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Future State of Smallpox Medical Countermeasures (2024)

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Suggested Citation:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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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1 Introduction “The price of freedom from smallpox disease is eternal vigilance.” Oyewale Tomori, International Congress of Virology, 1993 Smallpox has long been feared as a lethal and disfiguring disease (Henderson, 2009). The global smallpox eradication achievements at the end of the 20th century set in motion preparedness efforts designed to quickly contain any natural, accidental, or deliberate emergence. Since the eradication of naturally occurring smallpox more than four decades ago, remaining collections of variola virus and advancements in genome ampli- fication, sequencing, editing, and synthesis have presented both a danger to and safeguard of a world free from smallpox. Lessons learned from recent public health emergencies shed new light on vulnerabilities in the nation’s readiness to swiftly contain emerging infectious disease threats, which calls into question the historical assumptions that underpin the smallpox medical countermeasures (MCMs) portfolio. New evidence from the use of smallpox in response to the 2022 multi-country mpox outbreaks, in- cluding administration of third-generation vaccines and recently approved therapeutics, may provide further insight to the utility of these MCMs against smallpox should it re-emerge. Moreover, the coronavirus disease 2019 (COVID-19) pandemic ushered in advancements in MCM technology and developments that have potential applications for smallpox MCMs. Simultaneously, major challenges in MCM development, manufacturing, distribution, and uptake surfaced during the response to COVID-19 that will have implications for future smallpox readiness and response. 19

20 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES The World Health Organization (WHO) Advisory Committee on Variola Virus Research (ACVVR) recently noted that “preparedness for smallpox is currently inadequate, that equitable provision of countermea- sures was not achieved during the global mpox outbreak, and that the global community must further invest in supporting access to resources arising from the variola virus research programme monitored by WHO” (WHO, 2024). Despite the importance of these recent lessons, the commit- tee also emphasizes the importance of not “fighting the last war,” or mak- ing the mistake of planning based on old challenges without taking into consideration new circumstances and possibilities. RATIONALE AND STUDY CHARGE Federal responsibility in the United States for maintaining a stockpile of MCMs to address smallpox and other threats lies with the Administra- tion for Strategic Preparedness and Response (ASPR), an operating divi- sion of the Department of Health and Human Services (HHS). The U.S. Strategic National Stockpile, or SNS, contains smallpox vaccines, drugs, and related supplies and medical devices that the secretary of HHS can deploy to state, local, tribal, and territorial jurisdictions at their request in the event of a smallpox emergency (Kuiken and Gottron, 2023). HHS has also pledged a proportion of its smallpox vaccine for international use since 2004 (BioSpace, 2004). Work with variola virus for research at the two WHO collaborating centers with official collections of variola, the U.S. Centers for Disease Control and Prevention (CDC) and State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Russia, has been overseen by the ACVVR since a 1999 World Health Assembly (WHA) decision (WHA52.10) to authorize the temporary retention of remaining collections (WHO, 1999). Work with live variola virus and its genes is limited in scope and highly regulated by WHO. ACVVR oversees research using live variola virus and approves or rejects research proposals with live virus, discussed further in Chapter 3 (Box 3-1). ASPR requested that the National Academies of Sciences, Engineering, and Medicine (National Academies) evaluate the current state of smallpox MCMs and implications for the SNS to inform the development of the U.S. government position and deliberations at the 77th World Health Assembly (see the statement of task in Box 1-1). Outcomes of this analysis can help ASPR reach an up-to-date understanding of smallpox MCM readiness and response in the context of these experiences, consider changes to its stockpiling strategy that can optimize a robust public health response, and develop research priorities that can help achieve that aim. This report builds on the Institute of Medicine’s (IOM’s) previous reports Assessment

