Blohmke Christoph J, Hill Jennifer, Darton Thomas C, Carvalho-Burger Matheus, Eustace Andrew, Jones Claire, Schreiber Fernanda, Goodier Martin R, Dougan Gordon, Nakaya Helder I, Pollard Andrew J
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom.
Front Immunol. 2017 Oct 12;8:1276. doi: 10.3389/fimmu.2017.01276. eCollection 2017.
The mechanisms by which oral, live-attenuated vaccines protect against typhoid fever are poorly understood. Here, we analyze transcriptional responses after vaccination with Ty21a or vaccine candidate, M01ZH09. Alterations in response profiles were related to vaccine-induced immune responses and subsequent outcome after wild-type Typhi challenge. Despite broad genetic similarity, we detected differences in transcriptional responses to each vaccine. Seven days after M01ZH09 vaccination, marked cell cycle activation was identified and associated with humoral immunogenicity. By contrast, vaccination with Ty21a was associated with NK cell activity and validated in peripheral blood mononuclear cell stimulation assays confirming superior induction of an NK cell response. Moreover, transcriptional signatures of amino acid metabolism in Ty21a recipients were associated with protection against infection, including increased incubation time and decreased severity. Our data provide detailed insight into molecular immune responses to typhoid vaccines, which could aid the rational design of improved oral, live-attenuated vaccines against enteric pathogens.
口服减毒活疫苗预防伤寒热的机制尚不清楚。在此，我们分析了接种Ty21a或候选疫苗M01ZH09后的转录反应。反应谱的改变与疫苗诱导的免疫反应以及野生型伤寒杆菌攻击后的后续结果相关。尽管基因相似度很高，但我们检测到每种疫苗的转录反应存在差异。接种M01ZH09七天后，发现有明显的细胞周期激活，且与体液免疫原性相关。相比之下，接种Ty21a与自然杀伤细胞（NK细胞）活性相关，并在体外外周血单核细胞刺激试验中得到验证，证实其对NK细胞反应的诱导效果更佳。此外，接种Ty21a者的氨基酸代谢转录特征与抗感染保护相关，包括延长潜伏期和减轻严重程度。我们的数据为伤寒疫苗的分子免疫反应提供了详细见解，这有助于合理设计改良的口服减毒活疫苗来对抗肠道病原体。
