Moderna mpox vaccine offers better protection against new strain

Mpox, an infectious disease spread by the monkeypox virus (MPXV), a member of the Orthopoxvirus  genus, first hit the headlines in 2022 when an outbreak in five Central African countries raised fears of a global catastrophe to match the COVID-19 pandemic. Those fears did not come to pass. 

Mpox re-entered headlines in August 2024 when World Health Organization Director-General Tedros Adhanom Ghebreyesus declared a public health emergency of international concern in response to rising case numbers in the Democratic Republic of the Congo and neighboring countries. 

This latest outbreak includes some key differences. MPXV has two genetic clades. While clade II was mainly responsible for outbreaks in 2022, clade I viruses have driven the spread in 2024. The new strain appears to be deadlier and is spreading faster (1). 

In a new study, researchers showed that the mRNA-based genetic tools that aided in rapidly producing vaccines against COVID-19 may now help suppress this latest mpox outbreak more effectively than currently available mpox vaccines (2). Scientists from the United States Army Medical Research Institute of Infectious Diseases, the National Institutes of Health, Boston University, and Moderna — who produced an mRNA vaccine against COVID-19 — led the research, which was published in Cell. 

In the 2022 mpox outbreak, a vaccine called the modified vaccinia Ankara (MVA) (brand name: JYNNEOS), which uses a weakened version of the vaccinia virus, protected people from the virus (3). MVA originated in the first vaccines used by Edward Jenner to combat smallpox in 1796. Galit Alter, an immunologist at Moderna and study coauthor, said that MVA is still a powerful tool. “This MVA vaccine does work incredibly well in really the major goal of these vaccines, which is to prevent death in the population,” she said. 

We're able to provide those antigens in such a way that they're able to stimulate an incredibly potent immune response.
- Alec Freyn, Moderna

However, the MVA vaccine has some notable associated setbacks including incomplete immunity, supply limitations, and an unclear ability to respond to more virulent clade I strains. The team turned to mRNA technology to develop an alternative. 

The researchers designed their new mpox mRNA vaccine, mRNA-1769, to target four MPXV antigens. One of the main benefits of the mRNA system is flexibility, said Peng George Wang, a biochemist at the Southern University of Science and Technology, who was not involved with the study. Scientists can quickly update the mRNA blueprint to address variant virus strains. 

The researchers not only designed mRNA-1769 quickly, but found that it protected macaques from severe disease more effectively than the MVA vaccine. Macaques immunized with mRNA-1769 had tenfold fewer mpox lesions than those given MVA. The vaccine reduced the animals’ viral load, and they were sick for shorter periods. A strong, vaccine-induced antibody response enabled this improved protection, said Moderna virologist and study coauthor Alec Freyn, who added that the team had built on decades of research to pick ideal antigens to encode in the vaccine. “We're able to provide those antigens in such a way that they're able to stimulate an incredibly potent immune response,” he said. 

Wang said that the results were “outstanding,” and that he felt “most certain” that the mRNA technology would offer protection against MPXV-like viruses. He highlighted research published earlier this year by scientists at Moderna’s rival BioNTech; their mRNA vaccine, BNT166, protected macaques from disease, although that study didn’t use an MVA comparison vaccine (4). 

Wang said that Moderna’s vaccine used a much higher dose than BNT166, which he said could raise the risk of side effects. Galit said that they calculated the current dose “so that we can really lend and drive the highest level of immunity to those individuals that are really on the front line.” Freyn said that the team is currently conducting dose de-escalation studies. “We may be able to find that balance between great immune responses, but also a better, more tolerable reactogenicity profile,” he added.

References

1. Americo, J.L., Earl, P.L., & Moss, B. Virulence differences of mpox (monkeypox) virus clades I, IIa, and IIb.1 in a small animal model. Proc Natl Acad Sci U S A  120, e2220415120 (2023). 
2. Mucker, E.M. et al. Comparison of protection against mpox following mRNA or modified vaccinia Ankara vaccination in nonhuman primates. Cell (2024).
3. Cohn, H. et al. Mpox vaccine and infection-driven human immune signatures: an immunological analysis of an observational study. Lancet Infect Dis  23, 1302-1312 (2023).
4. Zuiani, A. et al. A multivalent mRNA monkeypox virus vaccine (BNT166) protects mice and macaques from orthopoxvirus disease. Cell  187, 1363–1373.e12 (2024).