INTRODUCTION 21 BOX 1-1 Statement of Task An ad hoc committee of the National Academies of Sciences, Engineering, and Medicine will conduct a study to examine lessons learned from the recent coronavirus disease 2019 (COVID-19) pandemic and mpox multi-country out- break to inform an evaluation of the current state of research, development, and stockpiling of smallpox medical countermeasures (MCMs). The committee will: 1. Consider how the COVID-19 pandemic and the mpox multi-country outbreak can inform improvements to smallpox readiness and response, including the availability of smallpox MCMs and the ability to meet poten- tial demand. 2. Examine the current state of MCMs for the diagnosis, prevention, and treatment of smallpox, including: a. How the mpox outbreak altered assumptions about the efficacy and utility of smallpox MCMs. b. The continued role of live variola virus for research and public health purposes. c. Implications for the composition of smallpox MCMs in the U.S. Strategic National Stockpile (SNS). 3. Explore the benefits and risks of scientific and technological advances on smallpox readiness and response and identify key priorities in research and development of smallpox MCMs. Building on the Institute of Medicine’s previous reports, Assessment of Future Scientific Needs for Live Variola Virus (1999) and Live Variola Virus: Consider- ations for Continuing Research (2009), and a review of existing literature, analy- ses, and other expert and public input, the committee will develop a report with its findings and conclusions on priorities for additional research or activities to improve the U.S. government readiness and response posture against smallpox, and on the composition of the SNS to ensure appropriate smallpox MCM response options. of Future Scientific Needs for Live Variola Virus (1999) and Live Variola Virus: Considerations for Continuing Research (2009). The committee was asked to provide only conclusions, not recommendations, on priorities for additional research or activities to improve smallpox readiness and response posture. To address its charge, the National Academies convened a committee of experts comprising 14 members with academic backgrounds and profes- sional expertise in fields including molecular microbiology and immunol- ogy; virology; infectious disease and health care; public health preparedness and epidemiology; vaccine and drug research, development, and produc- tion; medical countermeasures; whole-genome sequencing and diagnostic technologies; biosecurity and biosafety; emerging technologies; biomedical

22 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES and public health ethics; and risk assessment. Appendix B provides the biographies of the committee members. ABOUT THIS REPORT Study Approach In developing this report and the conclusions presented herein, the committee deliberated from November 2023 through February 2024 and held five virtual meetings. The committee heard from subject-matter ex- perts across the federal government, industry, academia, and professional associations on key lessons and opportunities for smallpox readiness and response during multiple open session days (all public meeting agendas can be found in Appendix A). The committee and National Academies staff also conducted a review of literature published since 2009 and were informed by reports and deliberations of the 154th session of the WHO Executive Board. Study Scope The committee was asked to examine the utility of smallpox MCMs and implications for smallpox readiness and response considering lessons learned from recent public health emergencies. Further clarification during open session meetings with the sponsor tasked the committee to specifi- cally consider strategic approaches for stockpiling smallpox MCMs and an enumeration of the ways in which research using live variola virus could provide benefits in a smallpox emergency (Sloane, 2023). This report does not address the special challenges with developing vaccines and therapeutics for special populations, such as pediatric popu- lations, pregnant and lactating persons, or immunocompromised persons. There are clearly challenges associated with developing vaccines and thera- peutics for special populations—which may not always mean something as simple as dose reduction or schedule modification. Development of such products suitable for these populations will require close consultation with regulators. It is important to note that the committee was not asked to decide about the destruction or retention of live variola virus collections; such a determination involves information beyond the purview of the commit- tee. The committee was also not asked to conduct detailed assessments of the threat and potential for a smallpox outbreak, the risks of live variola virus research, or the risks of dual-use research of concern. The commit- tee supports the position that any research with live variola virus requires rigorous scientific evaluation before being conducted as well as necessary

INTRODUCTION 23 laboratory safeguards to protect researchers and the public and proper infrastructure and research capacity. Lastly, this report does not contain recommendations. Report Audiences and Key Stakeholders This report is intended for the immediate use, by request, of ASPR on behalf of the U.S. government. However, there are a variety of domestic and global stakeholders involved in the smallpox MCM enterprise (Figure 1-1), and the committee designed this report to help these stakeholders understand and use available information to inform their decision making. Smallpox readiness and stockpiling decisions must account for the threat FIGURE 1-1  Public Health Emergency Medical Countermeasures Enterprise stake- holders and engagement. SOURCES: NASEM (2021). Originally from Korch (2016).

