Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Dentistry, Bamako, Mali.
Malar J. 2010 Jun 21;9:175. doi: 10.1186/1475-2875-9-175.
Extensive genetic diversity in vaccine antigens may contribute to the lack of efficacy of blood stage malaria vaccines. Apical membrane antigen-1 (AMA1) is a leading blood stage malaria vaccine candidate with extreme diversity, potentially limiting its efficacy against infection and disease caused by Plasmodium falciparum parasites with diverse forms of AMA1.
Three hundred Malian children participated in a Phase 2 clinical trial of a bivalent malaria vaccine that found no protective efficacy. The vaccine consists of recombinant AMA1 based on the 3D7 and FVO strains of P. falciparum adjuvanted with aluminum hydroxide (AMA1-C1). The gene encoding AMA1 was sequenced from P. falciparum infections experienced before and after immunization with the study vaccine or a control vaccine. Sequences of ama1 from infections in the malaria vaccine and control groups were compared with regard to similarity to the vaccine antigens using several measures of genetic diversity. Time to infection with parasites carrying AMA1 haplotypes similar to the vaccine strains with respect to immunologically important polymorphisms and the risk of infection with vaccine strain haplotypes were compared.
Based on 62 polymorphic AMA1 residues, 186 unique ama1 haplotypes were identified among 315 ama1 sequences that were included in the analysis. Eight infections had ama1 sequences identical to 3D7 while none were identical to FVO. Several measures of genetic diversity showed that ama1 sequences in the malaria vaccine and control groups were comparable both at baseline and during follow up period. Pre- and post-immunization ama1 sequences in both groups all had a similar degree of genetic distance from FVO and 3D7 ama1. No differences were found in the time of first clinical episode or risk of infection with an AMA1 haplotype similar to 3D7 or FVO with respect to a limited set of immunologically important polymorphisms found in the cluster 1 loop of domain I of AMA1.
This Phase 2 trial of a bivalent AMA1 malaria vaccine found no evidence of vaccine selection or strain-specific efficacy, suggesting that the extreme genetic diversity of AMA1 did not account for failure of the vaccine to provide protection.
疫苗抗原的广泛遗传多样性可能导致血期疟疾疫苗的功效缺乏。顶膜抗原 1（AMA1）是一种主要的血期疟疾疫苗候选物，具有极高的多样性，可能限制了其对由具有不同 AMA1 形式的恶性疟原虫寄生虫引起的感染和疾病的功效。
300 名马里儿童参加了一种双价疟疾疫苗的 2 期临床试验，该试验未发现保护效力。该疫苗由基于恶性疟原虫 3D7 和 FVO 株的重组 AMA1 组成，用氢氧化铝佐剂（AMA1-C1）。在接种研究疫苗或对照疫苗前后，从感染中测序编码 AMA1 的基因。使用几种遗传多样性衡量标准，比较疟疾疫苗和对照组中 ama1 的序列与疫苗抗原的相似性。比较了免疫重要多态性方面与疫苗株相似的携带 AMA1 单倍型的寄生虫感染时间，以及感染疫苗株单倍型的风险。
基于 62 个多态 AMA1 残基，在纳入分析的 315 个 ama1 序列中鉴定出 186 个独特的 ama1 单倍型。8 个感染的 ama1 序列与 3D7 相同，而没有一个与 FVO 相同。几种遗传多样性衡量标准表明，疟疾疫苗和对照组的 ama1 序列在基线和随访期间都具有可比性。两组的免疫前后 ama1 序列与 FVO 和 3D7 ama1 的遗传距离相似。在与 AMA1 结构域 I 簇 1 环中的有限数量免疫重要多态性相关的时间或感染与 3D7 或 FVO 相似的 AMA1 单倍型的风险方面，未发现差异。
这项双价 AMA1 疟疾疫苗的 2 期试验没有发现疫苗选择或菌株特异性疗效的证据，这表明 AMA1 的极端遗传多样性并没有导致疫苗无法提供保护。
