Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
Infect Immun. 2013 Oct;81(10):3843-54. doi: 10.1128/IAI.00522-13. Epub 2013 Jul 29.
The C-terminal 19-kDa domain of Plasmodium falciparum merozoite surface protein 1 (PfMSP119) is an established target of protective antibodies. However, clinical trials of PfMSP142, a leading blood-stage vaccine candidate which contains the protective epitopes of PfMSP119, revealed suboptimal immunogenicity and efficacy. Based on proof-of-concept studies in the Plasmodium yoelii murine model, we produced a chimeric vaccine antigen containing recombinant PfMSP119 (rPfMSP119) fused to the N terminus of P. falciparum merozoite surface protein 8 that lacked its low-complexity Asn/Asp-rich domain, rPfMSP8 (ΔAsn/Asp). Immunization of mice with the chimeric rPfMSP1/8 vaccine elicited strong T cell responses to conserved epitopes associated with the rPfMSP8 (ΔAsn/Asp) fusion partner. While specific for PfMSP8, this T cell response was adequate to provide help for the production of high titers of antibodies to both PfMSP119 and rPfMSP8 (ΔAsn/Asp) components. This occurred with formulations adjuvanted with either Quil A or with Montanide ISA 720 plus CpG oligodeoxynucleotide (ODN) and was observed in both inbred and outbred strains of mice. PfMSP1/8-induced antibodies were highly reactive with two major alleles of PfMSP119 (FVO and 3D7). Of particular interest, immunization with PfMSP1/8 elicited higher titers of PfMSP119-specific antibodies than a combined formulation of rPfMSP142 and rPfMSP8 (ΔAsn/Asp). As a measure of functionality, PfMSP1/8-specific rabbit IgG was shown to potently inhibit the in vitro growth of blood-stage parasites of the FVO and 3D7 strains of P. falciparum. These data support the further testing and evaluation of this chimeric PfMSP1/8 antigen as a component of a multivalent vaccine for P. falciparum malaria.
裂殖子表面蛋白 1（PfMSP119）的 C 端 19kDa 结构域是保护性抗体的既定靶标。然而，PfMSP142 的临床试验结果表明，这是一种领先的血阶段候选疫苗，包含 PfMSP119 的保护性表位，但免疫原性和疗效并不理想。基于在约氏疟原虫鼠模型中的概念验证研究，我们制备了一种嵌合疫苗抗原，该抗原包含与 PfMSP119 融合的重组 PfMSP119（rPfMSP119）和缺乏低复杂度天冬酰胺/天冬氨酸丰富结构域的 Pf 裂殖子表面蛋白 8（rPfMSP8（ΔAsn/Asp）。用嵌合 rPfMSP1/8 疫苗免疫小鼠可引发针对 rPfMSP8（ΔAsn/Asp）融合伴侣相关保守表位的强烈 T 细胞反应。虽然针对 PfMSP8，但这种 T 细胞反应足以产生针对 PfMSP119 和 rPfMSP8（ΔAsn/Asp）成分的高滴度抗体。这在使用 Quil A 或 Montanide ISA 720 加 CpG 寡脱氧核苷酸（ODN）佐剂的制剂中都可以观察到，并且在近交系和远交系小鼠中都可以观察到。PfMSP1/8 诱导的抗体与 PfMSP119 的两种主要等位基因（FVO 和 3D7）高度反应。特别有趣的是，PfMSP1/8 免疫可诱导比 rPfMSP142 和 rPfMSP8（ΔAsn/Asp）联合制剂更高滴度的 PfMSP119 特异性抗体。作为功能的衡量标准，PfMSP1/8 特异性兔 IgG 被证明可有效抑制 FVO 和 3D7 株恶性疟原虫的体外血期寄生虫生长。这些数据支持进一步测试和评估这种嵌合 PfMSP1/8 抗原作为恶性疟原虫多价疫苗的一个组成部分。
