SARS-CoV-2-derived RNA replicons as safe and effective vaccines

Area of Science:

• Virology
• Immunology
• Vaccine Development

Background:

• Severe acute respiratory syndrome 2 (SARS-CoV-2) poses a significant global health threat.
• Existing vaccine technologies face challenges in eliciting broad and durable immunity.
• Development of novel vaccine platforms is crucial for pandemic preparedness.

Purpose of the Study:

• To construct and evaluate a novel RNA replicon (RR) vaccine candidate derived from SARS-CoV-2.
• To assess the immunogenicity, safety, and protective efficacy of the RR vaccine in preclinical models.
• To investigate the potential of RRs for inducing mucosal immunity and cross-protection against SARS-CoV-2 variants.

Main Methods:

• Genetic engineering using bacterial artificial chromosomes to create SARS-CoV-2-derived RNA replicons (RRs) with deletions in non-essential genes.
• In vitro characterization of RR-infected cells for virus-like particle formation and RNA replication.
• Intranasal immunization of transgenic mice expressing human ACE2 with the RR vaccine candidate.
• Assessment of humoral and cellular immune responses, including antibody production (IgG, IgM, IgA) and T cell responses (CD4+, CD8+, memory T cells).
• Evaluation of vaccine safety through observation of inflammatory reactions and side effects.
• Testing of an updated RR expressing the XBB.1.5 spike protein for neutralization of homologous virus and protection against variants.

Main Results:

• The RR vaccine candidate formed non-secreted virus-like particles, enhancing vaccine safety.
• RRs maintained RNA production encoding key viral proteins (S, M, N) for extended periods.
• Intranasal immunization induced robust respiratory mucosal immunity and systemic antibody responses against SARS-CoV-2 proteins.
• Immunization conferred protection against SARS-CoV-2 challenge, eliciting comprehensive humoral and cellular immunity.
• Coinfection demonstrated significant inhibition of wild-type SARS-CoV-2 replication by the RR vaccine.
• The RR vaccine exhibited minor inflammatory reactions, no major side effects, and good temperature stability.
• An updated RR expressing XBB.1.5 spike protein generated neutralizing antibodies and provided full protection against recent SARS-CoV-2 variants.

Conclusions:

• The engineered SARS-CoV-2 RNA replicon (RR) represents a promising and safer vaccine candidate.
• Intranasal administration of the RR vaccine effectively induces both mucosal and systemic immunity against SARS-CoV-2.
• The RR vaccine demonstrates potential for broad protection against current and emerging SARS-CoV-2 variants, offering a valuable tool for future pandemic preparedness.