Super-Vaccine · Exploring the potential applications of live viral vaccine encoded small-hairpin-RNAs in improving both vaccine safety and efficacy through RNA-interference and stimulation of the innate immune system

Exploring the potential applications of live viral vaccine encoded small-hairpin-RNAs in improving both vaccine safety and efficacy through RNA-interference and stimulation of the innate immune system

Live viral vaccines consist of attenuated (non-pathogenic) forms of harmful viruses and represent one of the most important and effective interventions against the spread of viral disease. Their widespread use has brought about vast improvements in both human and animal health and also facilitated more cost-effective livestock production. As such, they will continue to be instrumental in addressing ongoing societal challenges in areas such as healthcare and global food security. However, their capacity to genetically recombine with wild type (WT) viruses circulating in the field remains a primary safety concern. Also, efforts to enhance the intrinsic potency of vaccine strains would be very beneficial in terms of reducing the manufacturing resources required to meet market needs and reducing cost of vaccination programs, all of which would represent a tremendous benefit to society. With this in mind, the objectives of this project were to explore a novel strategy to improve both the safety and efficacy of live viral vaccine strains by modifying them to express small-hairpin-RNAs (or shRNAs, a type of non-coding RNA) that have been specifically designed to: i) Exclusively inhibit WT virus replication/propagation via RNA-interference (RNAi) during co-infections i.e. improving safety ii) Increase live vaccine strain stimulation of the innate immune system by functioning as RIG-I agonists and thus act as potent inducers of Type-1 Interferon (IFN-I) expression in host cells during vaccination, essentially acting as adjuvants i.e. enhancing efficacy. Notably, RIG-I stimulated IFN-I expression represents an important step in the initiation of a Th2 polarized immune response, which is vital for establishing long-term adaptive immunity against viral pathogens. This concept was explored using Cyprinid Herpesvirus-3 (CyHV-3) and its host, carp (Cyprinus carpio), as a virus-host model. In conclusion, the project represented an important starting point in the exploration of this novel vaccine design strategy. Moreover, it allowed us to rationally scrutinize our widely held assumptions related to our chosen virus-host model which we had factored into our initial plans. Through this process, we have gained extremely valuable insights into the biology of our virus-host model that would have otherwise remained elusive. Taken together, this work puts us in a strong position to proceed towards the testing of several exogenously expressed RIG-I agonists (and our own custom molecules) in carp cells, with the ultimate aim of using such expression systems to improve live vaccine potency through enhanced immune stimulation.

Data: CORDIS, © European Union