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Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope.

ABSTRACT: In pregnant women, Plasmodium falciparum-infected red blood cells adhere to the placenta via the parasite protein VAR2CSA. Two vaccine candidates based on VAR2CSA are currently in clinical trials; however, these candidates failed to elicit strain-transcending antibody responses. We previously showed that a cross-reactive monoclonal antibody (3D10) raised against the P. vivax antigen PvDBP targets epitopes in VAR2CSA. We now aim to design a peptide vaccine against VAR2CSA based on the epitope that generated 3D10. We mapped the epitope to subdomain 1 (SD1) of PvDBP and identified a peptide that contained the minimal sequence. However, this peptide did not elicit cross-reactive VAR2CSA antibodies in mice. When tested against a broader, overlapping peptide array spanning SD1, 3D10 in fact recognized a discontinuous epitope consisting of three segments of SD1. These findings presented the challenge to generate this larger structural epitope as a synthetic peptide since it is stabilized by two pairs of disulfide bonds. We overcame this using a synthetic scaffold to conformationally constrain the SD1 peptide and coupled it to keyhole limpet hemocyanin (KLH). The SD1-KLH conjugate elicited antibodies in mice that cross-reacted with VAR2CSA. This strategy successfully recapitulated a discontinuous epitope with a synthetic peptide and represents the first heterologous vaccine candidate against VAR2CSA.

SUBMITTER: Mitran CJ

PROVIDER: S-EPMC7564767 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope.

Mitran Catherine J CJ Higa Lauren M LM Good Michael F MF Yanow Stephanie K SK

Vaccines 20200718 3

In pregnant women, <i>Plasmodium falciparum-</i>infected red blood cells adhere to the placenta via the parasite protein VAR2CSA. Two vaccine candidates based on VAR2CSA are currently in clinical trials; however, these candidates failed to elicit strain-transcending antibody responses. We previously showed that a cross-reactive monoclonal antibody (3D10) raised against the <i>P. vivax</i> antigen PvDBP targets epitopes in VAR2CSA. We now aim to design a peptide vaccine against VAR2CSA based on t ...[more]

PMID: 32708370

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Project description:COVID-19 caused by SARS-CoV-2 was declared a global pandemic by WHO (World Health Organization) in March, 2020. Within 6 months, nearly 750,000 deaths are claimed by COVID-19 across the globe. This called for immediate social, scientific, technological, public and community interventions. Considering the severity of infection and the associated mortalities, global efforts are underway to develop preventive measures against SARS-CoV-2. Among the SARS-CoV-2 target proteins, Spike (S) glycoprotein (a.k.a S Protein) is the most studied target known to trigger strong host immune response. A detailed analysis of S protein-based epitopes enabled us to design a novel B-cell-derived T-cell Multi-epitope-based peptide (MEBP) vaccine candidate. This involved a systematic and comprehensive computational protocol consisting of prediction of dual-purpose epitopes and designing an MEBP vaccine construct. This was followed by 3D structure validation, MEBP complex interaction studies, in silico cloning and vaccine dose-based immune response simulation to evaluate the immunogenic potency of the vaccine construct. The dual-purpose epitope prediction protocol was designed such that the same epitope elicits both humoral and cellular immune response unlike the earlier designs. Further, the epitopes predicted were screened against stringent criteria to ensure selection of a potent candidate with maximum antigen coverage and best immune response. The vaccine dose-based immune response simulation studies revealed a rapid antigen clearance through antibody generation and elevated levels of cell-mediated immunity during repeated exposure of the vaccine. The favourable results of the analysis strongly indicate that the vaccine construct is indeed a potent vaccine candidate and ready to proceed to the next steps of experimental validation and efficacy studies.Supplementary informationThe online version contains supplementary material available at 10.1007/s13205-020-02574-x.

Project description:BACKGROUND: A radiation-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccine, PfSPZ Vaccine, protected 6 of 6 subjects (100%) against homologous Pf (same strain as in the vaccine) controlled human malaria infection (CHMI) 3 weeks after 5 doses administered intravenously. The next step was to assess protective efficacy against heterologous Pf (different from Pf in the vaccine), after fewer doses, and at 24 weeks. METHODS: The trial assessed tolerability, safety, immunogenicity, and protective efficacy of direct venous inoculation (DVI) of 3 or 5 doses of PfSPZ Vaccine in non-immune subjects. RESULTS: Three weeks after final immunization, 5 doses of 2.7 × 105 PfSPZ protected 12 of 13 recipients (92.3% [95% CI: 48.0, 99.8]) against homologous CHMI and 4 of 5 (80.0% [10.4, 99.5]) against heterologous CHMI; 3 doses of 4.5 × 105 PfSPZ protected 13 of 15 (86.7% [35.9, 98.3]) against homologous CHMI. Twenty-four weeks after final immunization, the 5-dose regimen protected 7 of 10 (70.0% [17.3, 93.3]) against homologous and 1 of 10 (10.0% [-35.8, 45.6]) against heterologous CHMI; the 3-dose regimen protected 8 of 14 (57.1% [21.5, 76.6]) against homologous CHMI. All 22 controls developed Pf parasitemia. PfSPZ Vaccine was well tolerated, safe, and easy to administer. No antibody or T cell responses correlated with protection. CONCLUSIONS: We have demonstrated for the first time to our knowledge that PfSPZ Vaccine can protect against a 3-week heterologous CHMI in a limited group of malaria-naive adult subjects. A 3-dose regimen protected against both 3-week and 24-week homologous CHMI (87% and 57%, respectively) in this population. These results provide a foundation for developing an optimized immunization regimen for preventing malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT02215707. FUNDING: Support was provided through the US Army Medical Research and Development Command, Military Infectious Diseases Research Program, and the Naval Medical Research Center's Advanced Medical Development Program.

Dataset Information

Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope.

Publications

Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope.

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