Future State of Smallpox Medical Countermeasures (2024) / Chapter Skim
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4 Way Forward: Priorities for Research, Development, and Stockpiling
4 Way Forward: Priorities for Research, Development, and Stockpiling
Pages 117-146
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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.
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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.
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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.
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From page 120... ...
of the live variola virus. Use of the support studies particularly against Live variola virus would be live virus will be necessary, however, mpox in field settings.
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From page 121... ...
The objective would be to identify ways in which the predictive value of the model for diagnostics, therapeutics, and vaccines might be improved. Discovery Research Live or replication-defective variola Discovery research to gain greater Only addressed whether to continue virus would be needed if studies understanding of human physiology current plans for MCM research of variola pathogenesis were to be and immunology, while not essential, undertaken to provide information would require use of the live variola about the response of the human virus and might ultimately support immune system.
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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)
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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.
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From page 124... ...
. As mentioned in Chapter 1, WHO oversees all research using live variola virus, with the ACVVR reviewing all research proposals that request to use one of the two sanctioned collections of live virus at CDC in Atlanta and the Russian State Centre for Research on Virology and Biotechnology (VECTOR)
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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)
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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.
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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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From page 128... ...
in humans for use as oncolytic and host features that can virotherapies, vaccine support improved vaccines: vectors, and gene deliveries • Vaccine immune to build population response mechanisms immunity against smallpox and durability and other orthopoxviruses. • Viral protein functions and functional interactions • Major targets of neutralizing antibodies • Immunodominant antigens/epitopes • Host and viral elements that determine breakthrough infections
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From page 129... ...
Antivirals • New drugs with different Studying basic Essential for No use Essential for Essential and diverse targets, orthopoxvirus processes development due some targets for optimal mechanisms of action, and to support new knowledge to the restricted verification of routes of administration. in basic orthopoxvirus access to VARV the MCM that • Drug cocktail effect science toward improved will be used in (combined treatment)
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From page 130... ...
pathogenesis, transmission, and host interaction • Major targets of neutralizing antibodies Applying research tools to study orthopoxvirus based vaccine vectors and oncolytic agents can support novel therapies. Animal • Understanding of vaccine Researching improved Essential No use Useful for Essential in models and therapeutic efficacy humanized mouse models propagation of developing (as they and utility.
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From page 131... ...
Goals 3 and 4 of the National Biodefense Strategy and Implementation Plan lay out the whole-of-society elements of a fast response, calling for expedited evaluation of novel vaccines, therapeutics, and diagnostics during outbreaks (White House, 2022)
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From page 132... ...
Conclusions on the Continued Role of Live Variola Virus for Research and Public Health Purposes (4-1) Research with live variola virus is essential for developing animal models to be used for MCM efficacy testing as a human surrogate, full verification of the potential efficacy of MCMs, and the development of certain targets for more effective therapeutic options, and it may be essential if advanced organoid or other sophisticated systems will be used to study these biologic interventions.
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From page 133... ...
. These threats remain substantive drivers of the SNS budget, and there is limited flexibility in terms of what other MCMs can be purchased with current appropriations, due to the portion of the budget allocated to anthrax and smallpox MCMs (GAO, 2022)
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From page 134... ...
The description of BARDA's investment in smallpox MCMs includes funding to support sustained investment in a lyophilized formulation of MVABN, manufacturing of additional doses of MVA-BN to bolster domestic supply, and procurement of oral and intravenous tecovirimat to replenish products used to respond to the mpox outbreak. Sustainment of stockpiled assets is a prudent course, given the years and billions of dollars that have gone into developing and procuring these assets.
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From page 135... ...
An important question raised from the mpox experience is whether the dual indications for both a national security threat and an emerging infectious disease will remain an outlier, or whether it can 2 Public Law: Project BioShield Act of 2004, Public Law 108-276, 108th Cong., 2d. sess.
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From page 136... ...
. Thus, the successes of the mpox response were tempered by major challenges, especially the short supply of immediately available vaccine doses, as well as by concerns over changes to dosing strategy during outbreak response, inequitable vaccine access, access to laboratory testing for patients, and overall federal, state, and local coordination (McQuiston, 2023; Mrsny, 2022)
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From page 137... ...
Considerations for the Smallpox MCM Portfolio The overall composition of the SNS has changed in the more than two decades since its inception (Kuiken and Gottron, 2023)
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To inform their future priorities for the smallpox MCM portfolio, BARDA and PHEMCE could develop new TPPs and refine existing TPPs for smallpox MCMs. This could include defining the product, including both the indication (i.e., disease/condition to be treated)
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From page 139... ...
• Diversifying stockpiled smallpox MCMs. The development and stockpiling of multiple MCMs may mitigate the risk of supply shortages and address potential efficacy, safety, pricing, administration, and uptake concerns, but it may also amplify sustainability concerns absent a commercial market for the products.
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From page 140... ...
Should sustaining stores of smallpox vaccines be viewed as an irrevocable obligation while purchases of other products for the SNS are discretion ary? And what is a reasonable price to pay for new vaccine doses to replace expiring doses?
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From page 141... ...
Based on the evidence and findings on the utility of live variola virus for research and the smallpox MCM portfolio planning, the committee drew the following overarching conclusions: For the foreseeable future, some research with live variola virus remains essential to achieving public health research goals against an ever evolving biothreat landscape and the potential for orthopoxviruses to emerge naturally or deliberately. The smallpox MCM portfolio is a mature portfolio, and the goals of a mature portfolio should differ from a relatively new MCM portfolio.
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2023. Strategic National Stockpilesmallpox medical countermeasuresoverview.
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1999. Assessment of future scientific needs for live variola virus.
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Presentation at Meeting 2 of the Committee on Current State of Research, Development, and Stockpiling of Smallpox MCMs. December 1.
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n.d. Research using live variola virus.
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2023. Mpox multi-antigen mRNA vaccine candidates by a simplified manufacturing strategy afford efficient protection against lethal orthopoxvirus challenge.
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