Enhanced respiratory syncytial virus disease or protection from infection depends on the subtype used for adenoviral vector vaccination

增强呼吸道合胞病毒病或预防感染取决于腺病毒载体疫苗接种所用的亚型

• 批准号: 419013006
• 负责人: Professor Dr. Matthias Tenbusch
• 金额: --
• 依托单位: Virologisches Institut - Klinische und Molekulare Virologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/419013006?language=en
• 关键词: Enhanced; respiratory; syncytial; virus; disease

The human respiratory syncytial virus (RSV) is the most common cause of severe respiratory tract infection of children under the age of five years. Currently, no licensed, prophylactic vaccine exists, which is at least partially also caused by the failure of former vaccine trials. In the 1960s, children immunized with a formalin-inactivated vaccine developed an enhanced respiratory disease (ERD) after acquiring natural RSV infection compared to placebo vaccinated children, even resulting in two deaths in the vaccine group. Several studies described possible causes for the vaccine-induced ERD. Since these causes could vary depending on the vaccination approach, every new vaccine candidate needs to be evaluated carefully in regard to possible ERD. Recently, we reported on a very efficient immunization protocol in mice and rhesus macaques based on DNA prime/adenoviral vector boost strategy with an adenovirus serotype Ad5. Due to the high seroprevalence of Ad5 and negative results from a large HIV vaccine trial (STEP study), rare human serotypes or monkey-derived adenoviruses reached into the focus of vaccine research. In our studies, a new adenoviral vector based on serotype Ad19a results in ERD after an RSV-infection in mice. This was highly unexpected since the same protocol with Ad5-based vectors efficiently protected mice from RSV infection. This demonstrates that minimal differences in the vector systems could hugely impact on the immunological consequences. In the proposed study, the underlying mechanism will be systematically analyzed. Although both vectors induced humoral and cellular immune response to RSV-F, the quality of the local, mucosal immunity seemed to be different. In the first part of the study, the different courses of disease progression will be analyzed in detail depending on the vector system and the application route. This includes kinetic studies of viral replication, local cytokine/chemokine milieu, cellular infiltrates as well as histological analyses of the infected lung tissue. Secondly, the immunological parameters correlated either with protection or ERD will be revealed by appropriate depletion or transfer experiments. Finally, the impact of vector-intrinsic properties on these differential vaccine-induced immune responses will be evaluated. Specifically, the role of the vector tropism of the two vectors will be elucidated. Particularly, the transduction and activation of antigen-presenting cells by Ad19a are rarely described, but might have huge implications for the resulting immunity.To understand how the use of so closely related vector systems can result in such contrary outcomes will be of great interest for the field of vaccinology.

人类呼吸道合胞病毒（RSV）是五岁以下儿童严重呼吸道感染的最常见原因。目前，尚无许可的预防性疫苗，至少部分是由于以前的疫苗试验失败引起的。在1960年代，与安慰剂疫苗接种儿童相比，获得了自然RSV感染后，用福尔马林灭活的疫苗免疫的儿童出现了增强的呼吸道疾病（ERD），甚至导致疫苗组的两次死亡。几项研究描述了疫苗诱导的ERD的可能原因。由于这些原因可能会根据疫苗接种方法而有所不同，因此需要在可能的ERD方面仔细评估所有新疫苗的候选者。最近，我们报告了基于DNA Prime/腺病毒载体增强策略的小鼠中非常有效的免疫方案，并用腺病毒血清型AD5进行了猕猴。由于AD5的血清阳性高以及大型HIV疫苗试验的阴性结果（Step研究），罕见的人类血清型或猴子衍生的腺病毒已进入疫苗研究的重点。在我们的研究中，基于血清型AD19A的新型腺病毒载体在小鼠感染后导致ERD。这是非常出乎意料的，因为与基于AD5的载体有效保护小鼠免受RSV感染的相同方案。这表明，向量系统的最小差异可能会对免疫学后果产生重大影响。在拟议的研究中，将系统地分析潜在的机制。尽管两个载体都诱导了对RSV-F的体液和细胞免疫反应，但局部粘膜免疫的质量似乎有所不同。在研究的第一部分中，将根据向量系统和应用途径进行详细分析疾病进展的不同过程。这包括病毒复制，局部细胞因子/趋化因子环境，细胞浸润以及感染肺组织的组织学分析的动力学研究。其次，与保护或ERD相关的免疫学参数将通过适当的耗竭或转移实验揭示。最后，将评估载体内部特性对这些差异疫苗诱导的免疫反应的影响。具体而言，将阐明两个矢量的向量向向向主义的作用。特别是，很少描述通过AD19A对抗原呈递细胞的转导和激活，但可能对产生的免疫具有很大的影响。了解，了解如此紧密相关的矢量系统的使用如何导致这种相反的结果对此产生极大的兴趣。疫苗学领域。