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Pages 100-127

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From page 100...
... 100 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES BOX 3-3 Opportunities to Strengthen National Laboratory Systems for Smallpox Biosafety • Collaborating with commercial laboratories for specimen transport during public health emergencies.a Test Development • Providing redundancy in the initial test development process using advanced public health laboratories.a Test Manufacturing • Proactively developing government contracts with test manufacturers for supplies.a Stockpiling • Robustly stocking the Strategic National Stockpile with testing kits, test com ponents, and other related supplies.b Testing Capacity • Updating current LRN assays by multiplexing and adapting to high throughput.* • Establishing guidelines to ensure consistency and predictability among tradi tional and nontraditional health care testing settings.b • Striving toward immediate access to validated methods, the ability to rapidly develop methods, and a trained testing workforce.b • Securing federal testing capacity by designating laboratories, medical centers and test manufacturers to respond during outbreaks.c • Establishing emergency funding mechanisms before outbreaks can greatly impact mobilization efforts and testing readiness.c Data Management • Developing a minimum dataset for the test request process and case definition.a • Standardizing laboratory information management systems to ensure data can be shared within the national laboratory system.b Regulatory • Collaborating with FDA to develop a portfolio of pre-vetted test protocols to speed regulatory test approval in an emerging biological crisis.a • Aspiring toward nationwide mandatory reporting requirements to coordinate mitigation efforts.b • Need for federal testing guidelines with enforcement and guidance structures.b • Creating and updating test protocols that are pre-reviewed by FDA could speed regulatory test approvals during public health emergencies.c
From page 101...
... Regulatory Readiness As noted in Chapter 1, access to smallpox MCMs in both domestic and global stockpiles depends considerably on the regulatory status of existing and new MCMs as well as on risk–benefit calculations that must be carried out with incomplete information. As such, these regulatory decisions reflect important scientific, legal, and ethical considerations.
From page 102...
... For instance, novel smallpox MCMs cannot be tested in humans with smallpox because the disease has been eradicated, but the use of MCMs developed for smallpox in the mpox outbreaks provided valuable proxy data indicating that they might have pan-orthopoxvirus applications (Dalton et al., 2023)
From page 103...
... permit to use these in a different way. Such regulatory mechanisms could also enable the use of other products such as the Aventis Pasteur smallpox vaccine (see Chapter 2)
From page 104...
... Relevant Ethical Questions for Smallpox MCMs Basic science research on smallpox may fit the definition of dual use research of concern and therefore receives additional ethical scrutiny (NASEM, 2017)
From page 105...
... The small number of manufacturers of smallpox MCMs is a readiness and response vulnerability -- and it is clear there is insufficient capacity to scale MCM production in the event of a large-scale smallpox event espe cially one of international scope.
From page 106...
... OVERARCHING CONCLUSIONS Based on the evidence and findings on the ongoing utility of orthopoxvirus research more broadly for smallpox readiness and response, on the implications of scientific and technological advancements on available smallpox MCMs, and on operational considerations affecting SNS planning, the committee drew the following overarching conclusions: In addition to smallpox readiness, research should continue to be used to enhance readiness and response for other orthopoxviruses, this includes supporting the validation, approval and licensure, and commercializa tion of existing and next-generation MCMs for use in the management of non-variola orthopoxviruses as an efficient way to expand readi ness more broadly by enabling vendor-managed inventory approaches to stockpiling. A comprehensive and ongoing risk–benefit analysis is needed for smallpox MCMs research using emerging technologies as well as ongoing careful oversight to mitigate the risks of this research and ensure the risk–benefit balance is maintained.
From page 107...
... 2023. Strategic National Stockpile smallpox medical countermeasures overview.
From page 108...
... 2023. Current state of research, development, and stockpiling of smallpox MCMs.
From page 109...
... for prevention of monkeypox disease in individuals determined to be at high risk for monkeypox infection. https://www.fda.gov/ media/160774/download (accessed February 15, 2024)
From page 110...
... 2009b. Live variola virus: Considerations for continuing research.
From page 111...
... https://www.nationalacademies.org/ event/41411_12-2023_meeting-3-of-the-committee-on-the-current-state-of-research-develop ment-and-stockpiling-of-smallpox-medical-countermeasures (accessed February 18, 2024)
From page 112...
... https://www.nti.org/news/new-international-biosecurity-organization-launched-to safeguard-bioscience (accessed February 29, 2024)
From page 113...
... 2016. Use of vaccinia virus smallpox vaccine in laboratory and health care personnel at risk for occupational exposure to orthopoxvi ruses -- Recommendations of the Advisory Committee on Immunization Practices (ACIP)
From page 114...
... 2024a. 154th session of the executive board, provisional agenda item 18 -- Smallpox eradication: Destruction of variola virus stocks (January 2)
From page 115...
... FACTORS INFLUENCING SMALLPOX READINESS AND RESPONSE 115 Yuan, S., H
From page 117...
