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Suggested Citation:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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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Summary1 Smallpox—caused by variola virus, a member of the orthopoxvirus genus in the Poxviridae family—is an ancient disease that devastated humanity for millennia. In 1980 the World Health Assembly declared smallpox eradicated, and no naturally occurring smallpox cases have occurred since that time. There are only two known World Health Organization (WHO) sanctioned collections where variola virus samples are stored and used for research: the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, and the State Research Center of Virology and Biotechnology (VECTOR) at Koltsovo in the Novosibirsk region of the Russian Federation. Yet, with advancements in genome amplification, sequencing, editing, and synthesis, it is now possible to recreate live smallpox virus from published genomes— raising the risks of both accidental and intentional releases. In other words, the destruction of known variola virus collections would no longer eliminate the threat of smallpox reemergence as a public health threat. It therefore remains important to maintain robust public health and health system capacities and readiness to rapidly identify—and effectively respond to—a potential smallpox outbreak. Real-world experiences with outbreaks have revealed major challenges in medical countermeasure (MCM) development, manufacturing, distribution, and uptake, while also providing useful lessons and data points. Some smallpox MCMs have recently been deployed for mpox, including a third-generation smallpox vaccine and recently approved smallpox therapeutics. The coronavirus disease 2019 (COVID-19) pandemic ushered in advancements in MCM 1 This Summary does not include references. Citations for the discussion presented in the Summary appear in the subsequent report chapters. 1

2 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES development and applicable technology that have potential applications for smallpox MCM development and utility. The COVID-19 pandemic and mpox multi-country outbreak, both declared Public Health Emergencies of International Concern (PHEIC) by WHO, underscore the need for further domestic global coordination for preparedness and response against novel pathogens including orthopoxvirus events. At the request of the Administration for Strategic Preparedness and Response, on behalf of the U.S. government, the National Academies of Sciences, Engineering, and Medicine (the National Academies) was asked to convene an ad hoc committee to examine lessons learned from the COVID-19 pandemic and mpox outbreaks to inform an evaluation of the current state of research, development, and stockpiling of smallpox MCMs. The full charge to the committee is presented in Chapter 1. This report presents findings and conclusions that build on the Institute of Medicine’s previous reports Assessment of Future Scientific Needs for Live Variola Vi- rus (1999) and Live Variola Virus: Considerations for Continuing Research (2009) and serves to inform the position of the U.S. government for the upcoming 77th World Health Assembly in May 2024. This report does not contain recommendations. STUDY APPROACH The committee formulated seven overarching conclusions across two key aspects of smallpox readiness and response: (1) medical countermea- sures readiness and (2) systems readiness. A set of more technical, chapter- specific conclusions based on the evidence are also presented in each chapter. Discussions and conclusions on MCM readiness refer to having the “right” MCM or suite of MCMs available. Although the discussions on MCM readiness were primarily focused on those relevant for the U.S. population in a smallpox event, the committee emphasized the interde- pendence of the U.S. and international community in efforts to effectively contain any smallpox outbreak (Chapter 1). Understanding and reaching consensus on the right MCMs involved deliberations on the efficacy, effectiveness, and utility of the suite of different smallpox MCMs at various stages of development and stockpiling (Chapter 2). Additionally, the committee considered the future research and development that would be needed to improve existing smallpox MCMs, including research with live variola virus (Chapter 4). Systems readiness discussions and conclusions refer to smallpox MCMs being available at the “right time” and for the “right people.” The committee emphasizes the importance of not making the mistake of planning based on older response paradigms and challenges without taking into consideration new circumstances and possibilities and in Chapter 4 discusses future states

