RARE DISEASE
Human infection by orthopoxvirus
Human infection by orthopoxvirus
Human infection by orthopoxvirus
Drug discovery
7
drugs
With orphan designations
Overview
Human infection by orthopoxvirus, primarily caused by monkeypox virus (MPXV) and cowpox virus, manifests as a febrile illness with lymphadenopathy and a centrifugal maculopapular rash progressing to pustules. Transmission occurs via zoonotic exposure or close human contact, particularly through skin lesions or respiratory droplets. Post-smallpox eradication, declining population immunity has increased susceptibility, with MPXV emerging as the most clinically significant orthopoxvirus globally. Recent outbreaks highlight expanded human-to-human transmission, particularly in men who have sex with men (MSM), necessitating heightened clinical vigilance [1][6][12][19].
Burden
Clade I (Congo Basin) mortality: ≤10%; clade II (West African): 1–5% [6][12][19].
90,000 global cases (2022–2024), with complications including secondary infections, keratitis, and psychosocial stigma [6][15][19].
Economic and healthcare strain in endemic regions due to limited diagnostics and vaccine access [2][5][15].
Therapies
Antivirals: Tecovirimat (first-line, FDA-approved for smallpox/mpox) and brincidofovir (reserved for severe cases); cidofovir used off-label [3][13][17].
Supportive care: Pain management, hydration, and infection control.
Combination therapies: Investigational use of tecovirimat with ACAM2000 vaccine or brincidofovir in high-risk cases [3][8][17].
Categories: rare infectious diseases
Research Papers
1,917 drug discovery papers about Human infection by orthopoxvirus, with 2 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,917 drug discovery papers about Human infection by orthopoxvirus, with 2 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | ACAM2000 vaccine safety and immunogenicity considerations for smallpox and mpox.
Smallpox, eradicated globally in 1980, remains a major biodefense concern due to retained Variola virus stocks and the absence of population immunity following cessation of routine vaccination. Monkeypox virus (MPXV), a related orthopoxvirus, has reemerged as a global public health threat, with major outbreaks in 2022 and renewed spread from 2024 onward. This review evaluates ACAM2000®, a second-generation live smallpox vaccine, summarizing its development, immunogenicity, efficacy, safety, regulatory status, and potential role in mpox prevention. ACAM2000 remains a critical medical countermeasure for smallpox preparedness and a valuable, though selective, tool for mpox prevention. Its high immunogenicity, rapid protection, and broad orthopoxvirus coverage must be balanced against a well-characterized safety risk profile.
2026-07-28 | Rapid protection from lethal Orthopoxvirus infection following vaccination with mRNA-LNP encoding the Type I Interferon Binding Protein 2259797
Abstract Introduction Orthopoxviruses (OPVs), such as monkeypox, pose ongoing public health threats, especially since the global herd immunity has declined following the cessation of routine smallpox vaccination. Current vaccine strategies have limitations due to safety and short-lived immunity. Most anti-viral vaccines aim to induce antibodies (Abs) that bind to structural viral proteins, preferentially those that can neutralize the viral particle. The Type I IFN-binding protein (IFN-I bp) is a highly conserved non-structural protein present in all OPVs, an immune evasion protein, and is essential for their pathogenicity. It has been previously shown that mice vaccinated with recombinant IFN-I bp or passively immunized with anti-IFN-I bp monoclonal antibodies (Abs), are protected from lethal challenge with the mouse OPV ectromelia virus (ECTV), a classic model for human smallpox and monkeypox infections. Methods We made mRNA-lipid nanoparticle (mRNA-LNP) vaccine encoding IFN-I bp. We evaluated Abs responses by ELISA, and protective efficacy by challenging the immunized mice with ECTV in the footpad or with the OPV vaccinia virus intranasally. Results We found that a single immunization of 5 ug of mRNA-LNPs encoding ECTV’s IFN-I bp induced much higher titers of IgG antibodies (as opposed to IgM) as early as six days post-immunization than control mRNA-LNP vaccines. Notably, vaccinated BALB/c and TLR9-deficient mice challenged with ECTV or VACV eight days post-immunization were fully protected from viral lethality. Conclusion These data indicate that the IFN-I bp is a promising antigen for OPV vaccines, particularly when rapid protection is crucial, such as during an epidemic. Ongoing studies aim to determine the mechanisms underlying rapid IgG induction. Funding Source grant Topic Categories Vaccines and Immunotherapy (VAC)
2026-07-25 | An experimentally validated structure-based computational framework for humanisation of anti-orthopoxvirus antibodies.