24 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES of a smallpox outbreak; the ability to detect and confirm cases; the ability to develop and manufacture MCMs for large populations; approvals from regulatory agencies for new or updated MCMs; the availability, rapid de- ployment, and uptake of smallpox MCMs; and the public’s understanding of the threat and their acceptance of the offered MCMs. Ultimately, effective uptake and utilization of MCMs depends on the willingness and health- seeking behaviors of the affected public and the interactions between them and the public health agencies and health care providers responsible for dispensing and administering MCMs. The audience for this report includes: • Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) and other federal partners like the Advanced Research Projects Agency for Health (ARPA-H) • Federal policy makers, including members of Congress • State, tribal, local, and territorial officials and policy makers • Industry, including suppliers, manufacturers, and distributors • Health systems and public health agencies • Public health practitioners and laboratorians, first responders, and health care providers • General public • Researchers, especially those who participate in the research agenda on variola virus and other orthopoxviruses (CDC, National Institutes of Health [NIH], U.S. Food and Drug Administration [FDA], Depart- ment of Defense [DoD], academic centers, and international partners) • Guidance-setting organizations and groups (e.g., CDC Advisory Committee on Immunization Practices [ACIP], WHO Strategic Ad- visory Group of Experts on Immunization [SAGE] for smallpox and mpox vaccines, etc.) • International partners, including WHO and other countries • Public, private, philanthropic, civil society organizations, and pro- fessional societies with a vested interest in the MCM enterprise Report Organization Chapter 1 discusses the high-level lessons learned from past public health emergencies, lessons in global cooperation, and potential emergence and response factors. Chapter 2 introduces the MCMs developed to detect, prevent, and protect against smallpox in the post-eradication era, within the context of potential smallpox containment strategies. Chapter 3 dis- cusses factors that may influence stockpiling considerations as well as other readiness planning decisions, including the impacts of orthopoxvirus char- acteristics, emerging technologies, and operational considerations on the development, testing, and deployment of smallpox MCMs. Chapter 3 also

INTRODUCTION 25 clarifies differences in viral characteristics and impacts in humans for the Poxviridae family of viruses and the Orthopoxvirus genus that primarily af- fects humans. While this report focuses on orthopoxviruses, their potential to cause disease in humans, and MCMs developed against them, the commit- tee recognizes the potential for spillover of other poxviruses to occur from animal reservoirs to humans. Chapter 4 presents ways forward to address gaps in research, understanding, and effectiveness of smallpox MCM options developed to date as well as considerations to inform stockpiling strategies. BACKGROUND AND CONTEXT Smallpox Research and Medical Countermeasures Post-Eradication Following the success of the globally coordinated WHO smallpox eradication program, WHA declared smallpox eradicated in 1980 after the last natural case occurred in 1977 (Fenner et al., 1988). In the post- eradication era, resolution WHA33.4 (1980) recommended measures for Member States to implement if smallpox should reemerge (WHO, 1980). Subsequent WHA resolutions directed the consolidation of remaining va- riola virus collections to two official locations: CDC in Atlanta, Georgia, and the VECTOR Institute in Koltsovo, Russia, with ACVVR oversight of research using variola virus (WHO, 2007, 2016). Following a 1986 recommendation of the WHO Ad Hoc Committee on Orthopoxvirus Infections to destroy the remaining viral specimens, the WHA set the date for the destruction of the live variola virus collections on June 30, 1999 (WHO, 1986, 1996). Implementation of that decision, however, has been deferred ever since in part based on a justification that the live viruses were needed to support further research and development of medical countermeasures to defend against natural, accidental, or inten- tional smallpox reemergence (IOM, 2009; WHO, 1999). Global and U.S. Smallpox Medical Countermeasures Stockpiles In 1980, WHA Resolution 33.4 recommended the establishment of a physical international reserve of smallpox vaccines, to be known as the Smallpox Vaccine Emergency Stockpile (SVES), comprising remain- ing vaccine doses from the Smallpox Eradication Program and additional WHO Member State donations (WHO, 1980, 2017). In 1999, the U.S. Congress directed CDC to establish a U.S. national pharmaceutical and vaccine stockpile for biological and chemical threats. The Department of Homeland Security determined smallpox, among other pathogens, to be “material threats” to national security following the September 11, 2001, terrorist attacks on the United States. Originally known as the National

