7

Sustainment: Aspects of Leadership and Support

The workshop’s fourth panel explored federal efforts to coordinate the responses to the COVID-19 pandemic and mpox outbreak. Nahid Bhadelia, senior policy advisor for global COVID response on the White House COVID-19 Response Team, discussed U.S. plans for future pandemic preparedness. Demetre Daskalakis, deputy coordinator for the White House National Mpox Response, highlighted components of the U.S. mpox response, as well as disparities and syndemic features that emerged in the outbreak. Gary Disbrow, director of BARDA, discussed his agency’s role in facilitating innovation and pandemic preparedness. Ezekiel Emanuel, vice provost for global initiatives at the University of Pennsylvania, moderated the discussion.

SUSTAINING LEADERSHIP FOR PREPAREDNESS AND RESPONSE

White House COVID-19 Preparedness Plans

Bhadelia discussed federal plans to increase pandemic preparedness and social and systemic factors to consider. Noting her background as an infectious disease physician and biomedical researcher, she emphasized the importance of planning a central government research response well in advance of a pandemic or biological threat. The types of advancements needed to meet these challenges require multiple years of research. Bhadelia noted that prioritizing this research clearly across agencies creates a common vision among the private sector, researchers, and academics, enabling a foundation that can yield advancements when a crisis strikes. In October

2022, the White House released its vision for future pandemic preparedness in the National Biodefense Strategy and Implementation Plan for Countering Biological Threats, Enhancing Pandemic Preparedness, and Achieving Global Health Security (White House, 2022). To protect the American people and global community from harm, the U.S. government strives to coalesce essential domestic and international partners within and outside of the government, as well as to assess, prevent, prepare for, respond to, and recover from biological events—whether naturally occurring, accidental, or deliberate. The strategy outlines a set of goals to be achieved through U.S. capabilities and investments. An implementation plan describes research priorities, the ready response currently needed, and the type of partnerships to be put into place.

In September 2021, the White House Office of Science and Technology Policy utilized an interagency process to create the American Pandemic Preparedness Plan (AP3), which delineates research and biomedical investment priorities (White House, 2021). One year later, Bhadelia and colleagues completed an annual report on the progress toward establishing the partnerships, investments, and priorities outlined in the plan (White House Steering Committee for Pandemic Innovation, 2022). The report identified gaps, both internal and external to the government, where additional investments are required. The aspects of the partnerships and investments that are working well can be built upon in continued efforts. She emphasized that these pandemic plans are limited by the absence of attached funding. The National Security Council has requested additional investments to support the National Biodefense Strategy via congressional funding for the Administration for Strategic Preparedness and Response.

Bhadelia stated that although pandemic investments often focus on the early stages of outbreaks and pandemics, the recovery phases of pandemics and epidemics also warrant funding. Currently, consequences of the COVID-19 pandemic appear to include changed patterns of endemic diseases, such as the rise of respiratory syncytial virus and influenza cases in the fall and winter of 2022. A study from the International Monetary Fund found that the Gini coefficient—a summary measure of income inequality—increases in the 5 years following an outbreak, based on data from outbreaks of severe acute respiratory virus (i.e., SARS), pandemic H1N1, Middle East respiratory syndrome (i.e., MERS), Ebola, and Zika (Emmerling et al., 2021). Bhadelia stated that this data point indicates a greater societal dynamic and suggests that investments from the biomedical community or society in understanding new health threats may be appropriate.

Although government plays an important role in coordinating and problem solving in pandemic preparedness and response, it cannot be a single actor, said Bhadelia. Rather, government and community can work together

during the preparedness phase and in a continual, fast-acting exchange when responding to a biological incident. Furthermore, every health system has unique advantages and challenges. Acknowledging the United Kingdom’s Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, she stated that the National Institutes of Health (NIH) has established the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) network and Accrual to Clinical Trials (ACT) networks. Because the U.S. public health and health care systems are inherently different—located within the public and private sectors, respectively—public-private partnerships are essential to complement government loans and efforts, she stated. Furthermore, the United States is a federated republic with democratic ideals, where plans are made at the state level and coordinated at the federal level. Therefore, ongoing partnerships between states, territories, and the federal government are needed before, during, and after a pandemic, she added.

