Protective immunity to pre-erythrocytic stage malaria

Schwenk, Robert; Richie, Thomas L.

doi:10.1016/j.pt.2011.02.002

Cited by 37 publications

(25 citation statements)

References 77 publications

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“…Regarding the role of cellular immunity in mediating protection, previous studies have shown that CD4 ϩ T cells specific for P. yoelii CSP eliminate infected hepatocytes in vitro and, when adoptively transferred, mediate protection in vivo (61,62). The protective role of CD4 ϩ effector cells against malaria was further substantiated in other murine and human malaria models (22,63,64).…”

Section: Discussionmentioning

confidence: 92%

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice

et al. 2013

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؉ T cell responses. Finally, protective immunity was also induced using the Toll-like receptor 4 agonist glucopyranosyl lipid adjuvantstable emulsion (GLA-SE) as the adjuvant, which also correlated with high antibody titers yet CD4 ؉ T cell immunity that was significantly less potent than that with poly(I·C)LC. Overall, these data suggest that full-length CS proteins and poly(I·C)LC or GLA-SE offer a simple vaccine formulation to be used alone or in combination with other vaccines for preventing malaria infection. Malaria infection with Plasmodium falciparum causes more than 600,000 deaths annually as well as significant morbidity worldwide (1). A range of efforts to control and treat malaria include public health measures such as insecticide-treated bed nets, indoor residual spraying, and widespread usage of antimalarial drugs. Despite the impact of these approaches, the most cost-effective solution to prevent infection and to ultimately control the malaria endemic is to develop a vaccine.Currently, the most advanced vaccine tested in humans against P. falciparum infection is RTS,S, which targets the circumsporozoite (CS) protein (CSP), the major and most abundant antigen expressed on the surfaces of infectious sporozoites. RTS,S given with the AS01 adjuvant (RTS,S/AS01) shows ϳ30% protection against clinical disease and severe malaria (2, 3). Thus, while these first results in phase III trials with RTS,S/AS01 are encouraging, there may be additional approaches for further optimizing the breadth, potency, and duration of immunity against the CSP using different immunogens or more-potent adjuvants. In terms of antigen design, RTS,S is comprised of a truncated form of CSP containing the central repeat region, NANP, which is a target for antibody-mediated neutralization, as well as CD8 ϩ and CD4 ϩ T cell epitopes at the C-terminal end. This truncated CS protein is then fused to the hepatitis B virus surface antigen, creating an immunogenic particle. Therefore, using a more-full-length CSP, including the N-terminal end and the R1 region of CSP as well as the minor repeat region (NVDP), might favor broader antibody responses than against the NANP repeat region alone (4-8). Moreover, a full-length CSP may provide additional T cell epitopes, leading to increased breadth of cellular immunity, which could also enhance protection. Another approach is to enhance the humoral and cellular immune responses by altering the type of adjuvant given with the full-length-CSP-based protein vaccine.Early studies in mice showed that protection was associated with high antibody titers (9-11). The next generation of malaria vaccines combined CSP with more-potent adjuvants, like Pseu-

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Section: Discussionmentioning

confidence: 92%

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice

et al. 2013

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“…In addition to antibodies, CD4 ϩ and CD8 ϩ T cells have been described as powerful mediators of preerythrocytic stage elimination in rodent experimental models (reviewed in references [32][33][34][35][36][37][38]. In fact, a number of T cell epitopes have been described by us and others in CSP (reviewed in references [32][33][34][35][36][37][38].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, a number of T cell epitopes have been described by us and others in CSP (reviewed in references [32][33][34][35][36][37][38]. The results obtained with the mouse model have fueled a number of human trials with plasmid DNA, recombinant viruses, and, more recently, radiation-attenuated sporozoites as vaccine formulations.…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity of a Prime-Boost Vaccine Containing the Circumsporozoite Proteins of Plasmodium vivax in Rodents

et al. 2014

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g Plasmodium vivax is the most widespread and the second most prevalent malaria-causing species in the world. Current measures used to control the transmission of this disease would benefit from the development of an efficacious vaccine. In the case of the deadly parasite P. falciparum, the recombinant RTS,S vaccine containing the circumsporozoite antigen (CSP) consistently protects 30 to 50% of human volunteers against infection and is undergoing phase III clinical trials in Africa with similar efficacy. These findings encouraged us to develop a P. vivax vaccine containing the three circulating allelic forms of P. vivax CSP. Toward this goal, we generated three recombinant bacterial proteins representing the CSP alleles, as well as a hybrid polypeptide called PvCSP-All-CSP-epitopes. This hybrid contains the conserved N and C termini of P. vivax CSP and the three variant repeat domains in tandem. We also generated simian and human recombinant replication-defective adenovirus vectors expressing PvCSP-All-CSP-epitopes. Mice immunized with the mixture of recombinant proteins in a formulation containing the adjuvant poly(I·C) developed high and long-lasting serum IgG titers comparable to those elicited by proteins emulsified in complete Freund's adjuvant. Antibody titers were similar in mice immunized with homologous (protein-protein) and heterologous (adenovirus-protein) vaccine regimens. The antibodies recognized the three allelic forms of CSP, reacted to the repeated and nonrepeated regions of CSP, and recognized sporozoites expressing the alleles VK210 and VK247. The vaccine formulations described in this work should be useful for the further development of an anti-P. vivax vaccine.

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“…There is substantial evidence that antibodies and T-cell-mediated immune responses to CSP can protect against the pre-erythrocytic stage of malaria (14). Owing to the escalating costs and regulatory constraints associated with human vaccine trials and due to the limitations of primate models of P. falciparum sporozoite challenge (7-9), there is an urgent need to develop rodent models for the routine down-selection of second-generation vaccine formulations of PfCSP vaccines.…”

Section: Discussionmentioning

confidence: 99%

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

Porter

Nicki

Pool

et al. 2013

Clin Vaccine Immunol

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dCircumsporozoite protein (CSP) of Plasmodium falciparum is a protective human malaria vaccine candidate. There is an urgent need for models that can rapidly down-select novel CSP-based vaccine candidates. In the present study, the mouse-mosquito transmission cycle of a transgenic Plasmodium berghei malaria parasite stably expressing a functional full-length P. falciparum CSP was optimized to consistently produce infective sporozoites for protection studies. A minimal sporozoite challenge dose was established, and protection was defined as the absence of blood-stage parasites 14 days after intravenous challenge. The specificity of protection was confirmed by vaccinating mice with multiple CSP constructs of differing lengths and compositions. Constructs that induced high NANP repeat-specific antibody titers in enzyme-linked immunosorbent assays were protective, and the degree of protection was dependent on the antigen dose. There was a positive correlation between antibody avidity and protection. The antibodies in the protected mice recognized the native CSP on the parasites and showed sporozoite invasion inhibitory activity. Passive transfer of anti-CSP antibodies into naive mice also induced protection. Thus, we have demonstrated the utility of a mouse efficacy model to down-select human CSP-based vaccine formulations.

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Protective immunity to pre-erythrocytic stage malaria

Cited by 37 publications

References 77 publications

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice

Immunogenicity of a Prime-Boost Vaccine Containing the Circumsporozoite Proteins of Plasmodium vivax in Rodents

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

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Protective immunity to pre-erythrocytic stage malaria

Cited by 37 publications

References 77 publications

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4+T Cell Immunity and Protection in Mice

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4+T Cell Immunity and Protection in Mice

Immunogenicity of a Prime-Boost Vaccine Containing the Circumsporozoite Proteins of Plasmodium vivax in Rodents

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

Contact Info

Product

Resources

About

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice