Research Article: A Role for Immune Responses against Non-CS Components in the Cross-Species Protection Induced by Immunization with Irradiated Malaria Sporozoites

Date Published: November 5, 2009

Publisher: Public Library of Science

Author(s): Marjorie Mauduit, Anne Charlotte Grüner, Rita Tewari, Nadya Depinay, Michèle Kayibanda, Jean-Marc Chavatte, Jean-François Franetich, Andrea Crisanti, Dominique Mazier, Georges Snounou, Laurent Rénia, Mauricio Martins Rodrigues.

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.

Partial Text: Sporozoites inoculated by the mosquito must invade and develop within hepatocytes in order to generate merozoites that can then initiate the pathogenic erythrocytic phase. Thus, this obligatory transient phase of the life cycle is an attractive target for interventions to inhibit parasite development fully, as this would prevent both disease and transmission. Sterile immunity against pre-erythrocytic (PE) stages is an all-or-none phenomenon, because merozoites produced by a single infected hepatocyte would lead to a patent blood infection. Immunization with large numbers of radiation-attenuated sporozoites has long been the only protocol that led to the induction of sterile immunity in rodents and humans [1], [2]. Subsequent investigations using the rodent malaria parasites, P. berghei and P. yoelii, revealed a role for both humoral and cellular immune responses targeting the sporozoite and the infected hepatocyte, respectively [3]. In the vaccinated hosts the antibody responses induced are predominantly directed against the antigenic repetitive central domain of circumsporozoite protein (CS) [4]. Additionally adoptive transfer of CS-specific CD8+ or CD4+ T cell clones, albeit in large numbers, could lead to full protection against sporozoite challenge [5]–[7]. 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]. However, this conclusion is mitigated by the demonstration in the same study that sterile protection did actually develop when three rather than two injections of IrrSpz were used to immunize the CS-tolerant transgenic mice [8], [9]. 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].

More than forty years have passed since the demonstration that immunization with irradiated sporozoites induces sterile protection against a sporozoite challenge [2]. The majority of investigations aimed at elucidating these protective mechanisms, and at developing vaccines that reproduce them, has been based on the CS, a protein that was quickly discovered to make up the bulk of the proteins at the sporozoite surface [14] and to be the main target of antibody responses [4]. Two independent studies using distinct approaches have recently put the central role of CS in the acquisition of sterile immunity into question. The first based on mice made tolerant to the CS of P. yoelii provided indirect evidence for the role of other parasite antigens [8]. The second based on gene replacement in P. berghei provided conclusive evidence that sterile immunity can be induced independently of specific immune responses to CS [10]. Demonstration that immunization with the IrrSpz of one species can induce sterile protection against a sporozoite challenge by another was subsequently made [11], [12]. The possibility that non-CS antigens were implicated in cross-protection was raised, but a role for CS was favoured because of the relative sequence similarities between the CS of the two rodent malaria species used, P. berghei and P. yoelii. Furthermore, previous observations had shown that adoptive transfer of a T cell clone derived from P. yoelii IrrSpz-immunized mice and specific to the P. yoelii CS immunodominant CD8 epitope protected against a P. berghei sporozoite challenge [12]. In the studies presented here, we exploited gene replacement technology to investigate the role of the P. yoelii and P. berghei CS in the acquisition of sterile protection induced by IrrSpz immunization, and to ascertain to what extent immune responses to CS are implicated in the cross-species protection.



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