The immunological perturbations induced by ongoing blood-stage infection during Plasmodium GAP (Genetically Attenuated Parasites) vaccination

Abstract

Abstract Plasmodium sporozoites (SPZ) are transmitted by mosquito bite, infect the liver, grow and differentiate as intrahepatocytic liver stages (LS) and ultimately form the first generation of red blood cell-infectious merozoites, which initiate the symptomatic blood stage infection. Immunization with replication-deficient radiation attenuated SPZ vaccine has shown to confer sterilizing immunity in animal models by preventing parasite growth into the liver before onset of symptomatic blood stage infection. This attenuated SPZ vaccine has undergone clinical testing and it was observed that sterilizing immunity was achieved high in malaria naïve subjects but lower in malaria pre-exposed subjects residing in malaria-endemic regions. Previous studies in rodent models indicate that the ongoing blood stage infection suppresses protection after immunization with replication deficient irradiated SPZ. We have shown that replication competent late liver stage arresting genetically attenuated parasites (RC-GAP) immunization confer superior protection when compared to irradiated SPZ. However, whether the blood stage infection would also affect the RC-GAP parasite vaccine mediated protective immunity by altering specific immune responses remains unknown. Here, we show that ongoing homologous blood stage infection during Plasmodium yoelii RC-GAP immunization suppress the vaccine mediated immunity in Balb/c mice. Our data suggest that the reduction in protection was associated with the perturbations of long-lived Ag specific antibody as well as tissue resident memory CD8 T cell (TRMs) responses generated against pre-erythrocytic SPZ and LS stages.