Next-Generation Mpox Vaccine Shows Promise for Durable Protection and Future Outbreak Preparedness

Although mpox no longer dominates headlines as it did during the 2022 global outbreak, the virus continues to circulate, new clades continue to emerge, and public health experts warn that preparedness remains essential. Current vaccines have helped reduce disease burden, but questions remain about the durability of protection, the need for booster doses, and how best to respond to future outbreaks caused by evolving orthopoxviruses. At the same time, researchers are developing next-generation vaccine candidates designed to provide broader, longer-lasting immunity while addressing limitations of existing options.

In this interview with Infection Control Today^® (ICT^®), Sina Bavari, PhD, executive vice president of infectious disease research and development at Tonix Pharmaceuticals, discusses new preclinical findings supporting the investigational vaccine TNX-801, the importance of improved animal models for understanding mpox virulence, lessons learned from the COVID-19 pandemic, and why infection preventionists should continue to view mpox preparedness as an important component of long-term infectious disease planning.

ICT: Your study provides new evidence supporting TNX-801 as a potential mpox vaccine. What are the most significant findings from the Journal of Virology paper, and how do they advance our understanding of protection against mpox?

Sina Bavari, PhD: The most significant finding from the Journal of Virology publication is that the new animal models identified can help open the door for investigators to better understand mpox infection, pathogenesis, and differences in virulence across mpox clades. The study found that the clade IIb isolate associated with the 2022 outbreak was approximately 100- to 100,000-fold less virulent than clade IIa isolates in multiple murine models.

For Tonix, these findings are important because they help address a major gap in mpox research: the need for better tools to rapidly characterize emerging mpox subclades and evaluate potential medical countermeasures, including vaccines. Mpox continues to evolve as a serious health challenge, and the ability to understand how different subclades behave is essential to developing vaccines that may support preparedness against both current and future outbreaks.

This work reflects Tonix's commitment to addressing serious health challenges that remain underserved despite their significant burden on patients, families, and society. The findings support Tonix's efforts to advance innovative approaches to disease prevention and infectious disease research, where unmet needs remain significant. TNX-801 reflects part of that commitment within Tonix's infectious disease portfolio.

TNX-801 is being developed as a live, attenuated, minimally replicative horsepox-based investigational vaccine candidate for the prevention of mpox and smallpox. TNX-801 is an investigational one-dose orthopoxvirus vaccine candidate that has produced innate, humoral, and T-cell immune responses in non-human primate studies and may have the potential to reduce forward transmission after viral challenge.

ICT: Recent research has raised questions about whether immunity from current mpox vaccines may wane over time. How does TNX-801 differ from currently available vaccines, and what advantages do you believe it could offer for long-term protection?

SB: This is an important consideration in the development of any new mpox/smallpox vaccine. The first-generation vaccines developed by Edward Jenner generated durable immunity that often lasted a person’s whole lifetime. The next generation of vaccines were descendants of Jenner’s vaccine but were faster-growing and had challenging tolerability and safety profiles. These were used during the global accelerated smallpox eradication.

In preclinical studies, TNX-801 has demonstrated durable immunity in all animals for at least 14 months following a single vaccination and has protected against both lesion development and lethal disease. These and other findings lead us to believe we have recreated a vaccine similar to Edward Jenner’s original. Tonix believes that TNX-801 vaccination could offer a significant advantage by generating robust, durable immunity against mpox and smallpox and with improved tolerability relative to the vaccines used in the eradication project.

ICT: From an infection prevention perspective, what role could a next-generation mpox vaccine play in preparedness for future outbreaks, particularly in health care settings where rapid containment is essential?

SB: This is an excellent question that requires some context. Mpox was first identified as a human pathogen in 1970, when the first confirmed human case of mpox was reported in an unvaccinated young boy in Zaire (now the Democratic Republic of the Congo). In the decades following its discovery, the monkeypox [now mpox] virus was classified into 2 genetic clades: clade I (Central African or Congo Basin) and clade II (West African), based on phylogenetic analyses, geographic distribution, and the severity of human disease. Between 1970 and 2020, sporadic outbreaks resulted in approximately 30,000 confirmed or suspected human cases. Clade I caused almost all reported cases during this period, whereas only a few hundred cases were attributed to clade II.

Many factors caused the 2022 global mpox outbreak. The end of routine smallpox vaccination in the mid-1970s built an immunologically naïve population susceptible to infection with closely related orthopoxviruses. In 2022, mpox emerged to cause the first global mpox outbreak.

Unlike previous outbreaks, however, most human infections were caused by the newly identified clade IIb lineage. Most human-to-human transmission occurred through sexual contact, a route previously not recognized for mpox transmission.

Additional outbreaks in Central Africa were associated with the emergence of another newly recognized clade Ib lineage. As a result, the monkeypox virus is now classified into 4 clades/subclades (Ia, Ib, IIa, and IIb), which vary in transmissibility, geographic distribution, virulence, and fatality rates. Since 2022, the outbreak IIb has spread quickly to 145 countries, causing more than 187,000 reported human cases.

Since 2024, the outbreak caused by clade Ib has had a more limited spread, but it is considerably more virulent and dangerous. The relatively indolent syndrome associated with IIb is probably responsible for why it spread so quickly and is now an established endemic in the U.S.

This background highlights how rapidly new mpox subclades can emerge and spread through previously unrecognized transmission routes in immunologically naïve populations, resulting in global outbreaks. The coordinated deployment of next-generation vaccines is critical to prevent and contain future mpox outbreaks.

