Future State of Smallpox Medical Countermeasures (2024)

4

Way Forward: Priorities for Research, Development, and Stockpiling

“In a smallpox emergency, a reemergence anywhere will likely create demand [for medical countermeasures] everywhere.”

Crystal Watson, in presentation to the committee
December 14, 2023

Decades of investments have reaped significant benefits for smallpox preparedness, even if the threat of a smallpox outbreak is of uncertain size and scope. The United States now has a smallpox stockpile of medical countermeasures (MCMs) far more robust and mature than it was at its inception. The committee was asked to provide its perspective on what the priorities could be going forward for additional research, development, and the stockpiling of smallpox MCMs that can further improve the U.S. readiness and response posture. What knowledge gaps remain that could be addressed through scientific research, and what capability gaps remain that could be addressed through amendment to the composition of the stockpile? This chapter briefly discusses future opportunities for live variola virus research as well as for non-variola orthopoxvirus research in developing smallpox MCMs and concludes with considerations for new directions in the national stockpiling approach for smallpox MCMs.

SMALLPOX RESEARCH AGENDA

Research that enhances the safety, efficacy, and utility of smallpox diagnostics, vaccines, and therapeutics provides a public health benefit in the context of smallpox readiness and has added benefits that improve the

nation’s response to other orthopoxvirus outbreaks. Objectives to date of the U.S. smallpox research program derive largely from the 1999 Institute of Medicine (IOM) report that addressed the scientific needs for live variola virus (IOM, 1999) and subsequent reports of the IOM (IOM, 2009) and the World Health Organization (WHO) Advisory Group of Independent Experts (WHO, 2010, 2013) and have been overseen by the WHO Advisory Group for Live Variola Virus Research (ACVVR) (WHO, n.d.). Table 4-1 highlights conclusions from the 1999 and 2009 IOM reports and the 2022 ACVVR report (WHO, 2023). The 2023 ACVVR report (in progress at the time of publication) was recently summarized at the 154th WHO Executive Board Session and concluded that access to and use of live variola virus remains essential for public health needs, including completing the sequencing of remaining variola virus isolates, further research on point-of-care diagnostics, the development of scalable less-reactogenic vaccines, and the development of small-molecule antiviral agents (WHO, 2024a). Figure 4-1, from the U.S. Centers for Disease Control and Prevention (CDC), illustrates a U.S. smallpox research agenda focused on next-generation vaccines, antiviral treatments, and nucleic acid- and protein-based diagnostic assays and shows nodes at which variola viral samples enable the evaluation of the diagnostics, vaccines, and therapeutics developed under this agenda.

U.S. investments in line with this agenda have expanded the smallpox assets available to the United States (and to other countries). These investments have also enabled benefits beyond smallpox readiness and response. These benefits were realized most clearly in the mpox response’s use of modified vaccinia Ankara-Bavarian Nordic (MVA-BN) and tecovirimat, countermeasures which at their inception were envisioned exclusively for smallpox preparedness. Inversely, one would expect a research program targeting non-variola orthopoxviruses to offer potential utility for smallpox preparedness and, further, that investments in products with broader and potentially commercial use may have more immediate utility and could be more attractive to industry partners. As discussed in Chapter 3, while orthopoxviruses in general offer great utilities, vaccinia virus, the prototype poxvirus and the smallpox vaccine, and the monkeypoxvirus are of particular significance in this regard. Both these viruses emerged as human pathogens post cessation of smallpox vaccination programs (Damaso et al., 2000).

Non-Variola Orthopoxvirus and Live Variola Virus Research

This section identifies gaps and opportunities in the discovery and development pipeline for smallpox MCMs and describes the ongoing role of the use of live variola virus. Research with live variola virus and with non-variola orthopoxviruses is necessary to the development of smallpox MCMs—leading to better diagnostics, better vaccines, and better

therapeutics. The necessary regulatory restrictions on research with live variola virus and the absence of circulating smallpox disease today make orthopoxvirus research using non-variola species critical to continued improvements in smallpox preparedness. Scientific and technological advancements in studying orthopoxviruses in humanized-mouse models, Cast E/J mice, other small animal models, nonhuman primate animal models, and in silico models have also created opportunities to complement the use of variola virus research (Hutson et al., 2021).