The U.S. Mpox Response

Daskalakis highlighted components of the U.S. mpox response, disparities in those affected, the syndemic nature of the disease, and features of a syndemic response. He maintained that a successful formula for addressing an outbreak of any size—from local epidemics to global pandemics—is good science, community engagement, and political will. In terms of the mpox response, science enabled swift development of diagnostic tests and distribution of these tests into the commercial space to scale and manufacture. Vaccine science was utilized in efforts to vaccinate as many people in the at-risk population as possible. The scientific aspect of the response also involved identifying knowledge gaps as quickly as possible, a step that necessitated transparency. He remarked on the value of posting a roster of all U.S. government-supported research in real time, as the outbreak is occurring. Community engagement was vital to the mpox response and serves as an example of a true community-driven response, said Daskalakis. “Nothing about us without us at the table” is a mantra from the HIV epidemic that is relevant to the mpox outbreak. He emphasized that although community participation can involve moments of discomfort, it was critical in creating an effective mpox response. Political will was demonstrated by an administration that worked to mobilize multiple efforts to ensure that the government was fully responsive to the needs of communities overwhelmingly affected by the outbreak.

Mpox Epidemiology in the United States

As of December 7, 2022, more than 29,000 cases of mpox were confirmed in the United States, said Daskalakis (see Figure 7-1).¹ Higher numbers of cases have occurred within states on the east and west coasts and in Texas. About 95 percent of all mpox cases were cisgender men who have sex with men (MSM); just under 3 percent of cases were cisgender women. Transgender men, transgender women, and people of other gender identities account for 0.3, 0.8, and 0.7 percent of cases, respectively. In terms of age distribution, cases are highest for people ages 31–35, most of whom are cisgender MSM. Substantial progress has been made in containing the outbreak, as indicated by a 97 percent decrease in the rolling daily average of case numbers from August to December 2022.² Black and Brown communities are overrepresented in mpox cases, Daskalakis pointed out. Approximately 50 percent of cases are among Black and Latino individuals, and this proportion persists as overall case numbers continue to decrease.

Mpox Vaccine Administration in the United States

Across the U.S. government, agencies collaborated to identify strategies for expanding the mpox vaccine supply, Daskalakis stated. These strategies included increasing production and data-supported shifting to intradermal dosing, which expanded the vaccine supply four-fold as opposed to traditional subcutaneous dosing.³ More than 1 million single doses of mpox vaccine were administered between May and November 2022. Since September, most administered doses have been second doses in the recommended two-dose regimen. He noted an inequity in vaccination, with vaccination rates for Black and Brown individuals lagging behind case rates in this group. However, progress has been made in increasing mpox vaccination among members of racial minority groups. From May 22 to June 25, 2022, only 6 percent of mpox vaccine recipients were Black and 15 percent were Latino (Kriss et al., 2022). From July 31 to October 10, these percentages increased to 13 percent and 23 percent, respectively. Yet, because greater than 50 percent of mpox cases occur in Black and Brown

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¹ Current mpox case rates are available at https://www.cdc.gov/poxvirus/monkeypox/response/2022/ (accessed February 12, 2023).

² More information about mpox is available at https://www.cdc.gov/poxvirus/monkeypox/index.html (accessed February 12, 2023).

³ Intradermal dosing involves administering a vaccine between layers of the dermis, with the needle not entering the body as deeply as a subcutaneous injection. A smaller volume of mpox vaccine administered via intradermal dosing has been found to achieve the same level of immunity as a standard dose via subcutaneous injection. More information about intradermal dosing of JYNNEOS vaccine is available at https://www.cdc.gov/poxvirus/monkeypox/interim-considerations/jynneos-vaccine.html (accessed February 12, 2023).

people, he emphasized that equity in vaccine administration relative to disease burden has not yet been achieved.

Syndemic Features of Mpox

Investments in the persistent infectious diseases programs of today are also investments in future acute infectious disease response, said Daskalakis. Mpox is not a virus that exists in isolation. In the United States, 38 percent of individuals diagnosed with mpox were also diagnosed with HIV, and 41 percent had a prior diagnosis of a sexually transmitted infection (STI) in the year prior to their mpox diagnosis (Curran et al., 2022). All told, 61 percent of people diagnosed with mpox had HIV or a STI diagnosis within the prior year. He explained that a syndemic arises from interacting epidemics that are worsened or magnified by social determinants of health. Mpox is a syndemic that requires a syndemic-based strategic response, he added. Additional evidence on the syndemic interaction of mpox and HIV is provided in Box 7-1.