26 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES Pharmaceutical Stockpile, a 2002 law changed its name to the SNS and further defined and expanded its mandate (Kuiken and Gottron, 2023). An interagency working group, PHEMCE, was established in the ensuing years to inform HHS decisions in determining which threats to stockpile against, including pandemic influenza, viral hemorrhagic fevers, antibiotic resistant bacteria, chemical threats, radiological and nuclear threats, ancillary sup- plies, and other targets and materiel (NASEM, 2021). Early domestic smallpox preparedness efforts coincided with pledges from the United States and other countries to contribute doses of smallpox vaccine to a “virtual global stockpile of pledged vaccine from around the world,” pursuant to the adoption of WHA55.16 in 2002 (CIDRAP, 2004). That resolution urged WHO Member States to share expertise, supplies, and resources in a global public health emergency (CIDRAP, 2004; WHO, 2002, 2017). The United States has maintained its commitment to the global small- pox vaccine stockpile, having affirmed its pledged vaccines for 20 million people in 2024 in advance of the 154th session of the WHO Executive Board (Lewis, 2023). The pledged vaccines are held in the SNS and are intended to be made available to WHO in the event of a smallpox emergency outside the United States (BioSpace, 2004). The donation would be a mix of all three vaccines held in the SNS in proportions that they are represented at the time.1 To obtain vaccine through the WHO SVES, a WHO Member State requests vaccine from WHO; WHO then decides on the type, quantity, and deployment of vaccines and arranges for importation, while the requesting country obtains authorization for use of the vaccine products and ancillary supplies locally. If a given vaccine lacks market authorization in either the donor or recipient country, the national regulatory authority of the request- ing country must be prepared to conduct an emergency assessment (WHO, 2017). Discussions on the composition of the WHO SVES reopened in 2021 to consider the addition of antivirals and diagnostics in virtual stockpile agreements, however these negotiations were delayed by the 2022 mpox multi-country outbreak and only recently resumed (Lewis, 2023). Conclusions on Global Stockpiling Based on the above evidence and findings, the committee drew the fol- lowing conclusions: (1-1) The ability for many countries to contain a smallpox outbreak is currently dependent on the U.S. readiness and response posture to rap- idly deploy MCMs upon request and in collaboration with WHO and 1 Personal communication, Margaret Sloane, Administration for Strategic Preparedness and Response (ASPR), January 16, 2024.

INTRODUCTION 27 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. LESSONS LEARNED FROM RESPONDING TO COVID-19 AND MPOX ASPR asked the committee to consider lessons learned from COVID-19 and mpox in its thinking about how national smallpox MCM assets could be optimized. The initial response failures to COVID-19 in the United States have been attributed to “the nation’s pre-existing structural and systemic features, which magnified the pandemic’s impact” as well as failures in government at many levels “to generate reliable information, communicate it in a timely and consistent manner, and translate it into sound policy” (Yamey et al., 2024). Diagnostic Availability and Testing Delays From the beginning of the COVID-19 pandemic, the United States quickly experienced a bottleneck in testing capacity as it attempted to re- spond. The U.S. delay in rolling out and scaling up laboratory-based testing was marked compared to the experiences of other countries. According to Our World in Data, a nonprofit that collated data from WHO and other sources, Argentina and Mexico reported starting testing individuals at single-digit levels in the second week of January 2020, followed by Taiwan and Thailand later that month. On February 5, Hong Kong reported 124 tests; South Korea followed by mid-February and quickly ramped up to hundreds of tests per day (Our World in Data, 2020). CDC was subject to extensive criticism for the delays in early testing. In its own after-action report, the agency identified contamination, poor design, and problems with quality control as proximal culprits, with inadequate planning, inadequate governance, and a failed incident management structure as fundamentally contributing factors (CDC, 2023). The advisory group that drafted the report issued a series of recommendations related to laboratory and testing leadership, oversight, and exercising. Once laboratory tests were up and running, it became clear that a significant level of potential testing capacity was going unused. Many aca- demic molecular biology laboratories pivoted their focus to become certified

28 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES testing laboratories but found in the spring of 2020 that they were nowhere near reaching throughput capacity despite significant wait times for test re- sults. Hospitals and clinics were sending their samples to laboratories with which they had preexisting contracts and compatible health record software (Maxmen, 2020). FDA authorized the first rapid COVID-19 test for at-home self-testing on November 17, 2020, through an Emergency Use Authorization (EUA) (FDA, 2020a). A sudden increase in the need for diagnostic testing in the face of new highly transmissible variants, such as Omicron, challenged both public and private laboratories as well as testing manufacturers (O’Donnell and Abouleneim, 2021; Smyth et al., 2022), and highlighted the importance of maintaining a large surge capacity. Some experts have argued that earlier research and development investment in years prior to the pandemic could have strengthened the fundamental science and knowledge base that would have supported quicker rapid diagnostic availability (Bipartisan Commis- sion on Biodefense, November 2020). In addition to the need for greater surge testing capacity, COVID-19 underscored the importance of maintain- ing a cadre of public health laboratory workforce and a dedicated supply chain for diagnostic test manufacturing, sample collection, and processing, (Behnam et al., 2020; Wolford et al., 2023). Unlike the development of novel COVID-19 diagnostics, the devel- opment of mpox diagnostics had occurred decades prior to the 2022 U.S. outbreak as part of global recommendations for smallpox prepared- ness (Cahill, 2023). No point-of-care diagnostics were available, but the science to support laboratory diagnosis of mpox was robust. Many laboratory-based tests have been described in the literature, including real-time polymerase chain reaction (PCR) assays used for mpox (Li et al., 2006, 2010) and an enzyme-linked immunoassay used on subjects from Wisconsin (Karem et al., 2005), the epicenter of the 2003 U.S. outbreak, as just a few examples. Two CDC-developed and FDA-approved real-time PCR laboratory test kits were already in use at Laboratory Response Net- work (LRN) laboratories. This differential availability of testing speaks to the investments made in known pathogens, including a designated mate- rial threat, compared to a novel infectious pathogen and one from a viral family that had received minimal attention. Despite the existence of FDA-approved test kits for mpox, testing dur- ing the 2022 multi-country outbreak was initially slow for the scope of the emergency. Frustration among doctors and patients over testing was common early on in the 2022 U.S. mpox outbreak. The Journal of the American Medical Association reported that despite availability of 8,000 tests weekly through upward of 67 public health labs, clinicians faced a cumbersome process in ordering tests (Suran, 2022). Testing was initially limited to LRN laboratories, and although commercial testing ramped up by late summer, some felt it was too slow and that the government was

