Genotype 1 and global hepatitis C T-cell vaccines designed to optimize coverage of genetic diversity
| Autor: | Bette T. Korber, Paul W. Fenimore, Georg M. Lauer, Will Fischer, James Thurmond, Carla Kuiken, Karina Yusim, Hyejin Yoon |
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| Rok vydání: | 2010 |
| Předmět: |
Viral Hepatitis Vaccines
Genotype T-Lymphocytes Hepatitis C virus Population Epitopes T-Lymphocyte Hepacivirus Viral Nonstructural Proteins Biology medicine.disease_cause Epitope Virus Virology Genetic variation medicine Humans education Genetics Vaccines Synthetic education.field_of_study NS3 Genetic diversity Genetic Variation Hepatitis C Recombinant Proteins |
| Zdroj: | Journal of General Virology. 91:1194-1206 |
| ISSN: | 1465-2099 0022-1317 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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