Syndemic Approach to Response

A syndemic-style response can also be applied to preparedness and research, said Daskalakis. For instance, as part of the effective U.S. mpox response, multiple agencies demonstrated supportive strategies for flexible use of staff and funding. The Health Resources and Services Administration allowed use of Ryan White HIV/AIDS Program funds for mpox testing, treatment, and vaccination (Cheever, 2022). CDC made grant resources available to cover mpox activities carried out in conjunction with HIV and STI prevention activities (Mermin, 2022). The Substance Abuse and Mental Health Services Administration allowed use of it funding for mpox activities conducted in conjunction with authorized grant-funded work (Delphin-Rittmon, 2022). The U.S. Department of Housing and Urban Development allowed allocation of housing resources to individuals at risk of mpox infection (Bryon, 2022).

The role of community engagement is evident in the recent renaming of the disease from “monkeypox” to “mpox,” Daskalakis remarked. Recognizing that the former name contributed to stigma and barriers, the World Health Organization (WHO) recommended the name change in November 2022 and the U.S. government adopted the new terminology (CDC, 2022d; HHS, 2022; WHO, 2022b). Moreover, an effective response involves (1) scientists willing to acknowledge any gaps in understanding in real time, (2) ongoing community engagement to address barriers and stigma, and (3) political will. He stated that authorization from the U.S. administration to focus the mpox response on populations of gay, bisexual, and other MSM and on Black and Brown individuals accelerated response efforts. Combining the elements of science, community engagement, and political will can drive an epidemic curve toward zero cases, he maintained.

IMPLEMENTING BARDA’S PANDEMIC PREPAREDNESS AND RESPONSE CAPABILITY

Disbrow outlined Biomedical Advanced Research and Development Authority (BARDA)’s mission and role in facilitating innovation and pandemic preparedness. BARDA was established under the Pandemic and All Hazards Preparedness Act of 2006 with a mandate and mission to develop vaccines, therapeutics, diagnostics, and devices to protect the United States in the event of chemical, biological, radiological, or nuclear (CBRN) threats, pandemic influenza, and emerging infectious diseases.⁴ He noted that the annual appropriations established to support the agency’s

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⁴ Pandemic and All Hazards Preparedness Act, Public Law 109-417, 109th Cong., 2d sess. (December 19, 2006).

activities for CBRN threats and influenza do not extend to emerging infectious diseases, and therefore the organization relies on supplemental funding to address them. Having responded to numerous outbreaks while at BARDA—including pandemic H1N1 influenza, Ebola, Zika, COVID-19, and mpox—Disbrow acknowledged that supplemental funding has not always been available. Independent of the federal funding situation, the organization also works with industry partners in the private sector to address outbreaks.

BARDA Innovation Ecosystem

BARDA is more than a funding agency and leverages scientific expertise in collaborating with companies, said Disbrow. Whether the agency is investing several hundred thousand dollars or $100 million with a company, a project coordination team is formed to bring together scientific, manufacturing, regulatory, clinical, and non-clinical expertise. BARDA partners with companies to push their products forward for the benefit of all stakeholders. The agency supports product development through an innovation ecosystem that includes the Blue Knight program; the Division of Research, Innovation, and Ventures (i.e., DRIVe) that support innovative investments; and BARDA Ventures, a corporate venture capital arm enabled by the 21st Century Cures Act.⁵ BARDA has also established an accelerator network containing 13 accelerators nationwide to amplify its footprint and connect with innovators. The agency is also a funder of the global nonprofit partnership Combating Antibiotic-Resistant Bacteria Accelerator (CARB-X) and recently renewed its commitment to CARB-X for an additional 10 years, he added. Furthermore, BARDA conducts advanced research and development (R&D) and supports licensure and procurement of products, either under a vendor-managed inventory system or for disposition into the strategic national stockpile.

Since BARDA’s inception, the agency has supported 65 FDA approvals, licensures, and clearances of vaccines, therapeutics, diagnostics, and devices across CBRN, pandemic influenza, and emerging infectious diseases. This output indicates a return on investment of funds appropriated by Congress, Disbrow stated. The availability of these products enables better protection for the U.S. population if such resources are needed. For example, BARDA supported the development of the JYNNEOS vaccine—approved by FDA in 2019 for the prevention of smallpox and mpox—that was utilized immediately in the 2022 response to the mpox outbreak. BARDA receives annual appropriations totaling approximately $2 billion each year. Although this sum is substantial, he noted, so too is the number of material threats against

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⁵ 21st Century Cures Act, Public Law 114-255, 114th Cong., 2d sess. (December 13, 2016).