SUMMARY 3 of readiness for the MCM enterprise, including stockpiling considerations and international sharing of burden and benefit. To reach these future states, uncertainty and information about the evolving biothreat landscape, evolving technological landscape, societal factors, and operational consid- erations need to be accounted for in readiness and stockpiling approaches to ensure flexibility and adaptability (Chapter 3). Challenges faced by the nation’s MCM enterprise in efforts to rapidly scale and deploy MCMs during recent COVID-19 and mpox public health emergencies highlight urgent priorities that must be addressed to “future- proof” the nation’s readiness and response postures against smallpox and other orthopoxviruses that may pose a biothreat. OVERARCHING CONCLUSIONS ON MEDICAL COUNTERMEASURES READINESS State of Smallpox MCM Readiness A variety of MCMs have been developed to detect (diagnostics), prevent (vaccines), and treat (biological agents and antivirals) smallpox disease and transmission. Table S-1 lists the vaccines and therapeutics that are currently held in the U.S. Strategic National Stockpile (SNS). The SNS currently has sufficient live, replicating vaccine for the general population, a small amount of non-replicating vaccine for use in populations contraindicated for live replicating vaccine, and two smallpox antivirals with different mechanisms of action. While significant progress has been made to enhance the nation’s readiness posture against smallpox since the disease was officially declared eradicated, challenges persist. Gaps in the nation’s readiness and response posture against unfamiliar pathogens were exposed during the COVID-19 pandemic and the 2022 mpox multi-country outbreak. One fundamental lesson learned from the COVID-19 and mpox emergencies is that research and development for new smallpox MCMs must not only consider the characteristics of the “product” but also must consider the ability to deploy at scale and ensure its equitable access. The mpox outbreak, in particular, tested the MCMs that had been developed and stockpiled for smallpox against a related, but less lethal, orthopoxvirus. Regarding diagnosis, detection, and surveillance, challenges in scaling laboratory testing during COVID-19 and mpox limited the initial understanding of the scope and severity of these new and emerging threats, respectively. In the event of a smallpox outbreak, identification of cases would rely on clinical recognition, the availability of diagnostic assays at CDC Laboratory Response Network (LRN) laboratories, and potential to scale testing to points-of-care (POCs) or points-of-need (PONs), per the

4 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES TABLE S-1  Summary of Smallpox Vaccines and Therapeutics in the U.S. Strategic National Stockpile Product Name Characteristics and Details Approved Usage or Indications APSV (Wetvax) 1st generation • Emergency Use Authorization Live, replicating vaccinia (EUA)/investigational new drug virus, NYCBOH-derived (IND) for smallpox. strain. • 1 dose regimen. • Multiple contraindications, especially for those who have immunocompromising, skin, or heart conditions. Contraindicated for those with serious allergy to a vaccine component. ACAM2000 2nd generation • FDA licensed for prevention of Live, replicating vaccinia smallpox in all age groups for virus, NYCBOH-derived persons determined to be at high strain. risk for smallpox infection. • 1 dose regimen. • Multiple contraindications, especially for those who have immunocompromising, skin, or heart conditions. Contraindicated for those with serious allergy to a vaccine component. MVA-BN (Imvamune, 3rd generation • FDA licensed for smallpox and Imvanex, JYNNEOS) Live, non-replicating mpox in adults 18 and older. vaccinia virus, MVA strain. • 2 dose regimen, 4 weeks apart. • Relatively few contraindications. Safely administered to individuals with immunocompromising, skin, or heart conditions. Contraindicated for those with serious allergy to a vaccine component. Tecovirimat Orthopoxvirus-specific • Treatment of smallpox (FDA (ST-246/TPOXX) inhibition of viral spread approved). from cell to cell by • Treatment of mpox under targeting p37, a major Investigational New Drug (IND), envelope protein required Expanded Access IND, Emergency for envelopment and IND (not FDA approved) excretion of extracellular - STOMP/A5418 (Study of forms of the virus. Tecovirimat for Human Mpox Virus)a - STOMP sub-study of open label tecovirimatb - Other Use: STOMP sub-study: Tecovirimat for Orthopox Virus Exposurec • No serious adverse events reported.

