A Breakthrough in Circular RNA Vaccines: B6M1 Bivalent Immunogen Opens a New Era for Smallpox Virus Vaccine Development

In today’s complex global public health landscape, every innovation in vaccine technology can become a decisive turning point in controlling infectious diseases. A recent study published in Cell Reports by a collaborative team from Shanxi Agricultural University, Peking University, Zhejiang University, and the Institute of Microbiology, Chinese Academy of Sciences, reports a circular RNA (circRNA) vaccine encoding a chimeric B6-M1 bivalent immunogen, demonstrating strong protective immunity against monkeypox virus (MPXV). This research highlights the potential of circRNA technology in vaccine development and offers a promising direction for vaccines targeting Orthopoxviruses, including smallpox.

1. Global Context: Monkeypox Outbreaks Highlight the Need for Vaccine Innovation

Since 2022, MPXV has caused repeated outbreaks worldwide and has been declared a “Public Health Emergency of International Concern (PHEIC)” by the World Health Organization twice. By August 2025, over 160,000 confirmed cases have been reported across 140 countries.

Although two cross-protective vaccines based on attenuated vaccinia virus (VACV)—ACAM2000 and JYNNEOS—are currently available, they were not specifically designed for MPXV. Their live-virus nature and potential side effects limit safety and efficacy. Consequently, next-generation RNA vaccines that are highly safe and precisely designable have become a major research focus.

2. Technological Innovation: Combining CircRNA with a Bivalent Immunogen

The researchers developed a circRNA platform encoding a chimeric immunogen comprising two key MPXV antigens: B6 and M1.

B6 originates from the extracellular enveloped virus (EEV) and is crucial for viral spread between hosts.

M1 comes from the intracellular mature virus (IMV) and plays a key role in viral dissemination within host cells.

By linking these antigens into a single chimeric construct, the circRNA vaccine can trigger dual immune activation in a single formulation, enhancing cost-effectiveness and clinical feasibility. Moreover, the naturally closed-loop structure of circRNA provides high stability and low immunogenicity, avoiding the need for chemical modifications required by traditional linear mRNA vaccines.

3. Experimental Results: Robust Immune Responses and Complete Protection

Preclinical studies in mouse models demonstrated that the CircRNA-B6M1 vaccine:

Induced high titers of neutralizing antibodies with significant cross-reactivity against both MPXV and VACV;

Activated T-cell responses, including IFN-γ, IL-2, and IL-4, generating comprehensive humoral and cellular immunity;

Achieved 100% protection in lethal virus challenge experiments, outperforming both control and single-antigen vaccines;

Showed excellent safety, with no notable changes in body weight, organ pathology, or liver/kidney function.

These results indicate that CircRNA-B6M1 can provide protective immunity comparable to or even exceeding that of conventional vaccines, without the need for live virus.

4. Outlook: The mRNA 2.0 Era of Vaccine Platforms

The success of mRNA vaccines has ushered in the “programmable vaccine era,” and circRNA technology—often described as mRNA 2.0—promises to overcome some of their limitations. Compared with linear mRNA, circRNA offers:

Longer-lasting antigen expression; Lower immunogenic side effects; Greater suitability for rapid industrial-scale production.

This study demonstrates that circRNA can efficiently express multivalent antigens and precisely induce immune responses. Its design principles can be extended to emerging infectious diseases, cancer vaccines, and veterinary vaccines. As corresponding author Dr. Zhida Liu noted: “This work provides critical validation for translating the circRNA platform from basic research to clinical application.”

5. Industry Impact: A Paradigm Shift in Vaccine Development

CircRNA vaccines represent not only a novel molecular construct but also a shift in vaccine industrialization thinking. They integrate antigen engineering, RNA design, and nanodelivery technologies, significantly enhancing immune breadth and safety while reducing production costs.

As circRNA synthesis and delivery systems advance, this platform could become a core technology for the next generation of rapid-response vaccines.

Conclusion

From mRNA to circRNA, vaccine technology is evolving at an accelerated pace. This groundbreaking research by a Chinese team demonstrates international leadership in next-generation RNA vaccines and provides new solutions for tackling re-emerging Orthopoxviruses such as MPXV and smallpox. The success of CircRNA-B6M1 may mark a key milestone in ushering humanity into the “Circular RNA era” of vaccines.