which BARDA develops medical countermeasures, which include 21 CBRN agents and pandemic influenza. A partnership between BARDA and the U.S. Department of Defense (DOD) has invested $80 billion into 146 partnerships and the development of 105 specific products. Almost 1 billion doses of COVID-19 vaccine—including bivalent vaccine—and more than 18 million therapeutics have been delivered through support from BARDA. More than 286 million BARDA-supported COVID-19 diagnostic kits have been shipped, and funds have supported three FDA-approved COVID-19 products, including one of the first COVID-19 diagnostics. Acknowledging the role of supplemental funding provided by Congress in these accomplishments, Disbrow emphasized that funds are needed before a crisis occurs to prepare for the next pandemic.

BARDA’s Role in Future Pandemic Preparedness

Disbrow highlighted the role of BARDA in the AP3 (White House, 2021).⁶ All agencies within the U.S. Department of Health and Human Services collaborated in strategy alignment and put forward a budget request for this coordinated effort. He stated his hopes that the request would be funded for fiscal year 2024, if not earlier. The AP3 strategy to transform U.S. medical defenses includes the goals to develop (1) prototype vaccines for specific pathogens within priority virus families, (2) a range of therapeutics suitable for any virus family, and (3) diagnostics available at large scale within weeks after recognition of an emerging pandemic threat. This strategy involves support for phase I and phase II clinical studies as well as commercial-scale manufacturing. He remarked that COVID-19 vaccine development was swift, but manufacturing was the greatest challenge in making vaccines available to the entire U.S. population. Clinical trials must be planned and conducted with anticipation of potential vaccine licensing, he added. When an outbreak occurs, the technology that supported the licensure of the prototype vaccine for a virus family member could be used with the new antigen. Manufacturing could then proceed at scale because the manufacturing issues would have been previously addressed with the licensed vaccine. Because many of the priority pathogens are not currently circulating in the United States, the government is dependent on the collaboration of international partners in supporting global trials. He noted that these strategies are aligned with the BARDA strategic plan (Assistant Secretary for Preparedness and Response, 2022).

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⁶ More information about the American Pandemic Preparedness plan is available at https://www.whitehouse.gov/briefing-room/statements-releases/2021/09/03/fact-sheet-biden-administration-to-transform-capabilities-for-pandemic-preparedness/ (accessed February 13, 2023).

The AP3 and the National Biodefense Strategy feature the ambitious 100 Day Mission vaccine development goal, said Disbrow (White House, 2022). During the COVID-19 response, the federal government partnered with the private sector and accomplished swift development of vaccines and therapeutics. Within 5 months of the start of the outbreak, a therapeutic already in phase III clinical trials was repurposed and received emergency use authorization (EUA) to treat COVID-19. Within 10 months, the first COVID-19 monoclonal antibodies received EUA. The mRNA vaccines were developed within 11 months, and oral antiviral medications received EUA within 24 months. The progress made in developing vaccines and monoclonal antibodies in less than 1 year demonstrates the potential to eventually realize the 100-day goal. To respond to an Ebola outbreak, licensed vaccines, therapeutics, and diagnostics are available to ship within 24 hours of an identified outbreak. A licensed vaccine was also available within 24 hours for mpox. In partnership with industry partners, the government was able to advance bivalent COVID-19 vaccines from FDA review into tens of millions of doses available within 62 days. Disbrow stated that this outcome indicates the potential of accomplishing the 100-day goal, but success will rely on the availability of licensed vaccines, therapeutics, and technologies that can be quickly pivoted to new outbreaks. Commencing this effort now will enable the United States to be far better prepared for the next pandemic than it was for COVID-19, he maintained.⁷

BARRIERS TO PANDEMIC PREPAREDNESS

Emanuel outlined several impediments to adequately addressing pandemic preparedness. He admitted that he is more skeptical than the panel about the U.S. COVID-19 response and the nation’s ability to respond to the next pandemic. Development of countermeasures, particularly in terms of the clinical research enterprise, is essential to establishing a state of preparedness, he remarked. The United States tends to forget crises, rather than build back stronger from them, and efforts to address structures in need of improvement have been poor, he said. In his opinion, several factors serve as barriers to the country’s ability to develop needed response capability. Establishment of a research foundation from which to innovate during a crisis relies heavily on clinical researchers, but the interests of researchers and research institutions do not necessarily coincide with the interests of the nation during a pandemic. Researchers and research institu-

