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Future State of Smallpox Medical Countermeasures (2024)

Chapter: 4 Way Forward: Priorities for Research, Development, and Stockpiling

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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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Suggested Citation:"4 Way Forward: Priorities for Research, Development, and Stockpiling." National Academies of Sciences, Engineering, and Medicine. 2024. Future State of Smallpox Medical Countermeasures. Washington, DC: The National Academies Press. doi: 10.17226/27652.
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4 Way Forward: Priorities for Research, Development, and Stockpiling “In a smallpox emergency, a reemergence anywhere will likely create demand [for medical countermeasures] everywhere.” Crystal Watson, in presentation to the committee December 14, 2023 Decades of investments have reaped significant benefits for smallpox preparedness, even if the threat of a smallpox outbreak is of uncertain size and scope. The United States now has a smallpox stockpile of medi- cal countermeasures (MCMs) far more robust and mature than it was at its inception. The committee was asked to provide its perspective on what the priorities could be going forward for additional research, development, and the stockpiling of smallpox MCMs that can further improve the U.S. readiness and response posture. 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 develop- ing smallpox MCMs and concludes with considerations for new directions in the national stockpiling approach for smallpox MCMs. SMALLPOX RESEARCH AGENDA Research that enhances the safety, efficacy, and utility of smallpox diagnostics, vaccines, and therapeutics provides a public health benefit in the context of smallpox readiness and has added benefits that improve the 117

118 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES nation’s response to other orthopoxvirus outbreaks. Objectives to date of the U.S. smallpox research program derive largely from the 1999 Institute of Medicine (IOM) report that addressed the scientific needs for live variola virus (IOM, 1999) and subsequent reports of the IOM (IOM, 2009) and the World Health Organization (WHO) Advisory Group of Independent Experts (WHO, 2010, 2013) and have been overseen by the WHO Advisory Group for Live Variola Virus Research (ACVVR) (WHO, n.d.). Table 4-1 highlights conclusions from the 1999 and 2009 IOM reports and the 2022 ACVVR report (WHO, 2023). The 2023 ACVVR report (in progress at the time of publication) was recently summarized at the 154th WHO Executive Board Session and concluded that access to and use of live variola virus remains essential for public health needs, including completing the sequenc- ing of remaining variola virus isolates, further research on point-of-care diagnostics, the development of scalable less-reactogenic vaccines, and the development of small-molecule antiviral agents (WHO, 2024a). Figure 4-1, from the U.S. Centers for Disease Control and Prevention (CDC), illustrates a U.S. smallpox research agenda focused on next-generation vaccines, anti- viral treatments, and nucleic acid- and protein-based diagnostic assays and shows nodes at which variola viral samples enable the evaluation of the diagnostics, vaccines, and therapeutics developed under this agenda. U.S. investments in line with this agenda have expanded the smallpox assets available to the United States (and to other countries). These invest- ments have also enabled benefits beyond smallpox readiness and response. These benefits were realized most clearly in the mpox response’s use of modified vaccinia Ankara-Bavarian Nordic (MVA-BN) and tecovirimat, countermeasures which at their inception were envisioned exclusively for smallpox preparedness. Inversely, one would expect a research program targeting non-variola orthopoxviruses to offer potential utility for smallpox preparedness and, further, that investments in products with broader and potentially commercial use may have more immediate utility and could be more attractive to industry partners. As discussed in Chapter 3, while ortho- poxviruses in general offer great utilities, vaccinia virus, the prototype pox- virus and the smallpox vaccine, and the monkeypoxvirus are of particular significance in this regard. Both these viruses emerged as human pathogens post cessation of smallpox vaccination programs (Damaso et al., 2000). 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. Research with live variola virus and with non-variola orthopoxviruses is necessary to the development of small- pox MCMs—leading to better diagnostics, better vaccines, and better

TABLE 4-1  List of Conclusions from the IOM Reports: Assessment of Future Scientific Needs for Live Variola Virus (1999) and Live Variola Virus: Considerations for Continuing Research (2009) 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. more extensive knowledge of the suffice for this purpose. genome variability, predicted protein Continue to work toward development sequences, virion surface structure, *NOTE: The 2009 IOM report is in and validation of (rapid, point-of-care) and functionality of variola virus conflict with the ACVVR 2022 report orthopoxvirus diagnostic tests and from widely dispersed geographic in that live variola virus is required for expedite their availability in a reliable sources would be needed. the further development of detection and equitable manner. and diagnostic methods. This reflects, lessons learned from past public Continue to work toward development health emergencies per the need for of protein-based orthopoxvirus diagnostics which are readily available diagnostics with continuing focus on to triage decision making. approaches that do not require the use of live variola virus, noting that development of nucleic acid–based diagnostics does not require the use of live variola virus. Consider development of target product profiles for smallpox diagnostics. continued 119

