Hepatology (Baltimore, Md.) · 2025
The development of a pan-genotypic T cell vaccine against hepatitis C virus using heterologous prime-boost strategies.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Strain Rebecca, Edmans Matthew, Montalvo Zurbia-Flores Gerardo, Frumento Nicole, Brown Anthony, Hutchings Claire, Board Callum, Knight Chanice, Flyak Andrew I, Bailey Justin, Lauer Georg, Cox Andrea, Klenerman Paul, Barnes Eleanor
Аннотация
BACKGROUND AND AIMS: An effective vaccine against hepatitis C virus (HCV) infection is required to achieve viral eradication. A previous viral vectored vaccine encoding a genotype-1b T cell antigen suppressed peak viral RNA but failed to prevent chronic infection. Previous studies showed dominant vaccine-induced T cell responses were not cross-reactive with common HCV strains, possibly contributing to vaccine failure. To address this, we evaluated 2 novel HCV vaccine strategies designed to elicit T cells targeting multiple HCV genotypes.
APPROACH AND RESULTS: HCV genetic segments highly conserved between genotypes 1-6 were encoded in chimpanzee adenoviral (ChAd-Gt1-6) and Modified Vaccinia virus Ankara (MVA-Gt1-6) vectors and tested in prime-boost regimens. This was compared with vaccinating with an ancestral genotype-1a non-structural antigen encoded in ChAd (ChAd-Bole1a-NS) boosted with a genotype-3a non-structural antigen encoded in MVA (MVA-Gt3a-NS). Immunogenicity was evaluated in C57BL/6 and transgenic HLA-A*02:01 mice. Splenocytes were stimulated with genotype-1a, genotype-1b, or genotype-3a peptide pools in ex vivo IFNγ ELISpot and intracellular cytokine assays. Priming with ChAd-Gt1-6 elicited broad T cell responses toward all genotypes, whereas ChAd-Bole1a-NS generated a focused response to genotype-1a. Boosting ChAd-Bole1a-NS with MVA-Gt3a-NS generated cross-reactive T cells targeting multiple genotypes, though some responses were genotype-specific. In contrast, ChAd-Gt1-6 and MVA-Gt1-6 prime-boost generated high-magnitude responses that were all cross-reactive between genotypes.
CONCLUSIONS: Vaccinating with conserved regions of genotypes 1-6 or sequentially vaccinating with genotype-1a and genotype-3a immunogens are 2 novel approaches to generate cross-reactive T cells. The proportion of intergenotypic cross-reactive T cells generated was higher using the conserved region antigen.
APPROACH AND RESULTS: HCV genetic segments highly conserved between genotypes 1-6 were encoded in chimpanzee adenoviral (ChAd-Gt1-6) and Modified Vaccinia virus Ankara (MVA-Gt1-6) vectors and tested in prime-boost regimens. This was compared with vaccinating with an ancestral genotype-1a non-structural antigen encoded in ChAd (ChAd-Bole1a-NS) boosted with a genotype-3a non-structural antigen encoded in MVA (MVA-Gt3a-NS). Immunogenicity was evaluated in C57BL/6 and transgenic HLA-A*02:01 mice. Splenocytes were stimulated with genotype-1a, genotype-1b, or genotype-3a peptide pools in ex vivo IFNγ ELISpot and intracellular cytokine assays. Priming with ChAd-Gt1-6 elicited broad T cell responses toward all genotypes, whereas ChAd-Bole1a-NS generated a focused response to genotype-1a. Boosting ChAd-Bole1a-NS with MVA-Gt3a-NS generated cross-reactive T cells targeting multiple genotypes, though some responses were genotype-specific. In contrast, ChAd-Gt1-6 and MVA-Gt1-6 prime-boost generated high-magnitude responses that were all cross-reactive between genotypes.
CONCLUSIONS: Vaccinating with conserved regions of genotypes 1-6 or sequentially vaccinating with genotype-1a and genotype-3a immunogens are 2 novel approaches to generate cross-reactive T cells. The proportion of intergenotypic cross-reactive T cells generated was higher using the conserved region antigen.