ICT: Tonix has described TNX-801 as part of a broader infectious disease strategy. How does this vaccine fit into the company's overall biodefense and emerging infectious disease portfolio, and what lessons from COVID-19 and the recent mpox outbreaks influenced its development?

SB: TNX-801 fits within Tonix's broader strategy of addressing serious health challenges where patients' needs are not adequately addressed by current treatment options. Tonix is a fully integrated, commercial-stage biopharmaceutical company committed to delivering differentiated medicines that improve the lives of people living with chronic and debilitating diseases with significant unmet medical needs, while advancing a purposefully curated pipeline spanning central nervous system disorders, infectious diseases, immunology conditions, and rare diseases.

Within Tonix’s infectious disease portfolio, TNX-801 platform represents Tonix’s vaccine-based approach to biodefense and emerging infectious disease preparedness. We are developing the program to address orthopoxvirus threats, including mpox and smallpox. TNX-801 is a live, minimally replicating, recombinant orthopoxvirus vaccine candidate based on horsepox.

Tonix’s infectious disease portfolio also includes TNX-4800, a long-acting, human monoclonal antibody for Lyme disease prevention in the US, and TNX-4200, a broad-spectrum antiviral program being developed under a US Department of Defense (DoD) Defense Threat Reduction Agency (DTRA) contract for up to $34 million over 5 years. These programs reflect Tonix’s deliberate approach to investing in disease prevention, infectious disease, and vaccine technologies where meaningful innovation could potentially address substantial unmet needs.

Tonix's curated portfolio is united by the same disciplined framework that drives all our drug development efforts: identify meaningful unmet need, follow the science, and pursue opportunities where the potential benefit to patients is significant.

ICT: The public often assumes mpox is no longer a significant concern, yet outbreaks continue to occur globally. How would you characterize the current state of mpox preparedness, and where do you see the greatest remaining vulnerabilities?

SB: Since the 2022 outbreak, mpox transmission has continued in the United States, with approximately 38,000 reported cases to date. Although cases declined after the initial 2022 surge, sustained transmission has resulted in approximately 1,700 to 2,800 cases annually. In 2026, 677 cases have been reported to date, demonstrating the continued need for effective mpox prevention strategies.

Outside the US, both clade IIb and Ib continue to spread. Clade Ib remains a significant cause of epidemics in Central Africa. A recent outbreak in Madagascar teaches us we are far from done with clade ib.

Currently, there are 2 vaccines approved in the United States for the prevention of smallpox and mpox: ACAM-2000 and JYNNEOS. ACAM-2000 is a live vaccinia virus vaccine derived from Dryvax, one of the vaccine strains used to eradicate smallpox. A single ACAM-2000 vaccination administered by scarification can induce durable immunity.

However, similar to its parental vaccine, it is associated with the risk of serious adverse events, including pericarditis, myocarditis, and encephalitis. In contrast, JYNNEOS has a better safety profile but requires a two-dose regimen administered 4 weeks apart to achieve optimal immune responses and may not provide durable immunity or block forward transmission.

There are several disadvantages to both vaccines. The administration of the ACM-2000 vaccine will leave a scar at the vaccination site. In addition, safety concerns include inflammation in or around the heart. The administration of the 2-dose JYNNEOS vaccine yields immunity that can wane considerably within 6 to 12 months. Consequently, following mpox infection causes milder illness with fewer lesions and lower hospitalization rates have been reported in breakthrough cases. There is a critical need to develop vaccines capable of inducing durable immunity via a single vaccination with minimal adverse events.

Tonix believes that our next-generation vaccine, TNX-801, has the potential to address this unmet need. In preclinical studies, TNX-801 has demonstrated a superior safety profile compared with older-generation vaccines while eliciting durable immunity that provided protection for at least 14 months following a single vaccination.

ICT: Can you walk us through the next steps in TNX-801's development? What milestones should clinicians, infection preventionists, and public health professionals be watching for over the next year?

SB: Tonix expects to advance TNX-801 into a phase 1 clinical study in 2027 for the prevention of mpox and smallpox, pending FDA clearance of an Investigational New Drug application.

Over the next year, clinicians, infection preventionists, and public health professionals should watch for updates on TNX-801’s entry into the clinic and further characterization of TNX-801’s safety, immunogenicity, durability, and potential protection across relevant mpox clades. Preclinical findings show single-dose protection, neutralizing antibody responses, protection against clinical disease and mortality following mpox challenge in animal models, with durability observed for at least 14 months post-vaccination.

ICT: Looking ahead, what do you think infection preventionists should take away from this research? How might these findings influence long-term vaccination strategies, outbreak preparedness, and infection control planning if TNX-801 ultimately reaches clinical use?

SB: Over the past 30 years, the incidence of emerging infectious diseases has increased substantially. Driven by human activity and the dramatic growth in global travel, diseases once confined to specific geographic regions have spread worldwide, including mpox. The international public remains vulnerable to emerging infectious disease threats.

Many high-consequence pathogens remain neglected, with critical gaps in our understanding of their biology hindering the rapid development of effective countermeasures. Consequently, fundamental questions are often addressed only after an outbreak has emerged, significantly delaying the development and deployment of urgently needed interventions.

In response to the mpox outbreak, Tonix Pharmaceuticals rapidly established and characterized mpox disease models to address critical scientific gaps and has leveraged these models to work towards phase I clinical studies.