Angelo Michael A, Grifoni Alba, O'Rourke Patrick H, Sidney John, Paul Sinu, Peters Bjoern, de Silva Aruna D, Phillips Elizabeth, Mallal Simon, Diehl Sean A, Kirkpatrick Beth D, Whitehead Stephen S, Durbin Anna P, Sette Alessandro, Weiskopf Daniela
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Genetech Research Institute, Colombo, Sri Lanka.
J Virol. 2017 Feb 14;91(5). doi: 10.1128/JVI.02147-16. Print 2017 Mar 1.
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. 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.
登革病毒（DENV）导致全球感染人数不断增加，已被证明是疫苗研发面临的重大挑战。我们之前证明，登革热减毒活病毒（DLAV）疫苗引发的CD8 T细胞反应与自然感染后观察到的反应相似。在本研究中，我们用登革病毒衍生的预测主要组织相容性复合体（MHC）II类结合肽库筛选了接种四价DLAV疫苗（TV005）的供体的外周血单个核细胞（PBMC）。活疫苗接种后CD4 T细胞反应的定义很重要，因为已知CD4 T细胞是宿主免疫的贡献者，包括细胞因子产生、对CD8 T细胞和B细胞的辅助以及对感染细胞的直接细胞毒性。虽然观察到对所有抗原的反应，但DENV特异性CD4 T细胞主要集中在衣壳以及非结构蛋白NS3和NS5抗原上。重要的是，疫苗接种者中的CD4 T细胞反应在强度和广度上与自然感染后的反应相似，识别相同的抗原层级，并且具有相似的HLA限制谱。我们得出结论，TV005疫苗接种能够引发与自然免疫人群中观察到的反应非常相似的CD4细胞反应。开发针对登革病毒感染的有效疫苗策略具有高度的全球公共卫生意义。在这里，我们研究了一种四价减毒活登革疫苗引发的CD4 T细胞反应，并表明它们类似于自然接触登革病毒的人类中观察到的反应。这是一个重要问题，因为疫苗诱导的最佳免疫可能需要诱导针对与自然感染中被识别为优势抗原相同的抗原的CD4反应。对T细胞反应的详细了解可能会进一步有助于确定针对登革病毒的强大保护相关性。