SUMMARY 5 TABLE S-1 Continued Product Name Characteristics and Details Approved Usage or Indications Brincidofovir Pro-drug of cidofovir; • Treatment of human smallpox (CMX001/Tembexa) following phosphorylation infections only (FDA approved) of the prodrug to the • Other usesd (EIND or EA IND): active form cidofovir - Study to Assess Brincidofovir diphosphate, the drug Treatment of Serious Diseases targets the orthopoxvirus or Conditions Caused by DNA polymerase, causing Double-Stranded DNA virusese disruption of replication of (phase 3 completed December the virus. 2022) - Adenovirus in immuno- compromised persons: under clinical trial • Potential for liver problems and increased risk for mortality with longer use. Potential for embryo- fetal toxicity, carcinogenicity, and male infertility based on animal studies. Vaccinia Immune Passive immunity • Treatment of complications due Globulin Intravenous for individuals with to vaccinia vaccination (FDA Human (VIGIV) complications to vaccinia approved) (CNJ-016) virus following vaccination; • Other uses (EA IND): Potential use exact mechanism of action of stockpiled VIGIV for treatment is not known. of orthopoxviruses in an outbreak. • Contraindicated for individuals with history of anaphylaxis and cautioned for patients with renal insufficiency. NOTES: Cidofovir (Vistide), another antiviral not currently stockpiled, targets orthopoxvirus DNA polymerase, causing disruption of replication of the virus. The licensed indication is for cytomegalovirus (CMV) retinitis and does not have licensed indication for OPXV/VARV therapy. However, it can be used “off label.” Cidofovir was used in therapy of mpox in those with compromised immune systems/uncontrolled HIV during the 2022–2023 multi-country outbreak, as this treatment was commercially available. Potential side effects include renal toxicity. CDC = U.S. Centers for Disease Control and Prevention; EA = expanded access; EIND = emergency investigational new drug; EUA = Emergency Use Authorization; FDA = U.S. Food and Drug Administration; IND = investigational new drug; OPXV = orthopoxvirus; VARV = variola virus. a NIH/NIAID-sponsored: Phase 3 randomized, placebo-controlled, double-blind study to establish the efficacy of tecovirimat for the treatment of people with laboratory-confirmed or presumptive human monkeypox virus disease (HMPXV) [NCT05534984]. b Open label for pregnant or breastfeeding persons; those with severe immune suppression, significant skin conditions, or severe disease. c For both mpox and smallpox for Department of Defense–affiliated personnel [NCT02080767]. d There are no registered clinical trials for brincidofovir at this time, could be used under EIND through CDC. e Phase 3 trial completed 12/2022 with posted results [NCT01143181].

6 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES scale of the outbreak. The mpox experience also highlighted the increased demand for the third-generation, live, non-replicating vaccine, MVA-BN, given safety concerns for first- and second-generation smallpox vaccines that have been stockpiled at a higher quantity in the SNS. Furthermore, the mpox outbreak highlighted gaps in the smallpox therapeutic options, specifically on the reliance on challenge studies in animals and animal model data for understanding potential efficacy in humans and predicting antiviral resistance, and on a lack of diverse therapeutic options with dis- tinct mechanisms of action. For these reasons, the committee drew the following overarching conclusion: 1. The COVID-19 pandemic revealed weaknesses in the ability for the nation’s public health and health care systems to rapidly and flexibly adapt the emergency response to an unfamiliar pathogen; whereas the 2022 mpox outbreak tested existing MCMs developed primarily for smallpox to contain a less lethal orthopoxvirus. The lessons learned from both emergencies call for strengthening the nation’s laboratory response systems and further development of point-of-care diagnostics and genomics surveillance capabilities. Additionally, safer, single-dose vaccines and a diverse set of thera- peutic options against smallpox would improve the U.S. readiness and response posture for immediate containment and long-term protection in a smallpox emergency. Specific conclusions in Chapter 2 on diagnostics and surveillance (2-1), vaccines (2-2), and therapeutics (2-3) are below: (2-1) Tests that can more accurately detect smallpox and other orthopoxviruses than those available today are needed; efforts should focus on (1) adapting multiplex nucleic acid assays for new platforms and field settings, (2) developing forward-deployed (POC/PON) assays to enhance equitable access to tests, including protein or antigen-based tests to rapidly test and isolate infected patients, (3) identifying FDA-approved serologic assays to assess individual and population levels of immunity against smallpox and history of related exposures, (4) validating nucleic acid testing using a variety of clinical samples, (5) developing different categories of laboratory tests for different biosafety levels, and (6) supporting a global network of laboratories to detect, diagnose, and conduct surveillance in humans and the environment. (2-2) Smallpox vaccines that have improved safety across different population subgroups and are available as a single dose would support faster and more effective response to contain smallpox and other orthopoxvirus outbreaks. The development of novel smallpox vaccines using multi-vaccine platforms (i.e., use common vaccine vectors, manufacturing ingredients, and processes) would

