Antigen recognition and immune response to monkeypox virus infection: implications for Mpox vaccine design - a narrative review

Abstract

Monkeypox virus (MPXV) is a DNA virus from the Orthopoxvirus genus, sharing significant genomic similarity with the variola virus that causes smallpox. The cessation of smallpox vaccinations has contributed to recent Mpox outbreaks, with reduced immunity levels, particularly in younger populations born after the vaccine was discontinued. The virus triggers innate and adaptive immune responses, with toll-like receptors (TLRs) playing a key role in recognizing viral components and activating proinflammatory cytokines. However, MPXV evades the immune system by producing proteins that inhibit immune signaling pathways. Natural killer (NK) cells and interferons are crucial for early defense, but MPXV impairs their function. Adaptive immunity involves robust antibody and T-cell responses, similar to smallpox vaccination responses. Various mRNA-based candidate vaccines have demonstrated strong immunogenicity, with preclinical studies confirming their ability to trigger potent B-cell and T-cell responses. However, the genetic changes observed in the current outbreak strains necessitate ongoing surveillance of MPXV mutations and their impact on immunogenic proteins. This review aimed to summarize current insights into antigen recognition and immune responses to MPXV, with a focus on key antigenic proteins relevant to vaccine development.

Keywords: Adaptive immune response; Antigen recognition; Innate immune response; MPXV; Monkeypox virus infection.

Figure 1

Innate immune evasion strategies of MPXV: evasion from detection, inhibition of host cell apoptosis, and disruption of host immune signaling pathways. The figure was produced with https://app.biorender.com Notes: RIG-1, retinoic acid-inducible gene I; MAVS, mitochondrial antiviral signaling; MPXV-F3, monkeypox virus protein F3; MPXV-P2, monkeypox virus protein 2; dsRNA, double-stranded RNA; PKR, protein kinase R; eIF2a, eukaryotic translation initiation factor 2a; TBK-1, TANK-binding kinase 1; IRF-3, interferon regulatory factor 3; IKB-a, inhibitor of kappa B alpha; IKK, inhibitor of nuclear factor-κB kinase; NFkB, nuclear factor kappa B; KPNA2, karyopherin subunit alpha 2

Figure 2

Activation of TLR signaling during MPXV infection and the mechanisms of viral evasion from the IFN response. The figure was produced using https://app.biorender.com Notes: dsRNA, double-stranded RNA; CpG DNA, cytosine-phosphate-guanosine DNA; TRIF, toll and interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon β; TLR, toll-like receptor; MyD88, myeloid differentiation factor 88; IRF, interferon regulatory factor; TRAF, tumor necrosis factor receptor-associated factor; TBK1, TANK binding kinase 1; MPXV, monkeypox virus; MPXV-B16, monkeypox virus protein B16; IKK, inhibitor of nuclear factor-κB kinase; IRAK, interleukin-1 receptor-associated kinase; IFNAR, interferon alpha/beta receptor; JAK2, Janus kinase 2; TYK2, tyrosine kinase 2; IFN, interferon; STAT, signal transducer and activator of transcription.

Figure 3

Adaptive immune response against MPXV and inhibition of T-cell costimulation. The figure was produced using https://app.biorender.com Notes: MPXV, monkeypox virus; IL, interleukin; TNF-α, tumor necrosis factor alpha; IFN-γ, interferon-gamma; IFN-α/β, interferon-alpha/beta; TCR, T-cell receptor; MHC, major histocompatibility complex.