Malaria is one of the most serious infectious diseases with most of the severe disease caused by Plasmodium falciparum (Pf). Naturally acquired immunity develops over time after repeated infections and the development of antimalarial antibodies is thought to play a crucial role. Neonates and young infants are relatively protected from symptomatic malaria through mechanisms that are poorly understood. The prevailing paradigm is that maternal antimalarial antibodies transferred to the fetus in the last trimester of pregnancy protect the infant from early infections. These antimalarial antibodies wane by approximately 6 months of age leaving the infant vulnerable to malaria, however direct evidence supporting this epidemiologically based paradigm is lacking. As infants are the target population for future malaria vaccines, understanding how they begin to develop immunity to malaria and the gaps in their responses is key. This review summarizes the antimalarial antibody responses detected in infants and how they change over time. We focus primarily on Pf antibody responses and will briefly mention Plasmodium vivax responses in infants.

With increasing malaria control and goals of malaria elimination, many endemic areas are transitioning from high-to-low-to-no malaria transmission. Reductions in transmission will impact on the development of naturally acquired immunity to malaria, which develops after repeated exposure to Plasmodium spp. However, it is currently unclear how declining transmission and malaria exposure will affect the development and maintenance of naturally acquired immunity. Here we review the key processes which underpin this knowledge; the amount of Plasmodium spp. exposure required to generate effective immune responses, the longevity of antibody responses and the ability to mount an effective response upon re-exposure through memory responses. Lastly we identify research priorities which will increase our understanding of how changing transmission will impact on malarial immunity.

Plasmodium vivax is the most geographically widespread of the malaria parasites causing human disease, yet it is comparatively understudied compared with Plasmodium falciparum. In this article we review what is known about naturally acquired immunity to P. vivax, and importantly, how this differs to that acquired against P. falciparum. Immunity to clinical P. vivax infection is acquired more quickly than to P. falciparum, and evidence suggests humans in endemic areas also have a greater capacity to mount a successful immunological memory response to this pathogen. Both of these factors give promise to the idea of a successful P. vivax vaccine. We review what is known about both the cellular and humoral immune response, including the role of cytokines, antibodies, immunoregulation, immune memory and immune dysfunction. Furthermore, we discuss where the future lies in terms of advancing our understanding of naturally acquired immunity to P. vivax, through the use of well-designed longitudinal epidemiological studies and modern tools available to immunologists.

The Plasmodium falciparum erythrocyte membrane protein 1 antigens that are inserted onto the surface of P. falciparum infected erythrocytes play a key role both in the pathology of severe malaria and as targets of naturally acquired immunity. They might be considered unlikely vaccine targets because they are extremely diverse. However, several lines of evidence suggest that underneath this molecular diversity there are a restricted set of epitopes which may act as effective targets for a vaccine against severe malaria. Here we review some of the recent developments in this area of research, focusing on work that has assessed the potential of these molecules as possible vaccine targets.

Gametocytes are the specialized form of Plasmodium parasites that are responsible for human-to-mosquito transmission of malaria. Transmission of gametocytes is highly effective, but represents a biomass bottleneck for the parasite that has stimulated interest in strategies targeting the transmission stages separately from those responsible for clinical disease. Studying targets of naturally acquired immunity against transmission-stage parasites may reveal opportunities for novel transmission reducing interventions, particularly the development of a transmission blocking vaccine (TBV). In this review, we summarize the current knowledge on immunity against the transmission stages of Plasmodium. This includes immune responses against epitopes on the gametocyte-infected erythrocyte surface during gametocyte development, as well as epitopes present upon gametocyte activation in the mosquito midgut. We present an analysis of historical data on transmission reducing immunity (TRI), as analysed in mosquito feeding assays, and its correlation with natural recognition of sexual stage specific proteins Pfs48/45 and Pfs230. Although high antibody titres towards either one of these proteins is associated with TRI, the presence of additional, novel targets is anticipated. In conclusion, the identification of novel gametocyte-specific targets of naturally acquired immunity against different gametocyte stages could aid in the development of potential TBV targets and ultimately an effective transmission blocking approach.

Malaria is one of the most serious infectious diseases with ~250 million clinical cases annually. Most cases of severe disease are caused by Plasmodium falciparum. The blood stage of Plasmodium parasite is entirely responsible for malaria-associated pathology. Disease syndromes range from fever to more severe complications, including respiratory distress, metabolic acidosis, renal failure, pulmonary oedema and cerebral malaria. The most susceptible population to severe malaria is children under the age of 5, with low levels of immunity. It is only after many years of repeated exposure, that individuals living in endemic areas develop clinical immunity. This form of protection does not result in sterilizing immunity but prevents clinical episodes by substantially reducing parasite burden. Naturally acquired immunity predominantly targets blood-stage parasites and it is known to require antibody responses. A large body of epidemiological evidence suggests that antibodies to Plasmodium antigens are inefficiently generated and rapidly lost in the absence of ongoing exposure, which suggests a defect in the development of B cell immunological memory. This review summarizes the main findings to date contributing to our understanding on cellular processes underlying the slow acquisition of humoral immunity to malaria. Some of the key outstanding questions in the field are discussed.

Naturally acquired immunity to the blood-stage of the malaria parasite develops slowly in areas of high endemicity, but is not sterilizing. It manifests as a reduction in parasite density and clinical symptoms. Immunity as a result of blood-stage vaccination has not yet been achieved in humans, although there are many animal models where vaccination has been successful. The development of a blood-stage vaccine has been complicated by a number of factors including limited knowledge of human-parasite interactions and which antigens and immune responses are critical for protection. Opinion is divided as to whether this vaccine should aim to accelerate the acquisition of responses acquired following natural exposure, or whether it should induce a different response. Animal and experimental human models suggest that cell-mediated immune responses can control parasite growth, but these responses can also contribute to significant immunopathology if unregulated. They are largely ignored in most blood-stage malaria vaccine development strategies. Here, we discuss key observations relating to cell-mediated immune responses in the context of experimental human systems and field studies involving naturally exposed individuals and how this may inform the development of a blood-stage malaria vaccine.

Controlled human malaria infections (CHMIs) are a powerful tool to assess the efficacy of drugs and/or vaccine candidates, but also to study anti-malarial immune responses at well-defined time points after infection. In this review, we discuss the insights that CHMI trials have provided into early immune activation and regulation during acute infection, and the capacity to induce and maintain immunological memory. Importantly, these studies show that a single infection is sufficient to induce long-lasting parasite-specific T- and B-cell memory responses, and suggest that blood-stage induced regulatory responses can limit inflammation both in ongoing and potentially future infections. As future perspective of investigation in CHMIs, we discuss the role of innate cell subsets, the interplay between innate and adaptive immune activation and the potential modulation of these responses after natural pre-exposure.

Immunomics is a relatively new field of research which integrates the disciplines of immunology, genomics, proteomics, transcriptomics and bioinformatics to characterize the host-pathogen interface. Herein, we discuss how rapid advances in molecular immunology, sophisticated tools and molecular databases are facilitating in-depth exploration of the immunome. In our opinion, an immunomics-based approach presides over traditional antigen and vaccine discovery methods that have proved ineffective for highly complex pathogens such as the causative agents of malaria, tuberculosis and schistosomiasis that have evolved genetic and immunological host-parasite adaptations over time. By using an integrative multidisciplinary approach, immunomics offers enormous potential to advance 21st century antigen discovery and rational vaccine design against complex pathogens such as the Plasmodium parasite.