Non-Variola Orthopoxvirus Research

The following narrative lays out important advances in smallpox MCMs using non-variola orthopoxvirus research. Working with non-variola orthopoxviruses can inform new strategies and approaches for scaling and improving MCM production and distribution. U.S. Food and Drug Administration (FDA)-approved smallpox vaccines are formulated using vaccinia virus, a non-variola orthopoxvirus. All first-, second-, and third-generation smallpox vaccines contain vaccinia virus, an orthopoxvirus

closely related to variola which has been proven to prevent most smallpox disease and deaths. In fact, the first-generation smallpox vaccine was labeled by FDA for “prevention of orthopoxvirus” disease, and the newest licensed smallpox vaccine, MVA-BN, is labeled for the prevention of both smallpox and mpox. Vaccinia research therefore has direct implications for vaccine safety, efficacy, shelf-life, improvement, production, cost reduction, and management. Additionally, mpox subunit and nucleic acid vaccines (including mRNA vaccines) in development are rooted in the understanding of other orthopoxviruses (Fang et al., 2023; Freyn et al., 2023; Hooper et al., 2003; Hou et al., 2023; Rcheulishvili et al., 2023; Sang et al., 2023; X. Yang et al., 2023; Zeng et al., 2023; Zhang et al., 2023).

Non-variola orthopoxviruses have also been used in the development and testing of smallpox drugs and can support future drug development for smallpox and other targets. Efforts to develop new therapeutics for smallpox have used non-variola orthopoxviruses in preclinical and clinical trials and have shown efficacy against them (Deng et al., 2007; Dower et al., 2012; Peng et al., 2020). The development processes of the smallpox drugs tecovirimat (Huggins et al., 2009; G. Yang et al., 2005) and brincidofovir (Olson et al., 2014; Stabenow et al., 2010) relied on experimentation with non-variola orthopoxviruses and supportive studies with variola virus. The scientific and logistical limitations of using smallpox virus in animal models necessitated establishing the efficacy of tecovirimat using related viruses. Tecovirimat use demonstrated benefit in a number of animal models (mice, prairie dogs, rabbits, nonhuman primates) that had been infected with different orthopoxviruses (ectromelia, monkeypox, rabbitpox) as well as nonhuman primates infected with smallpox virus (variola virus) (Russo et al., 2021). Recent studies demonstrated benefit of tecovirimat in the treatment of humanized mice infected with smallpox virus (WHO, 2023). Pivotal studies for regulatory approval used nonhuman primates challenged with monkeypox virus and rabbits with rabbitpox virus and demonstrated improved survival in animals that received the drug (FDA, n.d.).

Because the presence of non-variola orthopoxviruses in the world complicates empirical diagnosis of smallpox, it thereby necessitates a research approach to diagnostics that differentiates between variola and these other viruses. The high similarity of orthopoxvirus DNA genome sequences and the recognition of new viruses have also posed challenges for accurate differentiation among orthopoxviruses using tests based on biophysical properties and sometimes nucleic acid–based tests, though reliable polymerase chain reaction (PCR) assays have been developed and continue to be reassessed as new viruses are discovered (Altindis et al., 2022; Hedberg and Zink, 2024; Low et al., 2023; Stefano et al., 2023). To date, serology-based approaches are challenged to distinguish among orthopoxviruses due to cross reactivity. The development of two FDA-approved nucleic acid-based assays—one for variola and one for non-

variola orthopoxviruses—was designed to address the need for effective testing tools and an algorithm with which to use them. Validation of the non-variola panel relied on use of human pathogenic orthopoxviruses including strains of cowpox, monkeypox, vaccinia, and variola virus species¹ (FDA, 2018; Li et al., 2006).

