Research roadmap for coronavirus vaccine development

Identity of protective antigens

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Identity of protective antigens

Research Question

Determine which antigens (or combination of antigens) give better protective and long-term immunity. In particular, we aim to identify protective antigens beyond the spike (S) protein for animal coronavirus vaccines, e.g. envelope (E), membrane (M), and nucleocapsid (N) proteins. The goal is to explore whether these alternative proteins can induce robust T-cell responses or non-neutralizing immune responses, such as antibody-dependent cellular cytotoxicity (ADCC), enhancing the breadth and durability of vaccines and whether they should be included with S in novel vaccines?
Identification of the appropriate protective antigen is probably the most important factor above vaccine platforms, mechanism of delivery, etc.

Was SARS2 a soft target? Need to develop a better understanding of expression strategies for more difficult/less amenable viral S glycoproteins – are all coronaviruses likely to be suitable and will all evolve in the way SARS2 has under vaccine selection (without evolving into an entirely new serotype)
Limited knowledge on non-spike proteins: While the spike protein is well studied, the protective potential of other viral proteins (E, M, N) is less understood, especially in generating cellular immunity. Research role on ADCC on non-spike proteins (but also non-neutralising Abs induced by spike?)
T-cell response: Current vaccines often focus on neutralizing antibodies, but inducing strong T-cell responses may be critical for long-term protection. Are the alternative antigens suitable T-cell targets?
Cross-species variation: Non-spike antigens may elicit varied immune responses across different species, complicating vaccine design for diverse animal hosts
Stability of antigen: Industry does not have the time/capability to study the best formulation of antigen so more basic research is needed for this – antigen structure, stability, optimal nucelotides/amino acids/UTRs etc
Antigen combinations: Multivalent antigens present a challenge

Immunogenicity studies: Investigate the T-cell and Ab (e.g. ADCCinducing potential) of E, M, N proteins through immunization studies and models
Multivalent vaccine design: Incorporate these alternative antigens into vaccine candidates to boost both humoral and cellular immunity. Combining antigens may broaden the response against different strains including more conserved structural proteins/epitopes, and may induce greater levels of protection and more cell-mediated immune responses. Also, it would be beneficial to have multivalent vaccines across different coronaviruses
Adjuvants and delivery systems: Use adjuvants or viral vector systems to enhance the presentation of non-spike proteins to the immune system.

Vaccine strategies should be tailored based on immune responses we would like to induce. Mapping epitopes on non-spike proteins from animal coronaviruses that are recognized by T cells or involved in non-neutralizing responses could help underpin vaccine design (what is known from SARS2 and is it applicable?). Study of immune responses to non-spike proteins across species would be required to ensure cross protection