Abstract
Human adenoviruses (AdVs) are one of the most common causes of acute respiratory viral infections worldwide. Multiple AdV serotypes with low cross-reactivity circulate in the human population, making the development of an effective vaccine very challenging. In the current study, we designed a cross-reactive AdV vaccine based on the T-cell epitopes conserved among various AdV serotypes, which were inserted into the genome of a licensed cold-adapted live attenuated influenza vaccine (LAIV) backbone. We rescued two recombinant LAIV-AdV vaccines by inserting the selected AdV T-cell epitopes into the open reading frame of full-length NA and truncated the NS1 proteins of the H7N9 LAIV virus. We then tested the bivalent vaccines for their efficacy against influenza and human AdV5 in a mouse model. The vaccine viruses were attenuated in C57BL/6J mice and induced a strong influenza-specific antibody and cell-mediated immunity, fully protecting the mice against virulent influenza virus infection. The CD8 T-cell responses induced by both LAIV-AdV candidates were functional and efficiently killed the target cells loaded either with influenza NP366 or AdV DBP418 peptides. In addition, high levels of recall memory T cells targeted to an immunodominant H2b-restricted CD8 T-cell epitope were detected in the immunized mice after the AdV5 challenge, and the magnitude of these responses correlated with the level of protection against pulmonary pathology caused by the AdV5 infection. Our findings suggest that the developed recombinant vaccines can be used for combined protection against influenza and human adenoviruses and warrant further evaluation on humanized animal models and subsequent human trials.
Highlights
Acute respiratory viral infections (ARVIs) are one of the leading causes of mortality and morbidity worldwide [1], and children often experience several episodes a year
The most effective system for the delivery of AdV T-cell epitopes to the epithelial cells of the upper respiratory tract are viral vectors that are capable of correctly presenting the target epitopes to the immune system [9], for attenuated influenza viruses, which are used worldwide in live attenuated influenza vaccines (LAIVs) [10]
We evaluated the processing of the selected regions and the ability of individual peptides to bind to the human major histocompatibility complex (MHC), as well as to the MHC molecules of the mouse species, which will be used as a model for the experimental assessment of the vaccine’s immunogenicity and protective potential
Summary
Acute respiratory viral infections (ARVIs) are one of the leading causes of mortality and morbidity worldwide [1], and children often experience several episodes a year. Most ARVIs are caused by a respiratory syncytial virus (RSV), influenza A and B, parainfluenza viruses types 1–4, adenoviruses, human metapneumovirus (hMPV), rhinoviruses, and coronaviruses [2,3]. A possible solution is the targeted induction of the immune response to the AdV epitopes that are conserved between different viral serotypes. In this case, the most effective system for the delivery of AdV T-cell epitopes to the epithelial cells of the upper respiratory tract are viral vectors that are capable of correctly presenting the target epitopes to the immune system [9], for attenuated influenza viruses, which are used worldwide in live attenuated influenza vaccines (LAIVs) [10]. The idea of designing a bivalent vaccine against AdV and influenza was explored by generating recombinant influenza viruses that carry the AdV hexon protein antigenic epitope sequence inserted either in the non-structural (NS1) protein gene of the PR8 virus [11]
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