Not only is non-variola orthopoxvirus research important in smallpox MCMs, but this research can also help reveal to scientists the reservoirs, evolutionary relationships, and virological properties of the genus, all of which can inform scientific understanding of variola virus and strategies to mitigate it. And since these viruses exist in nature and some are the cause of occasional or ongoing outbreaks, research on non-variola orthopoxviruses has a greater potential for near-term clinical and public health benefits. Use of these poxviruses could drive basic research in other areas as well, such as the study of viral vectors for vaccine development, gene therapy, and oncolytic virus therapy, as described in Chapter 3.

Live Variola Virus Research

While there are advantages to conducting research with non-variola orthopoxviruses, these species cannot fully replace the knowledge gained by working with live variola virus (Damon et al., 2014). In a presentation to the committee, CDC shared salient examples of the ways that strains of variola virus (or samples derived from live virus) have been or are being used, which include:

• Validation of diagnostic assays and iterative assessment of Laboratory Response Network tests with newly sequenced variola virus isolates in silico to determine if wet lab testing is needed.
• Provision of comparative data on vaccine immunogenicity, such as an ongoing study to provide “non-inferiority” data on MVA-BN at the request of FDA.
• Provision of comparative data on antiviral effectiveness to test an expanded panel of variola virus isolates for their sensitivity to tecovirimat at the request of FDA (Hutson, 2023).

As mentioned in Chapter 1, WHO oversees all research using live variola virus, with the ACVVR reviewing all research proposals that request to use one of the two sanctioned collections of live virus at CDC in Atlanta and the Russian State Centre for Research on Virology and Biotechnology (VECTOR), Koltsovo, Novosibirsk Region, Russian Federation. Box 4-1 highlights completed and ongoing research for use of live variola virus from

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¹ Variola virus was used in the testing panel to confirm the assay did not detect variola virus.

2020 to 2023. The 2022 ACVVR report of the 24th meeting also details specific research proposals for use of live variola virus presented for 2023, and the forthcoming 2023 report of the 25th meeting will detail specific research proposals presented for 2024 (in progress at the time of publication).

Notably, the ACVVR reports also describe a considerable amount of work using non-variola orthopoxviruses as surrogates and as useful tools in their own right for non-variola diseases like mpox (WHO, 2023).

Despite considerable similarities in genetic identity, host range, transmission, pathogenesis, and other viral characteristics and host interactions, research reveals significant differences across orthopoxvirus species (Satheshkumar and Damon, 2021). It is believed that genes in the left and right ends of the genomes, which are more variable across orthopoxviruses and are described to interact with multiple host proteins (e.g., interferons, complement, apoptosis, chemokines), are responsible for these differences (Moss and Smith, 2021). The genomic sequencing of variola virus isolates held in CDC and VECTOR repositories (still in progress) can contribute to the understanding of poxvirus evolution, host-range, virulence, and transmission and to the future assessment and evaluation of diagnostic assays and modern molecular techniques for diagnostics, and identification of variants that may be resistant to future antiviral drugs (WHO, 2023). Additional work in genomic sequencing of live variola virus will be required to advance the fundamental understanding of smallpox and related poxviruses, and WHO has recommended that sequence data for all available isolates be made publicly available as soon as possible.

In 1999, IOM concluded:

The most compelling need for long-term retention of live variola virus would be for the development of antiviral agents or novel vaccines to protect against a reemergence of smallpox due to accidental or intentional release of variola virus. (IOM, 1999)

IOM’s 1999 finding that live virus is needed for certain aspects of research remains true today. Further elucidation of some of the secrets of variola virus that remain hidden—and which could help advance the development of modernized smallpox MCMs—would necessitate research with live variola. For example, having live variola virus collections, before treatment with tecovirimat, will be important for understanding drug resistant mutants when they arise. Taking what is now known, Table 4-2 looks at smallpox MCM readiness as a function of research with live variola and non-variola orthopoxviruses. It maps the potential for using these viruses or their components against specific knowledge gaps and MCM goals that could support improved public health benefit.