TABLE 4-1 Continued 120 Conclusions from the 1999 Conclusions from the 2009 Recommendations from the 2022 Type of Research IOM Report IOM Report ACVVR Report Therapeutics The most compelling reason for For both scientific and regulatory Continue development and discovery long-term retention of live variola reasons, the final developmental of small molecule antivirals for use virus stocks is their essential role in stages leading to licensure of smallpox by themselves or in combination to the identification and development therapeutics cannot occur without the give maximal protection in case of a of antiviral agents for use in use of live variola virus. Furthermore, smallpox event and to delay or slow anticipation of a large outbreak of although the regulatory environment down the emergence of resistance. smallpox. It must be emphasized may change, the scientific reasons will that if the search for antiviral agents remain. Therapeutic agents need to Continue work to identify genetic with activity against live variola virus be evaluated against a representative markers of resistance to antivirals. were to be continued, additional panel of variola strains to reduce the public resources would be needed. 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. 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. necessary if certain approaches to for the development and licensure of the development of novel types of any vaccine that does not manifest Continue work to characterize and smallpox vaccine were pursued. such a cutaneous lesion at the site of harmonize potency testing protocols for inoculation all smallpox vaccines. Continue efforts to improve the shelf life of vaccines. Include minimally- or non-replicating vaccines in WHO strategic reserves.

Genomic Analysis Genomic sequencing and limited Live variola virus is not needed for Complete full genome sequencing of study of variola surface proteins variola genome sequence analysis if variola virus strains or isolates without derived from geographically dispersed specimens containing viral DNA of amplification of virus and make specimens is an essential foundation adequate quantity and quality are sequence data for all available isolates for important future work. Such available. Live variola virus would be publicly available directly or via WHO research could be carried out now needed for functional genomics–based as soon as possible. and could require a delay in the experimental approaches. destruction of known stocks but would not necessitate their indefinite retention. Animal Models The existence of animal models That a comprehensive evaluation of the No recommendations made in this area would greatly assist the development work done to date on the nonhuman and testing of antiviral agents and primate model of variola pathogenesis vaccines as well as studies of variola be undertaken by CDC, in conjunction pathogenesis. Such a program could with an expert panel knowledgeable be carried out only with live variola about poxviruses and animal models of virus. viral infection. 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. efforts to discover and evaluate therapeutics and vaccines. Further, Variola virus proteins have potential research with live variola virus and as reagents in studies of human research with variola proteins could immunology. 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.

122 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES FIGURE 4-1  Smallpox research agenda. SOURCE: Hutson (2023). therapeutics. 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 im- provements in smallpox preparedness. Scientific and technological advance- ments 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). Non-Variola Orthopoxvirus Research The following narrative lays out important advances in smallpox MCMs using non-variola orthopoxvirus research. Working with non-vari- ola orthopoxviruses can inform new strategies and approaches for scaling and improving MCM production and distribution. U.S. Food and Drug Administration (FDA)-approved smallpox vaccines are formulated using vaccinia virus, a non-variola orthopoxvirus. All first-, second-, and third- generation smallpox vaccines contain vaccinia virus, an orthopoxvirus

PRIORITIES FOR RESEARCH, DEVELOPMENT, AND STOCKPILING 123 closely related to variola which has been proven to prevent most smallpox disease and deaths. In fact, the first-generation smallpox vaccine was la- beled by FDA for “prevention of orthopoxvirus” disease, and the newest licensed smallpox vaccine, MVA-BN, is labeled for the prevention of both smallpox and mpox. Vaccinia research therefore has direct implications for vaccine safety, efficacy, shelf-life, improvement, production, cost reduction, and management. Additionally, mpox subunit and nucleic acid vaccines (including mRNA vaccines) in development are rooted in the understanding of other orthopoxviruses (Fang et al., 2023; Freyn et al., 2023; Hooper et al., 2003; Hou et al., 2023; Rcheulishvili et al., 2023; Sang et al., 2023; X. Yang et al., 2023; Zeng et al., 2023; Zhang et al., 2023). Non-variola orthopoxviruses have also been used in the development and testing of smallpox drugs and can support future drug development for smallpox and other targets. Efforts to develop new therapeutics for smallpox have used non-variola orthopoxviruses in preclinical and clinical trials and have shown efficacy against them (Deng et al., 2007; Dower et al., 2012; Peng et al., 2020). The development processes of the smallpox drugs tecovirimat (Huggins et al., 2009; G. Yang et al., 2005) and brincidofovir (Olson et al., 2014; Stabenow et al., 2010) 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. Tecovirimat use demonstrated benefit in a number of animal models (mice, prairie dogs, rabbits, nonhuman primates) that had been infected with different orthopoxviruses (ectromelia, monkeypox, rabbitpox) as well as nonhuman primates infected with smallpox virus (variola virus) (Russo et al., 2021). Recent studies demonstrated benefit of tecovirimat in the treatment of humanized mice infected with smallpox virus (WHO, 2023). Pivotal studies for regulatory approval used nonhuman primates challenged with monkeypox virus and rabbits with rabbitpox virus and demonstrated improved survival in animals that received the drug (FDA, n.d.). Because the presence of non-variola orthopoxviruses in the world complicates empirical diagnosis of smallpox, it thereby necessitates a research approach to diagnostics that differentiates between variola and these other viruses. The high similarity of orthopoxvirus DNA genome sequences and the recognition of new viruses have also posed challenges for accurate differentiation among orthopoxviruses using tests based on biophysical properties and sometimes nucleic acid–based tests, though reliable polymerase chain reaction (PCR) assays have been developed and continue to be reassessed as new viruses are discovered (Altindis et al., 2022; Hedberg and Zink, 2024; Low et al., 2023; Stefano et al., 2023). To date, serology-based approaches are challenged to distinguish among orthopoxviruses due to cross reactivity. The development of two FDA- approved nucleic acid-based assays—one for variola and one for non-

