Background: Vaccination and naturally acquired immunity against microbial pathogens may have complex\ninteractions that influence disease outcomes. To date, only vaccine-specific immune responses have routinely been\ninvestigated in malaria vaccine trials conducted in endemic areas. We hypothesized that RTS,S/A01E immunization\naffects acquisition of antibodies to Plasmodium falciparum antigens not included in the vaccine and that such\nresponses have an impact on overall malaria protective immunity.\nMethods: We evaluated IgM and IgG responses to 38 P. falciparum proteins putatively involved in naturally\nacquired immunity to malaria in 195 young children participating in a case-control study nested within the African\nphase 3 clinical trial of RTS,S/AS01E (MAL055 NCT00866619) in two sites of different transmission intensity\n(Kintampo high and Manhica moderate/low). We measured antibody levels by quantitative suspension array\ntechnology and applied regression models, multimarker analysis, and machine learning techniques to analyze\nfactors affecting their levels and correlates of protection.\nResults: RTS,S/AS01E immunization decreased antibody responses to parasite antigens considered as markers of\nexposure (MSP142, AMA1) and levels correlated with risk of clinical malaria over 1-year follow-up. In addition, we show\nfor the first time that RTS,S vaccination increased IgG levels to a specific group of pre-erythrocytic and blood-stage\nantigens (MSP5, MSP1 block 2, RH4.2, EBA140, and SSP2/TRAP) which levels correlated with protection against clinical\nmalaria (odds ratio [95% confidence interval] 0.53 [0.3-0.93], p = 0.03, for MSP1; 0.52 [0.26-0.98], p = 0.05, for SSP2) in\nmultivariable logistic regression analyses.
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