NOTE: VARV = variola virus.

Research Readiness

The ability to evaluate the safety and efficacy of MCMs (particularly those that have only animal data on efficacy) in a larger population during a public health emergency is a critical component of MCM readiness. Clinical trial infrastructure serves as the backbone for evaluating urgently needed diagnostics, vaccines, and therapeutics during outbreaks (NASEM, 2017).

Advancement of therapeutics for COVID-19 lagged behind the successes with vaccines because at the outset of the pandemic, when little was known about the virus, but hospitalization rates were high, it was important to determine if existing antiviral agents could be repurposed for use. This was initially successful with Remdesivir. Thereafter, the drug discovery was slow knowing that because direct acting antiviral treatments work best when given early in the course of most diseases to halt viral replication and to be initiated on treatment, patients or participants must have access to diagnostics to confirm the presence of disease (Griffin et al., 2021; Mulangu et al., 2019). While clinical trial networks enabled rapid recruitment for hospitalized and moderately to severely ill patients, some argued that the lack of an established framework outside of hospitalized patients to support clinical trials was a significant challenge for research on early/mild COVID that led to small, underpowered studies with repurposed drugs (Robinson et al., 2022). This meant that the trials that were run offered limited insight into pre- or post-hospital stages of COVID-19. The COVID-19 pandemic highlighted the need for adaptive and outpatient trial designs, including community or nursing home based as well cluster trials for early access to treatment and for evaluation of pre- and post-exposure interventions (Griffin et al., 2021; Mulangu et al., 2019). Decentralizing and taking clinical trials closer to the community has the potential to also reduce social inequities and logistical barriers in research participation (Petrini et al., 2022). Even hospital-based trials faced immense delays in initiation and were fraught with inequity in participation by diverse patient populations (Linas and Cunningham, 2019). Had the government established an organized network of hospitals for the execution of large clinical trials and rapid data sharing, some argued, science could have produced more answers and potentially more solutions for health care providers who faced a high burden of hospitalizations and deaths with very few therapeutic tools in the first year of the pandemic (Zimmer, 2021).

Delays in initiating and conducting clinical trials can translate to lost lives and prolonged control efforts. Goals 3 and 4 of the National Biodefense Strategy and Implementation Plan lay out the whole-of-society elements of a fast response, calling for expedited evaluation of novel vaccines, therapeutics, and diagnostics during outbreaks (White House, 2022). WHO also recognizes the value of rapid research in a crisis, stating that strengthening clinical trial capacity within and across countries

is essential for the timely development and evaluation of countermeasures (WHO, 2022a).

Additionally, emerging infectious diseases often present unique challenges that require tailored or adaptive study designs and infrastructure. These may include limited knowledge of the pathogen, difficulty recruiting participants, and complex logistical hurdles in outbreak settings. The preplanning of trials can not only increase the speed of response but also provide time for necessary consideration of ethical and logistic hurdles as well as for developing a strategy for the inclusion of diverse patient populations. COVID-19 and mpox emergencies have illustrated the importance of:

• Pre-pandemic preparedness: Establishing networks of trained researchers and clinical sites ready to pivot to emerging threats.
• Streamlined and adaptive trial designs: Developing flexible and efficient trial designs suitable for outbreak settings that allow evaluation of interventions in all phases of disease and bring trials closer to the patient in the community.
• Enhanced recruitment strategies: Implementing community engagement and outreach to ensure diverse participation.
• Regulatory planning and agility: Creating a streamlined and anticipatory review and approval process for clinical protocols for investigational MCMs to address emerging threats and fostering collaboration between regulatory bodies for faster and more efficient evaluation and approval of promising interventions.

Conclusions on the Continued Role of Live Variola Virus for Research and Public Health Purposes

(4-1) Research with live variola virus is essential for developing animal models to be used for MCM efficacy testing as a human surrogate, full verification of the potential efficacy of MCMs, and the development of certain targets for more effective therapeutic options, and it may be essential if advanced organoid or other sophisticated systems will be used to study these biologic interventions.

