A two-component mRNA vaccine combining B-cell and T-cell immunogens of SARS-CoV-2 induces humoral and cellular immune responses in mice

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Abstract
INTRODUCTION. Despite the effectiveness of existing COVID-19 vaccines, the emergence of new SARS-CoV-2 variants necessitates the development of immunogens capable of eliciting a broad, cross-reactive immune response. A promising approach is the development of mRNA vaccines that induce both humoral and T-cell responses, which could provide protection against viral variants that evade neutralizing antibodies. AIM. This study aimed to investigate the immunogenicity of an experimental two-component mRNA vaccine encoding an artificial multi-epitope T-cell immunogen and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, to demonstrate the potential of this vaccine to elicit a broad, cross-reactive response required for effective protection against highly variable viruses. MATERIALS AND METHODS. The mRNAs were synthesized in vitro : mRNA-RBD encoded the RBD, and mRNA-BSI encoded the multi-epitope T-cell immunogen. The vaccine mRNA was encapsulated in lipid nanoparticles (LNPs); particle size was assessed using dynamic light scattering. BALB/c mice (24 females) were divided into 4 groups of 6 animals each. For immunization, 10 μg of mRNA-LNP (either alone or as a mixture of the two constructs) was administered intramuscularly twice, 3 weeks apart. Humoral response was evaluated by titers of virus-specific and neutralizing antibodies; T-cell response was assessed by ELISpot (spot-forming units, SFUs), sandwich ELISA, intracellular cytokine staining, and flow cytometry. RESULTS. The LNPs encapsulating the vaccine mRNA had a size of 115.4–123.7 nm and a low polydispersity index (0.165–0.211). The two-component vaccine (mRNA-RBD + mRNA-BSI) induced high titers of RBD-specific antibodies (1:131,322) and neutralizing antibodies against the Wuhan-Hu-1 strain (1:3,620) and the Omicron BA.5.2 strain (1:718). The T-cell response in the two-component vaccine group was characterized by high IFN-γ production: the number of IFN-γ-producing lymphocytes and the IFN-γ concentration in splenocyte culture were 660 SFUs/million cells (ELISpot) and 990 pg/mL (ELISA), respectively; both significantly exceeded the corresponding values in the mRNA-RBD group (343 SFUs/million and 60 pg/mL, respectively). Intracellular staining revealed an increased proportion of cytokine-producing CD4 + and CD8 + T cells (IFN-γ, IL-2, TNF-α) in all immunized groups. CONCLUSIONS. The combination of B-cell and T-cell immunogens in a two-component mRNA vaccine enhances the humoral response and promotes a broad T-cell response, ensuring effective recognition of emerging SARS-CoV-2 variants. The data support the potential of this platform for the development of vaccines against highly variable viral infections.

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