124 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES variola orthopoxviruses—was designed to address the need for effective testing tools and an algorithm with which to use them. Validation of the non-variola panel relied on use of human pathogenic orthopoxviruses including strains of cowpox, monkeypox, vaccinia, and variola virus spe- cies1 (FDA, 2018; Li et al., 2006). 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. And since these viruses exist in nature and some are the cause of occasional or ongoing outbreaks, research on non-variola orthopoxviruses has a greater potential for near-term clinical and public health benefits. Use of these poxviruses could drive basic research in other areas as well, such as the study of viral vectors for vaccine development, gene therapy, and oncolytic virus therapy, as described in Chapter 3. Live Variola Virus Research While there are advantages to conducting research with non-variola orthopoxviruses, these species cannot fully replace the knowledge gained by working with live variola virus (Damon et al., 2014). In a presentation to the committee, CDC shared salient examples of the ways that strains of variola virus (or samples derived from live virus) have been or are being used, which include: • Validation of diagnostic assays and iterative assessment of Labora- tory Response Network tests with newly sequenced variola virus isolates in silico to determine if wet lab testing is needed. • Provision of comparative data on vaccine immunogenicity, such as an ongoing study to provide “non-inferiority” data on MVA-BN at the request of FDA. • Provision of comparative data on antiviral effectiveness to test an expanded panel of variola virus isolates for their sensitivity to tecovirimat at the request of FDA (Hutson, 2023). As mentioned in Chapter 1, WHO oversees all research using live va- riola 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), Koltsovo, Novosibirsk Region, Russian Federation. Box 4-1 highlights completed and ongoing research for use of live variola virus from 1 Variola virus was used in the testing panel to confirm the assay did not detect variola virus.

PRIORITIES FOR RESEARCH, DEVELOPMENT, AND STOCKPILING 125 BOX 4-1 Research Program Using Live Variola Virus, 2020–2023 CDC • Genomic sequencing: Completing genomic sequencing of 40 isolates • Diagnostics: Adapting and optimizing multiplex nucleic acid diagnostic tests for new platforms and settings. Continuing development and optimization of protein-based tests • Antivirals: Tecovirimat, ST-357, completing screens of monoclonal antibodies (mAbs) 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) • BSL-4 level laboratory biosafety security measures in place to restrict access to variola virus • Regular inspections and emergency drills; biannual WHO inspections • Annual submission of proposals to work with live variola virus reviewed by the WHO ACVVR SOURCES: Hutson (2023); Lewis (2023).

126 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES 2020 to 2023. The 2022 ACVVR report of the 24th meeting also details specific research proposals for use of live variola virus presented for 2023, and the forthcoming 2023 report of the 25th meeting will detail specific re- search proposals presented for 2024 (in progress at the time of publication). Notably, the ACVVR reports also describe a considerable amount of work using non-variola orthopoxviruses as surrogates and as useful tools in their own right for non-variola diseases like mpox (WHO, 2023). Despite considerable similarities in genetic identity, host range, trans- mission, pathogenesis, and other viral characteristics and host interac- tions, research reveals significant differences across orthopoxvirus species (Satheshkumar and Damon, 2021). It is believed that genes in the left and right ends of the genomes, which are more variable across orthopoxviruses and are described to interact with multiple host proteins (e.g., interferons, complement, apoptosis, chemokines), are responsible for these differences (Moss and Smith, 2021). The genomic sequencing of variola virus isolates held in CDC and VECTOR repositories (still in progress) can contribute to the understanding of poxvirus evolution, host-range, virulence, and trans- mission and to the future assessment and evaluation of diagnostic assays and modern molecular techniques for diagnostics, and identification of variants that may be resistant to future antiviral drugs (WHO, 2023). Ad- ditional work in genomic sequencing of live variola virus will be required to advance the fundamental understanding of smallpox and related pox- viruses, and WHO has recommended that sequence data for all available isolates be made publicly available as soon as possible. In 1999, IOM concluded: The most compelling need for long-term retention of live variola virus would be for the development of antiviral agents or novel vaccines to protect against a reemergence of smallpox due to accidental or intentional release of variola virus. (IOM, 1999) IOM’s 1999 finding that live virus is needed for certain aspects of research remains true today. Further elucidation of some of the secrets of variola virus that remain hidden—and which could help advance the develop- ment of modernized smallpox MCMs—would necessitate research with live variola. For example, having live variola virus collections, before treat- ment with tecovirimat, will be important for understanding drug resistant mutants when they arise. Taking what is now known, Table 4-2 looks at smallpox MCM readiness as a function of research with live variola and non-variola orthopoxviruses. It maps the potential for using these viruses or their components against specific knowledge gaps and MCM goals that could support improved public health benefit.

