New Candidate Vaccines against Blood-Stage Plasmodium falciparum Malaria: Prime-Boost Immunization Regimens Incorporating Human and Simian Adenoviral Vectors and Poxviral Vectors Expressing an Optimized Antigen Based on Merozoite Surface Protein 1
New Candidate Vaccines against Blood-Stage Plasmodium falciparum Malaria: Prime-Boost Immunization Regimens Incorporating Human and Simian Adenoviral Vectors and Poxviral Vectors Expressing an Optimized Antigen Based on Merozoite Surface Protein 1
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DOI：
10.1128/iai.00315-10
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发表时间：
2010-11-01
影响因子：
3.1
通讯作者：
Draper, S. J.
中科院分区：
文献类型：
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作者：
Goodman, Anna L.;Epp, C.;Draper, S. J.
尽管裂殖子表面蛋白 1 (MSP-1) 是血期疟疾的主要候选疫苗抗原，但其在临床试验中的功效部分受到抗原多态性以及可能由于佐剂蛋白疫苗无法诱导强大的细胞免疫的限制。在这里，我们报告了能够克服这些局限性的新型载体恶性疟原虫疫苗的设计。我们优化了包含四个 MSP-1 保守块的抗原插入片段，该片段与串联排列的序列融合，代表二态性 42-kDa C 端区域的两种等位基因形式。插入片段由腺病毒和痘病毒载体表达，并用于异源初免-加强方案。使用猿猴腺病毒载体是为了规避预先存在的对人类腺病毒的免疫力。在临床前研究中，这些疫苗诱导了有效的细胞免疫反应和针对 MSP-1 的高滴度抗体。发现诱导的抗体对恶性疟原虫的二态性等位基因家族具有生长抑制活性。这些载体疫苗应该能够在人体中评估诱导针对恶性疟原虫 MSP-1 的强细胞和跨菌株体液免疫的安全性和有效性。
Although merozoite surface protein 1 (MSP-1) is a leading candidate vaccine antigen for blood-stage malaria, its efficacy in clinical trials has been limited in part by antigenic polymorphism and potentially by the inability of protein-in-adjuvant vaccines to induce strong cellular immunity. Here we report the design of novel vectored Plasmodium falciparum vaccines capable of overcoming such limitations. We optimized an antigenic insert comprising the four conserved blocks of MSP-1 fused to tandemly arranged sequences that represent both allelic forms of the dimorphic 42-kDa C-terminal region. Inserts were expressed by adenoviral and poxviral vectors and employed in heterologous prime-boost regimens. Simian adenoviral vectors were used in an effort to circumvent preexisting immunity to human adenoviruses. In preclinical studies these vaccines induced potent cellular immune responses and high-titer antibodies directed against MSP-1. The antibodies induced were found to have growth-inhibitory activity against dimorphic allelic families of P. falciparum. These vectored vaccines should allow assessment in humans of the safety and efficacy of inducing strong cellular as well as cross-strain humoral immunity to P. falciparum MSP-1.