Identification of two new protective pre-erythrocytic malaria vaccine antigen candidates

US Military Malaria Vaccine Program, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD, USA.
Malaria Journal (Impact Factor: 3.11). 03/2011; 10(1):65. DOI: 10.1186/1475-2875-10-65
Source: PubMed


Despite years of effort, a licensed malaria vaccine is not yet available. One of the obstacles facing the development of a malaria vaccine is the extensive heterogeneity of many of the current malaria vaccine antigens. To counteract this antigenic diversity, an effective malaria vaccine may need to elicit an immune response against multiple malaria antigens, thereby limiting the negative impact of variability in any one antigen. Since most of the malaria vaccine antigens that have been evaluated in people have not elicited a protective immune response, there is a need to identify additional protective antigens. In this study, the efficacy of three pre-erythrocytic stage malaria antigens was evaluated in a Plasmodium yoelii/mouse protection model.
Mice were immunized with plasmid DNA and vaccinia virus vectors that expressed one, two or all three P. yoelii vaccine antigens. The immunized mice were challenged with 300 P. yoelii sporozoites and evaluated for subsequent infection.
Vaccines that expressed any one of the three antigens did not protect a high percentage of mice against a P. yoelii challenge. However, vaccines that expressed all three antigens protected a higher percentage of mice than a vaccine that expressed PyCSP, the most efficacious malaria vaccine antigen. Dissection of the multi-antigen vaccine indicated that protection was primarily associated with two of the three P. yoelii antigens. The protection elicited by a vaccine expressing these two antigens exceeded the sum of the protection elicited by the single antigen vaccines, suggesting a potential synergistic interaction.
This work identifies two promising malaria vaccine antigen candidates and suggests that a multi-antigen vaccine may be more efficacious than a single antigen vaccine.