(4-2) Discovery research and pathogenesis research with live variola virus has merit as biomedical research without an immediate obvious connection to smallpox readiness and response.

(4-3) It is important to plan for clinical trials (e.g., of vaccine comparative 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.

STOCKPILING CONSIDERATIONS

The committee was asked to help the Administration for Strategic Preparedness and Response (ASPR) think about the future of the smallpox MCM portfolio for the U.S. Strategic National Stockpile (SNS). A smallpox outbreak of any size (even a single case) will be initially perceived as an event of national and possible international (pandemic) potential, and the SNS will need to be forward leaning in its response until the source and scope of the outbreak are clear.

Historically, the SNS has prioritized and devoted most of its resources to just two threats—smallpox and anthrax (GAO, 2022; Kuiken and Gottron, 2023). These threats remain substantive drivers of the SNS budget, and there is limited flexibility in terms of what other MCMs can be purchased with current appropriations, due to the portion of the budget allocated to anthrax and smallpox MCMs (GAO, 2022). The president’s fiscal year (FY) 2024 budget request for the SNS is $995 million. The request does not delineate the specific products it intends to procure with these funds, but the most recent multi-year budget from the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) offers insight into how the dollars, if appropriated, are likely to be spent. The budget proposed by PHEMCE describes increased funding needs in FY 2024 driven largely by higher spending on the anthrax, Ebola, and smallpox portfolios (HHS, 2023). Over the course of the five-year budget plan (FY 2022–2026), “sustainment of Anthrax and Smallpox capacity is expected to account for approximately two-thirds of SNS’s procurement budget.” If these PHEMCE projections become reflected in future budgets, then anthrax and smallpox expenditures will continue to dominate SNS spending.

The budget outlook also reveals a potential for a minimal emphasis in the coming years on basic smallpox or smallpox-relevant research at the National Institutes of Health (NIH) that would support the insertion of new drug candidates into the pipeline and a modest advanced development emphasis at the Biomedical Advanced Research and Development Agency (BARDA) for smallpox innovations. NIH is supporting the development of broadly protective monoclonal antibodies and mRNA-based vaccines for orthopoxviruses; BARDA is investing in a next-generation monoclonal antibody–based smallpox therapeutic. Citing lessons learned from COVID-19, the budget plan also relates “multidisciplinary” portfolios for BARDA and NIH that are designed to develop tools and platforms that cut across the CBRN space. PHEMCE expects a significantly increased need for funding in these multidisciplinary efforts, far outstripping any individual pathogen-specific budgetary line. The committee is interested to see how the predicted $16.5 billion over 5 years of investment (if funded) will support vaccine platforms, broad-spectrum therapeutics, and more rapid manufacturing options and the ways that such activities could benefit the smallpox portfolio.

The multi-year budget goes on to describe the smallpox MCM portfolio as “relatively more mature” in that it has reached a stage where costs are driven by sustainment and “investments in replenishment” rather than new investments (HHS, 2023). That is, the SNS is anticipating spending to primarily maintain a holding pattern regarding smallpox readiness. The description of BARDA’s investment in smallpox MCMs includes funding to support sustained investment in a lyophilized formulation of MVA-BN, manufacturing of additional doses of MVA-BN to bolster domestic supply, and procurement of oral and intravenous tecovirimat to replenish products used to respond to the mpox outbreak. Sustainment of stockpiled assets is a prudent course, given the years and billions of dollars that have gone into developing and procuring these assets. Indeed, the lapse in BARDA’s sustainment of stockpiled MVA-BN made national headlines when an outbreak forced the lapse—and its real-world impacts—into the light of day (Goldstein, 2022). These assets should not be developed only to be discarded.

