mRNA Vaccine Against Mpox: A Promising Healthcare Strategy

Mpox, formerly known as monkeypox, is a zoonotic disease caused by the monkeypox virus (MPXV), which belongs to the genus Orthopoxvirus of the family Poxviridae. It is an enveloped brick-shaped virus with a double-stranded DNA genome of approximately 200,000 bp in length that has two distinct genetic clades: clade I (Ia and Ib) endemic to Central Africa, usually in the Congo, and clade II (IIa and IIb) endemic to West Africa [1]. These two clades showed different patterns of transmission and disease severity. Clade I has a higher potential for human-to-human transmission, mostly through men-to-men sexual contact, and causes severe outcomes with approximately 10% mortality among those infected [2]. In contrast, clade II is less infectious, causes less severe disease, and has a lower mortality rate, around 1%, but has demonstrated the ability to spread more efficiently to nonendemic areas. Since its discovery, Mpox has been associated with small-scale endemic outbreaks in West and Central Africa. However, the number of outbreaks has recently increased. An outbreak of clade II has spread worldwide since May 2022, and the World Health Organization (WHO) declared it a Public Health Emergency of International Concern (PHEIC) on July 23, 2022. As of October 25, 2023, more than 91,328 Mpox infections have been reported in 116 countries with 170 deaths [3]. Another outbreak of clade Ib began in the Democratic Republic of the Congo (DRC) in December 2023 and spread to neighboring states such as Burundi, Kenya, Rwanda, and Uganda. From 2023 to 29 March 2024, the DRC reported 18,922 Mpox cases, including 1007 deaths [4]. As of 14 August 2024, an additional 15,600 confirmed cases and 537 deaths [5], and as of 5 January 2025, another 4058 confirmed cases and 13 deaths [6] were reported.

Vaccines, notably smallpox vaccines, offer protection against Mpox infection. In contrast, in a recent study, mRNA-1769 showed superior preclinical efficacy in reducing symptoms and viral replication compared to modified vaccinia Ankara (MVA) in monkeys, highlighting potential healthcare strategies against future Mpox epidemics as a scalable, safe, and effective alternative vaccine [7]. This commentary discussed the progress in developing mRNA vaccines as a promising healthcare strategy against Mpox.

The MPXV genome is closely related to other members of the Orthopoxvirus, ranging from the most virulent, variola virus (which causes smallpox) to the less virulent, vaccinia virus (VACV). Vaccines produced from one member of the genus confer immunity against another member. The U.S. Strategic National Stockpile contains several conventional vaccines against smallpox: Aventis Pasteur Smallpox Vaccine (APSV), ACAM2000, JYNNEOS, and LC16m8. Although these vaccines were highly effective, providing lifelong immunity and playing a key role in eradicating smallpox, the APSV and ACAM2000 were reported to have serious side effects such as myopericarditis [8, 9]. However, because of a few side effects, JYNNEOS, LC16m8, and OrthopoxVac were approved against Mpox infection during the global Mpox outbreak in 2022. JYNNEOS was developed using multiple passages of the MVA-Bavarian Nordic strain of VACV in primary cell culture or eggs. It was approved in 2019 by the WHO and the US FDA for adults aged 18 years and older at high risk of Mpox infection [10]. Studies have shown that two doses of the vaccine 4 weeks apart can provide 66%–85% protection against Mpox [11-13]. LC16m8 is a live, replicated vaccine produced from the Lister strain of VACV attenuated, it was officially approved for smallpox in Japan in 1975. Because of its improved safety profile and attenuated phenotype, this can be used in immunocompromised patients [14, 15]. Furthermore, OrthopoxVac was developed by Vector Laboratory in Siberia and licensed in the Russian Federation after clinical trials in 2022. It is also safe and effective. However, all conventional vaccines are only recommended for pre-exposure prevention against Mpox in individuals at risk of Mpox infection and have limited protective efficacy when given post-exposure. Furthermore, these vaccines face significant challenges at all stages of the development process, such as increasing time and financial costs. An emerging alternative is a genetic vaccine made from mRNA known as an mRNA vaccine.

