Identification of a Potent Combination of Key Plasmodium falciparum Merozoite Antigens That Elicit Strain-Transcending Parasite-Neutralizing Antibodies

Pandey, Alok Kumar; Reddy, K. Sony; Sahar, Tajali; Gupta, Sonal; Singh, Himanshu; Reddy, E. Jyotheeswara; Asad, Mohd; Siddiqui, Faiza Amber; Gupta, Pankaj; Singh, Bijender; More, Kunal R.; Mohmmed, Asif; Chitnis, Chetan E.; Chauhan, Virander S.; Gaur, Deepak

doi:10.1128/iai.01107-12

Cited by 53 publications

(72 citation statements)

References 46 publications

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“…Other merozoite antigens could also play important roles. Vaccination with conserved microneme and rhoptry proteins, such as P. falciparum Rh1 (PfRh1), PfRh2, PfRh4, EBA-175, and PfRh5, can elicit cross-reactive neutralizing antibodies against different P. falciparum strains (36)(37)(38). Whether these antigens or MSP3 family SPAM domains are important targets for merozoite opsonization remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Merozoite Antigens of Plasmodium falciparum Elicit Strain-Transcending Opsonizing Immunity

et al. 2016

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h It is unclear whether naturally acquired immunity to Plasmodium falciparum results from the acquisition of antibodies to multiple, diverse antigens or to fewer, highly conserved antigens. Moreover, the specific antibody functions required for malaria immunity are unknown, and hence informative immunological assays are urgently needed to address these knowledge gaps and guide vaccine development. In this study, we investigated whether merozoite-opsonizing antibodies are associated with protection from malaria in a strain-specific or strain-transcending manner by using a novel field isolate and an immune plasmamatched cohort from Papua New Guinea with our validated assay of merozoite phagocytosis. Highly correlated opsonization responses were observed across the 15 parasite strains tested, as were strong associations with protection (composite phagocytosis score across all strains in children uninfected at baseline: hazard ratio of 0.15, 95% confidence interval of 0.04 to 0.63). Opsonizing antibodies had a strong strain-transcending component, and the opsonization of transgenic parasites deficient for MSP3, MSP6, MSPDBL1, or P. falciparum MSP1-19 (PfMSP1-19) was similar to that of wild-type parasites. We have provided the first evidence that merozoite opsonization is predominantly strain transcending, and the highly consistent associations with protection against diverse parasite strains strongly supports the use of merozoite opsonization as a correlate of immunity for field studies and vaccine trials. These results demonstrate that conserved domains within merozoite antigens targeted by opsonization generate strain-transcending immune responses and represent promising vaccine candidates.

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Section: Discussionmentioning

confidence: 99%

Merozoite Antigens of Plasmodium falciparum Elicit Strain-Transcending Opsonizing Immunity

et al. 2016

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“…Soluble parasite proteins were obtained from 3D7 culture supernatants as described previously (16,20,29). Briefly, 500 l of culture supernatant was incubated with a 100-l packed volume of human erythrocytes at 37°C, following which the suspension was centrifuged through dibutyl phthalate (Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…Animal immunizations and total IgG purification were done as reported previously (29). Briefly, five rats and three rabbits were immunized intramuscularly with 50 g and 100 g of rPfRH5 63 , respectively.…”

Section: Methodsmentioning

confidence: 99%

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Bacterially Expressed Full-Length Recombinant Plasmodium falciparum RH5 Protein Binds Erythrocytes and Elicits Potent Strain-Transcending Parasite-Neutralizing Antibodies

