US)
Article numbereabb4757
JournalScience translational medicine
Issue number553
StatePublished - Jul 22 2020

ASJC Scopus subject areas

  • Medicine(all)


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