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⁷ More information about BARDA’s initiatives and investments is available at https://www.medicalcountermeasures.gov/, https://sam.gov/content/home, https://www.usajobs.gov/, https://aspr.hhs.gov/MCM/Pages/default.aspx and https://drive.hhs.gov/accelerators.html (accessed February 13, 2023).

tions seek prestige, fame, recognition, and funding, but coordination and collaboration may not deliver these incentives, said Emanuel. For instance, individuals tend to receive less recognition when working within a large team. However, the research breakthroughs required for pandemic preparedness will not be achieved via individual efforts, he maintained. Thus, mechanisms to encourage collaboration are needed for those who will not voluntarily enter into collaborations. An excellent program structure will falter if the private community does not collaborate, he added, pointing to the use of convalescent plasma as a therapeutic option as an example of an uncoordinated effort.

Establishing priorities early in a pandemic and generating buy-in within the research and production communities are important, said Emanuel. He noted that during the COVID-19 pandemic, developing monoclonal antibodies was prioritized over developing oral antivirals despite indications that monoclonal antibodies were not necessarily the best approach given the evolution capacity of the virus. The establishment of clear, shared priorities between the research, development, and manufacturing arenas can enable quick pivots when pathogen responses are needed. However, a mechanism to establish shared priorities and ensure participation from all parties is not yet in place, he stated. Furthermore, greater flexibility is needed in funding sources, which tend to be categorical and can limit emergency response, he added. Placing more trust in the expertise of civil servants to determine how funding is best spent could enable faster pivots in emergency situations. The venture and early startup development fields reflect the importance of flexibility in innovation, Emanuel pointed out, because most startup companies pivot three to four times before determining a path for continued growth. A categorical funding approach is not conducive to effectively responding to a fast-moving pandemic, he stated, adding that the legislative process cannot be relied upon for this flexibility.

The United States has a poor approach to clinical research and trial design, Emanuel contended. The success of the U.K. RECOVERY trial was due not only to a national health service and non-privatized health care system, but also to a culture of large, simple, randomized trials. In contrast, the United States has opted for trials with highly specific and narrow inclusion criteria. He remarked that this approach hampers the ability to quickly establish and conduct trials. Simple inclusion criteria aiming for large sample size would improve U.S. clinical trial design, said Emanuel. He added that the United States could improve its contracting mechanism by leveraging funding to require state and local governments, public health, and institutions receiving federal funds to agree to research priorities and to provide data. Although the blame is often directed at the institutional review board process, contracting is a main source of substantial delays in conducting trials, he maintained. RECOVERY utilizes take-it-or-leave-it contracts that do

not allow much negotiation, and the United States could implement similar contracts to leverage the tens of billions of dollars distributed to contractors, thereby facilitating rapid clinical work during health crises. In addition, the United States could take a more creative approach to recruiting participants for clinical trials. Generally, the federal government relies on academic centers to utilize their networks for recruitment. However, other networks and mechanisms could be leveraged. For instance, the notification process for COVID-19 test results could double as a clinical trial recruitment mechanism. Emanuel emphasized that a different approach is needed in the United States to achieve pandemic preparedness, but that the current response to researching “long COVID” indicates that learnings from the pandemic have not yet been incorporated into developing a different approach.

DISCUSSION

Role of Federal Investment

Emanuel welcomed discussion in response to his comments or the panel presentations. Bhadelia remarked that government plays a unique research role in pushing investment into enterprises that market forces and independent researchers cannot accomplish alone. These investments precede randomized controlled trials. For example, the Biden administration is currently investing in next generation, pan-coronavirus and sarbecovirus vaccines and therapeutics, including mucosal vaccines. Such vaccines could potentially protect against the next coronavirus outbreak and accelerate the vaccine R&D timeline. The scale of these investments requires government funding, she noted. Operation Warp Speed built upon previously conducted government-funded work. Beyond research, government can take a broader, sector-wide view to R&D by investing in the raw materials and supply chains that are likely to be needed during a crisis. The U.S. federal government, in collaboration with other national governments, could support global partnerships and commitments from multiple multilateral partners. The 100 Day Mission is an example of the vision that requires investment across borders. She added that the Biden administration is supporting international research capacity via numerous global efforts, including the 100 Day Mission and the Pandemic Fund established by The World Bank.