INTRODUCTION 29 repeating the mistakes of COVID-19 (Lewis, 2022). One of the limiting factors for expansion of testing was the lack of diversity of testing assays and platforms at the beginning of the outbreak. Once again supply chain for materials presented a challenge, making LRN sites depedent on manual nucleic acid extraction kits from one manufacturer which could be used with the FDA 510(k) cleared assay (Wolford et al., 2023). Once reagents and automation were added, availability was expanded to several commercial labs by June 2022. Testing capacity would reach 80,000 per week by July 2022 (CDC, 2022). On September 7, after an of- ficial declaration of a public health emergency, FDA issued EUA authorities to further expand in vitro diagnostic testing availability for monkeypox virus; the declaration was drafted broadly to include testing options that detect or diagnose infection with non-variola orthopoxvirus (FDA, 2023b). Moving forward, collaboration and communication between CDC and FDA would help the agencies expand the use of the CDC-approved ortho- poxvirus laboratory test (Gerald, 2023). Between September 2022 and March 2023, eight additional tests were authorized under EUA: three automated laboratory tests; two automated point-of-care tests; one lab-based test with high daily testing capacity; and two manual test kits that used different reagents and instrumentation (Gerald, 2023). FDA’s goal with these approvals was to reduce reliance on single platforms. The Independent Test Assessment Program (ITAP), estab- lished as part of NIH’s Rapid Acceleration of Diagnostics (RADx) Tech program to support the COVID-19 response, was pivotal in bringing some of these mpox tests to market (NIBIB, n.d.). ITAP’s purpose was to acceler- ate regulatory review of accurate and reliable diagnostics, initially during the COVID-19 crisis and continuing to support mpox diagnostics (NIBIB, 2022). The first point-of-care test for mpox (Xpert Mpox by Cepheid) received EUA in February 2023 with the support of ITAP (FDA, 2023b). Vaccine and Therapeutic Availability, Access, and Uptake The successes of Operation Warp Speed (Chapter 3) in developing safe and effective vaccines in record time were tempered by major issues with accessibil- ity and uptake domestically and globally. While the foundations of coronavirus research, on which COVID-19 vaccine was developed, was anchored largely in post-SARS investment by NIH, some experts have questioned whether we would have been as ready for a virus from another family (Branswell, 2022), and note an overall lack of revolutionary, intergovernmental effort on MCMs for emerging infectious diseases until the nation was in crisis (Bipartisan Com- mission on Biodefense, 2021). Additionally, while mRNA-based COVID-19 vaccines helped reduce serious illness and hospitalization, an unanticipated level of vaccine hesitancy and vaccine related mis- and dis-information ham- pered uptake and had not been planned for.

