Plasmodium vivax is the predominant species causing malaria in the Americas and Asia-Pacific regions (WHO, 2014). Due to its unique biology, P. vivax is less susceptible to commonly-used vector control measures (Mueller et al., 2009). With renewed funding and commitment towards the goal of eliminating malaria, the development and deployment of an effective vaccine against P. vivax has become a high priority (malERA Consultative Group on Vaccines, 2011).

The epidemiology of P. vivax provides strong indication that the development of an effective vaccine is feasible. Clinical immunity to P. vivax is acquired more rapidly than to P. falciparum and, in moderate and highly endemic areas, clinical disease is virtually absent in children older than five years (Phimpraphi et al., 2008; Lin et al., 2010; Robinson et al., 2015). Sub-microscopic infections are common even in areas where malaria transmission has been substantially reduced (Cheng et al., 2015; Bousema et al., 2014), suggesting the development of effective immunity that provides good control of parasitemia. Whilst our understanding of the protective immune effector mechanisms is incomplete, the humoral component is thought to be essential for the development of anti-P. vivax immunity, and antibodies confer protection by both preventing high-density parasitemia and inhibiting blood-stage replication (Longley et al., 2016). Evidence of relatively long-lived IgG levels and/or seropositivity to P. vivax proteins such as circumsporozoite protein (CSP), merozoite surface protein 1 (MSP1), apical membrane antigen 1 (AMA1) and Duffy binding protein (DBP) have been reported even in the absence of detectable P. vivax infections (Longley et al., 2015; Wipasa et al., 2010; Achtman et al., 2005).

A highly-efficacious malaria vaccine has unfortunately not yet been achieved for any of the Plasmodium spp. parasites, and the vast majority of vaccines in development are based on single recombinant protein antigens (Halbroth and Draper, 2015). For P. falciparum, more than 15 antigens are under pre-clinical or clinical testing, including the pre-erythrocytic, CSP-based RTS,S/AS01 vaccine, which has recently completed Phase 3 trials (Agnandji et al., 2012; RTS,S Clinical Trials Partnership, 2014). In contrast, for P. vivax only a handful of proteins have been studied, with the blood-stage DBP, MSP1, and transmission-blocking protein Pvs25 as the main vaccine candidates (Halbroth and Draper, 2015; Mueller et al., 2015). The moderate success of the P. falciparum RTS,S vaccine has also made P. vivax CSP a main vaccine candidate (Mueller et al., 2015; Salman et al., 2017; Bennett et al., 2016). The potential of novel, pre-erythrocytic candidate antigens, including P. vivax cell-traversal protein for ookinetes (CelTOS) and thrombospondin-related anonymous protein (TRAP) is being investigated in animal models (Mueller et al., 2015; Alves et al., 2017; Bauza et al., 2014).

Recent serological screens of large panels of P. falciparum proteins in naturally-exposed populations have identified several antigenic targets associated with protective immunity, and strongly support the hypothesis that a multicomponent vaccine possibly including antigens from different stages of the parasites life cycle would offer a higher degree of protection than a single component vaccine (Halbroth and Draper, 2015; Richards et al., 2013; Osier et al., 2014a). For P. vivax, the availability of the genome sequence (Carlton et al., 2008) and transcriptome (Bozdech et al., 2008) have enhanced our understanding of the parasite’s biology, facilitating the identification of many proteins that are homologous to P. falciparum antigens (Chen et al., 2010; Lu et al., 2014; Finney et al., 2014). Given the lack of methods to continuously culture P. vivax to study specific proteins in vitro, or animal models for extensive in vivo assays, the study of targets of human natural immunity in exposed populations must play an essential role in identifying and prioritizing P. vivax antigens for further functional characterization for vaccine or biomarker development (Chia et al., 2014). To date, however, the number, identity, and relative importance of P. vivax antigenic targets remains poorly explored (Cutts et al., 2014). Antibodies to proteins such as MSP3α, MSP9 (30) and DBP (King et al., 2008; Cole-Tobian et al., 2009) have shown strong associations with reduced risk of clinical disease or blood-stage infection. Screening studies to extend the pool of P. vivax vaccine candidates remain scarce (Cutts et al., 2014).

