Novel mRNA vaccines that encode monkeypox virus proteins are showing promise in preclinical studies


In a recent study published in bioRxiv* Prepress server, researchers in China demonstrated effectiveness Three messenger ribonucleic acid (mRNA) vaccines for monkeypox virus (MPXV) combat lethal vaccinia virus (VACV) challenge in murine models.

Study: Novel mRNA vaccines encoding monkeypox virus M1R and A35R protect mice from a deadly virus challenge.  Image credit: NIAID

Stady: Novel mRNA vaccines encoding monkeypox virus M1R and A35R protect mice from a deadly virus challenge.. Image credit: NIAID

background

MPXV belongs to the Poxviridae family, which also has Variola (variola) virus and VACV. In the 1980s, live viral preparations of infectious vaccinia viruses eliminated smallpox globally. Although live attenuated virus vaccines, like all approved MPXV vaccines, express several viral proteins, this raises safety concerns.

Extracellular envelope virus (EEV) and mature intracellular virus (IMV) are the two infectious forms of MPXV; However, subunit vaccines using these profiles have shown better safety than live virus vaccines in small animal models. For example, Lai et al. showed that vaccination with Escherichia coli expressing A27L, a truncated surface protein of IMV, protected mice from lethal VACV challenge. Thus, there is a need to explore more MPXV antigens and combination strategies for better vaccines against MPXV.

In addition, more high-potency MPXV vaccines are needed since MPXV was declared a public health emergency by the World Health Organization (WHO) in July 2022. mRNA vaccine technology has shown promise against SARS-CoV-2. 2), as all vaccines based on mRNA technology demonstrate high efficacy and safety.

about studying

Taking into account the success of mRNA vaccines against SARS-CoV-2, the researchers of the current study developed three mRNA vaccines, VGPox1, VGPox2, and VGPox3, against MPXV. These vaccines express the MPXV EEV A35R protein and the IMV M1R protein, homologues of the A33R and L1R in VACV, respectively. While VGPox 1 and 2 were single mRNA particles encoding a fusion protein composed of the full-length A35R EEV and M1R, VGPox 3 was a mixture of mRNA-lipid particle (LNP) complexes encoding A35R and M1R, respectively. The only difference between the VGPox 1 and 2 was that the latter lacked the A35R’s stem area.

The researchers tested these three vaccines for humoral and cellular immunity against VACV and the protection it conferred against potentially fatal viral infection in mice. The team inoculated each mouse intranasally with 1×106 Plaque-forming units (PFU) of VACV-WR virus 36 days after vaccination.

They measured their body weight and monitored their symptoms daily until sacrifice. They sacrificed animals on the ninth day after virus challenge or when they had lost more than 15% of their weight. They harvested the animals’ lungs and ground them in a tissue homogenizer followed by three times freeze-thaw to release the virus from the cells. They then added supernatants at different dilutions to VeroE6 cells for plaque assay.

Results

Study results showed that all three mRNA vaccines elicited similar anti-A35R antibody levels, but only VGPox 1 and 2 produced higher anti-M1R antibody levels. Thus, only VGPox 1 and 2 immunized sera could neutralize live viruses at early time points. As expected, VGPox 3 vaccine was ineffective in in the laboratory Neutralization assay. Interestingly, VGPox 2 showed higher levels of total immunoglobulin G (IgG) versus M1R than VGPox 1 and VGPox 3 at all times. Also, VGPox1 had a lower protein expression level than VGPox 2′ T cells. However, the researchers were unable to determine how the difference in protein expression levels contributed to the IgG levels induced by the two vaccines.

conclusions

mRNA vaccines encoding A35R and M1R fusion forms (VGPox 1 and VGPox 2) effectively induced high levels of both A35R and M1R IgGs and neutralizing live virus in cell cultures at all time points. However, the mixture of these two mRNAs (VGPox 3) could not achieve the same results as VGPox 3-inducible M1R-specific antibodies at a later time. However, the three mRNA vaccines tested in the study conferred 100% protection during the virus challenge test. Possibly, when all test animals on day 36 were challenged with live virus, both anti-A35R and anti-M1R neutralizing antibodies Obtained by all three vaccines.

Neutralizing antibodies against EEV and IMV may confer protection against live virus challenge. Thus, it remains unknown how VGPox3 protected mice during a lethal virus challenge, despite late induction of M1R antibodies. In conclusion, due to the high homology between the vaccines and MPXV, both VGPox 1 and 2 could be effective mRNA vaccines against MPXV because they fully protect mice during a lethal vaccine virus challenge.

*Important note

bioRxiv It publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, directing clinical practice/health-related behaviour, or treated as hard information.

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