30 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES Clinical trial networks to test therapeutics against COVID-19 enabled rapid recruitment for intensive care unit patients, however some argued that the lack of an established framework outside of intensive care unit patients to support clinical trials was a significant challenge that led to small, underpowered studies with repurposed drugs (Robinson et al., 2022). This resulted in limited insight into pre- or post-hospital stages of CO- VID-19 through these trials. Moving forward, some argued that a govern- ment established and organized network of hospitals for large clinical trial implementation and rapid data sharing could have produced more answers and potentially more solutions for health care providers who faced a high burden of hospitalizations with very few therapeutic tools (Zimmer, 2021). In May 2020, FDA issued an EUA for Veklury (Remdesivir), an existing antiviral repurposed for SARS-CoV-2; the agency granted full approval in October of that year under Fast Track and Priority Review designations and provided the company a Material Threat Medical Countermeasure Priority Review Voucher (FDA, 2020b). Ultimately, FDA provided full approval for three additional drugs for the treatment of COVID: Actemra (Tocilizumab) and Olumiant (baricitinib), both repurposed, and Paxlovid (nirmatrelvir and ritonavir), a novel combination of one new antiviral and one existing HIV protease inhibitor. Remdesivir, Tocilizumab, and baricitinib received indications for hospitalized patients, while Paxlovid as well as Remdesivir were indicated for mild to moderate COVID-19 cases at high risk for pro- gression. Other drugs were available on an EUA basis. A 2022 Kaiser Family Foundation analysis of Paxlovid and another oral therapy being used under an EUA, Lagevrio (molnupiravir), found disparities in access to at-home orally administered treatments in the United States, with impoverished counties and those that were majority Black, Hispanic, or American Indian or Alaska Native facing reduced access—the same populations that disproportionately suffered poor COVID-19 out- comes (Hill et al., 2022; Leggat-Barr et al., 2021; Magesh et al., 2021). The potential role of effective therapeutics was salient in a pandemic characterized by a concerning level of vaccine hesitancy. The relationship between vaccine and antiviral hesitancy appears complex. One analysis found that Paxlovid use (but not Lagevrio) was higher in states with higher vaccination rates (Murphy et al., 2022). On the other hand, more anec- dotal reports indicate a greater acceptance of therapeutics among some with anti-vaccine tendencies (Craven, 2021; Facher, 2022). Understanding the dynamic interplay between vaccine and therapeutic acceptance will be important for modeling acceptance scenarios for smallpox MCMs. In marked contrast to the start of the COVID-19 pandemic, the U.S. government had stockpiled MCMs that would be effective to respond to the 2022 mpox multi-country outbreak through the SNS smallpox MCMs portoflio. Specifically, the SNS had stockpiles of modified vaccinia Ankara vaccine developed by Bavarian Nordic (MVA-BN), an attenuated live, non-replicating vaccine indicated for smallpox and mpox (ASPR, n.d.;

INTRODUCTION 31 FDA, 2023a). MVA-BN had received full FDA approval for the prevention of smallpox and monkeypox disease in 2019. Originally developed to ad- dress smallpox, it was also approved for an mpox indication by virtue of the vaccine challenge studies in animals having employed the monkeypox virus. Additionally, tecovirimat was made available during the mpox out- break through a CDC investigational protocol and a National Institute of Allergy and Infectious Diseases clinical trial, as tecovirimat was not FDA approved for treating mpox (NLM, 2022; O’Laughlin et al., 2022). CDC distributed more than 80,000 bottles of oral tecovirimat and more than 13,000 vials of intravenous tecovirimat (Hruby, 2023). The investi- gational protocol may have allowed access but may also have created its own barriers, as the administrative burden of investigational new drug (IND) protocols is high and, some argue, may only be easily assumed by well-resourced health organizations (Cahill, 2023). Multiple factors led to limited vaccine availability to initially respond to the 2022 mpox multi-country outbreak (Kota et al., 2023a). The stockpiling assumptions for MVA-BN were based on smallpox scenarios with a focus on accidental and deliberate release. BARDA had funded the advanced development of MVA-BN for its use as a smallpox preventive in immuno- compromised persons, and acquired it for the SNS via Project BioShield. While the stockpile had originally held 20 million doses of MVA-BN for use in a smallpox outbreak, most of those had expired, leaving the SNS in possession of 1.4 million filled doses (Chaplin, 2023). Of these, 372,000 doses were held in a Bavarian Nordic warehouse in Denmark and were ready to ship, but HHS was reportedly slow to request the full number of available doses, while 786,000 more doses met FDA inspection delays at the Danish facility before they could be shipped (LaFraniere et al., 2022).2 Most of the supply owned by the U.S. government was available in bulk frozen product—as much as 15 million dose equivalents—but this could not be quickly formulated into individual thawed doses. In addition to initial bottlenecks in providing MVA-BN at scale, demand for the this vaccine to contain mpox was not an anticipated SNS planning scenario. As the sole stockpile of vaccines approved for mpox, SNS leader- ship needed to evaluate releasing material potentially to the detriment of national security purposes. During the first year of the 2022 mpox outbreak, 748,329 first doses of MVA-BN were administered in the United States (Kota et al., 2023a). As of April 2023—nearly the 1-year mark of the outbreak— about two-thirds of vaccine-eligible people were still not vaccinated. Though vaccination rates were higher among ethnic minority groups, mpox incidence was also higher among these groups. Additionally, vaccination rates among Black and Hispanic males were disproportionate to incidence, revealing a higher unmet need for vaccination in these groups (Kota et al., 2023b). 2  This information regarding vaccine shipments was modified after release of the prepublica- tion version of the report in order to be more consistent with the cited reference.

