3 F). Chronic PF-04929113 (SNX-5422) antigen stimulation in persistent viral infections can drive T cell exhaustion in addition to T cell senescence. Introduction Human CMV is usually a highly prevalent -herpes computer virus that establishes life-long latent infections. Around 40%C60% of young adults in developed countries are infected (Zuhair et al., 2019), increasing to >90% in elderly adults (Staras et al., 2006). CMV seroprevalence in developing countries is usually often higher, with 80%C90% of young adults seropositive (Zuhair et al., 2019). There is increasing evidence that CMV plays a significant role in immunosenescence and is characterized by a gradual accumulation of highly differentiated effector memory T cells in a process known as memory inflation (Karrer et al., 2003; Sylwester PF-04929113 (SNX-5422) et al., 2005; OHara et al., 2012; Hosie et al., 2017). Although inflationary T cells do not express classical exhaustion markers such as programmed cell death protein 1 (PD-1), PF-04929113 (SNX-5422) they typically drop expression of costimulatory receptors CD27 and CD28 and gain expression of the inhibitory receptor killer cell lectin-like receptor G1 (KLRG1) and the terminal differentiation marker CD57 (Henson et al., 2012; Klenerman and Oxenius, 2016). Functionally, these cells have reduced proliferative capacity, increased activation of senescence signaling pathways, and a greater susceptibility to apoptosis in vitro (Henson et al., 2012). In elderly populations, these CMV-driven immune changes have been associated with reduced vaccine responses and an increased risk of mortality ETS2 (Wikby et al., 1994, 2002; Ferguson et al., 1995; Trzonkowski et al., 2003; Moro-Garca et al., 2012; Derhovanessian et al., 2013, 2014). However, although marked changes in immune phenotype and significant proportions of CMV-specific T cells are also observed in healthy younger seropositive adults and children (Turner et al., 2014; Brodin et al., 2015; van den Heuvel et al., 2016), the impact on responses to vaccination or contamination is usually less clear, and most studies have been conducted in populations within developed countries (Sidorchuk et al., 2004; Holder et al., 2010; Saghafian-Hedengren et al., 2013; Turner et al., 2014; Furman et al., 2015; van den Berg et al., 2018). Reduced vaccine responses are frequently observed in developing countries, with an increased burden of pathogen exposure thought to be one driving factor (Lagos et al., 1999; Qadri et al., 2003; Serazin PF-04929113 (SNX-5422) et al., 2010; Lopman et al., 2012). However, direct evidence of an association between pathogen exposure, altered immune phenotypes, and reduced vaccine responses is lacking. During the 2014C2016 Ebola outbreak in West Africa, we conducted two Phase I clinical trials of the Ebola PF-04929113 (SNX-5422) vaccine candidates chimpanzee adenovirus serotype 3 (ChAd3) and altered vaccinia computer virus Ankara (MVA), both expressing Zaire Ebola glycoprotein (EBO-Z; Venkatraman et al., 2018). The trials were run concurrently in Oxford, UK, and Dakar, Senegal, with healthy UK adults aged 18C50 yr (= 16; average, 33 yr) and Senegalese adults aged 18C50 yr (= 40; average, 28 yr) in the matched dose groups receiving the same vaccine regimen: 3.6 1010 viral particles of ChAd3CEBO-Z at day 0, boosted with 1 108 plaque-forming units of MVACEBO-Z 1 wk later. This trial design provided a rare opportunity for direct comparison of vaccine immunogenicity in populations within a developed country and a developing country. We discovered a novel association between CMV-associated changes to the T cell repertoire and a reduction in Ebola vaccine responses in healthy young UK and Senegalese adults. Results and discussion CMV seropositivity is usually associated with reduced responses to ChAd3-MVACEBO-Z vaccination Of the UK cohort, 50% (8/16) of.