To explore the reservoir of antigenic targets and prioritize candidates for functional characterization, we investigated the association between IgG to a comprehensive library of 38 P. vivax recombinant antigens and risk of vivax malaria in a cohort of young Papua New Guinean (PNG) children with well-characterized differences in exposure to P. vivax infections (Lin et al., 2010). To our knowledge, the potential existence of synergistic or additive effects of combinations of antibody responses to a large panel of P. vivax antigens has never been explored. We applied a novel simulated annealing algorithm to efficiently explore the vast space of antigen combinations and thus identify combinations with optimal potential protective efficacy (PPE). High antibody levels to multiple antigens, including several novel proteins were strongly associated with reduced risk of vivax malaria, independently of individual differences in exposure, age, and transmission season. Combinations of antigens were identified with a PPE of >90%. These data identify several antigens that should be prioritized for further functional characterization. The naturally-acquired anti-malarial immunity explored in this study supports the development of a highly-efficacious, multicomponent P. vivax vaccine.

The development and deployment of an effective P. vivax vaccine has become a priority for accelerating malaria elimination in the Asia-Pacific and the Americas (Tanner et al., 2015). To date, however, remarkably few P. vivax vaccine candidates are close to or have reached clinical trials (Mueller et al., 2015). To expand and prioritize the reservoir of antigenic targets for further functional characterization for use in vaccine or biomarker development, we measured total IgG antibody levels to 38 P. vivax recombinant proteins, investigating their relationship with prospective risk of vivax malaria in a longitudinal cohort of PNG children aged 1–3 years. For the first time, the potential protective efficacy of combination of antigens, and the thresholds necessary for an association with protection were investigated.

Although the young children included in the present study are actively acquiring clinical immunity, as indicated by a highly-significant decrease in incidence of clinical P. vivax episodes (Lin et al., 2010), most still had relatively low antibody responses, with more than 10% of children exceeding 10% of adult levels to only 22 proteins. Antibodies to almost all proteins were boosted by concurrent P. vivax infections (n = 30), and 29 increased with age and/or lifetime exposure, indicating the antibody levels are both a marker of concurrent and past exposure to P. vivax. Despite these generally low IgG antibody levels, high levels to 31 of 38 proteins (81.6%) were significantly associated with protection, indicating that these antibody levels have started to exceed the threshold above which antibody levels are biomarkers of protection rather than exposure (Stanisic et al., 2015).

Antibody levels were often moderately or even highly correlated between antigens, and not only to different regions of the same antigen, such as MSP3α (rho = 0.52–0.93), or to different alleles of the same antigen such as PvDBP (rho = 0.76–0.995). In particular, antibodies to the WGCF-expressed, highly-immunogenic proteins showed very high correlations (rho = 0.61–0.95). Without further functional investigation, it is difficult to determine if these correlations indicate co-acquisition or cross-reactivity, or whether cross-reactive antibodies are functional or merely recognize different proteins.

The high correlations of antibody levels to different DBP alleles were expected, as some are very similar in sequence (e.g. the variants AH and C differ only at amino acid residue 371), thus antibody responses are likely to be highly cross-reactive between variants. However, despite 50% identity, correlations between antibodies to the different alleles of DBPII and EBP were only moderate (rho = 0.36–0.48, p<0.001) and not higher than those with other merozoite surface proteins, indicating only a limited potential for cross-reactive antibodies between these proteins. For the RBP proteins included in this study, we have previously showed that polyclonal antibodies raised in rabbits recognize the homologous but not heterologous proteins (França et al., 2016b). The correlated responses are therefore likely due to co-acquisition, and the combination of several RBPs may have synergistic or additive effects (França et al., 2016b). For DBPII, although this and previous studies observed the presence of strain-specific antibodies (Cole-Tobian et al., 2009), strain-transcending antibodies (in particular those targeting the binding pocket) have been described (King et al., 2008; Chen et al., 2016; Wongkidakarn et al., 2016), indicating that a DBPII vaccine targeting these strain-transcending epitopes may be able to overcome the large genetic diversity of DBPII. Nevertheless, the analyses of antigen combinations clearly indicated that combining DBPII with other antigens such as one of several RBPs is likely to be beneficial.

