Cellular response to modified Plasmodium falciparum MSP119 antigens in individuals previously exposed to natural malaria infection
Background:
Epitopes on the 19kDa C-terminal region of the merozoite surface protein 1 (MSP119), recognized by processing-inhibitory and blocking monoclonal antibodies, had been previously modified to yield proteins that can bind MSP1 processing inhibitory antibodies, but not blocking antibodies. Immunization with these proteins, therefore, has the potential to induce beneficial protective antibodies without inducing antibodies that interfere with the function of the protective antibody. However, it was unclear whether the modification of MSP119 would affect critical T-cell response to epitopes on this antigen.
Methods:
To establish the baseline responses, the cellular responses to wild-type MSP119 and a panel of site-directed mutagenetically modified antigens was studies and compared in a group of adults naturally exposed to Plasmodium falciparum infection and a group of malaria naive individuals using in-vitro assays. The cellular responses to all of the mutants using cells from malaria-exposed infants children and adults were compared.
Results:
Interestingly, stimulation indices induced by some of the mutants were at least two-fold higher than those elicited by the wild-type MSP1-protein. A mutant protein with four-amino-acid-substitution: Glu27->Tyr, Leu31->Arg, Tyr34->Ser and Glu43->Leu (27+31+34+43); residues numbered from the N-terminus of MSP119) had the highest stimulation index (SI=360) and it induced significant response in 64% of those that had significant cellular response to the mutants.
Conclusion:
This preliminary study suggests that this specific mutant MSP119 27+31+34+43, which also abrogates the binding of all known blocking monoclonal antibodies without affecting the processing-inhibitory antibody epitope, might be a better choice for an MSP1-based malaria vaccine.