And yet, the stockpile may be at an inflection point. With the SNS now more than two decades old, it stands to reason that some of its assets will have stood the test of time more than others. Ciprofloxacin and doxycycline are held to support anthrax response, and until BARDA’s investments in antibacterial innovations begin to produce benefits, these antibiotics should be sustained. For smallpox, the scientific and technological opportunity for innovative and improved vaccines, therapeutics, and diagnostics may be a good argument for a transitional phase in which investments made to date are sustained to ensure a ready stockpile, while building a smallpox MCM stockpile of the future.

International Sharing of Burden and Benefit

The ongoing research and development of smallpox and orthopoxvirus MCMs need not be an enterprise taken on by the U.S. government alone. Collaborations and partnerships with other nations and organizations could offer platforms that would at once create a shared burden and enable a pathway toward international sharing of benefits.

Regional and global organizations are being founded to provide a pathway toward innovation and toward securing a regional or global supply of MCMs that can benefit populations beyond those that exist within national boundaries. The European Commission’s 2021 Health Emergency Preparedness and Response Authority, or HERA, is designed to address market challenges in MCM readiness while fostering the international cooperation that will ensure availability and accessibility of those countermeasures globally (European Commission, n.d.). In 2022, Japan established the Strategic Center of Biomedical Advanced Vaccine Research and Development for Preparedness

and Response, or SCARDA, to support commercialization of vaccines during non-pandemic settings with a view to achieving the G7 100 Days Mission for pandemic response (AMED, n.d.). The Coalition for Epidemic Preparedness, or CEPI, was established prior to the COVID-19 pandemic to accelerate MCM development for epidemic and pandemic threats and is a major player in 100-day efforts (CEPI, 2024). Philanthropies and governments invest in CEPI to support MCM research and development for pathogens from a number of viral families. CEPI has demonstrated success in developing partnerships and targeting investments to make new vaccines and make them accessible and affordable. For example, CEPI partnered with the EU’s Horizon 2020 program in 2019 to invest $24.6 million in the first vaccine against chikungunya, IXCHIQ. CEPI’s funding is devoted toward efforts to make IXCHIQ accessible to countries with the highest burden of disease, and not just available to travelers from high-income countries as originally anticipated (CEPI, 2023)

Such funders are well situated to support the development of next-generation smallpox and orthopoxvirus MCMs, and even to expand the use of those currently available. How the global community can most effectively build and leverage such organizations to support MCM innovation, development, stockpiling, and equitable dissemination remains under discussion. While the details lie outside the scope of this report, the committee emphasizes that the use of such structures could reduce the burden on the U.S. government alone to fund smallpox and orthopoxvirus MCMs.

Lessons From Mpox MCM SNS Deployment

BARDA investment in the advanced development of MCMs and SNS procurement of these and other assets, dating to the Project BioShield Act of 2004² have resulted in the nation being better protected against public health emergencies. Nevertheless, there is room for improvement.

The 2022 mpox outbreak may hold specific relevance to SNS considerations. The U.S. mpox response relied upon deploying stockpiled vaccines and antivirals, as would be the case for smallpox. MVA-BN was stockpiled for smallpox preparedness but had been approved by FDA for both smallpox and mpox (Adams, 2023; Wolfe, 2023). This reality meant that it became the go-to option for controlling the further spread of the mpox virus in the United States. An important question raised from the mpox experience is whether the dual indications for both a national security threat and an emerging infectious disease will remain an outlier, or whether it can

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² Public Law: Project BioShield Act of 2004, Public Law 108-276, 108th Cong., 2d. sess. (July 21, 2004), 15.

and should be replicated. Such dual indications can meet BARDA’s stated strategy to pursue solutions to emerging infectious disease that that can be adapted to and applied against a range threats (BARDA, 2022).

Unlike ACAM2000, the smallpox vaccine intended for the general population and thus stored in the large quantities, MVA-BN was intended for use in a subset of the population. So it was intentionally stockpiled in smaller amounts (Wolfe, 2023). This strained the response to mpox, which was not the pathogen for which it had been stockpiled. But critically, BARDA had let most of the millions of its finished SNS doses expire in favor of purchasing raw vaccine product to be held by the manufacturer internationally, dramatically affecting response time (Goldstein, 2022). This constrained the mpox response and would have also constrained a smallpox response.

