Evaluating the safety and efficacy of a smallpox vaccine for preventing mpox

In recent years, the world has seen a surge in new and deadly infectious diseases, posing a major threat to global health. Outbreaks of COVID-19, H1N1 (swine flu), Ebola, Zika, and monkeypox are a stark reminder of our vulnerability. While some of these viruses are new and relatively unknown, others, like the monkeypox virus (mpox virus or MPXV) have been around since the 1970s but have been endemic to parts of Africa. However, the recent global outbreak of mpox -- caused by a newly identified variant that is more infectious than previous strains -- has raised concerns across the world, highlighting the urgent need for an effective, safe, and multivalent vaccine.

LC16m8 is an attenuated vaccinia virus strain that was originally developed in Japan for smallpox and was later approved for monkeypox in 2022. LC16m8 has demonstrated efficacy and immunogenicity in preclinical and clinical settings with non-human primates, confirming its potential against MPXV. However, further immunological and pathological analyses are required to fully characterize its properties in order to develop broadly effective mpox vaccines. To address this paucity in research, a new study evaluated the immunogenicity and safety of LC16m8 across three animal species. The study was led by Associate Professor Kouji Kobiyama, from the Division of Vaccine Science, Institute of Medical Science, The University of Tokyo, along with Professor Ken J. Ishii, also from The University of Tokyo. This study was made available online on April 15, 2025, and was published in Volume 115 of the journal eBioMedicine on May 1, 2025.

"We evaluated the immunogenicity of LC16m8 in three mouse strains and human specimens and conducted pathological analysis using a non-human primate model," says Dr. Kobiyama. The team vaccinated three strains of mice (BALB/c, C57BL/6J, and CAST/EiJ) with LC16m8 and assessed the vaccine-induced immune responses and how well it protected the mice against mpox. Similarly, they administered a high dose of LC16m8 in cynomolgus monkeys and monitored them for safety by measuring changes in body weight, temperature, and any local or systemic reactions. Finally, they vaccinated healthy adult volunteers with LC16m8 and studied their blood samples for immune responses, including the presence of neutralizing antibodies against different MPXV strains.

Their experiments showed that LC16m8 induced strong humoral responses in all three mouse models and directly targeted MPXV antigens. This promoted germinal center B cells and follicular helper T cells that are essential for long-term immunity. Furthermore, the vaccinated CAST/EiJ mice exhibited reduced viral loads in the lung tissue, proving the vaccine's efficacy. In the cynomolgus monkeys, the vaccine induced localized pox lesions without significantly affecting their weight, temperature, or hematological parameters, signifying the vaccine's safety. Finally, in humans, the vaccine enhanced neutralizing antibodies against multiple MPXV variants with no serious adverse events in the follow-up period, suggesting LC16m8's broad coverage and reinforcing its safety.

These results underscore the viability of LC16m8 as a safe, effective, and scalable choice for mpox vaccination. Furthermore, the cross-species, comprehensive analysis employed in this study provides a blueprint for developing next-generation vaccines against other poxviruses and emerging pathogens, potentially shortening response times from outbreaks to regulatory approvals to widespread public inoculation.

"Since our research validates the efficacy and safety of LC16m8, it could accelerate approval and deployment of this vaccine in regions and populations highly susceptible to mpox outbreaks, particularly in Africa. In the long run, vaccinating more people could see a significant reduction in mpox transmission rates, alleviating the pressures caused by an outbreak on healthcare systems, with the possibility of completely eliminating mpox as a public health threat," adds Dr. Kobiyama.

Of course, further studies are still required to optimize the vaccine's effectiveness and safety, particularly in naïve and immunocompromised populations and to explore alternative vaccine platforms. But for now, this study lays down the foundation for transforming global management strategies for mpox and other infectious diseases. "Our work can shape and guide the development of a permanent global surveillance and response system for new infectious diseases, creating more resilient societies that are better prepared for future pandemic threats," concludes Dr. Kobiyama.