32 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES Global Cooperation COVID-19 and the ongoing mpox outbreak demonstrated the speed with which biothreats occurring anywhere in the world can impact and overwhelm national medical and public health response systems—which is a sobering reality of today’s global interconnected supply chains and populations as well as the ongoing lack of health system capacities and coordination in health emergencies. The COVID-19 pandemic highlighted the critical importance of global preparedness and international coopera- tion for equitable and effective responses to emerging infectious diseases. Similarly, the mpox outbreak underscored the need for rapid detection, containment, and coordinated response efforts locally to mitigate impacts at national, regional, and global scales. The shortfalls of the global MCM enterprise during these events to ensure equitable access to MCMs in the United States and globally, along with enduring concerns about public ac- ceptability of countermeasures, hindered disease containment around the globe. In response to these lessons, WHO Member States established an in- tergovernmental negotiating body “to draft and negotiate a WHO conven- tion, agreement, or other international instrument on pandemic prevention, preparedness, and response” (WHO, 2023). Strengthening smallpox MCM preparedness requires prioritizing proac- tive global cooperation, information sharing, capacity building, and joint research efforts to effectively respond to an outbreak anywhere in the world. COVID-19 underscored how effective response cannot be assumed based on better preparedness (IPPPR, 2021). Since eradication, understand- ably, most countries have not stockpiled smallpox MCMs or the other resources needed to respond to an outbreak. Therefore, global cooperation, information sharing and sharing financial and facility support for research to develop smallpox MCMs would be an essential first step in improving global readiness to a smallpox event. While this report focuses primarily on smallpox MCMs developed for use in the United States and maintained in the SNS, WHO Member States may benefit from, and in some cases depend on, U.S. donations of smallpox vaccines or other MCMs. Moreover, in the event of a non-U.S. smallpox outbreak, the United States would derive significant health and security benefits by assisting other countries in the response to prevent the outbreak from spreading internationally. SMALLPOX EMERGENCE AND RESPONSE CONSIDERATIONS The needs of an MCM response will depend on the scale and circum- stances of a potential smallpox outbreak. Since the eradication of naturally occurring smallpox, preparedness plans have focused on the potential for an accidental or deliberate reintroduction of smallpox. These scenarios have

INTRODUCTION 33 been based on intelligence of foreign bioweapons programs and the poten- tial for breaches in biosafety at official laboratories with ongoing variola virus research (Bipartisan Commission on Biodefense, 2024; Department of State, 2023). Several factors have implications for the types, quantities, and potential utility of MCMs to contain smallpox. A few of the factors the committee considered in their deliberations are listed in Box 1-2. However, this summary is not exhaustive, and a comprehensive threat assessment, ac- companied by scenario-based planning, as discussed in Chapter 4, is crucial to determining the appropriate assumptions. Chapter 3 further expands on specific factors that may influence readiness and response. The relative utility of MCMs for immediate and long-term containment after a smallpox event can also help inform planning. As noted in past scenario-based assessments of smallpox readiness, most of the same activi- ties are needed in terms of planning before an event, however, there will be greater variability in the resources and activities required for response (IOM, 2005). The demands that various smallpox containment strategies will place on the MCM enterprise in an outbreak will need to be consid- ered in planning. For example, Biggs and Littlejohn describe a “hierarchy of MCMs against emerging biological threats” where higher-order MCMs (e.g., vaccines) offer increased protection with less frequency of administra- tion over a longer period of time and therefore may be considered more effective for protection, compared with lower-order MCMs (e.g., personal protective equipment [PPE]) (Biggs and Littlejohn, 2022).3 Figure 1-2 pres- ents a conceptual hierarchy of MCMs, adapted for the smallpox readiness and response context. Though the use of PPE is important to infection prevention and included in the figure, the utility of this MCM was not considered in scope for this report. OVERARCHING CONCLUSION Based on the evidence and findings on the implications of the U.S. smallpox MCM enterprise for potential global smallpox events, the com- mittee drew the following overarching conclusion: In a smallpox event, the U.S. readiness and response posture will be sig- nificantly affected by the ability of other countries around the world to adequately detect smallpox and contain transmission. Given global inter- dependence and global supply chains, supporting MCM capacities and capabilities internationally (i.e., a global MCM platform) will improve security against biothreats in the United States. 3 Biggs describes durability as referring to the scope of protection, duration, and frequency to be administered, while resource use is inversely related due to the investment needed to sustain protection.

