Evolving Threats: Adaptive Mechanisms of Monkeypox Virus (MPXV) in the 2022 Global Outbreak and Their Implications for Vaccine Strategies.

Monkeypox virus (MPXV) experienced an unprecedented global outbreak in 2022, characterized by a significant departure from historical patterns: a rapid spread of the epidemic to more than 110 non-traditional endemic countries, with more than 90,000 confirmed cases; a fundamental shift in the mode of transmission, with human-to-human transmission (especially among men who have sex with men (MSM)) becoming the dominant route (95.2%); and genetic sequencing revealing a key adaptive mutation in a novel evolutionary branch (Clade IIb) that triggered the outbreak. These features highlight the significant evolution of MPXV in terms of host adaptation, transmission efficiency, and immune escape ability. The aim of this paper is to provide insights into the viral adaptive evolutionary mechanisms driving this global outbreak, with a particular focus on the role of immune escape (e.g., novel mechanisms of M2 proteins targeting the T cell co-stimulatory pathway) in enhancing viral transmission and pathogenicity. At the same time, we systematically evaluate the cross-protective efficacy and limitations of existing vaccines (ACAM2000, JYNNEOS, and LC16), as well as recent advances in novel vaccine platforms, especially mRNA vaccines, in inducing superior immune responses. The study further reveals the constraints to outbreak control posed by grossly unequal global vaccine distribution (e.g., less than 10% coverage in high-burden regions such as Africa) and explores the urgency of optimizing stratified vaccination strategies and facilitating technology transfer to promote equitable access. The core of this paper is to elucidate the dynamic game between viral evolution and prevention and control strategies (especially vaccines). The key to addressing the long-term epidemiological challenges of MPXV in the future lies in continuously strengthening global surveillance of viral evolution (early warning of highly transmissible/pathogenic variants), accelerating the development of next-generation vaccines based on new mechanisms and platforms (e.g., multivalent mRNAs), and resolving the vaccine accessibility gap through global collaboration to build an integrated defense system of "Surveillance, Research and Development, and Equitable Vaccination," through global collaboration to address the vaccine accessibility gap.