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<p>The global re-emergence of monkeypox virus (MPXV) has exposed a widening immunity gap following cessation of routine smallpox vaccination and renewed interest in next-generation orthopoxvirus vaccines. Unlike acute RNA viruses, MPXV is a large double-stranded DNA virus with a dual-virion architecture intracellular mature virion (IMV) and extracellular enveloped virion (EEV) and encodes multiple immune evasion proteins that complicate vaccine design. These biological features necessitate multivalent antigen targeting and coordinated humoral and cellular immunity for effective protection. Messenger RNA (mRNA) vaccines provide a programmable, non-replicating platform capable of endogenous antigen expression and simultaneous targeting of conserved IMV and EEV structural proteins, including A29L, M1R, A35R, and B6R. In this review, we integrate current knowledge of MPXV immunobiology with advances in immunoinformatics and structural vaccinology to define rational design principles for multivalent mRNA constructs. We examine computational epitope mapping, structural validation, multi-antigen optimization strategies, and lipid nanoparticle–mediated delivery as enabling technologies for cross-clade and pan-orthopox coverage. Preclinical evidence demonstrates that multivalent mRNA vaccines induce robust neutralizing antibodies, Th1-biased CD4⁺ responses, and functional CD8⁺ T-cell activation in murine and early non-human primate models, with protection against lethal orthopoxvirus challenge. Comparative analysis with live-attenuated vaccinia and protein subunit platforms highlights the balance achieved by mRNA vaccines between endogenous antigen presentation and improved safety relative to replication-competent vectors. However, key scientific uncertainties remain, including long-term durability of plasma cell and memory T-cell responses, the influence of immunological imprinting in smallpox-vaccinated individuals, and resilience to antigenic evolution across MPXV clades. We discuss translational and regulatory considerations, immune correlates of protection, and the role of AI-driven structural optimization in next-generation vaccine refinement. Collectively, this review provides a mechanistically grounded framework for rational MPXV mRNA vaccine development and outlines the experimental and clinical priorities required to establish durable, broad, and adaptable orthopoxvirus immunity.</p>

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mRNA vaccines against monkeypox: bridging immunoinformatics, structural vaccinology, and translational advances toward pan-orthopox immunity

  • 期刊论文

  • 发表日期：

    2026年4月6日

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  • Qamar Abuhassan,
  • Kamel Saleh,
  • S. Renuka Jyothi,
  • Pusparaj Samantsinghar,
  • P. Prakash,
  • Gunjan Mukherjee,
  • Aashna Sinha,
  • Turabek Boyqulov

摘要

The global re-emergence of monkeypox virus (MPXV) has exposed a widening immunity gap following cessation of routine smallpox vaccination and renewed interest in next-generation orthopoxvirus vaccines. Unlike acute RNA viruses, MPXV is a large double-stranded DNA virus with a dual-virion architecture intracellular mature virion (IMV) and extracellular enveloped virion (EEV) and encodes multiple immune evasion proteins that complicate vaccine design. These biological features necessitate multivalent antigen targeting and coordinated humoral and cellular immunity for effective protection. Messenger RNA (mRNA) vaccines provide a programmable, non-replicating platform capable of endogenous antigen expression and simultaneous targeting of conserved IMV and EEV structural proteins, including A29L, M1R, A35R, and B6R. In this review, we integrate current knowledge of MPXV immunobiology with advances in immunoinformatics and structural vaccinology to define rational design principles for multivalent mRNA constructs. We examine computational epitope mapping, structural validation, multi-antigen optimization strategies, and lipid nanoparticle–mediated delivery as enabling technologies for cross-clade and pan-orthopox coverage. Preclinical evidence demonstrates that multivalent mRNA vaccines induce robust neutralizing antibodies, Th1-biased CD4⁺ responses, and functional CD8⁺ T-cell activation in murine and early non-human primate models, with protection against lethal orthopoxvirus challenge. Comparative analysis with live-attenuated vaccinia and protein subunit platforms highlights the balance achieved by mRNA vaccines between endogenous antigen presentation and improved safety relative to replication-competent vectors. However, key scientific uncertainties remain, including long-term durability of plasma cell and memory T-cell responses, the influence of immunological imprinting in smallpox-vaccinated individuals, and resilience to antigenic evolution across MPXV clades. We discuss translational and regulatory considerations, immune correlates of protection, and the role of AI-driven structural optimization in next-generation vaccine refinement. Collectively, this review provides a mechanistically grounded framework for rational MPXV mRNA vaccine development and outlines the experimental and clinical priorities required to establish durable, broad, and adaptable orthopoxvirus immunity.