Human CD4+ T Cell Responses to an Attenuated Tetravalent Dengue Vaccine Parallel Those Induced by Natural Infection in Magnitude, HLA Restriction, and Antigen Specificity
Human CD4+ T Cell Responses to an Attenuated Tetravalent Dengue Vaccine Parallel Those Induced by Natural Infection in Magnitude, HLA Restriction, and Antigen Specificity
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DOI：
10.1128/jvi.02147-16
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发表时间：
2017-03-01
影响因子：
5.4
通讯作者：
Weiskopf, Daniela
中科院分区：
文献类型：
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作者：
Angelo, Michael A.;Grifoni, Alba;Weiskopf, Daniela
登革热病毒(DENV)是世界范围内感染人数不断增加的罪魁祸首，已被证明是疫苗开发的重大挑战。我们之前证明了登革热减毒活病毒(DLAV)疫苗诱导的CD8(+)T细胞反应与自然感染后观察到的相似。在这项研究中，我们从接种了四价DLAV疫苗(TV005)的捐赠者的外周血单核细胞(PBMC)中筛选出登革病毒来源的预测主要组织相容性复合体(MHC)II类结合肽库。活疫苗接种后对CD4(+)T细胞应答的定义是重要的，因为已知的CD4(+)T细胞是宿主免疫的贡献者，包括细胞因子的产生，对CD8(+)T细胞和B细胞的帮助，以及对感染细胞的直接细胞毒作用。在观察到对所有抗原的反应时，DENV特异性的CD4(+)T细胞主要集中在衣壳和非结构性NS3和NS5抗原上。重要的是，疫苗接种者的CD4(+)T细胞反应在大小和广度上与自然感染后相似，识别相同的抗原层次，并具有相似的人类白细胞抗原限制性图谱。我们的结论是，TV005疫苗能够激发与自然免疫相关的人群中观察到的CD4(+)细胞反应。重要的是，开发有效的疫苗接种策略来对抗登革热病毒感染具有高度的全球公共卫生利益。在这里，我们研究了四价减毒登革热疫苗引发的CD4T细胞反应，并表明它们类似于自然暴露于登革热病毒的人类的反应。这是一个重要的问题，因为疫苗诱导的最佳免疫可能需要诱导针对那些在自然感染中被认为占主导地位的抗原的CD4(+)反应。对T细胞反应的详细了解可能进一步有助于确定预防登革热病毒的强大相关性。
Dengue virus (DENV) is responsible for growing numbers of infections worldwide and has proven to be a significant challenge for vaccine development. We previously demonstrated that CD8(+) T cell responses elicited by a dengue live attenuated virus (DLAV) vaccine resemble those observed after natural infection. In this study, we screened peripheral blood mononuclear cells (PBMCs) from donors vaccinated with a tetravalent DLAV vaccine (TV005) with pools of dengue virus-derived predicted major histocompatibility complex (MHC) class II binding peptides. The definition of CD4(+) T cell responses after live vaccination is important because CD4(+) T cells are known contributors to host immunity, including cytokine production, help for CD8(+) T and B cells, and direct cytotoxicity against infected cells. While responses to all antigens were observed, DENV-specific CD4(+) T cells were focused predominantly on the capsid and nonstructural NS3 and NS5 antigens. Importantly, CD4(+) T cell responses in vaccinees were similar in magnitude and breadth to those after natural infection, recognized the same antigen hierarchy, and had similar profiles of HLA restriction. We conclude that TV005 vaccination has the capacity to elicit CD4(+) cell responses closely mirroring those observed in a population associated with natural immunity.IMPORTANCE The development of effective vaccination strategies against dengue virus infection is of high global public health interest. Here we study the CD4 T cell responses elicited by a tetravalent live attenuated dengue vaccine and show that they resemble responses seen in humans naturally exposed to dengue virus. This is an important issue, since it is likely that optimal immunity induced by a vaccine requires induction of CD4(+) responses against the same antigens as those recognized as dominant in natural infection. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection against dengue virus.