Groundbreaking research reveals a new single-stranded mRNA vaccine provides 100% protection against lethal MPOX challenge in mice, far outperforming conventional vaccines. Ta.
Study: Single-chain A35R-M1R-B6R trivalent mRNA vaccine protects mice against both mpox and vaccinia viruses. Image credit: Pormezz/Shutterstock.com
In a recent study published in eBioMedicine, researchers developed a single-chain trivalent messenger ribonucleic acid (mRNA) vaccine against both vaccinia (VACV) and mpx virus (MPXV).
background
Currently, three live attenuated VACV-based vaccines are available for mpx: ACAM2000, JYNNEOS, and LC16. These were originally smallpox vaccines but were later approved for mpox.
The replication-defective JYNNEOS vaccine is safer than the replication-competent VACV-based vaccine, including in immunocompromised patients, but one study found that only 63% of JYNNEOS vaccine recipients developed neutralizing antibodies against MPXV. I did.
Developing a new generation of vaccines against specific antigens based on mRNA technology may enhance the efficacy and safety of mpox vaccines. MPXV has two forms of infection: extracellular enveloped virus (EEV) and intracellular mature virus (IMV).
Research has provided candidate MPXV antigens such as A29L and M1R for IMV and B6R and A35R for EEV. These antigens showed varying levels of protection against poxviruses in mice.
research and discovery
In this study, researchers developed a single-strand trivalent mRNA vaccine against MPXV and VACV. First, we determined the essential antigens needed in the vaccine for optimal immunogenicity and efficacy.
Single-gene mRNA vaccines were synthesized using the MPXV B6R, M1R, or A35R genes. Soluble forms (sB6R, sM1R, and sA35R) of mRNA vaccines were also synthesized.
Mice were immunized with the vaccine or a mixture of 2/3 vaccines. Groups of mice vaccinated with A35R, sB6R, or sM1R developed antibodies against these antigens by day 27, whereas sA35R, B6R, or M1R recipients did not.
Mice immunized with a cocktail of all three soluble antigens produced the broadest spectrum of antibodies that bound to both sB6R and sM1R. The two-antigen cocktail induced antibodies that bound only to sM1R or sA35R.
Furthermore, plaque reduction neutralization assays showed that mice immunized with sM1R produced neutralizing antibodies against VACV IMV. Additionally, splenocytes in each group were stimulated with overlapping peptide pools of the three antigens. Enzyme-linked immunospot (ELISpot) assays showed that immunization with either the vaccine or the cocktail induced a strong intracellular interferon (IFN)-γ response.
The efficacy of the vaccine/cocktail was then evaluated based on body weight change and survival probability after lethal challenge with the VACV Western Reserve (WR) strain.
For each antigen, the group with a strong antibody response was well protected, with 100% protection in the A35R vaccine group. Of note, all sA35R recipients lacking detectable antibodies died within 5 days.
Furthermore, B6R did not induce antigen-specific antibodies but stimulated specific T cell responses. B6R vaccination also provided partial protection against VACV. A35R, B6R, and M1R cocktails also provided 100% protection. The team then designed three mpox vaccines (AMAB-wt, AMAB-C140S, and AMB-C140S) containing single-chain chimeric immunogens containing sB6R, sA35R, and sM1R.
Since sA35R alone does not induce antibodies, AMAB-C140S and AMAB-wt contained two copies of sA35R to increase A35R-specific immunogenicity. Structural prediction analysis exposed neutralizing antibody epitopes of these immunogens and showed that these immunogens were capable of inducing antigen-specific immunoglobulin G (IgG) antibodies.
Therefore, the research team evaluated the immunogenicity of three single-chain vaccines, using the live attenuated VACV Tian Tan (VTT) vaccine as a control.
All three vaccines induced high levels of specific IgG antibodies by day 27. The two AMAB vaccines induced significantly higher levels of A35R-specific IgG than the control or AMB-C140S vaccines. Furthermore, all single-chain vaccines induced neutralizing antibodies against MPXV and VACV-WR IMV.
ELISpot assays also confirmed that the three single-chain vaccines induced strong cellular immunogenicity. Cellular responses were more potent after stimulation with the A35R peptide pool, suggesting that sA35R may contain potent epitopes for T cell responses.
Finally, we evaluated the efficacy of single-chain vaccines by administering MPXV or VACV-WR to mice. Mice administered empty lipid nanoparticles (LNPs) died within 4 days of VACV-WR challenge.
In contrast, mice receiving any single-chain vaccine showed 100% protection after VACV-WR challenge with minimal weight loss.
Additionally, mice receiving empty LNPs showed >5% weight loss after MPXV challenge, whereas the vaccine group did not. Additionally, viral loads in the spleen, ovaries, and lungs of vaccinated mice were orders of magnitude lower compared to LNP recipients.
conclusion
In summary, this study developed three trivalent mRNA vaccines containing soluble B6R, M1R, and A35R antigens of MPXV in a single polypeptide chain and evaluated their safety and immunogenicity.
These vaccines showed effective neutralization against both VACV and MPXV, provided complete protection against lethal VACV-WR challenge, and significantly reduced viral load after MPXV or VACV-WR challenge. I let it happen.