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    • "Sedegah et al [43] studied protection using only Vaxfectin with a CSP DNA construct that lacked the MIP3α component and obtained maximum bloodstream protection of 54%, similar to what we observed with that construct, but clearly less than the 80–100% protection observed with the addition of the MIP3α component. In a more recent trial, Limbach et al. [91] could protect only 57% of mice challenged intravenously with 300 P. yoelii sporozoites after immunization with plasmid DNA followed by a vaccinia virus vector boost that expressed one, two or three different P. yoelii vaccine antigens. In one of the few studies to show a high level of protection, Scheiblhofer et al. demonstrated that DNA immunization with a CSP construct from which the glycosylphosphatidylinositol signal sequence was deleted elicited 100% protection of Balb/c mice from intradermal challenge with P. berghei [92]. "
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    ABSTRACT: Although sterilizing immunity to malaria can be elicited by irradiated sporozoite vaccination, no clinically practical subunit vaccine has been shown to be capable of preventing the approximately 600,000 annual deaths attributed to this infection. DNA vaccines offer several potential advantages for a disease that primarily affects the developing world, but new approaches are needed to improve the immunogenicity of these vaccines. By using a novel, lipid-based adjuvant, Vaxfectin, to attract immune cells to the immunization site, in combination with an antigen-chemokine DNA construct designed to target antigen to immature dendritic cells, we elicited a humoral immune response that provided sterilizing immunity to malaria challenge in a mouse model system. The chemokine, MIP3αCCL20, did not significantly enhance the cellular infiltrate or levels of cytokine or chemokine expression at the immunization site but acted with Vaxfectin to reduce liver stage malaria infection by orders of magnitude compared to vaccine constructs lacking the chemokine component. The levels of protection achieved were equivalent to those observed with irradiated sporozoites, a candidate vaccine undergoing development for further large scale clinical trial. Only vaccination with the combined regimen of adjuvant and chemokine provided 80-100% protection against the development of bloodstream infection. Treating the immunization process as requiring the independent steps of 1) attracting antigen-presenting cells to the site of immunization and 2) specifically directing vaccine antigen to the immature dendritic cells that initiate the adaptive immune response may provide a rational strategy for the development of a clinically applicable malaria DNA vaccine.
    PLoS ONE 03/2014; 9(3):e90413. DOI:10.1371/journal.pone.0090413 · 3.23 Impact Factor
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    • "However, the level and duration of immunity induced by RTS,S is relatively modest. The efficacy of RTS,S, or any other subunit malaria vaccine can be potentially enhanced by incorporating additional malaria antigens into the vaccine, thereby broadening the immune response elicited by the vaccine [6]. Hence, in the present scenario, a multi-stage and multi-component vaccine is required to provide sufficient protection against disease [7] [8] [9]. "
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    ABSTRACT: Incorporation of parasite's subcellular fractions in subunit vaccines can be a possible approach for formulation of vaccine against malaria. In this study, the immunogenicity and protective efficacy of 10,000g fraction of blood stage Plasmodium berghei was evaluated in mouse model. This fraction induced higher levels of anti parasite antibodies and provided complete and long lasting protection as compared to whole parasite antigens. Antiserum raised against it was immunoadsorbed on CNBr activated sepharose-4B to elute antigens from this fraction. Eluted antigens were characterized electrophoretically, and after lyophilization these were designated as ML-I (having 55, 64, 66, 74kDa proteins), ML-II (having 51, 64, 66, 72kDa proteins) and ML-III (having only 47kDa protein) sub-fractions. Mice were immunized with these sub-fractions and immune responses induced by various immunization regimens were evaluated and compared with that of 10,000g fraction. These sub-fractions imparted partial protection except ML-III, which was non-protective. 10,000g fraction as a whole provided complete protection and generated significantly higher level of IL-2 and IFN-γ in immune mice. ML-I produced significant amount of IL-1 and IL-4 as compared to ML-II. Enhanced level of malaria-specific IgG1 was produced by ML-II, but IgG2a was significantly higher in ML-I immunized mice. Conclusively, this study identifies 10,000g fraction as a promising blood stage vaccine candidate and suggests that a vaccine based upon multiple antigens may be more efficacious as compared to single antigen based formulations.
    Parasitology International 10/2012; 62(3). DOI:10.1016/j.parint.2012.10.002 · 1.86 Impact Factor
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    • "The number and categories of tick antigens with potential for protecting against tick infestation is rising, with a good number of these molecules demonstrating strong cross-reactivity . However, whether combining multiple antigens into a cocktail vaccine can lead to cumulative vaccine efficacy remains to be properly determined (Limbach et al., 2011), since immunodominant and immunosuppressive effects have been observed with DNA (Nascimento et al., 2002; Sedegah et al., 2004) and protein (Ruth et al., 2008) vaccines. "
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    ABSTRACT: As blood-sucking parasites, ticks inflict great damage to animals and humans in many parts of the world. The continued use of chemical acaricides is not sustainable due to increasing tick resistance, growing public concern over drug residues in food and in the environment, and the high cost of developing new acaricides. Therefore, an alternative control strategy is urgently needed. Vaccines against ticks have been shown to be functionally feasible, as highlighted by the success of Bm86 vaccines against Rhipicephalus (Boophilus) microplus and closely related tick species. However, a limited number of tick antigens with cross-protective epitopes have been characterized so far, limiting widespread deployment of the available vaccines, including those derived from Bm86. Therefore, identifying tick antigens with potential broad-spectrum protection against multiple tick species is subject of vigorous research at present. In this paper, progress towards effective anti-tick vaccines is reviewed in the light of emerging data from studies including heterologous tick challenge. Taken together, these studies indicate that the decades-long search for a universal tick vaccine is making progress, with such a vaccine likely to be based on multiple cross-reactive antigens.
    The Veterinary Journal 07/2012; 194(2). DOI:10.1016/j.tvjl.2012.05.023 · 1.76 Impact Factor
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