Although mRNA vaccines have been used since the coronavirus disease 2019 (COVID-19) outbreak in 2020, the first report of successful RNA transfection was in 1990 [16]. This technology was initially challenging due to the instability of single-stranded mRNA and the inefficiency of in vivo delivery. The optimization of mRNA sequence schemes [17], development of more efficient delivery vectors [18], and control of inflammatory responses have now made this technology widely applicable. With such advances, the mRNA vaccine production process is safe, time-saving, highly effective, and more easily adaptable than conventional vaccines. Furthermore, their cell-free production allows for rapid production on a large scale, which reduces the risk of contamination. In addition, mRNA vaccines do not integrate into the host genome and are designed to rapidly express the encoded antigen in the body, thereby rapidly eliciting an immune response [19]. This vaccine is beneficial in pandemic situations, where time is of essence and vaccines are desperately needed; this has been proven in the recent global pandemic of the COVID-19 mRNA vaccine, which has contributed to an unprecedented acceleration of vaccine production [20]. Several clinical and randomized controlled trials of COVID-19 mRNA vaccines have demonstrated that the immunization platform is easy to develop, has an acceptable safety profile, induces humoral and cell-mediated immunity, and can be produced on a large scale. The overwhelming success of the COVID-19 mRNA vaccine has generated widespread interest in developing Mpox mRNA vaccines [20].

MPXV generates two distinct antigenic virions: extracellular enveloped (EEV) and intracellular mature virions (IMV). Indeed, EEVs attach to infected cells, whereas IMVs remain inside the infected cells until lysis and are responsible for binding and entry of the virus. In recent years, researchers have developed several promising MPXV mRNA vaccine candidates that have shown enhanced immunogenicity against most EEV and IMV antigens and have become an excellent alternative to conventional vaccines for protection against Mpox (Table 1). Several recent studies have shown that mono-, bi-, and tetravalent Mpox mRNA vaccines encoding at least one EEV and IMV antigen induce robust antigen-specific humoral and cellular immune responses in mice [21-27]. The protective effects of tetra- and quadrivalent vaccines were superior to those of mono- and bivalent mRNA vaccines [22, 24, 29]. In a recent study in monkeys, a quadrivalent (BNT166a) and trivalent (BNT166c) vaccine induced robust T-cell immunity and IgG antibodies, including neutralizing antibodies to both MPXV and VACV. In addition, vaccination with BNT166a was 100% effective in preventing death and suppressing lesions in a lethal clade I MPXV challenge [29]. Another study compared mRNA vaccines with JYNNEOS: all monkeys vaccinated with JYNNEOS and mRNA-1769 survived the test, whereas five of six in the unvaccinated control group died of the disease; mRNA-1769-vaccinated monkeys had a maximum of 54 Mpox lesions, compared with 607 in the JYNNEOS group and 1448 in the unvaccinated group; MPXV loads in the blood and throat of the mRNA-1769 group were lower than in the JYNNEOS group, and the duration of the disease was reduced by more than 10 days, indicating that the mRNA-1769 vaccine was superior to its competitors in reducing symptoms and potential transmission in monkeys [7]. Recent advances in mRNA vaccine technology and its delivery have enabled mRNA-based therapeutics to enter a new era in the medical field. The rapid, potent, and transient nature of mRNA vaccines, without the need to enter the entire viral genome, will make them the tools of choice for treating various infectious diseases, including Mpox.

As mRNA vaccine technology gradually matures, its benefits in preventing infectious diseases are becoming increasingly clear. Recent experimental and preclinical studies have shown that MPXV mRNA vaccines outperform conventional vaccines by providing almost complete protection against the Mpox challenge. High potency, low-cost production, rapid development, safe administration, and the ability to provide humoral and cellular immunity are the advantages of Mpox mRNA vaccines that pave the way for a viable alternative to conventional vaccines to combat future Mpox pandemic threats. Although preclinical studies have shown great advantages of mRNA vaccines over conventional vaccines regarding efficacy, immunogenicity, and flexibility in design and production, large-scale clinical and randomized controlled trials in humans are crucial for FDA approval.

A clinical trial, Phase I/II (NCT05995275), is underway in the United Kingdom to test mRNA-1769 in humans to ensure safety and immunogenicity. Data scheduled for mid-2025 will inform the design of Phase III. Another clinical trial, Phase I/II (NCT05988203), is also underway to test another mRNA vaccine, BNT166, against Mpox. Preliminary results of both vaccines showed protective efficacy in monkeys against a lethal Mpox challenge [7, 29].

Mohammad Shah Alam: conceptualization, writing – original draft, writing – review and editing, supervision, validation, visualization. Md. Arman Sharif: visualization, writing – review and editing. Md. Aminul Islam: visualization, writing – review and editing. M. Nazmul Hoque: visualization, writing – review and editing.

The authors declare no conflicts of interest.