What Is Known about the Immune Response Induced by Plasmodium vivax Malaria Vaccine Candidates?
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SUBMITTER: Lopez C
PROVIDER: S-EPMC5304258 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
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What Is Known about the Immune Response Induced by <i>Plasmodium vivax</i> Malaria Vaccine Candidates?
López Carolina C Yepes-Pérez Yoelis Y Hincapié-Escobar Natalia N Díaz-Arévalo Diana D Patarroyo Manuel A MA
Frontiers in immunology 20170213
Malaria caused by <i>Plasmodium vivax</i> continues being one of the most important infectious diseases around the world; <i>P. vivax</i> is the second most prevalent species and has the greatest geographic distribution. Developing an effective antimalarial vaccine is considered a relevant control strategy in the search for means of preventing the disease. Studying parasite-expressed proteins, which are essential in host cell invasion, has led to identifying the regions recognized by individuals ...[more]
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Project description:Plasmodium vivax is responsible for the majority of malaria cases outside Africa. Unlike P. falciparum, the P. vivax life-cycle includes a dormant liver stage, the hypnozoite, which can cause infection in the absence of mosquito transmission. An effective vaccine against P. vivax blood stages would limit symptoms and pathology from such recurrent infections, and therefore could play a critical role in the control of this species. Vaccine development in P. vivax, however, lags considerably behind P. falciparum, which has many identified targets with several having transitioned to Phase II testing. By contrast only one P. vivax blood-stage vaccine candidate based on the Duffy Binding Protein (PvDBP), has reached Phase Ia, in large part because the lack of a continuous in vitro culture system for P. vivax limits systematic screening of new candidates. We used the close phylogenetic relationship between P. vivax and P. knowlesi, for which an in vitro culture system in human erythrocytes exists, to test the scalability of systematic reverse vaccinology to identify and prioritise P. vivax blood-stage targets. A panel of P. vivax proteins predicted to function in erythrocyte invasion were expressed as full-length recombinant ectodomains in a mammalian expression system. Eight of these antigens were used to generate polyclonal antibodies, which were screened for their ability to recognize orthologous proteins in P. knowlesi. These antibodies were then tested for inhibition of growth and invasion of both wild type P. knowlesi and chimeric P. knowlesi lines modified using CRISPR/Cas9 to exchange P. knowlesi genes with their P. vivax orthologues. Candidates that induced antibodies that inhibited invasion to a similar level as PvDBP were identified, confirming the utility of P. knowlesi as a model for P. vivax vaccine development and prioritizing antigens for further follow up.
| S-EPMC8279373 | biostudies-literature
Project description:BACKGROUND: For many malarious regions outside of Africa, development of effective transmission-blocking vaccines will require coverage against both Plasmodium falciparum and P. vivax. Work on P. vivax transmission-blocking vaccines has been hampered by the inability to clone the vaccine candidate genes from this parasite. MATERIALS AND METHODS: To search for genes encoding the ookinete surface proteins from P. vivax, the DNA sequences of the eight known proteins in the P25 subfamily (Pfs25, Pgs25, Pys25, Pbs25) and in the P21/28 subfamily (Pfs28, Pgs28, Pys21, Pbs21) of zygote/ookinete surface proteins were aligned. Regions of highest identity were used to design degenerate PCR oligonucleotides. Genomic DNA from the Sal I strain of P. vivax and genomic and splinkerette DNA libraries were used as PCR templates. To characterize the polymorphisms of Pvs25 and Pvs28, these two genes were PCR amplified and the DNA sequences were determined from genomic DNA extracted from patients infected with P. vivax. RESULTS: Analysis of the deduced amino acid sequence of Pvs28 revealed a secretory signal sequence, four epidermal growth factor (EGF)-like domains, six copies of the heptad amino acid repeat (GSGGE/D), and a short hydrophobic region. Because the fourth EGF-like domain has four rather than six cysteines, the gene designated Pvs28 is the presumed homologue of P21/28 subfamily members. Analysis of the deduced amino acid sequence of Pvs25 revealed a similar structure to that of Pvs28. The presence of six rather than four cysteines in the fourth EGF-like domain suggested that Pvs25 is the homologue of P25 subfamily members. Several regions of genetic polymorphisms in Pvs25 and Pvs28 were identified in field isolates of P. vivax. CONCLUSIONS: The genes encoding two ookinete surface proteins, Pvs28 and Pvs25, from P. vivax have been isolated and sequenced. Comparison of the primary structures of Pvs25, Pvs28, Pfs25, and Pfs28 suggest that there are regions of genetic polymorphism in the P25 and P21/28 subfamilies.
