Sterile Protection against Malaria Is Independent of Immune Responses to the Circumsporozoite Protein

Abstract

BackgroundResearch aimed at developing vaccines against infectious diseases generally seeks to induce robust immune responses to immunodominant antigens. This approach has led to a number of efficient bacterial and viral vaccines, but it has yet to do so for parasitic pathogens. For malaria, a disease of global importance due to infection by Plasmodium protozoa, immunization with radiation-attenuated sporozoites uniquely leads to long lasting sterile immunity against infection. The circumsporozoite protein (CSP), an important component of the sporozoite's surface, remains the leading candidate antigen for vaccines targeting the parasite's pre-erythrocytic stages. Difficulties in developing CSP-based vaccines that reproduce the levels of protection afforded by radiation-attenuated sporozoites have led us to question the role of CSP in the acquisition of sterile immunity. We have used a parasite transgenic for the CSP because it allowed us to test whether a major immunodominant Plasmodium antigen is indeed needed for the induction of sterile protective immunity against infection.Methodology/Main FindingsWe employed a P. berghei parasite line that expresses a heterologous CSP from P. falciparum in order to assess the role of the CSP in the protection conferred by vaccination with radiation-attenuated P. berghei parasites. Our data demonstrated that sterile immunity could be obtained despite the absence of immune responses specific to the CSP expressed by the parasite used for challenge.ConclusionsWe conclude that other pre-erythrocytic parasite antigens, possibly hitherto uncharacterised, can be targeted to induce sterile immunity against malaria. From a broader perspective, our results raise the question as to whether immunodominant parasite antigens should be the favoured targets for vaccine development.

Minimal Role for the Circumsporozoite Protein in the Induction of Sterile Immunity by Vaccination with Live Rodent Malaria Sporozoites

“…Ultimately, the main conclusion from this work and our previous observations using another immunization scheme that also induces sterile immunity against sporozoite infection (10,15) is that one or more antigens other than CSP are actually responsible for the induction of sterile immunity against preerythrocytic malaria parasites. Although other preerythrocytic antigens have been studied (TRAP, STARP, SALSA, LSA1, and LSA3 for P. falciparum) (11), the identities and natures of most antigens expressed by the sporozoites and, possibly more pertinently, by the hepatic parasite have remained inaccessible to detailed investigations until recently (9,24,28,32).…”

“…The immunodominance of CSP notwithstanding, we have previously demonstrated, using a parasite of one species made transgenic for CSP of another species, that immune responses specifically induced against the CS by RAS immunization in mice did not contribute to the consequent sterile protection (10,15). Here, we have demonstrated that the full protection induced by Spz plus CQ in inbred BALB/c mice is obtained with a minimal role for responses against CSP.…”

“…The resulting humoral responses were assessed by IFAT on whole sporozoites and by ELISA using CSP speciesspecific long peptides, one spanning the N terminus (Nt) and the other the C terminus (Ct), and short peptides representing the repeat region. T-cell responses were assessed in an IFN-␥ ELISPOT assay using splenocytes restimulated by CSP long peptides containing all potential CD4 ϩ and CD8 ϩ epitopes (10).…”

A T-cell response to a liver-stagePlasmodiumantigen is not boosted by repeated sporozoite immunizations

“…However, as described earlier, CSP-specific immunity is not absolutely necessary or sufficient to attain immunological protection against challenge (11,(21)(22)(23)(24). Thus, there is a need to identify individual immunogenic antigens so that they can be evaluated for inclusion in multicomponent subunit vaccines.…”

“…Thus, CSP is an important but currently insufficient target for use as a single-antigen vaccine. Because responses to non-CSP antigens can protect in the absence of CSP-specific immunity in mice (11,(22)(23)(24)(25), we and others are working to discover novel protective antigens to broaden the immune repertoire.…”