SUMMARY 7 improve the capacity for rapid vaccine production in response to a smallpox event and reduce the need for stockpiling in the SNS at current levels. (2-3) To treat smallpox, the following would be advantageous to develop in order to supplement the therapeutic options currently approved and stock- piled in the SNS (1) new, safer antivirals with different and diverse targets, mechanisms of action, and routes of administration that minimize damage to host cells and have a high barrier to the development of resistance; (2) com- bination antiviral treatments and treatments based on novel technologies and platforms (e.g., genome editing, non-conventional targets, etc.); (3) vaccinia immune globulin intravenous (VIGIV) repurposed as part of combination therapy; (4) diverse options for non-vaccine biologics including monoclonal antibodies and antibody cocktails. Evolving Biothreat and Technology Landscape As the understanding of orthopoxviruses and biotechnologies advances, there is an opportunity to address the known gaps and deficiencies of MCMs against smallpox and other orthopoxviruses. Additionally, the range of risks and biothreats caused by orthopoxviruses and synthetic biology is broad, and the changing threat landscape is further evidenced by the increasing frequency and scope of orthopoxvirus outbreaks in recent years, including the first case of Alaskapox infection resulting in hospitaliza- tion and death and the recent increase of clade I mpox in the Democratic Republic of Congo (and with new cases in geographic areas that had not previously reported mpox). For these reasons, the committee drew the following overarching conclusion: 2. 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 commercialization of existing and next-generation MCMs for use in the management of non-variola orthopoxviruses as an ef- ficient way to expand readiness more broadly by enabling vendor- managed inventory approaches to stockpiling. Conclusions in Chapter 2 (2-4) and Chapter 3 (3-1) on benefits to investing in orthopoxvirus research more broadly include: (3-1) The increasing recognition of orthopoxvirus illnesses in humans merits on- going research and development of MCMs to detect, prevent, treat, and respond to these diseases. This is of particular importance for mpox that is an ongoing global outbreak and is expected to be a long-term threat. Other emerging orthopoxviruses (e.g., Alaskapox, cowpox, and vaccinia-like viruses) also need

8 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES to be closely monitored as the population immunity against orthopoxviruses continues to wane. (2-4) Most mpox therapeutics were developed because of investments in smallpox therapeutics, resulting in products found to have activity against mpox. Direct investment in developing therapeutics targeting circulating orthopoxviruses could similarly benefit smallpox therapeutic preparedness and could likely have more immediate utility and potentially achieve commercial viability. As biotechnologies continue to evolve at a remarkable pace—a pace increasingly accelerated by major advances in artificial intelligence—it is incumbent on decision makers to consider what impacts and opportunities may arise in response to different MCM strategies. The malicious exploita- tion of such technologies to create novel bioterror agents could render an established MCM ineffective. Beneficial uses, if strategically developed and promulgated, could significantly mitigate infectious diseases as threats to personal, public, political, and environmental health. For these reasons, the committee drew the following overarching conclusion: 3. 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. Conclusions in Chapter 3 on the implications of scientific and tech- nological advancements on available smallpox MCMs (3-4, 3-5) include: (3-4) The potential exists to synthesize the complete or partial variola virus genome and to manufacture infectious viral particles based on published ge- nomes. Targeted modifications to the genome are also possible, which could alter functional components of the virus that could affect transmissibility or virulence. This capacity means that even the guaranteed complete eradication of all existing smallpox collections today would not guarantee against its reemer- gence as a threat. It also introduces greater challenges in readiness planning by introducing the possibility of atypical epidemiological or clinical presentations of the disease. (3-5) Advances in emerging biotechnologies could also allow for the rapid development and deployment of MCMs. A global, real-time, distributed, manufacturing network could enable safe and equitable production of small- pox diagnostics, vaccines, and therapeutics when and where needed to rapidly bring an outbreak anywhere in the world under control. A strategic research and development program promoting the development of general capability in this regard has the potential to unlock such a future.

