Rapid protection from lethal Orthopoxvirus infection following vaccination with mRNA-LNP encoding the Type I Interferon Binding Protein 2259797

Abstract Introduction Orthopoxviruses (OPVs), such as monkeypox, pose ongoing public health threats, especially since the global herd immunity has declined following the cessation of routine smallpox vaccination. Current vaccine strategies have limitations due to safety and short-lived immunity. Most anti-viral vaccines aim to induce antibodies (Abs) that bind to structural viral proteins, preferentially those that can neutralize the viral particle. The Type I IFN-binding protein (IFN-I bp) is a highly conserved non-structural protein present in all OPVs, an immune evasion protein, and is essential for their pathogenicity. It has been previously shown that mice vaccinated with recombinant IFN-I bp or passively immunized with anti-IFN-I bp monoclonal antibodies (Abs), are protected from lethal challenge with the mouse OPV ectromelia virus (ECTV), a classic model for human smallpox and monkeypox infections. Methods We made mRNA-lipid nanoparticle (mRNA-LNP) vaccine encoding IFN-I bp. We evaluated Abs responses by ELISA, and protective efficacy by challenging the immunized mice with ECTV in the footpad or with the OPV vaccinia virus intranasally. Results We found that a single immunization of 5 ug of mRNA-LNPs encoding ECTV’s IFN-I bp induced much higher titers of IgG antibodies (as opposed to IgM) as early as six days post-immunization than control mRNA-LNP vaccines. Notably, vaccinated BALB/c and TLR9-deficient mice challenged with ECTV or VACV eight days post-immunization were fully protected from viral lethality. Conclusion These data indicate that the IFN-I bp is a promising antigen for OPV vaccines, particularly when rapid protection is crucial, such as during an epidemic. Ongoing studies aim to determine the mechanisms underlying rapid IgG induction. Funding Source grant Topic Categories Vaccines and Immunotherapy (VAC)