TABLE 4-2  Smallpox MCM Readiness as a Function of Live Variola and Non-Variola Viral Research: Opportunities for MCM Improvement Note to reader: This table is designed to emphasize smallpox MCM and research, but other orthopoxviruses are inte- grated where appropriate to smallpox preparedness. Rather than emphasizing the maintenance of existing MCM and incremental improvements on them, it highlights areas where more significant innovation could improve public health readiness and response outcomes. Smallpox MCM Knowledge Viral Research Element Replication- of 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. • Orthopoxvirus • FDA-approved serologic epidemiology assays to assess individual • Orthopoxvirus/variola and population levels of genomic evolution immunity against smallpox • Orthpoxvirus immune and history of exposures. responses • Nucleic acid testing of clinical samples (e.g., nasopharyngeal, saliva, urine, etc.) to test for disease prior to onset of rash illness. 127 continued

TABLE 4-2 Continued 128 Element Replication- of 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 Vaccines • Vaccines against smallpox Advancing research on Essential for No use Useful for Arguably with improved efficacy, orthopoxvirus replication, almost every measuring essential safety, utility, and pathogenesis, host aspect of vaccine functional for optimal scalability. interactions, and immune development immune verification of • Ancillary benefits of responses to improve with vaccinia response (e.g., potential efficacy vaccinia-based vaccines understanding of virus virus neutralization) 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

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). antivirals: humans • Viral evolution, including genomic mutations from orthopoxvirus patients • Transmission • Pathogenesis and host interaction • Mechanisms of entry and receptors, DNA replication, transcription, membrane assembly, virion assembly and egress, and resistance • Viral protein functions and functional interactions • Major targets of neutralizing antibodies • Factors that determine host range • Cellular mechanisms promoting zoonotic infection continued 129

TABLE 4-2 Continued 130 Element Replication- of 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 Non-vaccine • Potential to repurpose Applying of new Essential for No use May be essential Essential optimal biologics vaccinia immune globulin technology to basic development due if advanced verification intravenous (VIGIV) poxvirus discovery research to the restricted organoid or other of MCM that as part of combination to support improved access to VARV sophisticated will be used in therapy. understanding of virus systems will be humans • Novel treatment concepts and host properties that used to study and development, e.g., can improve biologics these biologic genome editing, non- development: interventions conventional targets. • Orthopoxvirus • Monoclonal antibodies and replication, antibody cocktails. 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. using VARV that can virus for testing models that relate to recapitulate aspects of in the animal can be used for MCMs) human smallpox to model system MCM efficacy support advances in testing as a vaccines and treatments. human surrogate NOTE: VARV = variola virus.

PRIORITIES FOR RESEARCH, DEVELOPMENT, AND STOCKPILING 131 Research Readiness The ability to evaluate the safety and efficacy of MCMs (particularly those that have only animal data on efficacy) in a larger population during a public health emergency is a critical component of MCM readiness. Clinical trial infrastructure serves as the backbone for evaluating urgently needed diagnostics, vaccines, and therapeutics during outbreaks (NASEM, 2017). Advancement of therapeutics for COVID-19 lagged behind the suc- cesses with vaccines because at the outset of the pandemic, when little was known about the virus, but hospitalization rates were high, it was impor- tant to determine if existing antiviral agents could be repurposed for use. This was initially successful with Remdesivir. Thereafter, the drug discovery was slow knowing that because direct acting antiviral treatments work best when given early in the course of most diseases to halt viral replication and to be initiated on treatment, patients or participants must have access to diagnostics to confirm the presence of disease (Griffin et al., 2021; Mulangu et al., 2019). While clinical trial networks enabled rapid recruitment for hospitalized and moderately to severely ill patients, some argued that the lack of an established framework outside of hospitalized patients to support clinical trials was a significant challenge for research on early/mild COVID that led to small, underpowered studies with repurposed drugs (Robinson et al., 2022). This meant that the trials that were run offered limited insight into pre- or post-hospital stages of COVID-19. The COVID-19 pandemic highlighted the need for adaptive and outpatient trial designs, including community or nursing home based as well cluster trials for early access to treatment and for evaluation of pre- and post-exposure interventions (Grif- fin et al., 2021; Mulangu et al., 2019). Decentralizing and taking clinical tri- als closer to the community has the potential to also reduce social inequities and logistical barriers in research participation (Petrini et al., 2022). Even hospital-based trials faced immense delays in initiation and were fraught with inequity in participation by diverse patient populations (Linas and Cunningham, 2019). Had the government established an organized network of hospitals for the execution of large clinical trials and rapid data sharing, some argued, science could have produced more answers and potentially more solutions for health care providers who faced a high burden of hos- pitalizations and deaths with very few therapeutic tools in the first year of the pandemic (Zimmer, 2021). Delays in initiating and conducting clinical trials can translate to lost lives and prolonged control efforts. 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). WHO also recognizes the value of rapid research in a crisis, stat- ing that strengthening clinical trial capacity within and across countries

