Malaria immunity in the infant: progress and pitfalls

We are at the dawn of a new era in the biomedical prevention of childhood malaria. The successful development and ongoing rollout of the first malaria vaccines, RTS,S/AS01 E and R21/Matrix-M, have injected much-needed optimism into the malaria prevention field. Additional new vaccines that use novel antigen-delivery platforms, including whole live-attenuated parasites, are on the horizon. Other immune-based preventive strategies, such as human monoclonal antibodies targeting the circumsporozoite protein (CSP), have demonstrated remarkable success in preventing malaria in field trials. Despite these advances, current malaria vaccines elicit suboptimal immunity in young infants and are recommended only for children five months of age or older. The infant immune system differs fundamentally from that of older children and adults in ways that influence responses to both natural infection and vaccination. Additionally, exposure to plasmodial antigens in utero may modulate the infant’s response to infection and vaccination, as may antimalarial antibodies that are transplacentally acquired from the mother. Here, we review key aspects of the epidemiology and biology of Plasmodium falciparum infection in the fetus and infant, highlight recent findings that illuminate age-related differences in the immune response to natural infection with P. falciparum , and summarize the successes and failures of current malaria vaccination approaches in infancy. We discuss how emerging mechanistic insights might inform the optimal deployment of existing tools, and the development of new ones, to protect infants from malaria. The successful development of RTS,S/AS01E and R21/Matrix-M malaria vaccines has brought renewed optimism to childhood malaria prevention. Novel approaches, including live-attenuated parasite vaccines and human monoclonal antibodies targeting CSP, are in development. However, existing vaccines elicit suboptimal immunity in young infants and are recommended only from five months of age. The infant immune system differs fundamentally from that of older children and adults in ways that influence responses to both natural infection and vaccination. Additionally, in utero plasmodial antigen exposure and transplacentally-acquired maternal antibodies may modulate infant immunity. Here, we review key aspects of the epidemiology and biology of P. falciparum infection in the fetus and infant, highlight recent findings regarding age-related differences in the immune response, and summarize current vaccination approaches in this vulnerable population. We discuss how emerging mechanistic insights might inform optimal deployment of existing preventive tools and guide development of next-generation strategies to protect infants from malaria. • Placental malaria exposes the fetus to malaria antigens, influencing immunity. • The efficacy of malaria vaccines, both current and novel, is poor in young infants. • Maternal antibodies against CSP may reduce the efficacy of infant RTS,S vaccination. • Broadly cross-reactive antibodies to CIDR1α can protect against severe malaria. • Tfh subset polarization and IgG fucosylation are strongly impacted by age.