Evaluation of immune responses to a Plasmodium vivax CSP-based recombinant protein vaccine candidate in combination with second-generation adjuvants in mice

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• 作者：Joanne M. Lumsden^a ; Saule Nurmukhambetova^a ; Jennifer H. Klein^a ; Jetsumon Sattabongkot^b ; ¹ ; Jason W. Bennett^a ; Sylvie Bertholet^c ; Christopher B. Fox^c ; Steven G. Reed^c ; Christian F. Ockenhouse^a ; Randall F. Howard^c ; Mark E. Polhemus^a ; Anjali Yadava^a ; ^{anjali.yadava@us.army.mil}
• 关键词：CSP ; circumsporozoite protein ; DC ; dendritic cells ; GLA ; glucopyranosyl lipid adjuvant ; MPL ; monophosphoryl lipid A ; Pv ; P. vivax ; SE ; stable emulsion ; TLR ; toll-like receptor
• 刊名：Vaccine
• 出版年：2012
• 期刊代码：89_0264410x
• 类别：imm
• 出版时间：9 May, 2012
• 卷：30
• 期：22
• 页码：3311-3319
• 文件大小：1475 K

摘要

Plasmodium vivax is the major cause of malaria outside of sub-Saharan Africa and causes morbidity and results in significant economic impact in developing countries. In order to produce a P. vivax vaccine for global use, we have previously reported the development of VMP001, based on the circumsporozoite protein (CSP) of P. vivax. Our interest is to evaluate second-generation vaccine formulations to identify novel combinations of adjuvants capable of inducing strong, long-lasting immune responses. In this study, groups of C57BL/6J mice were immunized subcutaneously three times with VMP001 emulsified with synthetic TLR4 (GLA) or TLR7/8 (R848) agonist in stable emulsion (SE), a combination of the TLR4 and TLR7/8 agonists, or SE alone. Sera and splenocytes were tested for the presence of antigen-specific humoral and cellular responses, respectively. All groups of mice generated high titers of anti-P. vivax IgG antibodies as detected by ELISA and immunofluorescence assay. GLA-SE promoted a shift in the antibody response to a Th1 profile, as demonstrated by the change in IgG2c/IgG1 ratio. In addition, GLA-SE induced a strong cellular immune response characterized by multi-functional, antigen-specific CD4⁺ T cells secreting IL-2, TNF and IFN-纬. In contrast, mice immunized with SE or R848-SE produced low numbers of antigen-specific CD4⁺ T cells, and these T cells secreted IL-2 and TNF, but not IFN-纬. Finally, R848-SE did not enhance the immune response compared to GLA-SE alone. Based on these results, we conclude that the combination of VMP001 and GLA-SE is highly immunogenic in mice and may serve as a potential second-generation vaccine candidate against vivax malaria.