The re-emergence of orthopoxviruses, most notably mpox virus (MPXV), poses a growing global public health threat. Well-characterised murine anti-orthopoxvirus antibodies are clinically limited by anti-mouse antibody responses, while traditional sequence-based humanisation often impairs antigen-binding activity. We developed an experimentally validated structure-guided computational humanisation framework prioritising 3D architectural congruence over sequence identity, integrating Foldseek-based structural alignment and interface-residue constraints. We applied this framework to humanise two murine anti-orthopoxvirus antibodies (7D11, A27D7), with comprehensive in vitro and in vivo validation. Structural superimposition confirmed high conformational conservation between the humanised variants (POX1.1 and POX2.1) and their parental mAbs, with root mean square deviation (RMSD) values below 0.6 Å for all variable domains. Both humanised variants retained full epitope specificity with natural humanness profiles. POX1.1 showed enhanced neutralisation potency against vaccinia virus (VACV) and MPXV, compared with the parental 7D11. POX2.1 preserved the broad cross-reactive binding and the extracellular enveloped virion neutralising activity of the parental A27D7. In the lethal VACV mouse model, both monotherapies conferred significant prophylactic and therapeutic protection, reducing pulmonary viral loads and improving survival. The dual-targeting combination of POX1.1 and POX2.1 achieved markedly improved in vivo efficacy compared with individual antibodies, delivering 100% survival even when administered 2 days post-challenge. In the MPXV CAST/EiJ mouse model, the combination significantly reduced splenomegaly and MPXV DNA loads in plasma, spleen and lung tissues, effectively suppressing systemic viral dissemination. These findings establish that the structure-centric workflow enables efficient humanisation of well-characterised murine anti-orthopoxvirus antibodies, providing a validated framework to support the development of countermeasures for orthopoxvirus pandemic. This work was supported by the National Natural Science Foundation of China, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the Scientific Research Innovation Capability Support Project for Young Faculty and the National Science and Technology Major Project.
2026-07-12 | Vaccinia virus and Monkeypox virus neutralizing and antigen-binding antibodies following subcutaneous and reduced intradermal doses of an MVA vaccine.
To expand the supply of the modified vaccinia Ankara (MVA) smallpox/mpox vaccine, fractional doses administered intradermally (ID) have been considered as alternatives to the standard dose given subcutaneously (SC). In a recent clinical trial, participants received the standard 108 infectious units of vaccine SC or a one-fifth (IDH) or a one-tenth (IDL) dose ID twice 28-days apart. Two weeks after the second dose, sera were analyzed using a vaccinia virus (VACV) strain Western Reserve plaque-reduction test (PRNT) with the conclusion that IDH but not IDL was non-inferior to SC. The present study extends the latter by quantifying neutralizing antibodies to the MVA vaccine and to monkeypox virus (MPXV) in the absence and presence of added complement and by assessing multiplex binding antibodies to individual VACV antigens (A27, A33, B5, D8 and L1) and the MPXV homologs (A29, A35, B6, E8 and M1). The main conclusions of the study are that the titers of MVA neutralizing antibodies induced by SC and IDH were not significantly different, whereas MVA neutralizing antibody titers induced by IDL were lower like the previous PRNT results. However, the titers of complement-enhanced MPXV neutralizing antibodies induced by SC were significantly higher than for both IDH and IDL immunizations, suggesting that the standard SC dose and reduced dose ID immunizations may not be equivalent. Additional analyses suggested that antibody binding to VACV B5 and D8 and MPXV B6 and E8 may serve as surrogates for neutralizing antibodies.
2026-07-10 | Severe mpox in an immunocompromised, non-traveller South African male.
Mpox is a zoonotic orthopoxvirus infection historically linked to being in endemic regions, travel and close physical contact, including within men who have sex with men (MSM) communities. We report a case of severe mpox in a heterosexual man with advanced human immunodeficiency virus (HIV) disease and no travel history to endemic areas. The patient developed extensive cutaneous disease and transmitted mpox to household contacts, illustrating non-sexual transmission. Management included supportive care and tecovirimat under Section 21 authorisation (a regulatory mechanism in South Africa permitting access to an unregistered medicine) with good clinical response. This case highlights the changing epidemiology of mpox, the risk of severe disease in immunocompromised patients, household and non-sexual transmission. We also emphasise the importance of early diagnosis, infection control and antiviral therapy when indicated.
