Enhanced respiratory syncytial virus disease or protection from infection depends on the subtype used for adenoviral vector vaccination
Final Report Abstract
Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in infants and toddlers. Since natural infections do not induce persistent immunity, there is the need of new vaccines providing long-term protection. Heterologous prime boost immunizations using nucleic-acid based vaccines, DNA or RNA, together with adenoviral vectors (rAd) were highly efficient in animal models. During the SARS-CoV-2 pandemic, adenoviral vectors vaccine types have been proven protective against severe COVID-19 disease in humans. In our study, we evaluated a new adenoviral vector vaccine based on the rare human serotype rAd19a and compared its immunogenicity and efficacy directly to the highly immunogenic, well-characterized rAd5 vector in a murine RSV model. The heterologous vaccination schedule consists of an initial intramuscular DNA vaccination and a booster immunization with the adenoviral vectors, which all encode the F protein of RSV as antigen. Interestingly, both adenoviral vectors induced systemic and mucosal immune responses, providing efficient protection against a subsequent RSV infection, when they are applied via the intranasal route. However, intramuscular booster immunization with rAd19 vectors resulted in a more rapid weight loss after RSV infection compared to non-vaccinated animals indicating a kind of enhanced disease severity. In contrast, rAd5 given intramuscularly also protects from RSV induced disease. In this project, we performed detailed analyses of the immunological responses induced by the different vaccination approaches and the subsequent RSV infection for a better understanding of the underlying mechanism defining protection or disease enhancement. One important difference between the intramuscular and the intranasal application of the rAd19 vectors is the capability of inducing mucosal immune responses. The presence of local IgA antibodies and tissue-resident memory T-cells in the respiratory tract correlate with a rapid control of RSV replication, whereas a delayed, but more expanded systemic recall response in the intramuscular immunized animals might be the driver of immune-mediated enhancement of RSV-induced disease. In summary, two major conclusions could be drawn from this study, which will be highly relevant for future vaccine development against existing and newly emerging respiratory viruses. Firstly, the benefits of local immunity regarding viral control clearly support the further development and optimization of mucosal vaccine for the translation into humans. Second, the unintended disease enhancement by just changing the serotype of the viral vector highlighted the need for intensive pre-clinical characterization of each new vaccine candidate in the respective disease model.
Publications
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Mucosal immunization with an adenoviral vector vaccine confers superior protection against RSV compared to natural immunity. Frontiers in Immunology, 13.
Maier, Clara; Fuchs, Jana; Irrgang, Pascal; Wißing, Michael Hermann; Beyerlein, Jasmin; Tenbusch, Matthias & Lapuente, Dennis
