Functional Comparison of Blood-Stage Plasmodium falciparum Malaria Vaccine Candidate Antigens

Illingworth, Joseph J.; Alanine, Daniel G. W.; Brown, Rebecca; Marshall, Joyce; Bartlett, Helen; Silk, Sarah E.; Labbé, Geneviève; Quinkert, Doris; Cho, Jee Sun; Wendler, Jason P.; Pattinson, David J.; Barfod, Lea; Douglas, Alexander D.; Shea, Michael William; Wright, Katherine E.; Cassan, Simone C. de; Higgins, Matthew K.; Draper, Simon J.

doi:10.3389/fimmu.2019.01254

Cited by 39 publications

(37 citation statements)

References 67 publications

(109 reference statements)

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“…The mean total IgG concentration giving 50% GIA for rabbits that received three vaccine doses was 0.94 mg/mL total IgG. This value lies within the broad range of GIA IC 50 values (between 0.38 mg/mL 17 and 5.07 mg/mL 24 ) that have been reported for total IgG generated by immunising rabbits with Immune sera of mice were tested for parasite binding in IFA with in vitro cultured P. falciparum blood-stage parasites. As a representative example, results obtained with sera from a NMRI mouse are shown.…”

Section: Discussionmentioning

confidence: 51%

“…The adjuvant used has not been reported. In the trial published by Illingworth et al, 24 rabbits were immunised three times and each dose consisted of 100 μg antigen and 200 μL AddaVax™ adjuvant. The differences in the GIA results could thus have arisen from factors such as differences in antigen dose, adjuvant activity, immunisation protocol and GIA assay format.…”

Section: Discussionmentioning

confidence: 99%

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Vaccination with virosomally formulated recombinant CyRPA elicits protective antibodies against Plasmodium falciparum parasites in preclinical in vitro and in vivo models

et al. 2020

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The Plasmodium falciparum (Pf) cysteine-rich protective antigen (PfCyRPA) has emerged as a promising blood-stage candidate antigen for inclusion into a broadly cross-reactive malaria vaccine. This highly conserved protein among various geographical strains plays a key role in the red blood cell invasion process by P. falciparum merozoites, and antibodies against PfCyRPA can efficiently prevent the entry of the malaria parasites into red blood cells. The aim of the present study was to develop a humancompatible formulation of the PfCyRPA vaccine candidate and confirming its activity in preclinical studies. Recombinant PfCyRPA expressed in HEK 293 cells was chemically coupled to phosphoethanolamine and then incorporated into the membrane of unadjuvanted influenza virosomes approved as antigen delivery system for humans. Laboratory animals were immunised with the virosome-based PfCyRPA vaccine to determine its immunogenic properties and in particular, its capacity to elicit parasite binding and growth-inhibitory antibodies. The vaccine elicited in mice and rabbits high titers of PfCyRPA-specific antibodies that bound to the blood-stage parasites. At a concentration of 10 mg/mL, purified total serum IgG from immunised rabbits inhibited parasite growth in vitro by about 80%. Furthermore, in a P. falciparum infection mouse model, passive transfer of 10 mg of purified total IgG from PfCyRPA vaccinated rabbits reduced the in vivo parasite load by 77%. Influenza virosomes thus represent a suitable antigen delivery system for the induction of protective antibodies against the recombinant PfCyRPA, designating it as a highly suitable component for inclusion into a multivalent and multi-stage virosomal malaria vaccine.npj Vaccines (2020) 5:9 ; https://doi.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Vaccination with virosomally formulated recombinant CyRPA elicits protective antibodies against Plasmodium falciparum parasites in preclinical in vitro and in vivo models

et al. 2020

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“…This could also explain the lack of CD8+ T cell responses in our cohort since all patients had an extensive blood phase with strong symptoms and the need to be hospitalized. It has been discussed that CD4+ T cells might play an important role in priming other immune cells (i.e., NK cells) and in evoking a strong antibody response which is necessary for immune control (64,65). If an efficient induction of immunity against plasmodial infection by CD8+ T cells depends on CD4+ T cells, is therefore an important question to address in the development of an effective vaccine.…”

Section: Discussionmentioning

confidence: 99%

Detection of EXP1-Specific CD4+ T Cell Responses Directed Against a Broad Range of Epitopes Including Two Promiscuous MHC Class II Binders During Acute Plasmodium falciparum Malaria

