The unique immune evasion mechanisms of the mpox virus and their implication for developing new vaccines and immunotherapies

Mpox is an infectious and contagious zoonotic disease caused by the mpox virus (MPXV), which belongs to the genus Orthopoxvirus . Since 2022, MPXV has posed a significant threat to global public health. The emergence of thousands of cases across the Western Hemisphere prompted the World Health Organization to declare an emergency. The extensive coevolutionary history of poxviruses with humans has enabled these viruses to develop sophisticated mechanisms to counter the human immune system. Specifically, MPXV employs unique immune evasion strategies against a wide range of immunological elements, presenting a considerable challenge for treatment, especially following the discontinuation of routine smallpox vaccination among the general population. In this review, we start by discussing the entry of the mpox virus and the onset of early infection, followed by an introduction to the mechanisms by which the mpox virus can evade the innate and adaptive immune responses. Two caspase-1 inhibitory proteins and a PKR escape-related protein have been identified as phylogenomic hubs involved in modulating the immune environment during the MPXV infection. With respect to adaptive immunity, mpox viruses exhibit unique and exceptional T-cell inhibition capabilities, thereby comprehensively remodeling the host immune environment. The viral envelope also poses challenges for the neutralizing effects of antibodies and the complement system. The unique immune evasion mechanisms employed by MPXV make novel multi-epitope and nucleic acid-based vaccines highly promising research directions worth investigating. Finally, we briefly discuss the impact of MPXV infection on immunosuppressed patients and the current status of MPXV vaccine development. This review may provide valuable information for the development of new immunological treatments for mpox. • The MPXV epidemic has become a new threat and challenge that human public health has to face. • The innate and adaptive immune responses to MPXV, as well as the immune evasion strategies employed by MPXV, are summarized. • Novel multi-epitope and nucleic acid-based vaccines are highly promising for MPXV vaccine development. • Understanding the immune response to MPXV and its evasion is crucial for developing treatments for mpox.