Los Alamos National Laboratory, Theory Division, Los Alamos, NM 87545, USA.
J Gen Virol. 2010 May;91(Pt 5):1194-206. doi: 10.1099/vir.0.017491-0. Epub 2010 Jan 6.
Immunological control of hepatitis C virus (HCV) is possible and is probably mediated by host T-cell responses, but the genetic diversity of the virus poses a major challenge to vaccine development. We considered monovalent and polyvalent candidates for an HCV vaccine, including natural, consensus and synthetic 'mosaic' sequence cocktails. Mosaic vaccine reagents were designed using a computational approach first applied to and demonstrated experimentally for human immunodeficiency virus type 1 (HIV-Delta). Mosaic proteins resemble natural proteins, but are assembled from fragments of natural sequences via a genetic algorithm and optimized to maximize the coverage of potential T-cell epitopes (all 9-mers) found in natural sequences and to minimize the inclusion of rare 9-mers to avoid vaccine-specific responses. Genotype 1-specific and global vaccine cocktails were evaluated. Among vaccine candidates considered, polyvalent mosaic sequences provided the best coverage of both known and potential epitopes and had the fewest rare epitopes. A global vaccine based on conserved proteins across genotypes may be feasible, as a five-antigen mosaic cocktail provided 90, 77 and 70% coverage of the Core, NS3 and NS4 proteins, respectively; protein coverage diminished with increased protein variability, dropping to 38% for NS2. For the genotype 1-specific vaccine, the H77 prototype vaccine sequence matched only 50% of the potential epitopes in the population, whilst a polyprotein three-antigen mosaic cocktail increased potential epitope coverage to 83%. More than 75% coverage of all HCV proteins was achieved with a three-antigen mosaic cocktail, suggesting that genotype-specific vaccines could also include the more variable proteins.
丙型肝炎病毒（HCV）的免疫控制是可能的，可能由宿主 T 细胞反应介导，但病毒的遗传多样性对疫苗的开发构成了重大挑战。我们考虑了丙型肝炎病毒疫苗的单价和多价候选物，包括天然、共识和合成的“嵌合”序列鸡尾酒。嵌合疫苗试剂是使用一种计算方法设计的，该方法首先应用于并通过实验证明了对人类免疫缺陷病毒 1 型（HIV-Delta）有效。嵌合蛋白类似于天然蛋白，但通过遗传算法从天然序列的片段组装而成，并经过优化以最大程度地覆盖天然序列中发现的潜在 T 细胞表位（所有 9 个氨基酸），并最小化罕见 9 个氨基酸的包含，以避免疫苗特异性反应。评估了针对基因型 1 的特异性和全球疫苗鸡尾酒。在所考虑的疫苗候选物中，多价嵌合序列提供了对已知和潜在表位的最佳覆盖，并且罕见表位最少。基于跨基因型保守蛋白的全球疫苗可能是可行的，因为基于保守蛋白的五抗原嵌合鸡尾酒分别提供了 90%、77%和 70%的核心、NS3 和 NS4 蛋白的覆盖率；随着蛋白质变异性的增加，蛋白质覆盖率降低，NS2 降至 38%。对于基因型 1 特异性疫苗，H77 原型疫苗序列仅与人群中 50%的潜在表位匹配，而多蛋白三抗原嵌合鸡尾酒则将潜在表位的覆盖率提高到 83%。三抗原嵌合鸡尾酒实现了所有 HCV 蛋白的覆盖率超过 75%，这表明基因型特异性疫苗也可以包含更具变异性的蛋白质。
