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. 2007 Dec 26;2(12):e1371.
doi: 10.1371/journal.pone.0001371.

Sterile protection against malaria is independent of immune responses to the circumsporozoite protein

Anne Charlotte Grüner  1 , Marjorie Mauduit, Rita Tewari, Jackeline F Romero, Nadya Depinay, Michèle Kayibanda, Eliette Lallemand, Jean-Marc Chavatte, Andrea Crisanti, Photini Sinnis, Dominique Mazier, Giampietro Corradin, Georges Snounou, Laurent Rénia
Affiliations

Sterile protection against malaria is independent of immune responses to the circumsporozoite protein

Anne Charlotte Grüner et al. PLoS One. .

Abstract

Background: Research 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 findings: We 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.

Conclusions: We 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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Comparison of the amino acid sequences of the P. berghei ANKA clone cy17 (34) and P. falciparum Welcome strain (35) CSP polypeptides.
Black dots represent identical amino acid residues while bars represent amino acid residues with similar characteristics. The repeat regions (including the pre- and post-repeat sequences) are underlined.
Figure 2
Figure 2. CSP-specific T cells induced by immunization with irradiated P. berghei sporozoites do not cross-react with the P. falciparum CSP expressed by the P. berghei [PfCS].
IFN-γ ELISPOT was used to determine the frequency of epitope-specific T cells in the spleens of immunised animals, using long peptides corresponding to the N-terminus (PbNt or PfNt) or the C-terminus (PbCt or PfCt) of P. berghei and P. falciparum, respectively. Results are expressed as the mean ± SEM of T cells from groups of 5 mice.
Figure 3
Figure 3. Antibody reactivity induced by immunization with irradiated sporozoites.
Pooled serum samples from groups of mice immunized with sporozoites from the different parasite lines were analyzed by ELISA to assay IgG and IgM responses induced against P. berghei CSP (A), or P. falciparum CSP (B), using long peptides covering the N-terminus or the C-terminus of the antigen, and short peptides that include some of the repeat units of the central repetitive region. Serums were also tested by IFAT against wet sporozoites to detect anti-CSP IgG and IgM antibodies(C). Titres are expressed as the log of the highest dilution of serum giving a positive staining.
Figure 4
Figure 4. Sterile protection in mice immunized with P. berghei irradiated sporozoites and challenged with P. berghei or P. berghei [PfCS] sporozoites.
Mice were immunized with 1 or 3 injections of P. berghei (indicated on the left of the panel) before challenge with 5 000 P. berghei or P. berghei [PfCS] sporozoites. All naive control mice developed a patent blood-stage infection. The data are representative of those obtained in duplicate experiments.
Figure 5
Figure 5. Sterile protection in [BALB/c×C57BL/6] F1 mice immunized three times with P. berghei or P. berghei [PfCS] and challenged with 5000 P. berghei or P. berghei [PfCS] sporozoites.
All animal groups (5 mice per group) were monitored for blood-stage infections by examination of Giemsa-stained blood smears obtained daily from day 2 to day 11 post-challenge. All naive control mice developed a patent blood-stage infection.
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References

    1. Nussenzweig RS, Vanderberg JP, Most H, Orton CG. Protective immunity produced by injection of X-irradiated sporozoites of Plasmodium berghei. . Nature. 1967;216:160–162. - PubMed
    1. Hoffman SL, Goh LM, Luke TC, Schneider I, Le TP, et al. Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites. J Infect Dis. 2002;185:1155–1164. - PubMed
    1. Druilhe P, Rénia L, Fidock DA. In: Malaria: Parasite Biology, Pathogenesis, and Protection, Sherman IW, editor. Vol. 34. Washington, D.C.: ASM Press; 1998. pp. 513–543.
    1. Romero P, Tam JP, Schlesinger DH, Clavijo P, Gibson H, et al. Multiple T helper cell epitopes of the circumsporozoite protein of Plasmodium berghei. . Eur J Immunol. 1988;18:1951–1957. - PubMed
    1. Romero P, Maryanski JL, Corradin G, Nussenzweig RS, Nussenzweig V, Zavala F. Cloned cytotoxic T cells recognize an epitope on the circumsporozoite protein and protect against malaria. Nature. 1989;341:323–325. - PubMed

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