The majority of the antigens associated with protection against vivax malaria in this cohort were newly described or understudied, such as EBP, P41, CyRPA, RBP1a, and RBP2b. Many of these proteins were similarly or more strongly associated with protective immunity than antibodies to well-studied vaccine candidate antigens such as MSP3α, AMA1, MSP1, and CSP (Bennett et al., 2016; Cutts et al., 2014; Stanisic et al., 2013), clearly demonstrating that the repertoire of possible antigenic targets present in the P. vivax genome should be further expanded. Interestingly, among the highly-immunogenic proteins expressed in the WGCF system, only two, PVX_122805, a conserved hypothetical protein and PVX_088820, a member of the Pv-fam-a tryptophan-rich antigen family showed substantial association with protection individually, and were regularly included in combinations of 5–15 antigens. This indicates that immunogenicity by itself is a relatively poor predictor of association with protection, and while such proteins may be good markers of exposure, it is less clear whether they would make effective vaccine candidate antigens.

There was a clear hierarchy in the order in which antigens were included into the best antigen-combinations. The top protective antigens were consistently at the top end of all possible random five-way combinations, an observation that is unlikely to be due to chance if all antigens were equally protective when in combinations. The best single antigen EBP followed by PVX_081550 were always present among the most frequently included proteins in higher combinations. Additional proteins common in combinations of three were CyRPA, RBP1a and RBP2b. Apart from RBP2b, these same proteins are also commonly found in four and five antigen-combinations, together with DBPII, P41 and PVX_099930 (RhopH2).

Literature on the little-studied P. vivax antigens associated with protection here is at best scarce. We have recently determined that RBP2b binds exclusively to reticulocytes, raising the prospect that RBP2b may be involved in P. vivax reticulocyte-specificity (França et al., 2016b). Among the other antigens strongly associated with protection, P41 is a GPI-anchored protein localized on the merozoite surface which forms a heterodimer with P12 (Hostetler et al., 2015). In P. falciparum, neither P41 nor P12 homologs are essential for in vitro parasite growth (Tonkin et al., 2013), but both are immunogenic, and antibodies have been associated with clinical protection (Richards et al., 2013; Osier et al., 2014a). The P. falciparum homolog of PVX_081550 has recently been identified as StAR-related lipid transfer protein localized on the parasitophorous vacuole (van Ooij et al., 2013). Both the P. falciparum homolog and P. vivax PVX_081550 proteins are immunogenic (Fan et al., 2013). It is, however, unclear whether antibodies to PVX_081550 interfere with parasite function or are simply elicited by proteins released from the parasitophorous vacuole upon schizont rupture and thus serve as markers of an individual’s immune status (França et al., 2016a). Lastly, also in P. falciparum, CyRPA forms a complex with PfRh5 and PfRipr on the merozoite surface. This complex is involved in binding basigin on the erythrocyte surface (Reddy et al., 2015). P. falciparum CyRPA seems to not be under immune selection pressure and is highly-conserved, with only a single polymorphism detected across 18 P. falciparum strains (Beeson et al., 2016). Antibodies raised against P. falciparum CyRPA were nevertheless capable of inhibiting merozoite invasion (Beeson et al., 2016), block binding of CyRPA to Rh5 and Rh5/CyRPA/Ripr complex formation (Chen et al., 2017), and both in vitro and in vivo parasite growth inhibitory activity, more stronger when in combination with PfRh5 (Favuzza et al., 2017). The P. vivax CyRPA seems to be highly-reactogenic (França et al., 2016a), suggesting that their function, or at least exposure to the immune system, may differ between the two species.

IgG subclass responses to some P. vivax antigens such as RBP1a, DBPII, MSP1 19, and CSP (França et al., 2016b; Tran et al., 2005; Maestre et al., 2010; Yildiz Zeyrek et al., 2011; Zeyrek et al., 2008), as well as several different P. falciparum antigens (Stanisic et al., 2015; Ahmed Ismail et al., 2014; Richards et al., 2010; Reiling et al., 2010; Noland et al., 2015; Tongren et al., 2006) have consistently shown that the presence of IgG1 and/or IgG3 in variable ratios is likely to play a role in protection against infection and/or clinical disease. The role of IgG2 and IgG4 antibodies however, remains mostly unclear. IgG2 antibodies have been correlated with lower P. falciparum parasitemia (Ahmed Ismail et al., 2014) and risk of infection (Aucan et al., 2000), while IgG4 levels were associated with an enhanced risk of infection and disease (Aucan et al., 2000). Neither showed significant ability to promote opsonic phagocytosis (Osier et al., 2014b), with IgG4 possibly inhibiting this process (Chaudhury et al., 2017). We have previously measured IgG subclass 1, 2, 3 and 4 responses to the 5 RBPs included in this study, showing that IgG1 and IgG3 are the predominant subclasses in this cohort of PNG children (França et al., 2016b). IgG1 to RBP1a and RBP2b showed the strongest association with protection in multivariate models. Interestingly, adults showed substantially higher levels of IgG3 for all antigens (IgG3 being predominant for RBP1a), and substantial levels of IgG2 for some (e.g. RBP2b) but not all antigens. Children showed some early evidence of switching to IgG3 for RBP1a and RBP2-P2 with maturation of immune responses, and increase in age and exposure to malaria parasites (França et al., 2016b).