... What knowledge gaps remain that could be addressed through scientific research, and what capability gaps remain that could be addressed through amendment to the composition of the stockpile? This chapter briefly discusses future opportunities for live variola virus research as well as for non-variola orthopoxvirus research in developing smallpox MCMs and concludes with considerations for new directions in the national stockpiling approach for smallpox MCMs.
From page 118...
... . Non-Variola Orthopoxvirus and Live Variola Virus Research This section identifies gaps and opportunities in the discovery and development pipeline for smallpox MCMs and describes the ongoing role of the use of live variola virus.
From page 119...
... and Recommendations from the 2022 ACVVR Report Conclusions from the 1999 Conclusions from the 2009 Recommendations from the 2022 Type of Research IOM Report IOM Report ACVVR Report Diagnostics If further development of procedures Live variola virus is not required for Continue work on roadmap to leverage for the environmental detection further development of detection and advances in smallpox diagnostics for of variola virus or for diagnostic diagnostic methods. Virus materials further development of point-of-care purposes were to be pursued, such as DNA and proteins would diagnostics for mpox.
From page 120...
... possibility that some strains might be naturally resistant. Vaccines Adequate stocks of smallpox vaccine The current development and licensure Continue efforts to characterize must be maintained if research is pathway for first- and second- the effectiveness against other to be conducted on variola virus generation vaccinia vaccines that orthopoxviruses of smallpox vaccines or if maintenance of a smallpox produce a "take" does not require use approved or in development, and vaccination program is required.
From page 121...
... Live variola virus lead to discoveries with broader would be needed for this purpose implications for human health. only until sufficient variola isolates 121 had been cloned and sequenced.
From page 122...
... The necessary regulatory restrictions on research with live variola virus and the absence of circulating smallpox disease today make orthopoxvirus research using non-variola species critical to continued improvements in smallpox preparedness. Scientific and technological advancements in studying orthopoxviruses in humanized-mouse models, Cast E/J mice, other small animal models, nonhuman primate animal models, and in silico models have also created opportunities to complement the use of variola virus research (Hutson et al., 2021)
From page 123...
... relied on experimentation with non-variola orthopoxviruses and supportive studies with variola virus. The scientific and logistical limitations of using smallpox virus in animal models necessitated establishing the efficacy of tecovirimat using related viruses.
From page 124...
... . Not only is non-variola orthopoxvirus research important in smallpox MCMs, but this research can also help reveal to scientists the reservoirs, evolutionary relationships, and virological properties of the genus, all of which can inform scientific understanding of variola virus and strategies to mitigate it.
From page 125...
... and antibody mixes to neutralize variola virus, assisting in creating a new universal orthopoxvirus monoclonal mix, evaluating mAbs and cocktails in vitro against variola virus • Vaccines: Finalize efficacy testing on long-term titer samples from MVA-BN and/or LC16m8 vaccine trials (as samples are available) • Animal models: Completing remaining in vitro work on humanized mouse models HU-BLT, continuing assessment of HU-BLT and HU-CD34 models using tecovirimat VECTOR • Genomic sequencing: Completing genomic sequencing of 50 of remaining 88 isolates • Diagnostics: Optimizing design of immunochemistry test kit and its acces sories using orthopoxviruses • Antivirals: NIOCH-14 oral formulation, 15 new compounds found to be highly active against orthopoxviruses, evaluating antivirals against variola virus based on monoclonal antibodies • Vaccine: VACdelta6 testing completed, licensure obtained in 2022 as OrthopoxVac for smallpox, mpox, and other orthopoxviruses WHO Oversight • Advisory Committee for Variola Virus Research established in 1999 to over see live variola virus research in accordance with World Health Assembly Resolution WHA52 • Oversight of live variola virus research, biosafety and biosecurity of both repository sites, sequencing the viral genome from variola virus isolates, and distribution of live variola DNA to other researchers (WHO, 2024b)
From page 126...
... Further elucidation of some of the secrets of variola virus that remain hidden -- and which could help advance the development of modernized smallpox MCMs -- would necessitate research with live variola. For example, having live variola virus collections, before treatment with tecovirimat, will be important for understanding drug resistant mutants when they arise.
From page 127...
... Smallpox MCM Knowledge Viral Research Element Replicationof MCM Opportunity for MCM Knowledge Gaps and Non-VARV Defective Live VARV in Live VARV in Readiness Improvement Research Possibilities Orthopoxviruses VARV Tissue Culture Animal Models Detection • Multiplex nucleic acid Increasing surveillance Useful to Useful for Useful for certain Full genome tools and assays for new platforms and sequencing of variola essential certain variola variola detection sequence is diagnostics and field settings. samples to provide new depending detection or or diagnostic required, and live • Forward-deployed point- knowledge about viral on specific diagnostic devices VARV is essential of-care assays including science that can advance pathogens devices for optimal protein- or antigen-based MCM science: verification of tests to rapidly test and • Orthopoxvirus ecology diagnostics isolate infected patients.


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