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Towards identification and development of alternative vaccines against pregnancy-associated malaria based on naturally acquired immunity

Pregnant women are particularly susceptible to Plasmodium falciparum malaria, leading to substantial maternal and infant morbidity and mortality. While highly effective malaria vaccines are considered an essential component towards malaria elimination, strides towards development of vaccines for pregnant women have been minimal. The leading malaria vaccine, RTS,S/AS01, has modest efficacy in children suggesting that it needs to be strengthened and optimized if it is to be beneficial for pregnant women. Clinical trials against pregnancy-associated malaria (PAM) focused on the classical VAR2CSA antigen are ongoing. However, additional antigens have not been identified to supplement these initiatives despite the new evidence that VAR2CSA is not the only molecule involved in pregnancy-associated naturally acquired immunity. This is mainly due to a lack of understanding of the immune complexities in pregnancy coupled with difficulties associated with expression of malaria recombinant proteins, low antigen immunogenicity in humans, and the anticipated complications in conducting and implementing a vaccine to protect pregnant women. With the accelerated evolution of molecular technologies catapulted by the global pandemic, identification of novel alternative vaccine antigens is timely and feasible. In this review, we discuss approaches towards novel antigen discovery to support PAM vaccine studies.