SUMMARY 9 Smallpox Research Agenda Orthopoxviruses can cause a spectrum of diseases, ranging from the very mild to the highly deadly, and understanding these distinctions requires understanding individual viruses. While there are advantages to conduct- ing research with non-variola orthopoxviruses, these species cannot fully replace the knowledge gained by working with live variola virus. Research with live variola and non-variola orthopoxviruses informs the development of more precise smallpox diagnostics, supports the development of live virus vaccines and, ultimately, novel subunit vaccines or other innovations, and advances the development of therapeutics through improved understanding of viral functions and structures. In 1999 the Institute of Medicine (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 re- emergence of smallpox due to accidental or intentional release of variola virus. IOM’s 1999 finding that live virus is needed for certain aspects of research remains true today. For these reasons, the committee drew the fol- lowing overarching conclusion: 4. 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 ortho- poxviruses to emerge naturally or deliberately. In Chapter 4, Table 4-2 shows 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 knowl- edge gaps and MCM goals that could support improved public health benefit. Conclusions in Chapter 3 (3-2, 3-3) and in Chapter 4 (4-1, 4-2) on a smallpox research agenda, including the utility of live variola virus research and clinical trial readiness (4-3), include: (3-2) Variola virus-specific research is extremely restricted and is only under- taken when it is necessary and essential for public health. It is not possible to fill knowledge gaps without the study of other orthopoxviruses. (3-3) Gaps exist in the fundamental understanding of variola virus and non- variola orthopoxvirus biology, pathogenesis, immunity and host-interactions, evolution, transmission, and ecology. Basic poxvirus research is beneficial to smallpox MCM development and contributes to readiness against other known and potential novel orthopoxviruses affecting humans. General advances in

10 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES developing orthopoxviruses as vaccine vectors, gene delivery, and oncolytic virotherapy can have multiple benefits, including enhancing smallpox MCMs. (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 effectiveness 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. OVERALL CONCLUSIONS ON SYSTEMS READINESS Operational Considerations for MCM Readiness and Stockpile Planning Federal smallpox planning in the post-eradication era has been charac- terized by strategies to reduce the population risk that an outbreak would pose, primarily through containment using MCMs. The effectiveness of smallpox MCMs (whether diagnostics, vaccines, or therapeutics) as agents of risk reduction rests on numerous factors, from a working knowledge of smallpox biology, pathogenesis, and epidemiology to the risks and benefits of emerging science and technology, to myriad operational planning deci- sions. Chapter 3 briefly discusses operational planning issues related to manufacturing capacity, administration and uptake, frontline readiness and biosafety, and regulatory readiness. For these reasons, the committee drew the following overarching conclusion: 5. Readiness and response efforts involving MCMs are complex due to many factors. MCM development, stockpiling, and distribution planning must be flexible, adaptable, and robust against multiple potential smallpox event scenarios. Planning strategies should ac- count for the complexities of each scenario and aim to support several health and well-being outcomes (e.g., health, justice, equity, and national/international demand).

SUMMARY 11 The conclusions in Chapter 3 on operational considerations that influ- ence readiness and response posture (3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12) are: (3-6) 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 outbreak especially one of international scope. (3-7) Given the lack of commercially available orthopoxvirus diagnostics, vaccines, and therapeutics, planning for logistics and supply chain management considerations is critical. Efforts could give consideration to developing plans to increase the number of smallpox vaccine and therapeutics manufacturers as well as optimizing current manufacturing capacities should they be needed in the shorter term. (3-8) Communicating the risk and benefits of smallpox vaccination versus infection will be critically important. But experience with COVID-19 and mpox demonstrated that effective risk communication has been a challenge, especially considering vaccine hesitancy and the politicization of vaccination, and misinformation and disinformation. These same challenges could occur in a smallpox outbreak. (3-9) Implementation research investigating the operational and social aspects of deploying and uptake of smallpox MCMs is needed to assess operational parameters that could affect readiness and response. (3-10) Those on the front line—health care providers, public health practi- tioners and laboratorians, and first responders—need to have the capabilities and capacities to effectively and equitably diagnosis, prevent, and treat in the event of a smallpox outbreak. Clinical and public health guidance should be updated to reflect new data and new MCMs and should take into consider- ation the range of response strategies beyond post-exposure programs (i.e., ring vaccination). (3-11) Regulatory readiness and responsiveness, applicable to all types of MCMs, will be critical in the event of a smallpox outbreak. This is especially relevant considering the additional laboratory biosafety concerns for smallpox compared with other orthopoxviruses. (3-12) New regulatory models that can quickly evaluate MCMs that use novel platforms and newer methodologies need to be developed and imple- mented. This could be achieved through the sharing of necessary prod- uct characteristics, detailed submission requirements, and setting accepted benchmarks and immune assays (in the case of vaccines) ahead of time, as well as planning for surge staffing to ensure timely review and real-time engagement for inquiries.