132 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES is essential for the timely development and evaluation of countermeasures (WHO, 2022a). Additionally, emerging infectious diseases often present unique chal- lenges that require tailored or adaptive study designs and infrastructure. These may include limited knowledge of the pathogen, difficulty recruit- ing participants, and complex logistical hurdles in outbreak settings. The preplanning of trials can not only increase the speed of response but also provide time for necessary consideration of ethical and logistic hurdles as well as for developing a strategy for the inclusion of diverse patient populations. COVID-19 and mpox emergencies have illustrated the im- portance of: • Pre-pandemic preparedness: Establishing networks of trained researchers and clinical sites ready to pivot to emerging threats. • Streamlined and adaptive trial designs: Developing flexible and efficient trial designs suitable for outbreak settings that allow eval- uation of interventions in all phases of disease and bring trials closer to the patient in the community. • Enhanced recruitment strategies: Implementing community engage- ment and outreach to ensure diverse participation. • Regulatory planning and agility: Creating a streamlined and an- ticipatory review and approval process for clinical protocols for investigational MCMs to address emerging threats and foster- ing collaboration between regulatory bodies for faster and more efficient evaluation and approval of promising interventions. 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. (4-2) Discovery research and pathogenesis research with live variola virus has merit as biomedical research without an immediate obvious connection to smallpox readiness and response. (4-3) It is important to plan for clinical trials (e.g., of vaccine comparative ef- fectiveness in conjunction with therapeutics and diagnostic testing) that will take place under real-world conditions during a smallpox outbreak to ensure that the following are in place: adaptive and streamlined trial designs, efforts toward diverse and equitable patient participation, and regulatory protocols that have been preapproved.

PRIORITIES FOR RESEARCH, DEVELOPMENT, AND STOCKPILING 133 STOCKPILING CONSIDERATIONS The committee was asked to help the Administration for Strategic Preparedness and Response (ASPR) think about the future of the smallpox MCM portfolio for the U.S. Strategic National Stockpile (SNS). A smallpox outbreak of any size (even a single case) will be initially perceived as an event of national and possible international (pandemic) potential, and the SNS will need to be forward leaning in its response until the source and scope of the outbreak are clear. Historically, the SNS has prioritized and devoted most of its resources to just two threats—smallpox and anthrax (GAO, 2022; Kuiken and Gottron, 2023). These threats remain substantive drivers of the SNS bud- get, 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). The president’s fiscal year (FY) 2024 budget request for the SNS is $995 million. The request does not delineate the specific products it intends to procure with these funds, but the most recent multi-year budget from the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) offers insight into how the dollars, if appropriated, are likely to be spent. The budget pro- posed by PHEMCE describes increased funding needs in FY 2024 driven largely by higher spending on the anthrax, Ebola, and smallpox portfolios (HHS, 2023). Over the course of the five-year budget plan (FY 2022–2026), “sustainment of Anthrax and Smallpox capacity is expected to account for approximately two-thirds of SNS’s procurement budget.” If these PHEMCE projections become reflected in future budgets, then anthrax and smallpox expenditures will continue to dominate SNS spending. The budget outlook also reveals a potential for a minimal emphasis in the coming years on basic smallpox or smallpox-relevant research at the National Institutes of Health (NIH) that would support the insertion of new drug candidates into the pipeline and a modest advanced development emphasis at the Biomedical Advanced Research and Development Agency (BARDA) for smallpox innovations. NIH is supporting the development of broadly protective monoclonal antibodies and mRNA-based vaccines for orthopoxviruses; BARDA is investing in a next-generation monoclonal an- tibody–based smallpox therapeutic. Citing lessons learned from COVID-19, the budget plan also relates “multidisciplinary” portfolios for BARDA and NIH that are designed to develop tools and platforms that cut across the CBRN space. PHEMCE expects a significantly increased need for funding in these multidisciplinary efforts, far outstripping any individual pathogen- specific budgetary line. The committee is interested to see how the predicted $16.5 billion over 5 years of investment (if funded) will support vaccine platforms, broad-spectrum therapeutics, and more rapid manufacturing op- tions and the ways that such activities could benefit the smallpox portfolio.

134 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES The multi-year budget goes on to describe the smallpox MCM portfo- lio as “relatively more mature” in that it has reached a stage where costs are driven by sustainment and “investments in replenishment” rather than new investments (HHS, 2023). That is, the SNS is anticipating spending to primarily maintain a holding pattern regarding smallpox readiness. The description of BARDA’s investment in smallpox MCMs includes funding to support sustained investment in a lyophilized formulation of MVA- BN, 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 stock- piled assets is a prudent course, given the years and billions of dollars that have gone into developing and procuring these assets. Indeed, the lapse in BARDA’s sustainment of stockpiled MVA-BN made national headlines when an outbreak forced the lapse—and its real-world impacts—into the light of day (Goldstein, 2022). These assets should not be developed only to be discarded. And yet, the stockpile may be at an inflection point. With the SNS now more than two decades old, it stands to reason that some of its assets will have stood the test of time more than others. Ciprofloxacin and doxycycline are held to support anthrax response, and until BARDA’s investments in antibacterial innovations begin to produce benefits, these antibiotics should be sustained. For smallpox, the scientific and technological opportunity for innovative and improved vaccines, therapeutics, and diagnostics may be a good argument for a transitional phase in which investments made to date are sustained to ensure a ready stockpile, while building a smallpox MCM stockpile of the future. International Sharing of Burden and Benefit The ongoing research and development of smallpox and orthopox- virus MCMs need not be an enterprise taken on by the U.S. government alone. Collaborations and partnerships with other nations and organiza- tions could offer platforms that would at once create a shared burden and enable a pathway toward international sharing of benefits. Regional and global organizations are being founded to provide a path- way toward innovation and toward securing a regional or global supply of MCMs that can benefit populations beyond those that exist within national boundaries. The European Commission’s 2021 Health Emergency Prepared- ness and Response Authority, or HERA, is designed to address market chal- lenges in MCM readiness while fostering the international cooperation that will ensure availability and accessibility of those countermeasures globally (European Commission, n.d.). In 2022, Japan established the Strategic Center of Biomedical Advanced Vaccine Research and Development for Preparedness

