Infectious Diseases - Research Publications
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ItemPatterns of protective associations differ for antibodies to &ITP&IT. &ITfalciparum&IT-infected erythrocytes and merozoites in immunity against malaria in children(WILEY, 2017-12)Acquired antibodies play an important role in immunity to P. falciparum malaria and are typically directed towards surface antigens expressed by merozoites and infected erythrocytes (IEs). The importance of specific IE surface antigens as immune targets remains unclear. We evaluated antibodies and protective associations in two cohorts of children in Papua New Guinea. We used genetically-modified P. falciparum to evaluate the importance of PfEMP1 and a P. falciparum isolate with a virulent phenotype. Our findings suggested that PfEMP1 was the dominant target of antibodies to the IE surface, including functional antibodies that promoted opsonic phagocytosis by monocytes. Antibodies were associated with increasing age and concurrent parasitemia, and were higher among children exposed to a higher force-of-infection as determined using molecular detection. Antibodies to IE surface antigens were consistently associated with reduced risk of malaria in both younger and older children. However, protective associations for antibodies to merozoite surface antigens were only observed in older children. This suggests that antibodies to IE surface antigens, particularly PfEMP1, play an earlier role in acquired immunity to malaria, whereas greater exposure is required for protective antibodies to merozoite antigens. These findings have implications for vaccine design and serosurveillance of malaria transmission and immunity.
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ItemNo Preview AvailableChallenges and strategies for developing efficacious and long-lasting malaria vaccines(AMER ASSOC ADVANCEMENT SCIENCE, 2019-01-09)Although there has been major recent progress in malaria vaccine development, substantial challenges remain for achieving highly efficacious and durable vaccines against Plasmodium falciparum and Plasmodium vivax malaria. Greater knowledge of mechanisms and key targets of immunity are needed to accomplish this goal, together with new strategies for generating potent, long-lasting, functional immunity against multiple antigens. Implementation considerations in endemic areas will ultimately affect vaccine effectiveness, so innovations to simplify and enhance delivery are also needed. Whereas challenges remain, recent exciting progress and emerging knowledge promise hope for the future of malaria vaccines.
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ItemAcquisition of Antibodies Against Endothelial Protein C Receptor-Binding Domains of Plasmodium falciparum Erythrocyte Membrane Protein 1 in Children with Severe Malaria(OXFORD UNIV PRESS INC, 2019-03-01)BACKGROUND: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates parasite sequestration in postcapillary venules in P. falciparum malaria. PfEMP1 types can be classified based on their cysteine-rich interdomain region (CIDR) domains. Antibodies to different PfEMP1 types develop gradually after repeated infections as children age, and antibodies to specific CIDR types may confer protection. METHODS: Levels of immunoglobulin G to 35 recombinant CIDR domains were measured by means of Luminex assay in acute-stage (baseline) and convalescent-stage plasma samples from Papua New Guinean children with severe or uncomplicated malaria and in healthy age-matched community controls. RESULTS: At baseline, antibody levels were similar across the 3 groups. After infection, children with severe malaria had higher antibody levels than those with uncomplicated malaria against the endothelial protein C receptor (EPCR) binding CIDRα1 domains, and this difference was largely confined to older children. Antibodies to EPCR-binding domains increased from presentation to follow-up in severe malaria, but not in uncomplicated malaria. CONCLUSIONS: The acquisition of antibodies against EPCR-binding CIDRα1 domains of PfEMP1 after a severe malaria episode suggest that EPCR-binding PfEMP1 may have a role in the pathogenesis of severe malaria in Papua New Guinea.
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ItemAntibody Targets on the Surface of Plasmodium falciparum-Infected Erythrocytes That Are Associated With Immunity to Severe Malaria in Young Children(Oxford University Press, 2019-03-01)BACKGROUND: Sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the microvasculature contributes to pathogenesis of severe malaria in children. This mechanism is mediated by antigens expressed on the IE surface. However, knowledge of specific targets and functions of antibodies to IE surface antigens that protect against severe malaria is limited. METHODS: Antibodies to IE surface antigens were examined in a case-control study of young children in Papua New Guinea presenting with severe or uncomplicated malaria (n = 448), using isolates with a virulent phenotype associated with severe malaria, and functional opsonic phagocytosis assays. We used genetically modified isolates and recombinant P. falciparum erythrocyte membrane protein 1 (PfEMP1) domains to quantify PfEMP1 as a target of antibodies associated with disease severity. RESULTS: Antibodies to the IE surface and recombinant PfEMP1 domains were significantly higher in uncomplicated vs severe malaria and were boosted following infection. The use of genetically modified P. falciparum revealed that PfEMP1 was a major target of antibodies and that PfEMP1-specific antibodies were associated with reduced odds of severe malaria. Furthermore, antibodies promoting the opsonic phagocytosis of IEs by monocytes were lower in those with severe malaria. CONCLUSIONS: Findings suggest that PfEMP1 is a dominant target of antibodies associated with reduced risk of severe malaria, and function in part by promoting opsonic phagocytosis.