12 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES The SNS and the Smallpox MCM Portfolio 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 pri- oritized and devoted most of its resources to just two threats—smallpox and anthrax—and these threats remain substantive drivers of the SNS budget. As a result, the smallpox MCM portfolio is a relatively mature MCM portfolio that includes both prevention and treatment MCMs, and this is an advantage. However, the 2022 mpox outbreak may hold specific relevance to SNS considerations. The successes of the mpox response were tempered by major challenges, especially the short supply of immediately available third generation licensed smallpox/mpox vaccine doses, as well as by concerns over needed changes in dosing and route of administration strategies not included in the vaccine’s label for use during the outbreak response, ineq- uitable access to vaccines and laboratory testing for patients, and overall federal, state, and local coordination. To aid SNS administrators in their review of the future of the SNS smallpox MCM portfolio, the committee poses the considerations offered in Box S-1 (adapted from Box 4-2 in Chapter 4). To inform future priorities for the smallpox MCM portfolio, target product profiles (TPPs) for smallpox medical countermeasures could be developed (or in the case of smallpox vaccine, refined). This would 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, the Biomedical Advanced Research and Development Agency (BARDA) has a TPP for smallpox vaccine, which could be refined and up- dated, 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. While the existing stockpiling strategy has dramatically increased the baseline national readiness level for smallpox from an MCM perspective, the SNS is now more than two decades old and has several responses under its belt. The stockpile may be at an inflection point. As part of the SNS an- nual review process, transition plans could be established for mature MCM portfolios, such as smallpox. For these reasons, the committee drew the following overarching conclusion:

SUMMARY 13 BOX S-1 Considerations for Smallpox MCMs in the SNS High-Level Assessment • Articulating different goals and milestones depending on MCM portfolio maturity. The smallpox MCM portfolio is a mature portfolio, and the goals of a mature portfolio should differ from a relatively new MCM portfolio. • Examining the potential uses of and implications for currently stockpiled MCMs for other orthopoxvirus outbreaks. Consider the threat of other orthopoxviruses 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 stock- pile, consider efforts and technology to reduce the cost of sustainment. For example, ongoing trials on freeze-dried formulation of MVA-BN could also pres- ent improved storage options for this vaccine compared with liquid formulation. • Reevaluating 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 manu- facturing capacity from any given company could affect readiness and response 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 stockpiled 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

14 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES BOX S-1  Continued • Planning for implementation, coordination, and communication considerations up front. This may include research and development on topics such as logistics, equitable access and distribution of smallpox MCMs (allocation frameworks, transparent decision-making processes), information sharing, risk communication, and education and training for frontline responders. MCM-Specific Stockpiling Considerations • Understanding the specific indications and requirements of each MCM (e.g., supply sources/challenges; delivery needs; handling and storage require- ments; shelf life and shelf-life extension, vendor-managed inventory, and optimal timing of administration for greatest efficacy; and adverse effects). NOTE: This box was adapted from Box 4-2 in Chapter 4. 6. 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 improved 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 partnerships with other nations and organiza- tions to build a diversified smallpox MCM stockpile and an agile, on-demand, distributed MCM response network of the future. Conclusions in Chapter 4 on strategies for smallpox MCM portfolio planning (4-4, 4-5, 4-6) include: (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 orthopoxvirus 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).