Little is known about the threshold necessary for antibody levels to switch from being biomarkers of exposure to biomarkers of protection (Stanisic et al., 2015). Large variation in the threshold levels associated with 50% reduction in vivax malaria risk was observed for the present antigen panel. Although this type of analysis cannot differentiate between direct, causal protective effect of antibodies and a statistical association, the observations that many of the antigens most consistently associated with protection in multi-antigen combinations (e.g. PVX_081550, EBP, CyRPA) show both relatively low immunogenicity and low 50% protection threshold levels suggests that for some of the most promising candidate antigens, low antibody levels may be sufficient for protection. It is possible that critical antigens or epitopes have to be weakly immunogenic to avoid acquisition of host immunity. Antigens with little reactivity and associated with acquired immunity at low antibody levels might thus be the most promising for vaccine development. It was, however, not possible to determine in this study whether antibodies to these proteins have better avidity/affinity than some antigens that induce very high antibody levels. One limitation of the dose-response model used in this study is that it only includes one antigen at a time, and thus doesn’t account for the complexity of highly-correlated antibody responses.

We focused on 1–3 years old children as early infancy is a critical time in the development of immunity to malaria (Longley et al., 2016). Nevertheless, further studies including older age groups from different transmission settings will be required to confirm the detected hierarchy in antibody responses and their association with protection. To our knowledge, the present study is the largest comprehensive panel of P. vivax antigens measured in a well-designed cohort study for identification of associations with malaria risk, and the first one to investigate both the effect of multiple combinations and the threshold antibody levels necessary for protection. Our results identify important targets of naturally-acquired immunity that may contribute to clinical protection and should thus be prioritized for functional studies. These results clearly indicate that examining multiple antigens simultaneously can best correlate with protection, as it might optimally define the breadth of the immune response required for clinical immunity. Taken together, our results suggest that a well-designed, multicomponent P. vivax vaccine may be more efficacious than single-component vaccines.

Future research should focus on uncovering the functional role of the unknown and understudied proteins identified in this study, and their potential for vaccines, biomarkers of immunity, or both. The measurement of functionality, e.g. antibodies’ capacity to promote opsonic phagocytosis or ability to block binding/invasion to red blood cells will be particularly important (Teo et al., 2016). Although it remains unclear which mechanisms are most important for protection from malaria infection or clinical disease, recent studies with P. falciparum suggest that a combination of functional mechanisms may be important for protective immunity (Osier et al., 2014b; Hill et al., 2013; Hill et al., 2016; Chiu et al., 2015; Joos et al., 2010; Murungi et al., 2016). Hence, the presence/levels of functional antibodies might possibly be even better correlates of protective immunity than total IgG antibody levels.

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Author details

1. Camila Tenorio França

   1. Division of Population Health and Immunity, Walter and Eliza Hall Institute, Parkville, Australia
   2. Department of Medical Biology, University of Melbourne, Parkville, Australia

   Contribution

   Formal analysis, Validation, Investigation, Visualization, Methodology, Writing—original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5885-4410

2. Michael T White

   1. Division of Population Health and Immunity, Walter and Eliza Hall Institute, Parkville, Australia
   2. MRC Center for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom

   Contribution

   Formal analysis, Visualization, Methodology, Writing—original draft

   Competing interests

   No competing interests declared

3. Wen-Qiang He

   1. Department of Medical Biology, University of Melbourne, Parkville, Australia
   2. Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Australia

   Contribution

   Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

4. Jessica B Hostetler

   1. Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom
   2. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, United States