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ItemNo Preview AvailableMalaria vaccine candidates displayed on novel virus-like particles are immunogenic and induce transmission-blocking activity(PUBLIC LIBRARY SCIENCE, 2019-09-10)The development of effective malaria vaccines remains a global health priority. Currently, the most advanced vaccine, known as RTS,S, has only shown modest efficacy in clinical trials. Thus, the development of more efficacious vaccines by improving the formulation of RTS,S for increased efficacy or to interrupt malaria transmission are urgently needed. The RTS,S vaccine is based on the presentation of a fragment of the sporozoite antigen on the surface of virus-like particles (VLPs) based on human hepatitis B virus (HBV). In this study, we have developed and evaluated a novel VLP platform based on duck HBV (known as Metavax) for malaria vaccine development. This platform can incorporate large and complex proteins into VLPs and is produced in a Hansenula cell line compatible with cGMP vaccine production. Here, we have established the expression of leading P. falciparum malaria vaccine candidates as VLPs. This includes Pfs230 and Pfs25, which are candidate transmission-blocking vaccine antigens. We demonstrated that the VLPs effectively induce antibodies to malaria vaccine candidates with minimal induction of antibodies to the duck-HBV scaffold antigen. Antibodies to Pfs230 also recognised native protein on the surface of gametocytes, and antibodies to both Pfs230 and Pfs25 demonstrated transmission-reducing activity in standard membrane feeding assays. These results establish the potential utility of this VLP platform for malaria vaccines, which may be suitable for the development of multi-component vaccines that achieve high vaccine efficacy and transmission-blocking immunity.
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ItemAntibody Responses to Plasmodium falciparum and Plasmodium vivax and Prospective Risk of Plasmodium spp. Infection Postpartum(AMER SOC TROP MED & HYGIENE, 2017)AbstractPostpartum women may have an altered susceptibility to Plasmodium falciparum and Plasmodium vivax. The relationship between naturally acquired malarial immunity and susceptibility to malaria postpartum is yet to be determined. IgG levels were measured against P. falciparum and P. vivax antigens from delivery in 201 postpartum and 201 nonpregnant controls over 12 weeks. Associations between time-varying antibody levels and time to first microscopically confirmed species-specific infection were determined by Cox regression. Associations between antibody levels and prospective risk of Plasmodium infection were similar in postpartum and control women. A 2-fold increase in P. falciparum antibody levels was associated with increased prospective risk of P. falciparum infection (hazard ratio [HR] range = 1.37-1.94). Antibody levels against most P. vivax antigens displayed no association with prospective risk of P. vivax infection (HR range = 1.02-1.05) with the exception of PvMSP119 antibodies that were weakly associated with prospective risk of P. vivax infection (HR = 1.14 (95% confidence interval = 1.02, 1.28) per 2-fold increase in levels). Associations between antibody levels and prospective risk of infection attenuated when adjusted for documented retrospective exposure. Serology may be a useful tool to predict and monitor women at increased risk of P. falciparum infection postpartum, particularly in the absence of a detailed history of retrospective infections.
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ItemDeclining Transmission and Immunity to Malaria and Emerging Artemisinin Resistance in Thailand: A Longitudinal Study(OXFORD UNIV PRESS INC, 2017-09-15)BACKGROUND: Reductions in malaria transmission decrease naturally acquired immunity, which may influence the emergence of Plasmodium falciparum artemisinin-resistant phenotypes and genotypes over time. METHODS: Antibodies specific for P. falciparum antigens were determined in uncomplicated hyperparasitemic malaria patients over a 10-year period of declining malaria transmission and emerging artemisinin resistance in northwestern Thailand. We investigated the association between antibody levels and both parasite clearance time (PCt½) and artemisinin resistance-associated kelch13 genotypes over time. RESULTS: Immunity to P. falciparum declined prior to 2004, preceding the emergence of artemisinin resistance-associated genotypes and phenotypes (maximum mean change in antibody level per year: anti-MSP142 = -0.17; 95% confidence interval [CI] = -.31 to -.04; P = .01). In this period of declining immunity, and in the absence of kelch13 mutations, PCt½ increased. Between 2007 and 2011, levels of antibodies fluctuated, and higher antibody levels were associated with faster PCt½ (maximum yearly change in PCt½, in hours: EBA140rII = -0.39; 95% CI = -.61 to -.17; P < .001). CONCLUSIONS: Understanding the impact of changing transmission and immunity on the emergence of artemisinin resistance is important particularly as increased malaria control and elimination activities may enhance immunological conditions for the expansion of artemisinin-resistant P. falciparum.
