Research roadmap for coronavirus vaccine development

Download 202402 Draft Coronavirus Vaccine research roadmap Final

Host-pathogen interactions

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Dependencies

18 Challenge models

Next steps

Host-pathogen interactions

Research Question

To improve understanding of the detailed mechanisms of host-pathogen interactions that unfold during the animal coronavirus life cycle, from entry to replication, and eventual persistence or clearance. How much can be applied from SARS-CoV-2 and what is clearly different. Ultimately, this knowledge would be crucial for improving vaccine designs by allowing the targeting of key stages of viral entry, replication, and immune evasion etc. To allow the prevention of severe disease outcomes. Additionally, what drives resistance to infection and rapid clearance in some hosts, which can guide future antiviral therapies and spillover prevention
Also, we need a better understanding of recombination and the speed of recombination?

Research Gaps and Challenges

Systemic infection mechanisms: It is unclear why some coronaviruses become systemic in certain cases, leading to severe disease and why some have gastrointestinal or respiratory tropism (or both). Understanding these mechanisms is critical for targeting vaccine responses to prevent systemic spread, e.g. by driving route of administration decisions. Deletion in NTD of spike (PRCV/TGEV), but also PRCV has partial deletion in accessory proteins – explore more differences outside of Spike too
Innate immunity, e.g. interferon-stimulated genes (ISGs): The role of ISGs in restricting coronavirus replication is not fully understood, limiting our ability to exploit these pathways for antiviral strategies and/or for enhanced rational design of vaccines. In addition, knowing how ISG variability between species affects outcome could also help
Cell entry pathways: The entry pathway of several animal coronaviruses, including infectious bronchitis virus (IBV), bovine coronavirus (BCoV), and swine acute diarrhoea syndrome coronavirus (SADS-CoV), is poorly characterized. Mapping these entry pathways is crucial for understanding viral tropism and improving vaccine efficacy as well as for the development of easy-to-use accompanying tests
Non-structural and accessory proteins: The functions of many non-structural proteins (NSPs) and accessory proteins in the viral life cycle are still unknown. These proteins could be potential targets for therapeutic interventions and vaccine development (see other sections on immunomodulators etc.)
In vitro study limitations: Some coronaviruses are difficult to propagate in cell culture, limiting their study in vitro and making it challenging to explore the full life cycle or test antiviral therapies, as well as the development of cheap LAVs and other easy to use tools
Understanding animal reservoirs: Animal-animal spread of coronaviruses and the mechanism needed to get to humans requires understanding, as well as the need to better understand emergence of new pandemic coronaviruses

Solution Routes

Investigating severe disease factors: Focus on identifying factors (e.g., viral genes or host conditions) that contribute to the severity of coronavirus infections, including how viral load, immune evasion strategies, and host responses differ between mild and severe cases.
Innate immune response to infection: Focus on studying the innate response, e.g. ISGs and their roles in restricting animal coronavirus replication. This can be potentially exploited to develop therapeutic strategies that enhance these natural host defences during vaccination (additional PAMPS, vectored cytokines etc.)
Mapping cell entry pathways: Further research on cell entry pathways, especially for under studied animal coronaviruses, is critical in particular the identification of novel entry factors
Organoid and ex vivo models: To study coronaviruses that are difficult to propagate in continuous cell cultures, organoid and ex vivo tissue culture models could be developed. These systems provide better simulation of natural sites of viral replication and enable deeper investigation into viral life cycles and can potentially be augmented with immune cells to even understand vaccine responses or correlated of protection
Functional omics of coronaviruses: Use omics to determine the functions of NSPs and accessory proteins, to identify conserved mechanisms of pathogenesis and potential targets for antiviral drugs or vaccines. Basic research should focus on the roles of these proteins in immune evasion, viral replication, and host cell manipulation

Dependencies

Cross-species viral research: Comparative studies of different coronavirus species and their host could be needed to determine if all viral families share the same risk of zoonotic spillover and identify any unique host-pathogen interactions that contribute to higher risk. This would support other aspects and make sure the questions asked do not become too big, so that they become impossible to answer
Advanced viral modeling: Development of more accurate animal and cell culture models that can simulate the full life cycle of coronaviruses is critical. Improved modeling systems will allow for better testing of antiviral treatments and vaccine candidates

State Of the Art

Entry mechanisms: Coronaviruses enter host cells via spike (S) protein binding to cell surface receptors such as ACE2, DPP4, and APN. This is well established for some animal coronaviruses but behind the human field for others. For example, knowing the IBV receptor would be a game changer for that field
Innate pathways: It has been shown that certain interferon-stimulated genes (ISGs) can restrict coronaviral replication, but how this extends to animal viruses is not very clear
Disease severity factors: Comorbidities and age have been shown to increase the probability of severe disease, but it is not clear how this applies to other animals. For example, the situation in cats is very complicated, with overlapping vaccination etc. Is it the same for other species? Projects What activities are planned or underway?