Broadly cross-reactive mRNA COVID-19 vaccine encoding trimeric RBDs and NSP12 mitigates immune imprinting

Area of Science:

• Virology
• Immunology
• Vaccine Development
• Molecular Biology

Background:

• SARS-CoV-2 variants, particularly mutations in the spike protein, evade antibody recognition from prior infection or vaccination.
• Original antigenic imprinting can weaken neutralizing antibody responses to new variants after updated vaccine administration.
• T cells offer cross-reactivity against SARS-CoV-2 variants due to conserved epitopes.

Purpose of the Study:

• To design next-generation mRNA vaccines that overcome variant immune evasion and original antigenic imprinting.
• To develop vaccines eliciting broad neutralizing antibody and cross-reactive T cell responses.
• To investigate a strategy for imprinting-resistant SARS-CoV-2 vaccines.

Main Methods:

• Designed mRNA vaccines encoding single-chain heterotrimers of receptor-binding domains (RBD) from natural variants (RBD-VOI) and consensus sequences (RBD-Cons).
• Developed a second mRNA component encoding the viral polymerase NSP12 to enhance cellular immunity.
• Evaluated neutralizing activity against omicron subvariants and immune imprinting effects.

Main Results:

• The RBD-Cons vaccine demonstrated broad neutralizing activity against omicron subvariants.
• Using RBD-Cons as a booster mitigated immune imprinting after Wuhan strain priming.
• The NSP12 component induced a cross-reactive T cell response.

Conclusions:

• A rational strategy for next-generation, imprinting-resistant SARS-CoV-2 vaccines was developed.
• Combining RBD-consensus and NSP12 components offers enhanced protection against evolving viral variants.
• The designed mRNA vaccines show promise for overcoming challenges posed by SARS-CoV-2 evolution.