| S-EPMC2230397 | biostudies-other
Project description:Plasmodium vivax, a major contributor to the malaria burden in India, has the broadest geographic distribution and shows higher genetic diversity than P. falciparum. Here, we investigated the genetic diversity of two leading P. vivax vaccine candidate antigens, at three geographically diverse malaria-endemic regions in India. Pvama1 and Pvmsp119 partial coding sequences were generated from one hundred P. vivax isolates in India (Chennai n = 28, Nadiad n = 50 and Rourkela n = 22) and ~1100 published sequences from Asia, South America, North America, and Oceania regions included. These data were used to assess the genetic diversity and potential for vaccine candidacy of both antigens on a global scale. A total of 44 single nucleotide polymorphism (SNPs) were identified among 100 Indian Pvama1 sequences, including 10 synonymous and 34 nonsynonymous mutations. Nucleotide diversity was higher in Rourkela and Nadiad as compared to Chennai. Nucleotide diversity measures showed a strong balancing selection in Indian and global population for domain I of Pvama1, which suggests that it is a dominant target of the protective immune response. In contrast, the Pvmsp119 region showed highly conserved sequences in India and across the Oceania, South America, North America and Asia, demonstrating low genetic diversity in the global population when compared to Pvama1. Results suggest the possibility of including Pvmsp119 in a multivalent vaccine formulation against P. vivax infections. However, the high genetic diversity seen in Pvama1 would be more challenging for vaccine development.
| S-EPMC8376102 | biostudies-literature
Project description:Understanding the targets and mechanisms of human immunity to malaria caused by Plasmodium falciparum is crucial for advancing effective vaccines and developing tools for measuring immunity and exposure in populations. Acquired immunity to malaria predominantly targets the blood stage of infection when merozoites of Plasmodium spp. infect erythrocytes and replicate within them. During the intra-erythrocytic development of P. falciparum, numerous parasite-derived antigens are expressed on the surface of infected erythrocytes (IEs). These antigens enable P. falciparum-IEs to adhere in the vasculature and accumulate in multiple organs, which is a key process in the pathogenesis of disease. IE surface antigens, often referred to as variant surface antigens, are important targets of acquired protective immunity and include PfEMP1, RIFIN, STEVOR and SURFIN. These antigens are highly polymorphic and encoded by multigene families, which generate substantial antigenic diversity to mediate immune evasion. The most important immune target appears to be PfEMP1, which is a major ligand for vascular adhesion and sequestration of IEs. Studies are beginning to identify specific variants of PfEMP1 linked to disease pathogenesis that may be suitable for vaccine development, but overcoming antigenic diversity in PfEMP1 remains a major challenge. Much less is known about other surface antigens, or antigens on the surface of gametocyte-IEs, the effector mechanisms that mediate immunity, and how immunity is acquired and maintained over time; these are important topics for future research.
| S-EPMC4160571 | biostudies-literature
Project description:BackgroundMalaria-associated anaemia, arising from symptomatic, asymptomatic and submicroscopic infections, is a significant cause of morbidity worldwide. Induced blood stage malaria volunteer infection studies (IBSM-VIS) provide a unique opportunity to evaluate the haematological response to early Plasmodium falciparum and Plasmodium vivax infection.MethodsThis study was an analysis of the haemoglobin, red cell counts, and parasitaemia data from 315 participants enrolled in IBSM-VIS between 2012 and 2019, including 269 participants inoculated with the 3D7 strain of P. falciparum (Pf3D7), 15 with an artemisinin-resistant P. falciparum strain (PfK13) and 46 with P. vivax. Factors associated with the fractional fall in haemoglobin (Hb-FF) were evaluated, and the malaria-attributable erythrocyte loss after accounting for phlebotomy-related losses was estimated. The relative contribution of parasitized erythrocytes to the malaria-attributable erythrocyte loss was also estimated.ResultsThe median peak parasitaemia prior to treatment was 10,277 parasites/ml (IQR 3566-27,815), 71,427 parasites/ml [IQR 33,236-180,213], and 34,840 parasites/ml (IQR 13,302-77,064) in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. The median Hb-FF was 10.3% (IQR 7.8-13.3), 14.8% (IQR 11.8-15.9) and 11.7% (IQR 8.9-14.5) in those inoculated with Pf3D7, PfK13 and P. vivax, respectively, with the haemoglobin nadir occurring a median 12 (IQR 5-21), 15 (IQR 7-22), and 8 (IQR 7-15) days following inoculation. In participants inoculated with P. falciparum, recrudescence was associated with a greater Hb-FF, while in those with P. vivax, the Hb-FF was associated with a higher pre-treatment parasitaemia and later day of anti-malarial treatment. After accounting for phlebotomy-related blood losses, the estimated Hb-FF was 4.1% (IQR 3.1-5.3), 7.2% (IQR 5.8-7.8), and 4.9% (IQR 3.7-6.1) in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. Parasitized erythrocytes were estimated to account for 0.015% (IQR 0.006-0.06), 0.128% (IQR 0.068-0.616) and 0.022% (IQR 0.008-0.082) of the malaria-attributable erythrocyte loss in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively.ConclusionEarly experimental P. falciparum and P. vivax infection resulted in a small but significant fall in haemoglobin despite parasitaemia only just at the level of microscopic detection. Loss of parasitized erythrocytes accounted for < 0.2% of the total malaria-attributable haemoglobin loss.
