Research roadmap for coronavirus vaccine development

Download 202402 Draft Coronavirus Vaccine research roadmap Final

Attenuated organisms

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Dependencies

Next steps

3 Rationally attenuated candidates
3A Safety
3B Delivery route
3C Delivery platform
3D Efficacy in challenge model
9 Adjuvant

Attenuated organisms

Research Question

What are we trying to achieve? The goal is to generate livestock (companion animals possibly) that are genetically engineered to be refractory to coronavirus infections. By modifying host genetics to prevent viral entry, replication, or transmission, we could create disease-resistant animal populations thus negating the need for vaccines

Research Gaps and Challenges

Genetic modifications and unintended consequences: Genetic engineering for virus resistance must ensure that the modifications do not lead to unintended health effects or compromised immune responses in livestock. Identifying the right gene targets that block coronavirus infection without affecting the animal’s overall health or performance is crucial. Weigh up the risk of using GMO with benefits. Focus on resilient animals at the immune level, rather than making animals highly resistant to a virus at the entry level, which could instead drive selection of more resistant strains or of different pathogens (e.g. bacteria/parasites). Also, it is important to determine how resistant to drought or high temperatures, changes in climate these animals will be. Also important to determine the stability of the genetically modified organisms (GMOs)
Restrictions in use: Will use be restricted to big commercial companies? What does this mean for small holders?
Ethical and regulatory concerns: The use of GMOs in food-producing animals raises ethical and regulatory challenges, including consumer acceptance and marketability of genetically engineered livestock products. Regulatory frameworks may need to be updated to accommodate these advancements
Viral escape mechanisms: There is a potential risk that coronaviruses could evolve to bypass the engineered resistance mechanisms, rendering the genetic modifications ineffective over time. Continuous monitoring and adaptation would be necessary
Lack of field data: While genetic engineering for viral resistance has been successful in model systems, there is a lack of large-scale field data for coronavirus resistance in livestock. Long-term studies are needed to validate the durability and safety of this approach

Solution Routes

Gene editing for receptor modification: One of the most promising strategies involves using CRISPR or other gene-editing technologies to modify or delete host receptor genes (e.g., ACE2 or DPP4)
Genome-wide association studies (GWAS): Conduct GWAS to identify naturally occurring genetic variants that confer resistance to coronaviruses in livestock populations. These findings can be used to guide targeted gene editing efforts
Synthetic biology: Advanced synthetic biology approaches could be used to introduce antiviral proteins or pathways into livestock genomes, allowing animals to detect and destroy coronaviruses before they can establish an infection
Epigenetic modifications: Explore whether heritable epigenetic changes can be induced to create viral resistance without altering the underlying DNA sequence. This might be a more flexible and reversible approach compared to permanent genetic engineering

Dependencies

Regulatory approval for genetically modified livestock: Streamlined and updated regulatory pathways are required for the approval of genetically engineered livestock. Regulations must address safety concerns, potential environmental impacts, and ethical issues surrounding the use of GMOs in agriculture
Public acceptance: Educational campaigns and transparent communication about the safety and benefits of genetically modified livestock are necessary to gain public acceptance, particularly concerning animal welfare and food safety
Surveillance for viral escape: Once genetically engineered livestock are in use, surveillance systems must be put in place to monitor for any viral adaptations or escape mechanisms that could render the modifications ineffective. And this could be selected for in the viral population if the resistance is not absolute

State Of the Art

PRRS-resistant pigs (not coronavirus): One of the most successful examples of genetic engineering for viral resistance is the development of pigs that are resistant to porcine reproductive and respiratory syndrome virus (PRRSV). These pigs were engineered to lack the CD163 receptor, which PRRSV uses for cell entry, making them refractory to infection. This model has paved the way for similar strategies targeting coronaviruses in livestock. Research is ongoing into modifying ACE2 and DPP4 receptors in animal models to prevent infection by coronaviruses like SARS-CoV-2 and MERS-CoV