2026-08-11 | ACAM2000 vaccine safety and immunogenicity considerations for smallpox and mpox.
Smallpox, eradicated globally in 1980, remains a major biodefense concern due to retained Variola virus stocks and the absence of population immunity following cessation of routine vaccination. Monkeypox virus (MPXV), a related orthopoxvirus, has reemerged as a global public health threat, with major outbreaks in 2022 and renewed spread from 2024 onward. This review evaluates ACAM2000®, a second-generation live smallpox vaccine, summarizing its development, immunogenicity, efficacy, safety, regulatory status, and potential role in mpox prevention. ACAM2000 remains a critical medical countermeasure for smallpox preparedness and a valuable, though selective, tool for mpox prevention. Its high immunogenicity, rapid protection, and broad orthopoxvirus coverage must be balanced against a well-characterized safety risk profile.
2026-07-28 | Rapid protection from lethal Orthopoxvirus infection following vaccination with mRNA-LNP encoding the Type I Interferon Binding Protein 2259797
Abstract Introduction Orthopoxviruses (OPVs), such as monkeypox, pose ongoing public health threats, especially since the global herd immunity has declined following the cessation of routine smallpox vaccination. Current vaccine strategies have limitations due to safety and short-lived immunity. Most anti-viral vaccines aim to induce antibodies (Abs) that bind to structural viral proteins, preferentially those that can neutralize the viral particle. The Type I IFN-binding protein (IFN-I bp) is a highly conserved non-structural protein present in all OPVs, an immune evasion protein, and is essential for their pathogenicity. It has been previously shown that mice vaccinated with recombinant IFN-I bp or passively immunized with anti-IFN-I bp monoclonal antibodies (Abs), are protected from lethal challenge with the mouse OPV ectromelia virus (ECTV), a classic model for human smallpox and monkeypox infections. Methods We made mRNA-lipid nanoparticle (mRNA-LNP) vaccine encoding IFN-I bp. We evaluated Abs responses by ELISA, and protective efficacy by challenging the immunized mice with ECTV in the footpad or with the OPV vaccinia virus intranasally. Results We found that a single immunization of 5 ug of mRNA-LNPs encoding ECTV’s IFN-I bp induced much higher titers of IgG antibodies (as opposed to IgM) as early as six days post-immunization than control mRNA-LNP vaccines. Notably, vaccinated BALB/c and TLR9-deficient mice challenged with ECTV or VACV eight days post-immunization were fully protected from viral lethality. Conclusion These data indicate that the IFN-I bp is a promising antigen for OPV vaccines, particularly when rapid protection is crucial, such as during an epidemic. Ongoing studies aim to determine the mechanisms underlying rapid IgG induction. Funding Source grant Topic Categories Vaccines and Immunotherapy (VAC)
2026-07-25 | An experimentally validated structure-based computational framework for humanisation of anti-orthopoxvirus antibodies.
The re-emergence of orthopoxviruses, most notably mpox virus (MPXV), poses a growing global public health threat. Well-characterised murine anti-orthopoxvirus antibodies are clinically limited by anti-mouse antibody responses, while traditional sequence-based humanisation often impairs antigen-binding activity. We developed an experimentally validated structure-guided computational humanisation framework prioritising 3D architectural congruence over sequence identity, integrating Foldseek-based structural alignment and interface-residue constraints. We applied this framework to humanise two murine anti-orthopoxvirus antibodies (7D11, A27D7), with comprehensive in vitro and in vivo validation. Structural superimposition confirmed high conformational conservation between the humanised variants (POX1.1 and POX2.1) and their parental mAbs, with root mean square deviation (RMSD) values below 0.6 Å for all variable domains. Both humanised variants retained full epitope specificity with natural humanness profiles. POX1.1 showed enhanced neutralisation potency against vaccinia virus (VACV) and MPXV, compared with the parental 7D11. POX2.1 preserved the broad cross-reactive binding and the extracellular enveloped virion neutralising activity of the parental A27D7. In the lethal VACV mouse model, both monotherapies conferred significant prophylactic and therapeutic protection, reducing pulmonary viral loads and improving survival. The dual-targeting combination of POX1.1 and POX2.1 achieved markedly improved in vivo efficacy compared with individual antibodies, delivering 100% survival even when administered 2 days post-challenge. In the MPXV CAST/EiJ mouse model, the combination significantly reduced splenomegaly and MPXV DNA loads in plasma, spleen and lung tissues, effectively suppressing systemic viral dissemination. These findings establish that the structure-centric workflow enables efficient humanisation of well-characterised murine anti-orthopoxvirus antibodies, providing a validated framework to support the development of countermeasures for orthopoxvirus pandemic. This work was supported by the National Natural Science Foundation of China, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the Scientific Research Innovation Capability Support Project for Young Faculty and the National Science and Technology Major Project.
