Public Funding for Conserv Bioscience Limited

Dengue, yellow fever, Zika, and West Nile viruses are mosquito-borne flaviviruses and global public health burdens that infect half a billion people annually, causing 250,000 deaths, and threaten nearly the entire human population. In a context of human-driven global changes, these threats will intensify with larger and more frequent epidemics, potentially leading to pandemics, will expand with geographic spreading of the mosquito vectors, and will multiply with the likely emergence of yet-unknown flaviviruses. Improving pandemic preparedness and response to these emerging and re-emerging diseases is a top priority both for the EU and WHO. However, there are no effective interventions against all flaviviruses and current vaccines targeting flaviviral proteins have severe safety issues. FLAVIVACCINE’s high-impact/low-risk/disruptive ambition is to develop a novel, broad-spectrum, mosquito saliva-targeted vaccine candidate that protects against multiple different flaviviruses and is ready for clinical evaluation by building upon an experimentally validated proof-of-concept. FLAVIVACCINE will define the immunogenicity of the pan-flavivirus target, develop and characterize a vaccine candidate against multiple flaviviruses, and prepare it for clinical evaluation. To reach these goals, FLAVIVACCINE creates a unique interdisciplinary environment of ten public and private institutions, including Universities, Research Institutions and a Vaccine Developer, from seven countries to cover all the required scientific expertise and knowledge in cell biology, virology, immunology and vaccinology. The pan-flavivirus vaccine candidate that will be validated against dengue, yellow fever, Zika and West Nile diseases in several preclinical models, together with the knowledge and networks resulting from FLAVIVACCINE, will have short- and long-term impact on the EU ability to combat epidemic and pandemic viral threats, and protect communities and citizens in the EU and around the world.

Zika and chikungunya are mosquito-borne viruses with epidemic potential, and both are transmitted by the bite of infected _Aedes_ female mosquitoes. Zika and chikungunya outbreaks have been reported in South and Central America, the Caribbean, the Pacific islands, Africa, and Asia. There is a risk that these viruses will spread geographically by infected travellers and by the expansion of _Aedes'_ habitat due to global warming and deforestation. There is currently no vaccine or antiviral to prevent or treat chikungunya and Zika virus infection and the only protection comes from preventing mosquito bites. _Aedes_ mosquitoes are also carriers of dengue and yellow fever viruses whereas viruses such as West Nile, St. Louis encephalitis, and Japanese encephalitis are mainly transmitted by _Culex_ mosquitoes. Infected female mosquitoes deposit virus into the skin dermis as they probe for a blood meal to provide the nutrition required to lay fertile eggs. Probing triggers activation of distinct inflammatory pathways in response to mosquito biting and to virus sensing. Whole mosquito saliva contains molecules that help control blood flow but also contains molecules that influence the course of the infection in the host. Immune cells resident in the skin and cells recruited to the bite site are susceptible to infection, hosting the first round of viral replication rather than being the first line of defence. Modifying the immune response to the saliva could translate in reduced viral replication in the skin and dramatically alter the course of the infection. ConserV Bioscience has designed a two-component vaccine: the first component is common to all _Aedes_ and _Culex_ mosquitoes and aims to stop the beneficial effects that mosquito saliva has on supporting viral infection; the second is a variable component that targets specific regions of viruses carried by mosquitoes. For this project, the focus is on Zika and chikungunya, but this approach could be applied to prevent other mosquito-borne diseases by only requiring a change of target in the second, virus specific component. The development of a vaccine that is aimed at disrupting the mechanism by which infection becomes established in the body, combined with pathogen specific targets, is highly innovative. This project will focus on the selection of the best antigens for the two vaccine components from an existing list of potential peptide candidates. The best candidates for the two components will be evaluated, separately and combined, for immunogenicity and efficacy against both Zika and chikungunya virus.

Coronaviruses are a family of viruses that can infect mammals and birds. As exemplified with SARS, MERS and COVID-19, viruses that infect animals can sometimes infect humans and because we have no preexisting exposure to them, this can lead to epidemics or pandemics. In many low- and-middle-income countries (LMICs) humans live near animals and the infrastructure around animal health and meat trade may not be sufficient to guarantee that an infection from animals will not spread into humans. The risk of further epidemics or pandemics starting in LMICs is high and the world needs to prepare for such likelihoods to mitigate the high mortality and the enormous burden to the global economy that such epidemics cause. ConserV specialises in antigen discovery and has identified immunoreactive protein regions, known as antigens, which are common to the coronavirus family of viruses and aiming to protect against a wide range of coronaviruses. Previous research demonstrated that the antigens delivered as synthetic peptides induce robust cellular and antibody responses. Efficacy was tested in a rabbit model of MERS, but viral replication and symptomatology were almost undetectable even in the unvaccinated group and therefore efficacy could not be determined. Also, the same antigens in the synthetic peptides were encoded in mRNA and encapsulated in nanoparticles for immunogenicity evaluation in mice, however, the immune responses on the synthetic peptides were superior to that of mRNA. This project will evaluate of the peptide formulation in suitable animal models developed at the University of Maryland. MERS-CoV does not readily infect mice and causes very mild infection in rabbits. By using mice that have incorporated the human receptor for MERS-CoV Spike protein, a clinically symptomatic infection can be developed in mice. We will evaluate efficacy against MERS-CoV but also against SARS-CoV-1 and SARS-CoV-2, so that the vaccine's breadth of protection can be demonstrated against a range of coronaviruses. We will also improve the mRNA construct aiming to achieve comparable immune responses to those induced by the peptide vaccine_. In silico_ approaches will be used to optimise the mRNA construct design which will be tested for translation _in vitro_ before evaluating immunogenicity. Large pharma companies are migrating towards mRNA vaccines due to the small footprint required for its manufacturing and ease of scalability. This technology also allows for combination of vaccines against different diseases in the same formulation decreasing the number of visits to the health practitioner.

Coronaviruses are a family of viruses that can infect mammals and birds. As has happened with SARS, MERS and Covid-19, viruses that infect animals can sometimes jump to infect humans and because humans have no protection against them, this can lead to epidemics or pandemics. In many low-and middle-income countries (LMICs) humans live in close proximity to animals and the infrastructure around animal health and meat trade may not be sufficient to guarantee that an infection from animals will not spread into humans. The risk of further epidemics or pandemics starting in LMICs is high and the world needs to prepare for that to mitigate the high mortality and the enormous burden to the global economy that diseases like Covid-19 cause. Covid-19 has drastically advanced the field of nucleic acid vaccines. It has taken decades to perfect the technology, devising methods to protect the nucleic acids and deliver them into the cells to allow synthesis of the protein encoded in the nucleic acid. This technology allows rapid vaccine design, targeting of specific cell types and extended protein production. ConserV specialises in antigen discovery and has identified immunoreactive protein regions, known as antigens, that are common to the coronavirus family of viruses. These antigens have been encoded in mRNA to design a vaccine that aims to protect against a wide range of coronaviruses. This project will address optimisation of the mRNA construct and formulation and dosage to maximise the immune response. The optimised vaccine will be tested for efficacy in a model of infection for MERS, which is a member of the coronavirus family that is in the priority list of viruses with epidemic/pandemic potential. ConserV will collaborate with Phion therapeutics, another UK company that has developed a novel method for nucleic acid delivery creating nanoparticles by interacting with RALA peptide. This technology allows intradermal delivery of nucleic acids offering immunological benefits and also removes the need for ultra-low temperature storage conditions. This makes the vaccine candidate suitable for a global roll-out.