Invited Review
Recent insights into humoral immunity targeting Plasmodium falciparum and Plasmodium vivax malaria

https://doi.org/10.1016/j.ijpara.2016.06.002Get rights and content

Highlights

  • Research highlights from 2016 Molecular Approaches to Malaria conference.

  • Humoral responses to Plasmodium falciparum and Plasmodium vivax malaria.

  • Use of ‘Big data’ and ‘omics’ approaches to identify vaccine candidates.

  • New assays to measure functional antibodies targeting malaria.

Abstract

Recent efforts in malaria control have led to marked reductions in malaria incidence. However, new strategies are needed to sustain malaria elimination and eradication and achieve the World Health Organization goal of a malaria-free world. The development of highly effective vaccines would contribute to this goal and would be facilitated by a comprehensive understanding of humoral immune responses targeting Plasmodium falciparum and Plasmodium vivax malaria. New tools are required to facilitate the identification of vaccine candidates and the development of vaccines that induce functional and protective immunity. Here we discuss recent published findings, and unpublished work presented at the 2016 Molecular Approaches to Malaria conference, that highlight advancements in understanding humoral immune responses in the context of vaccine development. Highlights include the increased application of ‘omics’ and ‘Big data’ platforms to identify vaccine candidates, and the identification of novel functions of antibody responses that mediate protection. The application of these strategies and a global approach will increase the likelihood of rapid development of highly efficacious vaccines.

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)

References (81)

  • R.W. Snow et al.

    Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa

    Lancet

    (1997)
  • J.-F. Trape et al.

    Malaria morbidity and pyrethroid resistance after the introduction of insecticide-treated bednets and artemisinin-based combination therapies: a longitudinal study

    Lancet Infect. Dis.

    (2011)
  • R. Ataide et al.

    Using an improved phagocytosis assay to evaluate the effect of HIV on specific antibodies to pregnancy-associated malaria

    PLoS One

    (2010)
  • A.E. Barry et al.

    The stability and complexity of antibody responses to the major surface antigen of Plasmodium falciparum are associated with age in a malaria endemic area

    Mol. Cell. Proteomics

    (2011)
  • J.G. Beeson et al.

    Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria

    FEMS Microbiol. Rev.

    (2016)
  • S. Bhatt et al.

    Coverage and system efficiencies of insecticide-treated nets in Africa from 2000 to 2017

    Elife

    (2015)
  • H. Bouharoun-Tayoun et al.

    Mechanisms underlying the monocyte-mediated antibody-dependent killing of Plasmodium falciparum asexual blood stages

    J. Exp. Med.

    (1995)
  • M.J. Boyle et al.

    Isolation of viable Plasmodium falciparum merozoites to define erythrocyte invasion events and advance vaccine and drug development

    Proc. Natl. Acad. Sci. U.S.A.

    (2010)
  • P. Brasseur et al.

    Changing patterns of malaria during 1996–2010 in an area of moderate transmission in southern Senegal

    Malar. J.

    (2011)
  • I. Carneiro et al.

    Age-patterns of malaria vary with severity, transmission intensity and seasonality in sub-Saharan Africa: a systematic review and pooled analysis

    PLoS One

    (2010)
  • S.J. Ceesay et al.

    Continued decline of malaria in The Gambia with implications for elimination

    PLoS One

    (2010)
  • J.-A. Chan et al.

    Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity

    J. Clin. Invest.

    (2012)
  • J.-A. Chan et al.

    Surface antigens of Plasmodium falciparum-infected erythrocytes as immune targets and malaria vaccine candidates

    Cell. Mol. Life Sci.

    (2014)
  • J.-A. Chan et al.

    A single point in protein trafficking by Plasmodium falciparum determines the expression of major antigens on the surface of infected erythrocytes targeted by human antibodies

    Cell. Mol. Life Sci.

    (2016)
  • S. Cohen et al.

    Gamma-globulin and acquired immunity to human malaria

    Nature

    (1961)
  • P.D. Crompton et al.

    A prospective analysis of the Ab response to Plasmodium falciparum before and after a malaria season by protein microarray

    Proc. Natl. Acad. Sci. U.S.A.

    (2010)
  • P.D. Crompton et al.

    In vitro growth-inhibitory activity and malaria risk in a cohort study in mali

    Infect. Immun.

    (2010)
  • C. Crosnier et al.

    Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum

    Nature

    (2011)
  • J.C. Cutts et al.

    Immunological markers of Plasmodium vivax exposure and immunity: a systematic review and meta-analysis

    BMC Med.

    (2014)
  • D.H. Davies et al.

    Profiling the humoral immune response to infection by using proteome microarrays: high-throughput vaccine and diagnostic antigen discovery

    Proc. Natl. Acad. Sci. U.S.A.

    (2005)
  • A.E. Dent et al.

    Antibody-mediated growth inhibition of Plasmodium falciparum: relationship to age and protection from parasitemia in Kenyan children and adults

    PLoS One

    (2008)
  • A.E. Dent et al.

    Plasmodium falciparum protein microarray antibody profiles correlate with protection from symptomatic malaria in Kenya

    J. Infect. Dis.

    (2015)
  • F. Diop et al.

    Dramatic declines in seropositivity as determined with crude extracts of Plasmodium falciparum schizonts between 2000 and 2010 in Dielmo and Ndiop, Senegal

    Malar. J.

    (2014)
  • D.L. Doolan et al.

    Profiling humoral immune responses to P. falciparum infection with protein microarrays

    Proteomics

    (2008)
  • A.D. Douglas et al.

    Neutralization of Plasmodium falciparum merozoites by antibodies against PfRH5

    J. Immunol.

    (2014)
  • A.F. Egan et al.

    Human antibodies to the 19kDa C-terminal fragment of Plasmodium falciparum merozoite surface protein 1 inhibit parasite growth in vitro

    Parasite Immunol.

    (1999)
  • C. Flück et al.

    Strain-specific humoral response to a polymorphic malaria vaccine

    Infect. Immun.

    (2004)
  • F.J.I. Fowkes et al.

    The relationship between anti-merozoite antibodies and incidence of Plasmodium falciparum malaria: a systematic review and meta-analysis

    PLoS Med.

    (2010)
  • C.T. França et al.

    An antibody screen of a Plasmodium vivax antigen library identifies novel merozoite proteins associated with clinical protection

    PLoS Negl. Trop. Dis.

    (2016)
  • B. Genton et al.

    A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1–2b trial in Papua New Guinea

    J. Infect. Dis.

    (2002)
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