Systems immunology of human malaria

Abstract

Plasmodium falciparum malaria remains a global public health threat. Optimism that a highly effective malaria vaccine can be developed stems in part from the observation that humans can acquire immunity to malaria through experimental and natural P. falciparum infection. Recent advances in systems immunology could accelerate efforts to unravel the mechanisms of acquired immunity to malaria. Here, we review the tools of systems immunology, their current limitations in the context of human malaria research, and the human 'models' of malaria immunity to which these tools can be applied.

Figure 1. Human ‘models’ of P. falciparum infection

Systems immunology can be applied to natural (a-b) and experimental (c-f) ‘models’ of P. falciparum infection. (a) For example, in areas of seasonal P. falciparum transmission, uninfected individuals enrolled in observational cohort studies before the malaria season can be classified prospectively during the ensuing malaria season as either malaria immune (asymptomatic P. falciparum infection) or susceptible (symptomatic P. falciparum infection). At the end of the malaria season, a nested case-control analysis can then be applied in which immune responses of age-matched immune and susceptible individuals are compared using stored biospecimens collected before, during and after P. falciparum infection. For any given study, the design (e.g. timing and frequency of biospecimen collection) will vary with the dynamics of P. falciparum transmission at the study site, the scientific questions of interest and the available resources. (b) A nested case-control study design can also be applied to Phase IIb and III malaria vaccine trials in malaria-endemic areas to identify relationships between vaccine-induced innate immune responses and the subsequent quality of vaccine-specific cellular and antibody responses and to potentially identify biomarkers or ‘signatures’ of vaccine efficacy (reviewed in [66]). (c-f) The controlled and predictable nature of human experimental P. falciparum infection permits high-resolution systems analyses of the host immune response at precise time points during the liver and early blood stages of infection. (c) Analysis of biospecimens collected before, during and after P. falciparum infection in naïve and previously exposed individuals can yield key insights into the ‘natural history’ of the human response to the early stages of P. falciparum infection. (d-e) Protection from malaria can be experimentally induced through repeated P. falciparum infections while on chemoprophylaxis [7] (d) and through exposure to irradiated sporozoites (e). Analyses of biospecimens collected before, during and after the ‘immunization’ and ‘challenge’ phases of these models may yield important insights into the mechanisms by which these models induce protection. (f) Systems analysis of Phase I and IIa malaria vaccine trials in which P. falciparum-naïve individuals are vaccinated and then challenged with infective mosquito bites may reveal early vaccine-induced molecular signatures of immunogenicity and efficacy that inform subsequent vaccine development and evaluation. Abbreviation: Pf, P. falciparum.