Streamlining Awards Processes

Disbrow shared his concern that infrastructure developed through the ACTIV and ACT networks and the investments in domestic supply chains to enable the manufacturing of vaccine at population scale within 100 days will not necessarily be sustained until the next pandemic. Acknowledging

the hefty regulations involved in contracting, he noted that the types of changes Emanuel suggested may be precluded by complicated dynamics for the near future. BARDA has worked to streamline its process for funding innovation, including implementation of the Easy Broad Agency Announcement mechanism, by which companies can request funding by submitting a 2,000-word abstract. The agency then decides whether to fund the request; awards are typically made within 30 days and occasionally in as few as 9 days. He stated that although this acquisitions process worked for preparedness, it fell short during the COVID-19 response. As a result, BARDA, which has 50 acquisition experts, partnered with DOD, which has approximately 180,000 acquisitions experts (DOD, 2022). In addition to drawing on employee expertise, DOD can also call upon the more than 500 companies that comprise the Medical CBRN Defense Consortium when immediate response action is needed. BARDA is considering establishing its own consortium to avoid reliance on another department, said Disbrow. BARDA Ventures is another mechanism by which the agency is working to streamline and expediate the process of awarding funds to companies.

Streamlining Research Efforts During Outbreaks

Clinical Research Infrastructure

Daskalakis remarked that pivotal work for mpox has involved therapeutics and clinical studies of immune correlates using different dosing strategies of the JYNNEOS vaccine. Leveraging the AIDS Clinical Trials Group (ACTG) was important to the mpox response, but additional efforts are needed to further accelerate future responsiveness, he added. A study of tecovirimat—a drug approved for smallpox—is being conducted for mpox, but it was launched after the outbreak was largely under control, posing challenges to recruitment efforts. Novel strategies are being utilized to address this barrier. For example, “remote consenting” is being developed in which a person diagnosed with mpox can utilize a virtual recruitment pathway to participate in a study without being physically present at an ACTG site. Ideally, this recruitment tool would have been available at the peak of the outbreak, he noted, emphasizing the need for a nimbler strategy for clinical study implementation. In contrast, vaccine studies move relatively quickly and were fully recruited during the outbreak. The importance of non-clinical trial studies was also highlighted in the mpox outbreak response, said Daskalakis. Real-time behavioral surveys and studies enabled identification of the populations affected by mpox, while surveillance-based studies were used to determine vaccine performance. Early vaccine performance data published by the CDC fostered continued interest in receiving the vaccination (Payne et al., 2022b). Additional data supporting the role of

JYNNEOS vaccine in the mpox response is forthcoming.⁸ Clinical trials and surveillance-based research—whether behavior or peer surveillance—aid in evaluating vaccine performance.

Biorepositories for Sample Sharing

Bhadelia stated that the federal government could alleviate some of the common challenges of data sharing and sample sharing that are encountered early in outbreaks. As an infectious disease emerges, clinical samples are required to test new diagnostics before clinical trials can be conducted. Clinical samples also enable the study of biomarkers and viral loads. During the COVID-19 pandemic, individual academic centers and networks established their own biorepositories of these clinical samples. The federal government could consider its role in creating biorepositories to enable sample exchange. Furthermore, regulatory components could share samples between centers. Emanuel reiterated that the federal government could leverage the funding it awards to research entities to increase the speed and efficacy of these processes.

Strategies to Streamline Research Efforts

Harris remarked that the power of large sample sizes in clinical trials also applies to diagnostics. The lengthy, time-consuming nature of federal processes leads researchers to share existing biorepositories. As the acute phase of the COVID-19 pandemic subsides, efforts could be made to streamline these processes, such as pre-establishing material transfer agreements (MTA) to enable rapid movement at level and scale to occur when the need arises. She added that processes in other countries are faster than in the United States, and this is an area that could be improved upon during inter-crisis periods. Emanuel replied that the institutions, private organizations, and private companies he has worked with often feature the same bureaucratic obstacles as the federal government, and that the latter is not slower than these other entities, all of which are focused on minimizing liability. That being said, the creation of ideal, paradigmatic contracts that are agreed upon before a crisis emerges could expedite processes by having contracts and MTAs already in place when a crisis occurs.

Disbrow remarked that preparation for future pandemics could involve the standardization of reagents so that different companies evaluating their products would all be using the same materials for assays, the same chal-

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⁸ This data was posted on the CDC website on December 8, 2022. See https://www.cdc.gov/poxvirus/monkeypox/cases-data/mpx-JYENNOS-vaccine-effectiveness.html (accessed April 30, 2023).

lenge strain, the same dose, and the same timeframe for intervention. This system needs to be developed now, given the steps required to put it in place within the United States and at a global level before the next pandemic, he maintained. The Coalition for Epidemic Preparedness Innovations is working on standardizing reagents and creating standards for assays, and efforts to develop a standardized system should be made in concert, he added.