PRIORITIES FOR RESEARCH, DEVELOPMENT, AND STOCKPILING 135 and Response, or SCARDA, to support commercialization of vaccines during non-pandemic settings with a view to achieving the G7 100 Days Mission for pandemic response (AMED, n.d.). The Coalition for Epidemic Prepared- ness, or CEPI, was established prior to the COVID-19 pandemic to acceler- ate MCM development for epidemic and pandemic threats and is a major player in 100-day efforts (CEPI, 2024). Philanthropies and governments invest in CEPI to support MCM research and development for pathogens from a number of viral families. CEPI has demonstrated success in develop- ing partnerships and targeting investments to make new vaccines and make them accessible and affordable. For example, CEPI partnered with the EU’s Horizon 2020 program in 2019 to invest $24.6 million in the first vaccine against chikungunya, IXCHIQ. CEPI’s funding is devoted toward efforts to make IXCHIQ accessible to countries with the highest burden of disease, and not just available to travelers from high-income countries as originally anticipated (CEPI, 2023) Such funders are well situated to support the development of next- generation smallpox and orthopoxvirus MCMs, and even to expand the use of those currently available. How the global community can most effectively build and leverage such organizations to support MCM in- novation, development, stockpiling, and equitable dissemination remains under discussion. While the details lie outside the scope of this report, the committee emphasizes that the use of such structures could reduce the burden on the U.S. government alone to fund smallpox and orthopoxvirus MCMs. Lessons From Mpox MCM SNS Deployment BARDA investment in the advanced development of MCMs and SNS procurement of these and other assets, dating to the Project BioShield Act of 20042 have resulted in the nation being better protected against public health emergencies. Nevertheless, there is room for improvement. The 2022 mpox outbreak may hold specific relevance to SNS consider- ations. The U.S. mpox response relied upon deploying stockpiled vaccines and antivirals, as would be the case for smallpox. MVA-BN was stock- piled for smallpox preparedness but had been approved by FDA for both smallpox and mpox (Adams, 2023; Wolfe, 2023). This reality meant that it became the go-to option for controlling the further spread of the mpox virus in the United States. An important question raised from the mpox ex- perience 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. (July 21, 2004), 15.

136 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES and should be replicated. Such dual indications can meet BARDA’s stated strategy to pursue solutions to emerging infectious disease that that can be adapted to and applied against a range threats (BARDA, 2022). Unlike ACAM2000, the smallpox vaccine intended for the general popu- lation and thus stored in the large quantities, MVA-BN was intended for use in a subset of the population. So it was intentionally stockpiled in smaller amounts (Wolfe, 2023). This strained the response to mpox, which was not the pathogen for which it had been stockpiled. But critically, BARDA had let most of the millions of its finished SNS doses expire in favor of purchasing raw vaccine product to be held by the manufacturer internationally, dramati- cally affecting response time (Goldstein, 2022). This constrained the mpox response and would have also constrained a smallpox response. Sufficient vaccine doses to support the population in need for mpox response were initially unavailable to meet demand. ASPR proceeded to order 5.5 million vials from the federal government’s bulk supply held by Bavarian Nordic to be filled and finished, bringing the SNS supply to about 7 million vials by the middle of 2023; ASPR ultimately released more than 1 million single-use vials of MVA-BN to jurisdictions (ASPR, n.d.). ASPR also released stockpiled tecovirimat, and CDC worked on ensuring the availability of laboratory diagnostics for orthopoxviruses within the Laboratory Research Network and in commercial testing facilities (Aden et al., 2022; ASPR, n.d.). 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 out- break response, inequitable vaccine access, access to laboratory testing for patients, and overall federal, state, and local coordination (McQuiston, 2023; Mrsny, 2022). It is important to learn from mpox while acknowledging and planning for the ways that a smallpox response would be different. The smallpox response plan assumes a full and fast mobilization (within 8 hours), or “push,” of vaccine assets to pre-identified “ship to” locations, whereas the use of such a strategy was not used for mpox (Adams, 2023). Therapeutic options would be delivered upon request (pull) and shipped separately to points of care. Adams (2023) noted that the response strategy would be determined at time of incident collectively by federal and state, local, tribal, and territorial health officials. Furthermore, SNS officials noted to the committee that mpox presented as a threat localized to a particular demographic and required nationwide outreach and access targeted to this demographic. While it is important to derive lessons from mpox outbreaks and SNS use, COVID-19 also provides many lessons, as described in prior chapters

