Invited ReviewRecent insights into humoral immunity targeting Plasmodium falciparum and Plasmodium vivax malaria
Graphical abstract
Introduction
Since 2000 there have been unparalleled increases in malaria control activities and re-invigorated goals of malaria elimination; there have been substantial increases in bed net usage, indoor residual spraying, chemoprophylaxis and the utilisation of highly efficacious artemisinin derivatives for the treatment of clinical malaria (World Health Organization, 2015). Consequently, infection prevalence has halved and the incidence of clinical disease and malaria mortality has dramatically reduced by more than 40% (Bhatt et al., 2015, World Health Organization, 2015). While the largest reductions have been primarily seen in areas of high stable transmission in Africa, substantial reductions have also been seen in areas of relatively low transmission in Asia. Despite these gains, malaria, caused predominantly by Plasmodium falciparum and Plasmodium vivax, remains a significant global public health problem causing approximately 200 million clinical cases and half a million deaths in 2015 (World Health Organization, 2015).
Reductions in malaria transmission are accompanied by changes in the epidemiology of malaria. In areas of stable medium–high transmission, the frequency of mild and severe malaria is highest in young children less than 5 years of age (reviewed in (Marsh and Kinyanjui, 2006, Carneiro et al., 2010)), whereas in areas with low transmission, severe malaria continues to occur in older children and adults (Snow et al., 1997, Carneiro et al., 2010). Decreases in transmission are often accompanied by a shift in the peak incidence of mild and severe malaria to later in childhood or adulthood, or rebounds of malaria in previously eliminated areas (Ceesay et al., 2010, Brasseur et al., 2011, Trape et al., 2011, Griffin et al., 2014). These observations have been attributed to declining naturally acquired immunity to malaria, which develops after repeated exposure to malaria in an age-dependent manner (Marsh and Kinyanjui, 2006). Anti-malarial antibody levels have reflected declines in malaria transmission in longitudinal studies spanning less than 5 years (Migot et al., 1993, Ceesay et al., 2010) and in serial cross-sectional studies 10 years apart (Diop et al., 2014). Recent longitudinal sero-epidemiological studies spanning decades have investigated how immunity to malaria changes in areas experiencing substantial reductions in malaria transmission. Recent studies have demonstrated considerable reductions in anti-merozoite immunity over a 10 year period in an area transitioning from low to very low transmission (Ataíde, R. and Fowkes, F., Burnet Institute, Australia, personal communication). In Kenya, which has transitioned from high to low transmission over the past 14 years, studies have demonstrated that in 2000 the magnitude and functional activity of antibodies against merozoite antigens, as quantified by the capacity of antibodies to fix complement to merozoites antigens, or to mediate opsonic phagocytosis, were associated with protection against clinical malaria. However by 2014, after a significant decline in malaria transmission and an increase in the median age of clinical presentation, anti-merozoite immunity had declined to below protective thresholds (Osier, F. and Marsh, K., KEMRI-Centre for Geographic Medicine Research-Coast, Kenya, personal communication). These studies highlight the importance of understanding how immunity to malaria is acquired and maintained over time in populations transitioning from high to low to no malaria transmission. The changes in sero-epidemiology with changing transmission emphasise the need to identify new targets of protective immunity and to understand functional mechanisms across diverse and changing transmission settings. Further, as studies have used only a few antigens which have not been comprehensively validated either as markers of exposure or as being associated with protection, more studies are needed to validate large numbers of antigens.
Section snippets
‘Big data’ – large screenings to identify vaccine candidates
Although antibodies have been known to be key components of acquired immunity against P. falciparum malaria for over 50 years (Cohen et al., 1961), it still remains unclear which of the thousands of parasite antigens presented to the human immune system induce protective antibodies and should thus be prioritised for malaria vaccine development. Prior to the completion of the genome of P. falciparum, a small number of antigens dominated studies aimed at identifying the targets of protective
Complement fixing antibodies targeting blood stages and beyond
Together with difficulties in vaccine candidate identification, a key issue that hampers the development of an effective anti-malarial vaccine is the lack of knowledge about mechanisms of acquired immunity. In order to progress, it is necessary to characterise potential effector mechanisms of antibodies that are associated with protection from malaria, so that vaccines can be developed that induce a functional and protective antibody response. Little is known about how antibodies mediate
Conclusions and future directions
While the most advanced anti-malarial vaccine, RTS,S, has recently completed Phase 3 clinical trials (RTS,S Clinical Trials Partnership, 2015), the low efficacy, safety concerns and feasibility of implementation of this vaccine has led to the World Health Organization concluding that it is not appropriate for wide-spread usage in its current form without further assessment (World Health Organization Secretariat, 2015). As the research community strives towards the development of improved and
Acknowledgments
This work is funded by the National Health and Medical Research Council, Australia (https://www.nhmrc.gov.au/) Early-Career Fellowship (MJB), and the Australian Research Council (future fellowship to FJIF), Burnet Institute, Australia is supported by the National Health and Medical Research Council Australia Infrastructure for Research Institutes Support Scheme and by the Victorian State Government Operational Infrastructure Support, Australia. FHO is supported by the Wellcome Trust (089833)
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