et al. 2014

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Plasmodium falciparum reticulocyte binding-like homologous protein 5 (PfRH5) is an essential merozoite ligand that binds with its erythrocyte receptor, basigin. PfRH5 is an attractive malaria vaccine candidate, as it is expressed by a wide number of P. falciparum strains, cannot be genetically disrupted, and exhibits limited sequence polymorphisms. Viral vector-induced PfRH5 antibodies potently inhibited erythrocyte invasion. However, it has been a challenge to generate full-length recombinant PfRH5 in a bacterial-cell-based expression system. In this study, we have produced full-length recombinant PfRH5 in Escherichia coli that exhibits specific erythrocyte binding similar to that of the native PfRH5 parasite protein and also, importantly, elicits potent invasion-inhibitory antibodies against a number of P. falciparum strains. Antibasigin antibodies blocked the erythrocyte binding of both native and recombinant PfRH5, further confirming that they bind with basigin. We have thus successfully produced full-length PfRH5 as a functionally active erythrocyte binding recombinant protein with a conformational integrity that mimics that of the native parasite protein and elicits potent strain-transcending parasite-neutralizing antibodies. P. falciparum has the capability to develop immune escape mechanisms, and thus, blood-stage malaria vaccines that target multiple antigens or pathways may prove to be highly efficacious. In this regard, antibody combinations targeting PfRH5 and other key merozoite antigens produced potent additive inhibition against multiple worldwide P. falciparum strains. PfRH5 was immunogenic when immunized with other antigens, eliciting potent invasion-inhibitory antibody responses with no immune interference. Our results strongly support the development of PfRH5 as a component of a combination blood-stage malaria vaccine.

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“…Since these effects could be mimicked (in theory) by directly applying the respective antibodies, one would speak about immunotherapy rather than vaccination. 22 Another difficulty in interpreting the results with recombinant vaccines comes from the fact that many of them were expressed in E. coli and affinity purified from crude extracts. Therefore, contaminations with immune-modulating agents from bacterial origin such as lipopolysaccharides cannot be ruled out, and controls with irrelevant proteins expressed in the same system or with lipopolysaccharide-depleted protein fractions 23 should always In mice, studies with vaccines on acute infection models are often terminated after 3-4 weeks post-challenge.…”

Section: Vaccination Against Neosporosismentioning

confidence: 99%

Vaccines and drugs against Neospora caninum, an important apicomplexan causing abortion in cattle and other farm animals

Hemphill¹,

Müller²

2015

RIP

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Abstract:The apicomplexan parasite Neospora caninum represents an important abortioncausing parasite in cattle. The economic impact of neosporosis has led to considerable investments to develop vaccines that would prevent infection and abortion. Live-attenuated vaccines have been shown to confer some protection against N. caninum infection, but may cause problems due to regulatory issues and other drawbacks. Therefore, efforts have been undertaken to develop recombinant subunit vaccines based on antigens involved in adhesion/invasion or other parasite-host cell interaction processes. Concerning chemotherapeutical agents, the currently known arsenal of active drugs that act against N. caninum is limited to a small number of compounds with suitable in vitro properties including low inhibition constants, parasitocidal effects, and low cytotoxicity. For in vivo studies, mostly small laboratory animal models that mimic cerebral infection, acute disease, and fetal loss upon infection during pregnancy have been applied for the assessment of vaccines or drug candidates. However, only a small number of recombinant vaccines and drug candidates have met the expectations, and small laboratory models for neosporosis need to be standardized in order to be able to compare the results of different laboratories. Few vaccines and compounds have made it into trials involving ruminant models such as cattle or sheep, including live-attenuated vaccines and the anticoccidial drug toltrazuril. We here summarize the current status of vaccine and drug development for neosporosis.

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Identification of a Potent Combination of Key Plasmodium falciparum Merozoite Antigens That Elicit Strain-Transcending Parasite-Neutralizing Antibodies

Cited by 53 publications

References 46 publications

Merozoite Antigens of Plasmodium falciparum Elicit Strain-Transcending Opsonizing Immunity

Merozoite Antigens of Plasmodium falciparum Elicit Strain-Transcending Opsonizing Immunity

Bacterially Expressed Full-Length Recombinant Plasmodium falciparum RH5 Protein Binds Erythrocytes and Elicits Potent Strain-Transcending Parasite-Neutralizing Antibodies

Vaccines and drugs against Neospora caninum, an important apicomplexan causing abortion in cattle and other farm animals

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