Impact of early-life pathogen exposures on pre-erythrocytic malaria vaccine effectiveness in Kenyan infants

ABSTRACT The rollout of two recently approved pre-erythrocytic malaria vaccines – RTS,S and R21 – is an important step in reducing the burden of malaria in highly vulnerable populations. However, strategies to optimize the effectiveness of these vaccines are needed to improve population level protection against childhood malaria and to hasten progress towards elimination. RTS,S is currently available and has been integrated into routine vaccine schedules in some areas, including our study sites in western Kenya. The efficacy of RTS,S is partial, short- lived, and varies widely according to age and geographic location. It is not clear why RTS,S induces protection in some individuals and not others, or what the immune mechanisms are that favor durable and protective immunity. Evidence suggests that previous malaria exposures negatively impact RTS,S antibody responses and clinical efficacy, though this has not been evaluated in prospective studies. This study will evaluate interactions between early-life malaria and innate immune development in infants living in an area with intense perennial transmission to identify clinical and immune factors that impact RTS,S effectiveness. Infants will be enrolled at birth in a prospective observational cohort in which RTS,S is given at 6, 7, and 9 months of age, with follow up through 24 months of age. In Aim 1, we will determine the impact of early-life malaria on RTS,S antibody responses and clinical effectiveness. The study design will account for heterogeneity in the intensity of malaria exposure and for the influence of other common childhood infectious exposures. RTS,S-induced antibody measures will include both magnitude and functional activity. In Aim 2, we will determine whether pro- inflammatory innate immune phenotypes at 6 months of age are negatively associated with RTS,S antibody magnitude and function. Assessment of innate immunity will include single cell transcriptomes of peripheral blood mononuclear cells, whole blood phenotypes using mass cytometry by time of flight (CyTOF), and whole blood cytokine production in response stimulation of innate pattern recognition receptors. This study will identify clinical and immune factors associated with sub-optimal responses to RTS,S that will inform the design of plausible public health interventions to improve vaccine-mediated protection. Findings are relevant to RTS,S, R21, and other malaria vaccines in clinical trials.