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

• Applicant: Professor Dr. Matthias Tenbusch
• Subject Area: Virology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419013006

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.

• DFG Programme: Research Grants