| S-EPMC8685492 | biostudies-literature
Project description:BackgroundPlasmodium vivax transmission-blocking vaccines (TBVs) are receiving increasing attention. Based on excellent transmission-blocking activities of the PbPH (PBANKA_0417200) and PbSOP26 (PBANKA_1457700) antigens in Plasmodium berghei, their orthologs in P. vivax, PVX_098655 (PvPH) and PVX_101120 (PvSOP26), were selected for the evaluation of their potential as TBVs.MethodsFragments of PvPH (amino acids 22-304) and PvSOP26 (amino acids 30-272) were expressed in the yeast expression system. The recombinant proteins were used to immunize mice to obtain antisera. The transmission-reducing activities of these antisera were evaluated using the direct membrane feeding assay (DMFA) using Anopheles dirus mosquitoes and P. vivax clinical isolates.ResultsThe recombinant proteins PvPH and PvSOP26 induced robust antibody responses in mice. The DMFA showed that the anti-PvSOP26 sera significantly reduced oocyst densities by 92.0 and 84.1% in two parasite isolates, respectively, whereas the anti-PvPH sera did not show evident transmission-reducing activity. The variation in the DMFA results was unlikely due to the genetic polymorphisms of the two genes since their respective sequences were identical in the clinical P. vivax isolates.ConclusionPvSOP26 could be a promising TBV candidate for P. vivax, which warrants further evaluation.
| S-EPMC8366161 | biostudies-literature
Project description:BackgroundGenetic polymorphism is an inevitable component of a multistage infectious organism, such as the malaria parasite. By means of genetic polymorphism, parasite opts particular polymorph and reveals survival advantage. Pvs25 and pvs28 are sexual stage antigen genes, expressed at the ookinete stage inside the mosquito gut, and considered as potential transmission-blocking vaccine candidates. This study presents sequence variations in two important transmission blocking antigen genes pvs25 and pvs28 in the field isolates of P. vivax from the Indian subcontinent.MethodsOne hundred microscopically diagnosed P. vivax isolates were collected from five geographical regions of India. Pvs25 and pvs28 genes were PCR amplified and sequenced to assess sequence variation among field isolates.ResultsA total of 26 amino acid substitutions were observed in Pvs25 (10) and Pvs28 (16) among field isolates of P. vivax. Tandem repeat polymorphism observed in pvs28 shows 3-6 tandem repeats in the field isolates. Seven and eight novel amino acid substitutions were observed in Pvs25 and Pvs28, respectively in Indian isolates. Comparison of amino acid substitutions suggests that majority of substitutions observed in global isolates were also present in Indian subcontinent. A single haplotype was observed to be major haplotype among isolates of Delhi, Nadiad, Chennai and Panna except in isolates of Kamrup. Further, population comparison analyses suggest that P. vivax isolates inhabiting in north-eastern region (Kamrup) were distantly related with the isolates from remaining parts of the country. Majority of the amino acid substitutions observed in Indian isolates were more identical to the substitutions reported from isolates of Thailand and Bangladesh.ConclusionStudy uncovered many new amino acid substitutions as well as a predominance of single haplotype in Indian subcontinent except in north-eastern region of the country. The amino acid substitutions data generated in this study from different geographical regions of the Indian subcontinent could be helpful in designing a more effective anti-malarial transmission-blocking vaccine.