Appetite for Systematic Change

Omer asked whether there is interest at the federal level to examine the full portfolio of trials and intervention studies and make necessary systematic changes. Referring to remarks made about the difficulty of conducting clinical trials within the federal system, he stated that public health trials—with public health outcomes—remain more challenging than clinical trials. For example, generating evidence for face masks during the COVID-19 pandemic was extremely challenging, despite the design of N95 or KN95 masks having existed for 10–12 years (and surgical masks have been available for even longer). He described the studies on masking conducted in the United States and abroad as “…half-baked, underpowered, small trials.” Although network-based trials—such as those conducted by ACTG—can be very useful, some networks within the federal system could offer a higher return on investment, said Omer. Innovation often comes from investigator-initiated trials, but these are difficult to conduct. The challenging nature of these trials accounts for the limited federal data available on these topics. For example, not only do field trials for diagnostic tests lack a standard protocol, but also the federal system lacks the vocabulary needed to accomplish such trials, he maintained.

Bhadelia remarked that this issue relates to levels of congressional support to change the system. Emanuel countered that much of the system is guided by self-imposed rules and priorities of the agencies themselves. Congress determines levels of funding, but many of the processes—such as whether trials are conducted for diagnostics or how clinical trial infrastructure is organized—are determined by the agencies. NIH has prioritized investigator-initiated awards instead of a more coordinated approach, he contended. Disbrow agreed that improvements are needed. He gave the example of ACTIV clinical trials for therapeutics, which swiftly enrolled independent companies and offered them support early in the COVID-19 pandemic. More than 900 trials were conducted, but they evaluated different products, were poorly designed, and lacked efficacy endpoints, said Disbrow. He stated that essentially, these trials amounted to expanded access and use of the product without ascertainment of true benefit, which created confusion. Furthermore, these efforts may have diverted potential patients or clinical trial participants from better-designed clinical trials for

demonstrating efficacy and providing valuable data. Improvement is also needed to ensure that clinical trials are inclusive and diverse, he added. Some progress was made in the vaccine trials supported by the federal government, which required each participating company to agree to harmonization in the clinical trials. Moreover, harmonization of locations where assays were conducted enabled comparison of clinical samples in common assays. Improvements are needed, because evidence of efficacy is meaningless unless people are willing to take the vaccine or therapeutic, he remarked.

Bhadelia contended that funding decisions are pivotal in creating an equitable clinical trials network, given that such a network would require shifting which institutions and personnel conduct the work. Systematic changes would incorporate a greater number of medical centers in areas that may lack infrastructure. Moreover, funding is required to maintain employment of people in research infrastructure. These systems would need to run trials outside of outbreaks—thereby being prepared to operate in a coordinated fashion during an emergency—which would involve upgrading the existing infrastructure to be able to support clinical trials research, she added. Emanuel replied that the RECOVERY trial was conducted with a modest budget and that the resources needed for the changes Bhadelia suggested could be covered by the $50 billion in funds distributed by NIH.

Addressing Disparities in Outbreaks

Lewis remarked that disparities continue to emerge in outbreaks—including the most recent examples of COVID-19 and mpox—and asked how the government plans to address the social determinants that contribute to those disparities and prevent them in future. Disbrow replied that BARDA is examining methods to decentralize clinical trials to create equal access to trial participation. Telehealth, telemedicine, urgent care facilities, and pharmacy chains are potential outreach mechanisms for enrolling people in clinical trials, not only during pandemics but also for products being developed outside of crises. Through its Blue Knight program, BARDA has partnered with Acclinate, a company that works to achieve diversity in clinical trials by engaging with communities of color, informing individuals about scientific and clinical research, and generating rosters of individuals across different U.S. regions who may want to participate. Disbrow believed that when clinical trials are more representative by including minority populations, people from those populations may be more willing to accept the product, thereby deriving its benefit.

Emanuel added that small or highly specific clinical research trials often feature inclusion criteria that exclude members of various minority groups or rural populations. Large and relatively simple trials expand the numbers

of people representing various subpopulations. Some of the COVID-19 vaccine trials, particularly in the pediatrics population, had small sizes of 1,200 people or less; if only 5–10 percent of trial participants were from minority populations, the number of people from these populations could total fewer than 100 individuals. Expanding trials and simplifying inclusion criteria could increase the participation of minority populations, said Emanuel.

