tetano
Editor, Senior Moderator
Front Immunol
. 2026 Jan 22:16:1718740.
doi: 10.3389/fimmu.2025.1718740. eCollection 2025.
Structure-guided design of a bivalent SARS-CoV-2 mRNA vaccine with NTD stabilizing mutations enhances broad immunity
Jinah Yeo[SUP] #[/SUP][SUP] 1 [/SUP], Mi-Ran Yun[SUP] #[/SUP][SUP] 1 [/SUP], Seo-Yeon Kim[SUP] #[/SUP][SUP] 1 [/SUP], Jong-Hyun Seok[SUP] 2 [/SUP], Ji Hyang Jeon[SUP] 1 [/SUP], Taeyoung Lee[SUP] 1 [/SUP], Jeonghun Kim[SUP] 2 [/SUP], Kisoon Kim[SUP] 2 [/SUP], Man-Seong Park[SUP] 2 [/SUP], Dokeun Kim[SUP] 3 [/SUP], You-Jin Kim[SUP] 1 [/SUP]
Affiliations
SARS-CoV-2 evolution, particularly the emergence of Omicron variants, has challenged vaccine efficacy, necessitating antigens with broad and variant-specific protection. To design mRNA vaccine antigens with broad-spectrum immunity and enhanced stability, we developed two spike antigens using in silico optimization: Css_dsg S, the ancestral strain-Delta variant consensus with stabilizing mutations, and Omi_dsg S, an Omicron-adapted design. Computational analysis identified two critical N-terminal domain stabilization sites consistently enhancing protein expression across variants, suggesting their potential as universal stabilizing elements. Css_dsg S elicited robust IFN-γ T cell responses and significantly elevated neutralizing antibody titers against variants in BALB/c mice. Omi_dsg S induced strong immune responses in vivo. A bivalent mRNA vaccine combining both antigens elicited superior neutralizing antibody responses and conferred enhanced protection against BN.1 and BA.5 challenges in K18-hACE2 mice. These findings support computationally optimized spike antigens, particularly the bivalent formulation, as a promising strategy for next-generation vaccines against SARS-CoV-2 variants.
Keywords: SARS-CoV-2; cross-variant immunity; mRNA vaccine; spike protein; stabilizing mutations; structure optimization.
. 2026 Jan 22:16:1718740.
doi: 10.3389/fimmu.2025.1718740. eCollection 2025.
Structure-guided design of a bivalent SARS-CoV-2 mRNA vaccine with NTD stabilizing mutations enhances broad immunity
Jinah Yeo[SUP] #[/SUP][SUP] 1 [/SUP], Mi-Ran Yun[SUP] #[/SUP][SUP] 1 [/SUP], Seo-Yeon Kim[SUP] #[/SUP][SUP] 1 [/SUP], Jong-Hyun Seok[SUP] 2 [/SUP], Ji Hyang Jeon[SUP] 1 [/SUP], Taeyoung Lee[SUP] 1 [/SUP], Jeonghun Kim[SUP] 2 [/SUP], Kisoon Kim[SUP] 2 [/SUP], Man-Seong Park[SUP] 2 [/SUP], Dokeun Kim[SUP] 3 [/SUP], You-Jin Kim[SUP] 1 [/SUP]
Affiliations
- PMID: 41660617
- PMCID: PMC12872526
- DOI: 10.3389/fimmu.2025.1718740
SARS-CoV-2 evolution, particularly the emergence of Omicron variants, has challenged vaccine efficacy, necessitating antigens with broad and variant-specific protection. To design mRNA vaccine antigens with broad-spectrum immunity and enhanced stability, we developed two spike antigens using in silico optimization: Css_dsg S, the ancestral strain-Delta variant consensus with stabilizing mutations, and Omi_dsg S, an Omicron-adapted design. Computational analysis identified two critical N-terminal domain stabilization sites consistently enhancing protein expression across variants, suggesting their potential as universal stabilizing elements. Css_dsg S elicited robust IFN-γ T cell responses and significantly elevated neutralizing antibody titers against variants in BALB/c mice. Omi_dsg S induced strong immune responses in vivo. A bivalent mRNA vaccine combining both antigens elicited superior neutralizing antibody responses and conferred enhanced protection against BN.1 and BA.5 challenges in K18-hACE2 mice. These findings support computationally optimized spike antigens, particularly the bivalent formulation, as a promising strategy for next-generation vaccines against SARS-CoV-2 variants.
Keywords: SARS-CoV-2; cross-variant immunity; mRNA vaccine; spike protein; stabilizing mutations; structure optimization.