There are an estimated 200 million people infected with malaria annually, with an estimated 400,000-500,000 deaths, and 40% of the world’s population at risk of contracting the disease.  While artemisinin and mosquito reduction are the current treatments, there are artemisinin-resistant parasites emerging, underscoring the need for the next generation of antimalarial drugs.  While the RTS,S (Mosquirix, GSK) recombinant protein-based vaccine (targets P. falciparum circumsporozoite protein, CSP) is a breakthrough as the first vaccine candidate in pilot studies for countering parasites, the efficacy remains low (25-50% in infants and children).

The process of merozoite invasion of erythrocytes (red blood cells) is complex and depends on multiple parasite proteins expressed on the merozoite surface, along with those released from the parasite’s organelles.  P. falciparum merozoite surface protein-1 (MSP-1) emerged during the 1980s as a viable vaccine target.  MSP-1 has been studied extensively and is arguably the most actively pursued blood-stage malaria vaccine antigen; however, significant obstacles to the development of MSP-1 and merozoite neutralizing vaccines remain.  The three key issues that have been a problem for MSP-1 based vaccines are 1) the polymorphism associated with T cell and B cell epitopes important for protection; 2) the low immunogenicity of MSP-1 subunit vaccines and 3) the recognition that other MSPs may partially compensate for an inhibition of MSP-1 function. 

Working in the Plasmodium yoelii rodent model, the Burns lab has shown that merozoite surface protein-8 (MSP-8) can be used to enhance the immunogenicity and efficacy of MSP-1 based vaccines.  MSP-8 is a second merozoite surface protein that is similar to MSP-1 in structure and function and is well-conserved among strains of P. falciparum.  The researchers designed, produced, and tested a chimeric P. yoelii MSP-1/8 vaccine antigen that joins relevant regions of MSP-1 and MSP-8 together in a single, chimeric vaccine candidate.  Immunization with a chimeric MSP-1/8 vaccine antigen significantly increased protection against challenge infection in the rodent model.  Improvement in vaccine performance was due to an increase in the immunogenicity of MSP-1 component and the concurrent targeting of both MSP-1 and MSP-8. 

In recent work, the Burns lab has demonstrated in non-human primates that the MSP-1/8 vaccine was highly effective in eliciting P. falciparum growth inhibitor antibodies upon immunization.  These data establish an effective strategy to improve the immunogenicity and protective efficacy of P. falciparum MSP-1 based vaccines, as well as the assessment of MSP-1/8 as a component of a multivalent vaccine for use in humans.