Heterologous Two-Dose Vaccination with Simian Adenovirus and Poxvirus Vectors Elicits Long-Lasting Cellular Immunity to Influenza Virus A in Healthy Adults.
Heterologous Two-Dose Vaccination with Simian Adenovirus and Poxvirus Vectors Elicits Long-Lasting Cellular Immunity to Influenza Virus A in Healthy Adults.
复制标题
DOI：
10.1016/j.ebiom.2018.02.011
复制
发表时间：
2018-03
期刊：
影响因子：
11.1
通讯作者：
Gilbert SC
中科院分区：
文献类型：
--
作者：
Coughlan L;Sridhar S;Payne R;Edmans M;Milicic A;Venkatraman N;Lugonja B;Clifton L;Qi C;Folegatti PM;Lawrie AM;Roberts R;de Graaf H;Sukhtankar P;Faust SN;Lewis DJM;Lambe T;Hill A;Gilbert SC
t细胞对高度保守的流感抗原的反应以前与保护有关。然而，这些免疫反应在流感感染恢复后维持得很差，并且不能通过灭活流感疫苗来增强。我们之前已经证明了两种病毒载体疫苗的安全性和免疫原性，改性安卡拉牛痘病毒（MVA）和黑猩猩腺病毒ChAdOx1表达保守的流感病毒抗原，核蛋白（NP）和基质蛋白-1 （M1）。我们现在报告这些疫苗在年轻人和老年人中多种组合方案的安全性和长期免疫原性。我们进行了一项I期开放标签、随机、多中心研究，纳入49名18-46岁的受试者和24名50岁或以上的受试者。接种疫苗后，记录不良事件，并在长达18个月的多个时间点确定T细胞反应的动力学。两种疫苗的耐受性都很好。在年轻人和老年人中，两剂异源疫苗接种方案显著增加了两剂后已有的t细胞对NP和M1的反应程度。与ChAdOx1 NP + M1相比，单次接种MVA-NP + M1后的免疫应答倍数和峰值显著增加。在混合回归模型中，在MVA/ChAdOx1 NP + M1两剂疫苗接种方案下，18个月以上的t细胞反应显着提高。MVA/ChAdOx1 NP + M1的两剂异源疫苗接种方案在年轻人和老年人中是安全的和免疫原性的，为诱导长期广泛交叉反应保护甲型流感提供了一种有希望的疫苗接种策略。MVA/ChAdOx1 NP+M1异源强化免疫方案在年轻人和老年人中是安全的和免疫原性的。所有MVA/ChAdOx1 NP+M1方案测试的交叉反应性t细胞均显著增加，免疫反应持续并在接种后18个月维持。与ChAdOx1 NP+M1相比，MVA-NP+M1单次接种后的应答率显著提高。它们极易受到抗原位点内突变积累的影响，从而逃避先前感染或接种疫苗所产生的血清学免疫。在这项I期临床研究中，我们展示了在四种不同的疫苗接种方案中使用两种表达保守甲型流感抗原的复制缺陷病毒载体的结果，接种间隔为8周或一年。我们发现接种疫苗是安全的，并且大大增强了T细胞对流感抗原的反应，在年轻人和老年人中，第二次接种疫苗后T细胞对流感抗原的反应进一步增加。
T-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP) and matrix protein-1 (M1). We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults. We conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18–46 years and 24 subjects aged 50 years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18 months. Both vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The fold-increase and peak immune responses after a single MVA-NP + M1 vaccination was significantly higher compared to ChAdOx1 NP + M1. In a mixed regression model, T-cell responses over 18 months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP + M1. A two dose heterologous vaccination regimen of MVA/ChAdOx1 NP + M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly cross-reactive protection against influenza A. Medical Research Council UK, NIHR BMRC Oxford. Heterologous prime-boost vaccination regimens of MVA/ChAdOx1 NP+M1 are safe and immunogenic in young and older adults All MVA/ChAdOx1 NP+M1 regimens tested significantly increased cross-reactive T-cells Responses were durable and were maintained 18 months after vaccination The fold-increase after a single MVA-NP+M1 vaccination was significantly higher compared to ChAdOx1 NP+M1 Current seasonal influenza vaccines induce antibody responses to external glycoproteins, which are highly susceptible to the accumulation of mutations within antigenic sites, allowing escape from serological immunity conferred by prior infection or vaccination. In this phase I clinical study, we present the results of using two replication-deficient viral vectors expressing conserved influenza A antigens in four different vaccination regimens, administered at intervals of either 8 weeks or one year. We found that vaccination was safe and boosted T cell responses to influenza antigens substantially, with a further increase after the second vaccination, both in young and older adults.
登录
查看更多内容
DOI：
10.1093/cid/cis327
发表时间：
2012-07
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Lillie PJ;Berthoud TK;Powell TJ;Lambe T;Mullarkey C;Spencer AJ;Hamill M;Peng Y;Blais ME;Duncan CJ;Sheehy SH;Havelock T;Faust SN;Williams RL;Gilbert A;Oxford J;Dong T;Hill AV;Gilbert SC
通讯作者：
Gilbert SC
影响因子：
12.4
作者：
Antrobus, Richard D.;Berthoud, Tamara K.;Gilbert, Sarah C.
通讯作者：
Gilbert, Sarah C.
影响因子：
11.8
作者：
Petrie, Joshua G.;Cheng, Caroline;Ohmit, Suzanne E.
通讯作者：
Ohmit, Suzanne E.
DOI：
10.1038/mt.2013.284
发表时间：
2014-03
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1164/rccm.201411-1988oc
发表时间：
2015-06-15
影响因子：
24.7
作者：
Hayward, Andrew C.;Wang, Lili;McMichael, Andrew J.
通讯作者：
McMichael, Andrew J.