| S-EPMC3104378 | biostudies-literature
Project description:BackgroundThere are no licensed vaccines against Plasmodium vivax , the most common cause of malaria outside of Africa.MethodsWe conducted two Phase I/IIa clinical trials to assess the safety, immunogenicity and efficacy of two vaccines targeting region II of P. vivax Duffy-binding protein (PvDBPII). Recombinant viral vaccines (using ChAd63 and MVA vectors) were administered at 0, 2 months or in a delayed dosing regimen (0, 17, 19 months), whilst a protein/adjuvant formulation (PvDBPII/Matrix-M™) was administered monthly (0, 1, 2 months) or in a delayed dosing regimen (0, 1, 14 months). Delayed regimens were due to trial halts during the COVID-19 pandemic. Volunteers underwent heterologous controlled human malaria infection (CHMI) with blood-stage P. vivax parasites at 2-4 weeks following their last vaccination, alongside unvaccinated controls. Efficacy was assessed by comparison of parasite multiplication rate (PMR) in blood post-CHMI, modelled from parasitemia measured by quantitative polymerase-chain-reaction (qPCR).ResultsThirty-two volunteers were enrolled and vaccinated (n=16 for each vaccine). No safety concerns were identified. PvDBPII/Matrix-M™, given in the delayed dosing regimen, elicited the highest antibody responses and reduced the mean PMR following CHMI by 51% (range 36-66%; n=6) compared to unvaccinated controls (n=13). No other vaccine or regimen impacted parasite growth. In vivo growth inhibition of blood-stage P. vivax correlated with functional antibody readouts of vaccine immunogenicity.ConclusionsVaccination of malaria-naïve adults with a delayed booster regimen of PvDBPII/ Matrix-M™ significantly reduces the growth of blood-stage P. vivax . Funded by the European Commission and Wellcome Trust; VAC069, VAC071 and VAC079 ClinicalTrials.gov numbers NCT03797989 , NCT04009096 and NCT04201431 .
| S-EPMC9164524 | biostudies-literature
Project description:Protein ?-helical coiled coil structures are known to induce antibodies able to block critical functions in different pathogens. In a previous study, a total of 50 proteins of Plasmodium vivax erythrocytic asexual stages containing ?-helical coiled coil structural motifs were identified in silico, and the corresponding peptides were chemically synthesized. A total of 43 peptides were recognized by naturally acquired antibodies in plasma samples from both Papua New Guinea (PNG) and Colombian adult donors. In this study, the association between IgG antibodies to these peptides and clinical immunity was further explored by measuring total IgG antibody levels to 24 peptides in baseline samples from a longitudinal study of children aged 1-3 years (n = 164) followed for 16 months. Samples were reactive to all peptides tested. Eight peptides were recognized by >50% of individuals, whereas only one peptide had < 20% reactivity. Children infected at baseline were seropositive to 23/24 peptides. No significant association was observed between antibody titers and age or molecular force of infection, suggesting that antibody levels had already reached an equilibrium. There was a strong association between antibody levels to all peptides and protection against P. vivax clinical episodes during the 16 months follow-up. These results suggest that the selected coiled coil antigens might be good markers of both exposure and acquired immunity to P. vivax malaria, and further preclinical investigation should be performed to determine their potential as P. vivax vaccine antigens.
| S-EPMC5484505 | biostudies-literature
Project description:BackgroundSignificant progress has been recently achieved in the development of Plasmodium vivax challenge infections in humans, which are essential for vaccine and drug testing. With the goal of accelerating clinical development of malaria vaccines, the outcome of infections experimentally induced in naïve and semi-immune volunteers by infected mosquito bites was compared.MethodsSeven malaria-naïve and nine semi-immune Colombian adults (n = 16) were subjected to the bites of 2-4 P. vivax sporozoite-infected Anopheles mosquitoes. Parasitemia levels, malaria clinical manifestations, and immune responses were assessed and compared.ResultsAll volunteers developed infections as confirmed by microscopy and RT-qPCR. No significant difference in the pre-patent period (mean 12.5 and 12.8 days for malaria-naïve and malaria-exposed, respectively) was observed but naïve volunteers developed classical malaria signs and symptoms, while semi-immune volunteers displayed minor or no symptoms at the day of diagnosis. A malaria-naïve volunteer developed a transient low submicroscopic parasitemia that cured spontaneously. Infection induced an increase in specific antibody levels in both groups.ConclusionSporozoite infectious challenge was safe and reproducible in semi-immune and naïve volunteers. This model will provide information for simultaneous comparison of the protective efficacy of P. vivax vaccines in naïve and semi-immune volunteers under controlled conditions and would accelerate P. vivax vaccine development.Trial registrationclinicaltrials.gov NCT01585077.
| S-EPMC4070897 | biostudies-literature