Sufficient vaccine doses to support the population in need for mpox response were initially unavailable to meet demand. ASPR proceeded to order 5.5 million vials from the federal government’s bulk supply held by Bavarian Nordic to be filled and finished, bringing the SNS supply to about 7 million vials by the middle of 2023; ASPR ultimately released more than 1 million single-use vials of MVA-BN to jurisdictions (ASPR, n.d.). ASPR also released stockpiled tecovirimat, and CDC worked on ensuring the availability of laboratory diagnostics for orthopoxviruses within the Laboratory Research Network and in commercial testing facilities (Aden et al., 2022; ASPR, n.d.).

Thus, the successes of the mpox response were tempered by major challenges, especially the short supply of immediately available vaccine doses, as well as by concerns over changes to dosing strategy during outbreak response, inequitable vaccine access, access to laboratory testing for patients, and overall federal, state, and local coordination (McQuiston, 2023; Mrsny, 2022).

It is important to learn from mpox while acknowledging and planning for the ways that a smallpox response would be different. The smallpox response plan assumes a full and fast mobilization (within 8 hours), or “push,” of vaccine assets to pre-identified “ship to” locations, whereas the use of such a strategy was not used for mpox (Adams, 2023). Therapeutic options would be delivered upon request (pull) and shipped separately to points of care. Adams (2023) noted that the response strategy would be determined at time of incident collectively by federal and state, local, tribal, and territorial health officials. Furthermore, SNS officials noted to the committee that mpox presented as a threat localized to a particular demographic and required nationwide outreach and access targeted to this demographic.

While it is important to derive lessons from mpox outbreaks and SNS use, COVID-19 also provides many lessons, as described in prior chapters

of this report. The constraints of CDC centrally managed diagnostics, a lack of research and development investment in rapid diagnostic technology in the years leading up to the outbreak, struggles with rapid vaccine manufacturing at scale, a dearth of therapeutics and inaccessibility of those treatments, and many other challenges provide a basis from which to make different decisions for smallpox preparedness.

Considerations for the Smallpox MCM Portfolio

The overall composition of the SNS has changed in the more than two decades since its inception (Kuiken and Gottron, 2023). It is not a static entity; its contents and concept of operations must evolve to meet evolving threats and to keep up with scientific and technological progress. These updates and changes are driven by the multi-step development process for the SNS annual review, including gap analyses and prioritizations, threat assessments (identifying new threats and revising existing threats), specific response scenarios, and by pharmaceutical advancements (GAO, 2022; Neumeister and Gray, 2021). The reality is that the time and expense required to research, develop, and approve new MCMs limits the ability to rapidly modify the SNS, but so too do entrenched ways of thinking about stockpiling strategies.

Over time, the SNS’s role, responsibilities, and operational activities, and those of the MCM enterprise in general, have continued to significantly expand, sometimes without concomitant increases in resources (Kuiken and Gottron, 2023). The SNS is challenged with addressing many potential threats (expanding from chemical, biological, radiological, and nuclear (CBRN) to all-hazards and emerging infectious diseases) but in a resource-constrained environment that requires making prioritization decisions, or in some cases, decisions as if there were no costs involved at all (GAO, 2022). These decisions have strained the resources of the SNS and PHEMCE partners. However, many aspects of these challenges, such as defining the roles of the federal stockpile versus state or local stockpiles (an issue highlighted by recent experiences with COVID-19 and mpox), are beyond the scope of this report but deserve further examination. Similarly, new production technologies could dramatically affect how the SNS operates and what types of materials make sense for stockpiling (e.g., stockpiling of raw materials might be efficient if manufacturing agreements are in place and platform technologies are developed that can rapidly produce a variety of different vaccines—or diagnostics or therapeutics—from the same materials). The committee believes that these platform technologies are worth pursuing and as mentioned in Chapter 3 the new Biopharmaceutical Manufacturing Preparedness Consortium could play a role in bringing new technologies

to bear, but until they are proven successful, the SNS will need to continue to stockpile MCMs (GAO, 2023).