SUMMARY 15 (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). Global Cooperation The COVID-19 pandemic and the mpox multi-country outbreak dem- onstrated the speed with which biothreats occurring internationally can affect and overwhelm national medical and public health response systems. These events also highlighted the shortfalls of the global MCM enterprise in ensuring equitable access to MCMs in the United States and globally, along with enduring concerns about public acceptability of countermeasures, presented a challenge in containing disease transmission around the globe. For these reasons the committee drew the following overarching conclusion: 7. In a smallpox event, the U.S. readiness and response posture will be significantly affected by the ability of other countries around the world to adequately detect smallpox and contain transmission. Given global interdependence and global supply chains, support- ing MCM capacities and capabilities internationally (i.e., a global MCM platform) will improve security against biothreats in the United States. Specific conclusions in Chapter 1 on the implications of the U.S. small- pox MCM enterprise for potential global smallpox events (1-1, 1-2) are: (1-1) The ability for many countries to contain a smallpox outbreak is currently dependent on the U.S. readiness and response posture to rapidly deploy MCMs upon request and in collaboration with WHO and global partners. Thus, U.S. stockpiling decisions must take international commitments and equity arrangements into account. (1-2) The U.S. pledge of smallpox vaccines to the WHO Smallpox Vaccine Emergency Stockpile (SVES) represents a substantial proportion of what has been promised by WHO Member States. However, the number of doses in the SVES would likely be inadequate for a global response and would require additional MCMs to be produced to meet the demands of a response to deliver equitable access globally.

16 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES CONCLUDING REMARKS A smallpox outbreak, regardless of whether it happens in the United States or in other countries, would pose a major public health and security threat and would create considerable public expectations of an effective and timely response. Findings from studies of past public health emergencies indicated a lack of adequate public health and health system readiness and response capabilities, the importance of global cooperation and collabora- tion, and the need to think beyond a “one-pathogen” approach. The United States maintains a national MCM stockpile and plans to diagnose, prevent, and treat smallpox. Despite the research done over re- cent decades and the fact that there are more smallpox MCMs available now than there were in the pre-eradication period, the nation’s readiness and response posture to a smallpox event could be strengthened. These MCM assets and the plans designed to make use of them must be continu- ally updated and forward-looking to account for changes in science and technology, populations at risk, and geopolitical factors. The committee envisions that the priorities set forth in this report and summarized in Box S-2 contribute to society’s ability to prepare for and respond to a po- tential smallpox event.

SUMMARY 17 BOX S-2 Summary of Priorities for Improved Smallpox Readiness and Response The following points collectively summarize at a high-level the priorities identified by the committee that are needed to improve the smallpox readiness and response posture. Medical Countermeasures Readiness • Smallpox Research Agenda – Research and development roadmap for live variola virus research and pathways to support the validation, approval and licensure, and commercialization of existing and next-generation MCMs for use in the management of non-variola orthopoxviruses. • Diagnostics and Surveillance – Expanded diagnostics and surveillance sup- ported by (1) multiplex nucleic acid assays for new platforms, field settings, and for use with clinical samples prior to onset of rash illness; (2) forward- deployed point-of-care assays including protein- or antigen-based tests to rapidly test and isolate infected patients; (3) FDA-approved serologic assays to assess individual and population levels of immunity against smallpox and history of exposures. • Vaccines – Safe and efficacious single-dose smallpox vaccines that (1) have utility for immediate outbreak containment as well as long-term protection, and (2) can be quickly adapted and developed at scale if needed to protect against a novel strain. • Therapeutics – Diverse, safer smallpox therapeutics options including (1) antivirals with different and diverse targets, mechanisms of action, and routes of administration; (2) combination antiviral treatments and treatments based on novel technologies and platforms (e.g., genome editing, non-conventional targets, etc.); (3) vaccinia immune globulin intravenous (VIGIV) repurposed as part of combination therapy; (4) diverse options for non-vaccine biologics including monoclonal antibodies and antibody cocktails. • Emerging Technologies – Ongoing risk/benefit analysis conducted periodically for smallpox MCM research and development using emerging technologies. Systems Readiness • Operational Considerations – Periodic assessment of implementation and operational factors that might influence smallpox readiness and response, including manufacturing capacity, frontline readiness, risk communication, and regulatory readiness. • Strategic National Stockpile – Transition plan for the smallpox MCM portfolio, in which investments made to date are sustained to ensure a ready stockpile—while working with other nations and organizations to build a diversified smallpox MCM stockpile and an agile, on-demand, distributed re- sponse MCM network of the future. Budgetary stress on stockpile purchases and maintenance could be reduced through the commercialization of these smallpox MCMs for non-variola orthopoxviruses. • Global Cooperation – U.S. investment and support in MCM research, devel- opment, and deployment capacities and capabilities internationally.

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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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