Malaria vaccine development entered a new era in 2015 when the pre-erythrocytic Plasmodium falciparum candidate RTS,S was favorably reviewed by the European Medicines Agency and subsequently introduced into national pilot implementation programs, marking the first human anti-parasite vaccine to pass regulatory scrutiny. Since the first trials published in 1997, RTS,S has been evaluated in a series of clinical trials culminating in Phase 3 testing, while testing of other pre-erythrocytic candidates (that target sporozoite- or liver-stage parasites), particularly whole sporozoite vaccines, has also increased. Interest in blood-stage candidates (that limit blood-stage parasite growth) subsided after disappointing human efficacy results, although new blood-stage targets and concepts may revive activity in this area. Over the past decade, testing of transmission-blocking vaccines (that kill mosquito/sexual-stage parasites) advanced to field trials and the first generation of placental malaria vaccines (that clear placenta-sequestering parasites) entered the clinic. Novel antigen discovery, human monoclonal antibodies, structural vaccinology, and improved platforms promise to expand on RTS,S and improve existing vaccine candidates.

Severe Plasmodium falciparum malaria is a major cause of death in children. The contribution of the parasite burden to the pathogenesis of severe malaria has been controversial. We documented P. falciparum infection and disease in Tanzanian children followed from birth for an average of 2 years and for as long as 4 years. Of the 882 children in our study, 102 had severe malaria, but only 3 had more than two episodes. More than half of first episodes of severe malaria occurred after a second infection. Although parasite levels were higher on average when children had severe rather than mild disease, most children (67 of 102) had high-density infection (>2500 parasites per 200 white cells) with only mild symptoms before severe malaria, after severe malaria, or both. The incidence of severe malaria decreased considerably after infancy, whereas the incidence of high-density infection was similar among all age groups. Infections before and after episodes of severe malaria were associated with similar parasite densities. Nonuse of bed nets, placental malaria at the time of a woman's second or subsequent delivery, high-transmission season, and absence of the sickle cell trait increased severe-malaria risk and parasite density during infections. Resistance to severe malaria was not acquired after one or two mild infections. Although the parasite burden was higher on average during episodes of severe malaria, a high parasite burden was often insufficient to cause severe malaria even in children who later were susceptible. The diverging rates of severe disease and high-density infection after infancy, as well as the similar parasite burdens before and after severe malaria, indicate that naturally acquired resistance to severe malaria is not explained by improved control of parasite density. (Funded by the National Institute of Allergy and Infectious Diseases and others.)

(See the Editorial Commentary by Awah and Kaneko, on pages 1145–7 .) Background. Iron supplementation may increase malaria morbidity and mortality, but the effect of naturally occurring variation in iron status on malaria risk is not well studied. Methods. A total of 785 Tanzanian children living in an area of intense malaria transmission were enrolled at birth, and intensively monitored for parasitemia and illness including malaria for up to 3 years, with an average of 47 blood smears. We assayed plasma samples collected at routine healthy-child visits, and evaluated the impact of iron deficiency (ID) on future malaria outcomes and mortality. Results. ID at routine, well-child visits significantly decreased the odds of subsequent parasitemia (23% decrease, P < .001) and subsequent severe malaria (38% decrease, P = .04). ID was also associated with 60% lower all-cause mortality (P = .04) and 66% lower malaria-associated mortality (P = .11). When sick visits as well as routine healthy-child visits are included in analyses (average of 3 iron status assays/child), ID reduced the prevalence of parasitemia (6.6-fold), hyperparasitemia (24.0-fold), and severe malaria (4.0-fold) at the time of sample collection (all P < .001). Conclusions. Malaria risk is influenced by physiologic iron status, and therefore iron supplementation may have adverse effects even among children with ID. Future interventional studies should assess whether treatment for ID coupled with effective malaria control can mitigate the risks of iron supplementation for children in areas of malaria transmission.

Antibodies acquired naturally through repeated exposure to Plasmodium falciparum are essential in the control of blood-stage malaria. Antibody-dependent functions may include neutralization of parasite–host interactions, complement activation, and activation of Fc receptor functions. A role of antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells in protection from malaria has not been established. Here we show that IgG isolated from adults living in a malaria-endemic region activated ADCC by primary human NK cells, which lysed infected red blood cells (RBCs) and inhibited parasite growth in an in vitro assay for ADCC-dependent growth inhibition. RBC lysis by NK cells was highly selective for infected RBCs in a mixed culture with uninfected RBCs. Human antibodies to P. falciparum antigens PfEMP1 and RIFIN were sufficient to promote NK-dependent growth inhibition. As these results implicate acquired immunity through NK-mediated ADCC, antibody-based vaccines that target bloodstream parasites should consider this new mechanism of action.