Project BioShield was designed to support the acquisition by the SNS of countermeasures under development for national security threats (Kuiken and Gottron, 2023). BARDA’s remit based upon this law has been to support the stockpiling of MCMs for CBRN threats. In general, MCMs for CBRN threats lack a commercial market and in some cases are explicitly disallowed from being sold to any entity other than the federal government. For smallpox-specific countermeasures, the federal government (and other governments internationally) have been the only buyers. State, local, tribal, or territorial governments are not required to maintain their own stockpiles of medical and ancillary equipment to prepare for and respond to any public health emergency, including smallpox (Kuiken and Gottron, 2023). The experience with mpox, however, may necessitate a change in the way smallpox readiness is viewed, in the sense that a growing need for commercially available mpox countermeasures could incentivize innovation and investment in MCMs that also support the federal government–centric responsibility for smallpox MCM preparedness.

To aid SNS administrators in their review of the future of the SNS smallpox MCM portfolio, the committee poses the following considerations (Box 4-2). The SNS may be the purchaser of available MCM and needed supplies, but BARDA is responsible for the advanced development that makes products possible, and members of the PHEMCE contribute to early development, regulatory, and other elements of the chain of investments and decisions that make SNS assets possible (NASEM, 2021). BARDA currently develops target product profiles (TPPs) for specific MCMs (BARDA, n.d.; FIND, n.d.; IOM, 2010; NIAID, 2023). TPPs can help guide industry, regulatory agencies, procurers, and funders on research and development priorities. To inform their future priorities for the smallpox MCM portfolio, BARDA and PHEMCE could develop new TPPs and refine existing TPPs for smallpox MCMs. This could include defining the product, including both the indication (i.e., disease/condition to be treated) and what an appropriate product would be to use in a public health emergency, prospectively establishing the metrics that define success for a product, and then building an experimental plan that assesses whether a product has critical attributes. Currently, BARDA has a TPP for smallpox vaccine, which could be refined and updated, and TPPs could be created for smallpox therapeutics and diagnostics. WHO also developed two diagnostic TPPs during the global mpox response and recommended that TPPs be developed for smallpox diagnostics (WHO, 2022b, 2023).

Conclusions on the SNS and Smallpox MCM Portfolio

(4-4) The nation relies on the SNS to deploy MCMs in response to a smallpox event because, currently, most of the necessary MCMs are not commercially available. Moving forward, leveraging collaborations and partnerships with other nations and organizations to develop next-generation smallpox and 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 deployed simultaneously before, and some are based on older technology and use outdated assumptions, including changes in population (e.g., demographic, physiological, and behavioral/risk perception).

(4-6) Threat assessments and specific response scenarios, based on different potential smallpox or orthopoxvirus events, are needed to assess and determine the necessary quantities and types of MCMs needed for various effective and equitable response strategies (e.g., early detection, immediate versus long-term response, isolation of patients, quarantine of contacts, use of therapeutics for prophylaxis and treatment including pre-exposure prophylaxis with therapeutics for first responders and health care providers, ring vaccination, or mass vaccination).

OVERARCHING CONCLUSIONS

Despite the research done over recent decades and the fact that there are more smallpox MCMs available now than there were in the pre-eradication period, the nation’s readiness and response posture to a smallpox outbreak could be strengthened. Based on the evidence and findings on the utility of live variola virus for research and the smallpox MCM portfolio planning, the committee drew the following overarching conclusions:

For the foreseeable future, some research with live variola virus remains essential to achieving public health research goals against an ever-evolving biothreat landscape and the potential for orthopoxviruses to emerge naturally or deliberately.

The smallpox MCM portfolio is a mature portfolio, and the goals of a mature portfolio should differ from a relatively new MCM portfolio. The scientific and technological opportunity for innovative and 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 organizations to build a diversified smallpox MCM stockpile and an agile, on-demand, distributed MCM response network of the future.

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