Development of a novel chimeric blood-stage malaria vaccine

James Randiak Alaro

doi:10.17918/00000379

An efficacious malaria vaccine remains elusive despite the concerted efforts. Using murine model, Plasmodium yoelii, we previously reported that immunization with the C-terminal 19 kDa domain of merozoite surface protein 1 (MSP119) fused to the conserved and immunogenic MSP8 protected against lethal P. yoelii, well beyond that achieved by single or combined immunizations with the component antigens. Further characterization of the vaccine-induced responses revealed that rPyMSP1/8 vaccine elicited an MSP8-restricted T cell response that was sufficient to provide help for both PyMSP119 and PyMSP8 specific B cells to produce high and sustained levels of protective antibodies. Unexpectedly, rPyMSP1/8 vaccine-induced antibody responses were not boosted by exposure to lethal P. yoelii infected RBCs. However, r PyMSP1/8-immunized and infected mice mounted robust responses to a diverse set of blood-stage antigens. The data support further development of an MSP1/8 vaccine but also suggest that vaccines that prime for responses to a diverse set of parasite proteins will be required to maximize efficacy. Distinct from PyMSP8, PfMSP8 contains an additional N-terminal asparagine and aspartic acid (Asn/Asp)-rich domain whose function is unknown. To evaluate the potential of PfMSP8 as a fusion partner for PfMSP119, we produced two recombinant proteins; full-length PfMSP8 and a truncated version devoid of the Asn/Asp-rich domain, PfMSP8 (AAsn/Asp), based on the codon-harmonized sequence of P. falciparum (FVO). Both proteins induced strong and comparable T cell and antibody responses in mice and rabbits. Remarkably, all the T cell epitopes mapped within PIMSP8 ([delta]Asn/Asp). The Asn/Asp-rich domain contributed modestly to the overall antibody response and its removal did not alter the conformational integrity or immunogenicity of Pf MSP8. Analysis of PIMSP8 expression revealed that, unlike any other MSP, PfMSP8 is expressed early with a uniform distribution on the surface of rings and trophozoites. Surprisingly, PfMSP8 is exclusively localized inside, but not on the surface of merozoites. As such, antibodies against PfMSP8 failed to inhibit parasite growth in vitro. In anticipation of efficacy studies in non-human primates, we have successfully produced recombinant chimeric PfMSP 19 + PfMSP8 ([delta]Asn/Asp) and shown it to elicit high levels of antibodies against both MSP119 and MSP8 components in mice and rabbits.

Development of a novel chimeric blood-stage malaria vaccine

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Development of a novel chimeric blood-stage malaria vaccine

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