34 FUTURE STATE OF SMALLPOX MEDICAL COUNTERMEASURES BOX 1-2 Summary of Factors Considered by the Committee The committee considered the following in their evaluation of the state of smallpox MCM readiness: Environmental Resurrection/Mutation and Engineered Variola or Variola- Like Virus The effectiveness of MCMs developed to detect, prevent, and treat smallpox have been established based on their use against eradicated strains of variola. While current smallpox MCMs are cross-reactive for other orthopoxviruses and are expected to provide some benefit against a novel orthopoxvirus, MCMs are likely to be less effective against a variola or variola-like strain that is deliberately engineered to evade current vaccines and antivirals. Accidental and Deliberate Release of Variola Virus Differences in exposure scenarios would impact the speed with which an immedi- ate response would need to be scaled. In the event of a laboratory accident or dis- covery of unofficial samples, direct and prolonged close contact would be needed for person-to-person transmission to continue to second- and third-generation smallpox cases. If these types of incidents occur in the United States, it would require reporting to CDC, with a response conducted in collaboration with WHO. A deliberate release, as in the case of bioterrorism, would depend on the delivery system used. A bioterrorism attack in a populous area would expose a larger than normal number of individuals to smallpox simultaneously. MCM effectiveness would depend on the strain of the virus used in the attack and response measures would need to be accelerated immediately to protect the public. Additionally, expo- sure to a higher viral dose could result in more severe presentations of smallpox, such as hemorrhagic disease, and greater viral shedding, morbidity, and mortality as has been observed with mpox in an animal model (Hutson et al., 2010). Delivery could also occur via an individual who has self-inoculated with variola or variola-like virus with the intent to spread disease, assuming the virus is viable through the delivery system over a defined period. Geographic Scope In the event of an accidental or deliberate smallpox outbreak, initial cases could be localized or across multiple locations. Regardless of the geographical scope, a smallpox outbreak of any size would likely constitute an international emergency, as it may indicate a nefarious actor with the motivation and capability to conduct subsequent attacks. Immediate Containment and Post-Event The MCMs needed and strategies used to implement them are likely to shift based on the goals of the response. The immediate response goals would be to contain transmission and mitigate morbidity and mortality. Longer term prevention would be implemented through a pre-exposure MCM program. Overall response

INTRODUCTION 35 BOX 1-2  Continued strategies would need to consider pre-exposure or post-exposure vaccination and antiviral prophylaxis and treatment (Chapter 2). MCM Development, Storage, and Administration (Chapters 2 and 3) • Commercial manufacturing capability – Currently, there is a lack of com- mercial market for smallpox MCMs and insufficient capacity to scale MCM production in the event of a large-scale smallpox event. The commercializa- tion of cross-protective orthopoxvirus MCMs and emerging biotechnologies could provide capabilities to respond and deploy smallpox MCMs on demand, when and where needed. • Future development and utility of MCMs – New MCM technologies could present opportunities to develop more effective MCMs against smallpox. A strategic approach to assessing the utility of newer MCMs, coupled with a research agenda, could improve readiness. • Storage requirements – Lyophilized second-generation vaccines have con- tinued to meet potency requirements, while the stability of third-generation vaccines will need to be assessed over time. Potency testing and shelf-life extension requirements are important to maintaining the utility of all stockpiled assets. • Distribution requirements – The scope and nature of the outbreak would determine the conditions under which distribution for vaccines and therapeu- tics may differ. • Vaccine administration – Multiple puncture (or scarification) is the technique used to administer first- and second-generation vaccines using a bifurcated needle. These vaccines produce a localized reaction (i.e., “take”) and carry safety concerns in some populations. MCM Utility and Acceptance (Chapters 2 and 3) • Vaccine and therapeutic safety and applicability – Different vaccines and therapeutics are more appropriate for certain sub-populations due to (a) con- traindications, (b) risk of exposure to smallpox, (c) containment strategy. • Acceptance and willingness to use MCMs (Chapter 3) – Despite vac- cine and therapeutics benefits, including protection from severe disease and reduced transmission, it is expected that segments of the public will refuse vaccination, testing, and/or therapeutics. These factors can be influenced by the willingness of state, tribal, local, and territorial governments to request and distribute MCMs, individual experiences in accessing MCMs, and concerns over safety or adverse reactions. Therefore, actual demand for MCMs may be lower than the forecasted needs. SOURCES: Costantino et al., 2018; Gaudioso et al., 2011; Hutson, et al. 2010; Sloane, 2023.

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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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