TY - JOUR
T1 - Mapping functional humoral correlates of protection against malaria challenge following RTS,S/AS01 vaccination
AU - Suscovich, Todd J.
AU - Fallon, Jonathan K.
AU - Das, Jishnu
AU - Demas, Allison R.
AU - Crain, Jonathan
AU - Linde, Caitlyn H.
AU - Michell, Ashlin
AU - Natarajan, Harini
AU - Arevalo, Claudia
AU - Broge, Thomas
AU - Linnekin, Thomas
AU - Kulkarni, Viraj
AU - Lu, Richard
AU - Slein, Matthew D.
AU - Luedemann, Corinne
AU - Marquette, Meghan
AU - March, Sandra
AU - Weiner, Joshua
AU - Gregory, Scott
AU - Coccia, Margherita
AU - Flores-Garcia, Yevel
AU - Zavala, Fidel
AU - Ackerman, Margaret E.
AU - Bergmann-Leitner, Elke
AU - Hendriks, Jenny
AU - Sadoff, Jerald
AU - Dutta, Sheetij
AU - Bhatia, Sangeeta N.
AU - Lauffenburger, Douglas A.
AU - Jongert, Erik
AU - Wille-Reece, Ulrike
AU - Alter, Galit
N1 - Publisher Copyright:
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
PY - 2020/7/22
Y1 - 2020/7/22
N2 - 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.
AB - 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.
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U2 - 10.1126/SCITRANSLMED.ABB4757
DO - 10.1126/SCITRANSLMED.ABB4757
M3 - Article
C2 - 32718991
AN - SCOPUS:85088811511
SN - 1946-6234
VL - 12
JO - Science translational medicine
JF - Science translational medicine
IS - 553
M1 - eabb4757
ER -