PRIORITIES FOR RESEARCH, DEVELOPMENT, AND STOCKPILING 137 of this report. The constraints of CDC centrally managed diagnostics, a lack of research and development investment in rapid diagnostic technology in the years leading up to the outbreak, struggles with rapid vaccine manu- facturing at scale, a dearth of therapeutics and inaccessibility of those treatments, and many other challenges provide a basis from which to make different decisions for smallpox preparedness. 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). It is not a static entity; its contents and concept of operations must evolve to meet evolving threats and to keep up with scientific and technological progress. These updates and changes are driven by the multi-step development process for the SNS annual review, including gap analyses and prioritizations, threat assessments (identifying new threats and revising existing threats), specific response scenarios, and by pharmaceutical advancements (GAO, 2022; Neumeister and Gray, 2021). The reality is that the time and expense re- quired to research, develop, and approve new MCMs limits the ability to rapidly modify the SNS, but so too do entrenched ways of thinking about stockpiling strategies. Over time, the SNS’s role, responsibilities, and operational activities, and those of the MCM enterprise in general, have continued to significantly expand, sometimes without concomitant increases in resources (Kuiken and Gottron, 2023). The SNS is challenged with addressing many poten- tial threats (expanding from chemical, biological, radiological, and nuclear (CBRN) to all-hazards and emerging infectious diseases) but in a resource- constrained environment that requires making prioritization decisions, or in some cases, decisions as if there were no costs involved at all (GAO, 2022). These decisions have strained the resources of the SNS and PHEMCE part- ners. However, many aspects of these challenges, such as defining the roles of the federal stockpile versus state or local stockpiles (an issue highlighted by recent experiences with COVID-19 and mpox), are beyond the scope of this report but deserve further examination. Similarly, new production tech- nologies could dramatically affect how the SNS operates and what types of materials make sense for stockpiling (e.g., stockpiling of raw materials might be efficient if manufacturing agreements are in place and platform technologies are developed that can rapidly produce a variety of different vaccines—or diagnostics or therapeutics—from the same materials). The committee believes that these platform technologies are worth pursuing and as mentioned in Chapter 3 the new Biopharmaceutical Manufacturing Preparedness Consortium could play a role in bringing new technologies

138 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES to bear, but until they are proven successful, the SNS will need to continue to stockpile MCMs (GAO, 2023). Project BioShield was designed to support the acquisition by the SNS of countermeasures under development for national security threats (Kuiken and Gottron, 2023). BARDA’s remit based upon this law has been to sup- port the stockpiling of MCMs for CBRN threats. In general, MCMs for CBRN threats lack a commercial market and in some cases are explicitly disallowed from being sold to any entity other than the federal govern- ment. For smallpox-specific countermeasures, the federal government (and other governments internationally) have been the only buyers. State, local, tribal, or territorial governments are not required to maintain their own stockpiles of medical and ancillary equipment to prepare for and respond to any public health emergency, including smallpox (Kuiken and Gottron, 2023). The experience with mpox, however, may necessitate a change in the way smallpox readiness is viewed, in the sense that a growing need for commercially available mpox countermeasures could incentivize innovation and investment in MCMs that also support the federal government–centric responsibility for smallpox MCM preparedness. To aid SNS administrators in their review of the future of the SNS smallpox MCM portfolio, the committee poses the following considerations (Box 4-2). The SNS may be the purchaser of available MCM and needed supplies, but BARDA is responsible for the advanced development that makes products possible, and members of the PHEMCE contribute to early development, regulatory, and other elements of the chain of investments and decisions that make SNS assets possible (NASEM, 2021). BARDA cur- rently develops target product profiles (TPPs) for specific MCMs (BARDA, n.d.; FIND, n.d.; IOM, 2010; NIAID, 2023). TPPs can help guide industry, regulatory agencies, procurers, and funders on research and development priorities. 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) and what an appropri- ate product would be to use in a public health emergency, prospectively establishing the metrics that define success for a product, and then building an experimental plan that assesses whether a product has critical attributes. Currently, BARDA has a TPP for smallpox vaccine, which could be refined and updated, and TPPs could be created for smallpox therapeutics and diagnostics. WHO also developed two diagnostic TPPs during the global mpox response and recommended that TPPs be developed for smallpox diagnostics (WHO, 2022b, 2023).

PRIORITIES FOR RESEARCH, DEVELOPMENT, AND STOCKPILING 139 BOX 4-2 Considerations for and Questions About Smallpox MCMs in the SNS High-Level Assessment • Articulating different goals and milestones depending on MCM portfolio ma- turity. The smallpox MCM portfolio is a mature portfolio, and the goals of the portfolio should differ from a relatively new MCM portfolio. • Examine the potential uses of and implications for currently stockpiled MCMs for other orthopoxvirus outbreaks. Consider the threat of other orthopoxvi- ruses that stockpiled smallpox MCMs could be used for, and furthermore, if mpox becomes a more serious global health problem, consider the risk of further depletion of stockpiled smallpox MCMs. • 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. • Developing a framework to guide decision making if new smallpox MCMs are developed. For example, there is the possibility that assets for non-variola orthopoxviruses could appear on the market through private investment or the investment of other governments. The SNS will need a basis for considering whether and how these could support progress toward smallpox preparedness. • Optimizing maintenance and sustainment of current smallpox MCM stockpile. As the SNS has shifted toward primarily sustaining the smallpox MCM stockpile, consider efforts and technology to reduce the cost of sustainment. For example, ongoing trials on freeze-dried formulation of MVA-BN could also present im- proved storage options for this vaccine compared with liquid formulation. • Re-evaluating assumptions. Stockpiling assumptions may need to consider the possibility of an increase or reduction in effective doses after potency testing against the disease-causing strain in an actual smallpox event. Similarly, ring vaccination or other vaccination strategies, vaccine hesitancy, and/or the exis- tence of effective therapeutics might alter assumptions of a vaccine stockpile. • Planning for loss of manufacturing capacity. Because the SNS relies on just a few manufacturers for smallpox MCMs, it is important to assess how a loss of manufacturing capacity from any given company could affect readiness and re- sponse and could inform strategies to ensure stability of the manufacturing base. Operationalization: Rapid Deployment • Reviewing the deployment-ready stockpile formulation. To ensure smallpox MCMs are ready to be deployed as quickly as possible. • Updating response plans and training and exercise tools to reflect current and potential new smallpox MCMs. Consider issues such as multiple outbreak scenarios, triggers, and the scope of the required response (scalable plans and surge capacity). For example, plans may need to include how existing stock- piled vaccines would be used in the classic ring vaccination strategy or other vaccination strategies, and the number of doses needed, based on transmission of three to six new cases (reproductive number) from each case. Similarly, plans for the deployment of treatments based on exercised scenarios could further assist in defining short-term and longer-term needs during the emergency. continued

