Alphaviruses are small, enveloped, RNA viruses responsible for a considerable number of human and animal diseases worldwide. Alphavirus members include chikungunya virus (CHIKV), Sindbis virus, Semliki Forest virus, the western, eastern and Venezuelan equine encephalitis viruses, o’nyong’nyong virus (ONNV) and the Ross River virus. Most common alphavirus infection symptoms are fever, rash and arthritis that may become chronic and last for months or even years. Some alphaviruses can also induce encephalitis in humans and animals. Alphaviruses are transmitted by arthropods and replicate in both mosquito vectors and vertebrate hosts.
Among alphaviruses, the CHIKV causes large outbreaks with high attack rates. Outbreaks have already occurred in Africa, Asia, Southern Europe, America, and India. The CHIKV is thus posing growing risks to citizens and travellers in infected regions. In view of the worldwide distribution of mosquitoes and the increasing flow of travellers, there is a serious risk of a CHIKV pandemic in a near future.
Despite the threat of a major outbreak, there is currently no commercially available vaccine or other medicine to prevent or treat CHIKV infections. There is thus still a strong need to provide effective vaccines for alphaviruses and especially for the CHIKV.
New, Patent Protected Solution
The inventors have developed alphavirus non-structural protein (nsP) mutants for use as vaccines against alphaviruses and in particular against the CHIKV. NsPs of alphaviruses are key proteins involved in the virus replication and pathogenesis. The mutations target several crucial mechanisms including virus replicase formation, the ability of the virus replicase to produce type I IFN inducing molecules, the ability to counteract host anti-viral mechanisms and the use of host-derived components of virus replicase.
The vaccine potential of the invention was evaluated in mice. The mutated virus demonstrated a reduced viral infectivity and replicative potential in mouse tail fibroblasts. The mutated virus also strongly increases Type 1 IFN immune response in mice, enhancing the innate immune response. Importantly, infection with the mutated CHIKV was found to provide an excellent protection against subsequent infection with wild type CHIKV in mice.
Mutated alphaviruses of the invention could be used to develop vaccines against any alphavirus such as the CHIKV, ONNV or equine encephalitis viruses. These vaccines would help to overcome the next major outbreaks and offer cross protection against related viruses such as CHIKV and ONNV. A CHIKV vaccine could also be developed as a military or traveller vaccine.
The mutated alphaviruses of the invention present unique features making them ideal for developing vaccines:
- The mutations target several key mechanisms of the virus, which should provide a strong and long-lasting immunity;
- The mutations do not impair the antigenic properties of viral structural proteins;
- The mutated alphaviruses are fully compatible with replication in Vero cells, one of the few cell lines authorized by regulatory agencies for the production of human vaccines. High titers of the mutated viruses can thus be obtained;
- The mutated alphavirus genomes can also be delivered using RNA or DNA vaccination technologies, which represent the future of vaccination;
- The mutations of the invention could easily be combined with other mutations affecting structural proteins without compromising their ability to induce antiviral immune response.
Intellectual Property Status
A PCT application (WO/2018/147802) has been filed and is currently in national phase in US and Europe.
This invention is co-owned by University of Tartu & the Agency for Science, Technology and Research of Singapore.
Technology adoption opportunity
The University of Tartu is looking for commercial partners to commercialize alphaviruses vaccines through licensing or sale of the IPR and associated support to fully transfer the technology.