C3d binding to the circumsporozoite protein carboxy-terminus deviates immunity against malaria

Abstract

The immunogenicity of recombinant protein or anti-viral DNA vaccines can be significantly improved by the addition of tandem copies of the complement fragment C3d. We sought to determine if the efficacy of a circumsporozoite protein (CSP)-based DNA vaccine delivered to mouse skin by gene gun was improved by using this strategy. Instead, we found that C3d suppressed the protective immunity against Plasmodium berghei malaria infection and deviated immunity, most notably by suppressing the induction of antibodies specific for the CSP C-terminal flanking sequence and by suppressing the induction of CSP-specific IL-4-producing spleen cells. We further showed that C3d bound to the C-terminal flanking sequence of the CSP, which may explain the immune deviation observed in CS/C3d chimeric antigen. We have thus identified C3d-mediated epitope masking and shifting of both the humoral and cellular immune responses as a potential novel escape mechanism, which plasmodia may use to divert the induction of protective immunity.

Transgenic Parasites Stably Expressing Full-Length Plasmodium falciparum Circumsporozoite Protein as a Model for Vaccine Down-Selection in Mice Using Sterile Protection as an Endpoint

“…Thus, these observations in mice might have implications for improving CSP vaccine design (18). Although the C-terminal region of P. berghei CSP has been associated with protection in mice (19,20), our C-terminal construct of PfCSP did not confer protection against a Tr P. berghei challenge. This result was reminiscent of a human trial in which a repeatless CSP construct did not protect the vaccinees (21).…”

Genetic fusion of three tandem copies of murine C3d sequences to diphtheria toxin fragment B elicits a decreased fragment B-specific antibody response

“…After submission of our manuscript for review, a report was published documenting a very similar pattern of attenuated antibody responses to plasmodial circumsporizoite protein (CSP) by fusion to three copies of C3d [23]. This report is of particular interest in that it provides evidence that physical interactions between C3d and the target antigen can decrease the immunogenicity of the C3d-antigen complexes.…”

Protective Efficacy of Baculovirus Dual Expression System Vaccine Expressing Plasmodium falciparum Circumsporozoite Protein

“…Past studies on sporozoite vaccines have revealed a poor correlation between the protective efficacy of a vaccine and antibody titers. For examples, the complement fragment C3d-based PbCSP vaccine was capable of inducing strong antibody responses against CSP, but its protective efficacy, compared with the parent PbCSP vaccine, was reduced [33]. Studies in our laboratory are in progress towards development of an evaluation system which can detect the specific antibodies that contributed to the protective efficacy of a vaccine.…”