2026-07-12 | Vaccinia virus and Monkeypox virus neutralizing and antigen-binding antibodies following subcutaneous and reduced intradermal doses of an MVA vaccine.
To expand the supply of the modified vaccinia Ankara (MVA) smallpox/mpox vaccine, fractional doses administered intradermally (ID) have been considered as alternatives to the standard dose given subcutaneously (SC). In a recent clinical trial, participants received the standard 108 infectious units of vaccine SC or a one-fifth (IDH) or a one-tenth (IDL) dose ID twice 28-days apart. Two weeks after the second dose, sera were analyzed using a vaccinia virus (VACV) strain Western Reserve plaque-reduction test (PRNT) with the conclusion that IDH but not IDL was non-inferior to SC. The present study extends the latter by quantifying neutralizing antibodies to the MVA vaccine and to monkeypox virus (MPXV) in the absence and presence of added complement and by assessing multiplex binding antibodies to individual VACV antigens (A27, A33, B5, D8 and L1) and the MPXV homologs (A29, A35, B6, E8 and M1). The main conclusions of the study are that the titers of MVA neutralizing antibodies induced by SC and IDH were not significantly different, whereas MVA neutralizing antibody titers induced by IDL were lower like the previous PRNT results. However, the titers of complement-enhanced MPXV neutralizing antibodies induced by SC were significantly higher than for both IDH and IDL immunizations, suggesting that the standard SC dose and reduced dose ID immunizations may not be equivalent. Additional analyses suggested that antibody binding to VACV B5 and D8 and MPXV B6 and E8 may serve as surrogates for neutralizing antibodies.
2026-07-10 | Severe mpox in an immunocompromised, non-traveller South African male.
Mpox is a zoonotic orthopoxvirus infection historically linked to being in endemic regions, travel and close physical contact, including within men who have sex with men (MSM) communities. We report a case of severe mpox in a heterosexual man with advanced human immunodeficiency virus (HIV) disease and no travel history to endemic areas. The patient developed extensive cutaneous disease and transmitted mpox to household contacts, illustrating non-sexual transmission. Management included supportive care and tecovirimat under Section 21 authorisation (a regulatory mechanism in South Africa permitting access to an unregistered medicine) with good clinical response. This case highlights the changing epidemiology of mpox, the risk of severe disease in immunocompromised patients, household and non-sexual transmission. We also emphasise the importance of early diagnosis, infection control and antiviral therapy when indicated.
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Drug Discovery Landscape
7 orphan drug designations for Human infection by orthopoxvirus, including 2 approved therapies.
7 orphan drug designations for Human infection by orthopoxvirus, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
brincidofovir [Tembexa] | small molecules | FDA | 2018-06-05 | 2021-06-04 | Emergent BioDefense Operations Lansing LLC |
Brincidofovir | small molecules | EMA | 2016-11-18 | — | Emergent Operations Ireland Limited |
Tecovirimat | small molecules | EMA | 2010-10-01 | — | SIGA Pharmaceuticals (Europe) Limited |
tecovirimat | small molecules | FDA | 2010-09-29 | — | SIGA Technologies, Inc. |
tecovirimat [TPOXX] | small molecules | FDA | 2006-12-27 | 2018-07-13 | SIGA Technologies, Inc. |
tecovirimat | small molecules | FDA | 2006-12-18 | — | SIGA Technologies, Inc. |
polyinosinic-polycytidilic acid (Poly-ICLC) | oligonucleotides | FDA | 2002-11-19 | — | Oncovir |
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