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

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，没有获得许可的预防性疫苗，这至少部分是由于以前的疫苗试验失败造成的。在20世纪60年代，与接种安慰剂疫苗的儿童相比，接种福尔马林灭活疫苗的儿童在自然感染RSV后患上了增强型呼吸道疾病(ERD)，甚至导致疫苗组中的两人死亡。几项研究描述了疫苗引起ERD的可能原因。由于这些原因可能因接种方法的不同而不同，因此需要仔细评估每一种新的候选疫苗是否可能出现ERD。最近，我们报道了一种在小鼠和猕猴中非常有效的免疫方案，该方案基于DNA Prime/腺病毒载体Boost策略与腺病毒血清Ad5型。由于Ad5的高血清阳性率和一项大型HIV疫苗试验(STEP研究)的阴性结果，罕见的人类血清型或猴子来源的腺病毒成为疫苗研究的重点。在我们的研究中，一种基于Ad19a血清型的新腺病毒载体在小鼠RSV感染后导致ERD。这是非常出乎意料的，因为相同的协议与基于Ad5的载体有效地保护小鼠免受RSV感染。这表明，载体系统中的微小差异可能会对免疫学后果产生巨大影响。在拟议的研究中，将系统地分析潜在的机制。虽然两种载体都能诱导对RSV-F的体液免疫和细胞免疫，但局部粘膜免疫的质量似乎不同。在研究的第一部分，将根据载体系统和应用路线详细分析不同的疾病进展过程。这包括对病毒复制、局部细胞因子/趋化因子环境、细胞渗透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来揭示。最后，将评估载体固有特性对这些不同疫苗诱导的免疫反应的影响。具体地说，将阐明这两个载体的载体取向的作用。特别是，Ad19a对抗原提呈细胞的转导和激活很少被描述，但可能对所产生的免疫产生巨大的影响。了解如此密切相关的载体系统的使用如何导致如此相反的结果将是疫苗领域的极大兴趣。

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.