   Contribution

   Resources, Writing—review and editing

   Competing interests

   No competing interests declared

5. Jessica Brewster

   Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Australia

   Contribution

   Validation, Investigation

   Competing interests

   No competing interests declared

6. Gabriel Frato

   Center for Global Health and Diseases, Case Western Reserve University, Cleveland, United States

   Contribution

   Resources, Methodology

   Competing interests

   No competing interests declared

7. Indu Malhotra

   Center for Global Health and Diseases, Case Western Reserve University, Cleveland, United States

   Contribution

   Resources, Methodology

   Competing interests

   No competing interests declared

8. Jakub Gruszczyk

   Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Australia

   Contribution

   Resources, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4536-2964

9. Christele Huon

   Malaria Parasite Biology and Vaccines Unit, Institut Pasteur, Paris, France

   Contribution

   Resources, Methodology

   Competing interests

   No competing interests declared

10. Enmoore Lin

    Malaria Immuno-Epidemiology Unit, PNG Institute of Medical Research, Yagaum, Papua New Guinea

    Contribution

    Resources, Methodology

    Competing interests

    No competing interests declared

11. Benson Kiniboro

    Malaria Immuno-Epidemiology Unit, PNG Institute of Medical Research, Yagaum, Papua New Guinea

    Contribution

    Resources, Methodology

    Competing interests

    No competing interests declared

12. Anjali Yadava

    Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, United States

    Contribution

    Resources, Writing—review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-6751-954X

13. Peter Siba

    Malaria Immuno-Epidemiology Unit, PNG Institute of Medical Research, Yagaum, Papua New Guinea

    Contribution

    Conceptualization, Resources, Funding acquisition

    Competing interests

    No competing interests declared

14. Mary R Galinski

    1. International Center for Malaria Research, Education, and Development, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, United States
    2. Infectious Diseases Division, Department of Medicine, Emory University, Atlanta, United States

    Contribution

    Resources, Writing—review and editing

    Competing interests

    No competing interests declared

15. Julie Healer

    1. Department of Medical Biology, University of Melbourne, Parkville, Australia
    2. Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Australia

    Contribution

    Resources, Writing—review and editing

    Competing interests

    No competing interests declared

16. Chetan Chitnis

    1. Malaria Parasite Biology and Vaccines Unit, Institut Pasteur, Paris, France
    2. International Centre for Genetic Engineering and Biotechnology, New Delhi, India

    Contribution

    Resources, Writing—review and editing

    Competing interests

    No competing interests declared

17. Alan F Cowman

    1. Department of Medical Biology, University of Melbourne, Parkville, Australia
    2. Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Australia

    Contribution

    Resources, Funding acquisition, Writing—review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5145-9004

18. Eizo Takashima

    Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, United States

    Contribution

    Resources, Writing—review and editing

    Competing interests

    No competing interests declared

19. Takafumi Tsuboi

    Division of Malaria Research, Proteo-Science Center, Ehime University, Matsuyama, Japan

    Contribution

    Resources, Funding acquisition, Writing—review and editing

    Competing interests

    No competing interests declared

20. Wai-Hong Tham

    1. Department of Medical Biology, University of Melbourne, Parkville, Australia
    2. Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Australia

    Contribution

    Resources, Funding acquisition, Writing—review and editing

    Competing interests

    No competing interests declared

21. Rick M Fairhurst

    Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, United States

    Contribution

    Resources, Funding acquisition, Writing—review and editing

    Competing interests

    No competing interests declared

22. Julian C Rayner

    Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom

    Contribution

    Resources, Funding acquisition, Writing—review and editing

    Competing interests

    No competing interests declared

23. Christopher L King

    Center for Global Health and Diseases, Case Western Reserve University, Cleveland, United States

    Contribution

    Conceptualization, Resources, Funding acquisition, Methodology, Writing—review and editing

    Competing interests

    No competing interests declared

24. Ivo Mueller

    1. Division of Population Health and Immunity, Walter and Eliza Hall Institute, Parkville, Australia
    2. Department of Medical Biology, University of Melbourne, Parkville, Australia
    3. Malaria Parasites and Hosts Unit, Department of Parasites and Insect Vectors, Institut Pasteur, Paris, France
    4. Barcelona Institute of Global Health, Barcelona, Spain

    Contribution

    Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Methodology, Project administration, Writing—review and editing

    For correspondence

    mueller@wehi.edu.au

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-6554-6889

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