140 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES BOX 4-2  Continued • Planning for implementation, coordination, and communication consider- ations up front. This may include research and development on topics such as logistics, equitable access and distribution of smallpox MCMs (e.g., allocation frameworks, transparent decision-making processes), informa- tion sharing, risk communication, and education and training for frontline responders. MCM-Specific Stockpiling Considerations and Questions • Understanding the specific indications and requirements of each MCM (e.g., supply sources/challenges; delivery needs; handling and storage requirements; shelf life and shelf-life extension, vendor-managed inven- tory, and optimal timing of administration for greatest efficacy; and adverse effects). • Vaccines  How often titer is checked on existing lots held by the SNS, in what form are they stored (e.g., lyophilized and refrigerated or frozen and at what temperature versus liquid frozen and at what temperature), and how often are the lots checked for titer and loss of same and the titer loss curves examined?  What is the appropriate mix of single-use vials, multidose vials, or pre-filled syringes?  What is the appropriate mix of frozen versus lyophilized?  Could the stockpiling strategy change to stockpile starter volumes of virus for vaccines?  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? • Therapeutics  What is the estimated minimal initial need, based on simulation exercises for smallpox as well as mpox?  Is there any repurposing of the therapeutic that would permit commercial- ization of the therapeutic agent and thereby reduce the needed size of the stockpile?  How long will it take to manufacture more of each needed therapeutic agents? • Diagnostics  Should the SNS include specimen collection supplies?  How are federal and state testing strategies for variola in an outbreak different from what was used during mpox (e.g., differences in biosafety designation, higher marginal cost of a false positive, and unique epide- miology), and how does this affect downstream choices in terms of test deployment and placement as well as specimen transportation?

PRIORITIES FOR RESEARCH, DEVELOPMENT, AND STOCKPILING 141 Conclusions on the SNS and Smallpox MCM Portfolio (4-4) The nation relies on the SNS to deploy MCMs in response to a smallpox event because, currently, most of the necessary MCMs are not commercially available. Moving forward, leveraging collaborations and partnerships with other nations and organizations to develop next-generation smallpox and or- thopoxvirus MCMs and expanding the use of the current ones could create a shared burden and enable a pathway toward international sharing of benefits. (4-5) To facilitate a successful response in the event of a smallpox outbreak, the suite of smallpox MCMs (diagnostics, vaccines, and therapeutics) will be deployed and must work in concert with one another. However, the smallpox MCM suite has not been tested or exercised in this way: These MCMs were not used during the smallpox eradication campaign, some have not been de- ployed simultaneously before, and some are based on older technology and use outdated assumptions, including changes in population (e.g., demographic, physiological, and behavioral/risk perception). (4-6) Threat assessments and specific response scenarios, based on different potential smallpox or orthopoxvirus events, are needed to assess and determine the necessary quantities and types of MCMs needed for various effective and equitable response strategies (e.g., early detection, immediate versus long-term response, isolation of patients, quarantine of contacts, use of therapeutics for pro- phylaxis and treatment including pre-exposure prophylaxis with therapeutics for first responders and health care providers, ring vaccination, or mass vaccination). OVERARCHING CONCLUSIONS Despite the research done over recent decades and the fact that there are more smallpox MCMs available now than there were in the pre-erad- ication period, the nation’s readiness and response posture to a smallpox outbreak could be strengthened. 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. The scientific and technological opportunity for innovative and im- proved smallpox MCMs supports a transitional phase for the smallpox MCM portfolio, in which investments made to date are sustained to ensure a ready stockpile—while leveraging collaborations and part- nerships with other nations and organizations to build a diversified smallpox MCM stockpile and an agile, on-demand, distributed MCM response network of the future.

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At the request of the Administration for Strategic Preparedness and Response, the National Academies convened a committee to examine lessons learned from the COVID-19 pandemic and mpox multi-country outbreak to inform an evaluation of the state of smallpox research, development, and stockpiling of medical countermeasures (MCM). In the resulting report, the committee presents findings and conclusions that may inform U.S. Government investment decisions in smallpox MCM readiness, as well as the official U.S. position on the disposition of live viral collections at future World Health Assembly meetings.

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