Future State of Smallpox Medical Countermeasures (2024) / Chapter Skim
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2023. Smallpox medical countermeasures.
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2009. Live variola virus: Considerations for continuing research.
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Presentation at Meeting 3 of the Committee on Current State of Research, Development, and Stockpiling of Smallpox MCMs of the National Academies. December 14.
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2024. 154th session of the executive board, provisional agenda item 18 -- Smallpox eradication: Destruction of variola virus stocks (January 2, 2024)
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One fundamental lesson learned from COVID-19 and mpox emergencies is that research and development for new smallpox MCMs must not only consider the characteristics of the "product" but also must consider the ability to deploy at scale and ensure equitable access. DIAGNOSTICS, DETECTION, AND SURVEILLANCE The ability to rapidly detect and diagnose a potential case of smallpox is central to all containment strategies.
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in 2017. The FDA-approved Variola Virus Nucleic Acid-Based Detection Assay is indicated for "individuals presenting with pustular or vesicular rash illness or other signs and symptoms of Variola virus infection" (FDA, 2024b)
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. During the 2022 mpox outbreak, once CDC and FDA began supporting orthopoxvirus testing in five commercial laboratory companies, clinicians preferred to use these laboratories over the public health laboratories of the LRN due to more streamlined patient data requirements and perhaps the perception of a more rapid availability of actionable results initially made possible by higher throughput testing capabilities at commercial laboratories (APHL, 2023)
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. Any work which uses live variola virus to validate smallpox diagnostics must also be approved by the World Health Organization (WHO)
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. Given the high public health concern regarding smallpox cases, rapid diagnostics aimed at the consumer are unlikely to have a role in most smallpox outbreaks.
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. Although the pathogenic mechanism for this observation may differ between clade IIb monkeypoxvirus infection and variola virus infection, this compares to reports of finding variola virus in saliva, conjunctiva, and urine in patients with hemorrhagic smallpox (Sarkar et al., 1973)
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. Ring vaccination is also still recommended by both WHO and CDC as the first-line response strategy for a smallpox outbreak (CDC, 2019b; WHO, 2023)
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previous reports Live Variola Virus: Considerations for Continuing Research (2009) includes a detailed summary of the history of smallpox vaccine development -- from early vaccine development to post-eradication era -- and describes how the development of smallpox vaccines has progressed in major phases (first-, second-, third-generation)
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1st generation • Emergency Use Formulation contains Live, replicating Authorization (EUA) / live vaccinia virus in vaccinia virus, Investigational New Drug 50% glycerol, 0.4% NYCBOH-derived (IND)
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. A phase 3 trial also observed fewer adverse events among those who received two doses of MVA-BN compared to individuals who only received Dryvax (Pittman et al., 2019)
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• Vaccines containing highly attenuated live vaccine or non-replicating strains of vaccinia virus. • Produced in mammalian cell culture, embryonated eggs, or Chicken Embryo Fibroblast cells (e.g., for MVA-BN specifically)
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. CDC's clinical use guidelines for smallpox vaccine indicate that there are no absolute contraindications for a smallpox vaccination in a post-event setting but that there are certain "relative" contraindications due to the possibility of adverse events associated with certain conditions (Table 2-2)
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, 1–2 deaths per million progressive vaccinia (fatality rate primary vaccinations. nearly 100% and eczema vaccinatum Often in young children or (10% before vaccinia immune globulin those with unrecognized [VIG]
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Non-infectious Generalized rash occurring 1–2 weeks 51.5–164.6 per million rashes (erythema after vaccination. Most resolve primary vaccinations multiforme)
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Reliance on the U.S. Strategic National Stockpile and Concerns with Manufacturing Capacity Dependence on the SNS smallpox vaccine stockpile as the primary form of smallpox readiness has required that sufficient inventory be maintained to respond to a smallpox event where the entire U.S.
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. Research on fourth generation smallpox vaccines could explore potential subunit or nucleic acid vaccines (protein, peptide, mRNA)
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The development of novel smallpox vaccines using multi-vaccine platforms (i.e., use common vaccine vectors, manufacturing ingredients, and processes) would improve the capacity for rapid vaccine production in response to a smallpox event and reduce the need for stockpiling in the SNS at current levels.
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. Mpox Virus)
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CDC = U.S. Centers for Disease Control and Prevention; EA = expanded access; EIND = emergency investigational new drug application; IND = investigational new drug application; OPXV = orthopoxvirus; VARV = variola virus.
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. More recent efforts have looked at therapeutic efficacy in nonhuman primates when initiated after rash onset following exposure to mpox (Russo et al., 2018)
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. Adverse events, such as serious renal toxicity, have been observed during treatment of CMV retinitis infections with cidofovir (Skiest et al., 1999)
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; (3) Vaccinia immune globulin intravenous (VIGIV)
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2023. Strategic National Stockpilesmallpox medical countermeasuresoverview.
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