Abstract
Immunization with irradiated Plasmodium sporozoites induces sterile immunity in rodents, monkeys and humans. The major surface component of the sporozoite the circumsporozoite protein (CS) long considered as the antigen predominantly responsible for this immunity, thus remains the leading candidate antigen for vaccines targeting the parasite's pre-erythrocytic (PE) stages. However, this role for CS was questioned when we recently showed that immunization with irradiated sporozoites (IrrSpz) of a P. berghei line whose endogenous CS was replaced by that of P. falciparum still conferred sterile protection against challenge with wild type P. berghei sporozoites. In order to investigate the involvement of CS in the cross-species protection recently observed between the two rodent parasites P. berghei and P. yoelii, we adopted our gene replacement approach for the P. yoelii CS and exploited the ability to conduct reciprocal challenges. Overall, we found that immunization led to sterile immunity irrespective of the origin of the CS in the immunizing or challenge sporozoites. However, for some combinations, immune responses to CS contributed to the acquisition of protective immunity and were dependent on the immunizing IrrSpz dose. Nonetheless, when data from all the cross-species immunization/challenges were considered, the immune responses directed against non-CS parasite antigens shared by the two parasite species played a major role in the sterile protection induced by immunization with IrrSpz. This opens the perspective to develop a single vaccine formulation that could protect against multiple parasite species.
Highlights
Sporozoites inoculated by the mosquito must invade and develop within hepatocytes in order to generate merozoites that can initiate the pathogenic erythrocytic phase
Whereas splenic T cells from mice immunized with P. berghei irradiated sporozoites only recognized peptides derived from the P. berghei circumsporozoite protein (CS), those from mice immunized with P. berghei [PyCS] or P. yoelii IrrSpz recognized the C-terminus peptides derived from P. berghei, in addition to the peptides derived from P. yoelii CS
This crossspecies recognition was more substantial for mice immunized with P. yoelii IrrSpz, which surprisingly recognized the long peptide derived from the heterologous N-terminus of the P. berghei
Summary
Sporozoites inoculated by the mosquito must invade and develop within hepatocytes in order to generate merozoites that can initiate the pathogenic erythrocytic phase. Adoptive transfer of CS-specific CD8+ or CD4+ T cell clones, albeit in large numbers, could lead to full protection against sporozoite challenge [5,6,7] Together these observations have led the CS to be considered as the parasite antigen responsible for the sterile protection induced by IrrSpz. Together these observations have led the CS to be considered as the parasite antigen responsible for the sterile protection induced by IrrSpz This view was recently reinforced by a report that concluded that CS is a protective immunodominant antigen from experiments where mice made tolerant to CS of P. yoelii were less likely to develop protective immune responses when immunized with P. yoelii IrrSpz [8]. Further indications that sterile protection can be obtained independently of immune responses to the CS were obtained when immunization with P. berghei IrrSpz whose endogenous CS was replaced by that of P. falciparum fully protected mice from challenge with wild type P. berghei sporozoites [10]
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