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ItemProteome-wide mapping of immune features onto Plasmodium protein three-dimensional structures(NATURE PORTFOLIO, 2018-03-12)Humoral immune responses against the malaria parasite are an important component of a protective immune response. Antibodies are often directed towards conformational epitopes, and the native structure of the antigenic region is usually critical for antibody recognition. We examined the structural features of various Plasmodium antigens that may impact on epitope location, by performing a comprehensive analysis of known and modelled structures from P. falciparum. Examining the location of known polymorphisms over all available structures, we observed a strong propensity for polymorphic residues to be exposed on the surface and to occur in particular secondary structure segments such as hydrogen-bonded turns. We also utilised established prediction algorithms for B-cell epitopes and MHC class II binding peptides, examining predicted epitopes in relation to known polymorphic sites within structured regions. Finally, we used the available structures to examine polymorphic hotspots and Tajima's D values using a spatial averaging approach. We identified a region of PfAMA1 involving both domains II and III under a high degree of balancing selection relative to the rest of the protein. In summary, we developed general methods for examining how sequence-based features relate to one another in three-dimensional space and applied these methods to key P. falciparum antigens.
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ItemContribution of Functional Antimalarial Immunity to Measures of Parasite Clearance in Therapeutic Efficacy Studies of Artemisinin Derivatives(OXFORD UNIV PRESS INC, 2019-10-01)BACKGROUND: Antibodies to the blood stages of malaria parasites enhance parasite clearance and antimalarial efficacy. The antibody subclass and functions that contribute to parasite clearance during antimalarial treatment and their relationship to malaria transmission intensity have not been characterized. METHODS: Levels of immunoglobulin G (IgG) subclasses and C1q fixation in response to Plasmodium falciparum merozoite antigens (erythrocyte-binding antigen [EBA] 175RIII-V, merozoite surface protein 2 [MSP-2], and MSP-142) and opsonic phagocytosis of merozoites were measured in a multinational trial assessing the efficacy of artesunate therapy across 11 Southeast Asian sites. Regression analyses assessed the effects of antibody seropositivity on the parasite clearance half-life (PC½), having a PC½ of ≥5 hours, and having parasitemia 3 days after treatment. RESULTS: IgG3, followed by IgG1, was the predominant IgG subclass detected (seroprevalence range, 5%-35% for IgG1 and 27%-41% for IgG3), varied across study sites, and was lowest in study sites with the lowest transmission intensity and slowest mean PC½. IgG3, C1q fixation, and opsonic-phagocytosis seropositivity were associated with a faster PC½ (range of the mean reduction in PC½, 0.47-1.16 hours; P range, .001-.03) and a reduced odds of having a PC½ of ≥5 hours and having parasitemia 3 days after treatment. CONCLUSIONS: The prevalence of IgG3, complement-fixing antibodies, and merozoite phagocytosis vary according to transmission intensity, are associated with faster parasite clearance, and may be sensitive surrogates of an augmented clearance capacity of infected erythrocytes. Determining the functional immune mechanisms associated with parasite clearance will improve characterization of artemisinin resistance.
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ItemDisplay of malaria transmission-blocking antigens on chimeric duck hepatitis B virus-derived virus-like particles produced in Hansenula polymorpha(PUBLIC LIBRARY SCIENCE, 2019-09-04)BACKGROUND: Malaria caused by Plasmodium falciparum is one of the major threats to human health globally. Despite huge efforts in malaria control and eradication, highly effective vaccines are urgently needed, including vaccines that can block malaria transmission. Chimeric virus-like particles (VLP) have emerged as a promising strategy to develop new malaria vaccine candidates. METHODS: We developed yeast cell lines and processes for the expression of malaria transmission-blocking vaccine candidates Pfs25 and Pfs230 as VLP and VLP were analyzed for purity, size, protein incorporation rate and expression of malaria antigens. RESULTS: In this study, a novel platform for the display of Plasmodium falciparum antigens on chimeric VLP is presented. Leading transmission-blocking vaccine candidates Pfs25 and Pfs230 were genetically fused to the small surface protein (dS) of the duck hepatitis B virus (DHBV). The resulting fusion proteins were co-expressed in recombinant Hansenula polymorpha (syn. Pichia angusta, Ogataea polymorpha) strains along with the wild-type dS as the VLP scaffold protein. Through this strategy, chimeric VLP containing Pfs25 or the Pfs230-derived fragments Pfs230c or Pfs230D1M were purified. Up to 100 mg chimeric VLP were isolated from 100 g dry cell weight with a maximum protein purity of 90% on the protein level. Expression of the Pfs230D1M construct was more efficient than Pfs230c and enabled VLP with higher purity. VLP showed reactivity with transmission-blocking antibodies and supported the surface display of the malaria antigens on the native VLP. CONCLUSION: The incorporation of leading Plasmodium falciparum transmission-blocking antigens into the dS-based VLP scaffold is a promising novel strategy for their display on nano-scaled particles. Competitive processes for efficient production and purification were established in this study.