et al. 2020

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Background: T cells are thought to play a major role in conferring immunity against malaria. This study aimed to comprehensively define the breadth and specificity of the Plasmodium falciparum (P. falciparum)-specific CD4+ T cell response directed against the exported protein 1 (EXP1) in a cohort of patients diagnosed with acute malaria. Methods: Peripheral blood mononuclear cells of 44 patients acutely infected with P. falciparum, and of one patient infected with P. vivax, were stimulated and cultured in vitro with an overlapping set of 31 P. falciparum-specific 13-17-mer peptides covering the entire EXP1 sequence. EXP1-specific T cell responses were analyzed by ELISPOT and intracellular cytokine staining for interferon-γ production after re-stimulation with individual peptides. For further characterization of the epitopes, in silico and in vitro human leukocyte antigen (HLA) binding studies and fine mapping assays were performed. Results: We detected one or more EXP1-specific CD4+ T cell responses (mean: 1.09, range 0-5) in 47% (21/45) of our patients. Responses were directed against 15 of the 31 EXP1 peptides. Peptides EXP1-P13 (aa60-74) and P15 (aa70-85) were detected by 18% (n = 8) and 27% (n = 12) of the 45 patients screened. The optimal length, as well as the corresponding most likely HLA-restriction, of each of these two peptides was assessed. Interestingly, we also identified one CD4+ T cell response against peptide EXP1-P15 in a patient who was infected with P. vivax but not falciparum. Conclusions: This first detailed characterization of novel EXP1-specific T cell epitopes provides important information for future analysis with major histocompatibility complex-multimer technology as well as for immunomonitoring and vaccine design.

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“…Antigens in the asexual stages of malaria parasites represent potential targets for malaria vaccines. Blood-stage vaccines point to target the subsequent disease-causing stage of the Plasmodium life cycle and may provide protection against disease severity, reducing blood stage asexual parasitaemia and transmission [17]. Merozoite surface protein 1 (MSP1) and apical membrane antigen (AMA1) are leading blood-stage malaria antigens and considered important vaccine candidates [15] , especially due to their association with protection in pre-clinical studies of mice and non-human primates [18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity analysis of conserved fragments in Plasmodium ovale species merozoite surface protein 4

Juliette

Chu

Kassegne

et al. 2020

Preprint

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Background : There is an urgent need for an effective vaccine to control and eradicate malaria, one of the most serious global infectious diseases. Plasmodium merozoite surface protein 4 (MSP4) has been listed as a blood-stage subunit vaccine candidate for malaria. Plasmodium ovale species (spp.) infection is also a source of malaria burden in tropical regions where it is sometimes mixed with other Plasmodium species. However, little is known about P. ovale spp. MSP4. Methods : The msp4 gene was amplified through polymerase chain reaction using genomic DNA extracted from blood samples of 46 patients infected with P. ovale spp. and amplified products were sequenced. Open reading frames predicted as immunogenic peptides consisting of 119 and 97 amino acids of P. ovale curtisi MSP4 (PocMSP4) and P. ovale wallikeri MSP4 (PowMSP4), respectively, were selected for protein expression. Recombinant proteins (rPoMSP4) were expressed in Escherichia coli , purified, analyzed, and immunized in BALB/c mice. The specificity of anti-MSP4-immunoglubulin (Ig) G antibodies was evaluated by Western blot and enzyme-linked immunosorbent assays, and cellular immune responses were analyzed via lymphocyte proliferation assays. Results : Full peptide sequences of PocMSP4 and PowMSP4 were completely conserved in all clinical isolates, except in the epidermal growth factor-like domain at the carboxyl terminus where only one mutation was observed in one P. ovale wallikeri isolate. Furthermore, we successfully expressed the truncated pocmsp4 and powmsp4 and purified as ~32 kDa proteins. Our results showed that PocMSP4 and PowMSP4 induced high antibody responses with end-point titers ranging from 1:10,000 to 1:2,560,000 in all immunized mouse groups and with high IgG avidity to PocMSP4 (80.5%) and PowMSP4 (92.3%). Furthermore, rPocMSP4 and rPowMSP4 cross-reacted with anti-PowMSP4-specific or anti-PocMSP4-specific antibodies. Additionally, anti-PoMSP4 IgG antibodies showed broad immuno-specificity in reacting against rPoMSP1 and rPoAMA1. Lastly, PocMSP4- and PowMSP4-immunized mice induced cellular immune responses with PocMSP4 (36%) and PowMSP4 cells (15.8%) as observed through splenocyte proliferation assays. Conclusion : Our study suggested conservation in PoMSP4 protein sequences and high immunogenicity was observed in rPoMSP4. Furthermore, PocMSP4- and PowMSP4-immunized mice induced cellular immune responses, suggesting that both humoral and cellular immune responses play crucial roles in the protection against any antigen.

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Functional Comparison of Blood-Stage Plasmodium falciparum Malaria Vaccine Candidate Antigens

Cited by 39 publications

References 67 publications

Vaccination with virosomally formulated recombinant CyRPA elicits protective antibodies against Plasmodium falciparum parasites in preclinical in vitro and in vivo models

Vaccination with virosomally formulated recombinant CyRPA elicits protective antibodies against Plasmodium falciparum parasites in preclinical in vitro and in vivo models

Detection of EXP1-Specific CD4+ T Cell Responses Directed Against a Broad Range of Epitopes Including Two Promiscuous MHC Class II Binders During Acute Plasmodium falciparum Malaria

Immunogenicity analysis of conserved fragments in Plasmodium ovale species merozoite surface protein 4

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