Zahn remarked that at the beginning of an outbreak, public health officials face pressure to maximize the number of people vaccinated, rather than focus on who is getting vaccinated. More attention tends to be given to the detailed metrics of the vaccinated population only after 2 or 3 months. Efforts to vaccinate as many people as possible will favor people with ready access to health care services. Disadvantaged groups are generally not the easiest to reach with vaccination efforts, and therefore ensuring equal access will require changing the vaccination strategy. Daskalakis responded that the disparities he has seen in both acute and persistent infectious threats are entrenched within the system at large. He stated that a community-driven response is needed to prevent disparities. Such an approach would identify ways to increase vaccine access via proximity, such as making vaccines available at nontraditional venues. For example, Disbrow shared that mpox vaccination was offered at Atlanta Black Pride, and 4,200 people were vaccinated at the event; unlike typical vaccine events, 50 percent of the vaccine recipients were Black and 70 percent were people of color. Similarly, engagement efforts for clinical studies can extend beyond the locations and networks routinely used for recruitment. Instead, trusted messengers from within communities can be engaged to move inclusive recruitment forward. Because 70 percent of new HIV infections occur in Black and Brown people, it was not surprising that similar disparities emerged with mpox. Changing long-standing patterns will involve engagement with communities that continue to be disproportionately affected in outbreaks as well as strategies to bring countermeasures closer to these communities, said Daskalakis. Concerted efforts are needed to achieve equity.

Bhadelia stated that the current moment—in contrast to the beginning of the next pandemic—is the time to discuss equity issues. Within the intellectual spaces where pandemic preparedness discussions are held, a spot must be made for representatives from varied disciplines and communities, she maintained. Without diversifying the perspectives guiding these conversations, the solutions generated are not likely to yield more equitable pandemic response outcomes.

Equity in Global Vaccine Allocation

Saenz remarked that many of the steps needed at the domestic level also apply to the global level. The workshop has included discussion of the

benefits for high-income countries of ensuring that low- and middle-income countries have timely access to vaccines. Constraints in global access to mpox vaccines are similar to those of COVID-19 vaccines. Through its revolving funds, PAHO has procured 130,000 doses of JYNNEOS mpox vaccine for countries in Latin America and the Caribbean. Noting that this amount is insufficient for the need, Saenz asked about actions that can be taken to advance global equity in vaccine allocation.

Daskalakis replied that the United States has a global team that is currently working through policy issues related to addressing vaccine needs from the U.S. perspective. Solutions have not yet been determined, but this area is being actively explored and discussed. He emphasized that problem solving should involve communication with nations to understand their needs, rather than domestic assumptions about other nations’ vaccine supplies. Although some stigma is associated with COVID-19, mpox is a highly stigmatized disease because of bias against some of the highly affected populations; this stigma can deter countries from disclosing their true need for vaccine. A strategy that enables open, frank conversations to identify true needs should be developed, he said.

Bhadelia stated that from a global perspective, equity regarding the COVID-19 vaccine—which carries a large portfolio—will not be reached via distribution alone. Distributed manufacturing capacity is also needed. She noted that developing a strategy for establishing this capacity requires the approach highlighted by Daskalakis: engaging with countries where capacity would be created around their priorities and needs. In addition, inequity can be addressed by increased support of research infrastructure and training. Researchers may be interested in endemic, priority pathogen diseases that are more relevant in their environment than in the United States, but numerous hurdles impede their ability to conduct clinical trials or create product at Current Good Manufacturing Practice regulation standards. Ensuring a healthy biomedical sector and bioeconomy requires careful consideration of the endemic diseases that would be addressed via distributed manufacturing, she maintained. Commitment is needed from the market sector to determine which vaccines will be manufactured and distributed within a given region, she added. Gavi, the Vaccine Alliance recently released a plan for expanding vaccine manufacturing in Africa (Gavi, 2022). Bhadelia commented that the current generation of COVID-19 vaccines will likely need to be administered regularly to offer continued protection. However, ongoing issues of equity will complicate efforts to integrate these vaccines into routine adult life course vaccination in resource-limited settings.

Disbrow stated that forward-thinking collaboration among global partners is needed. He noted that the JYNNEOS vaccine has been licensed for mpox since 2019, yet demand was very low until a crisis occurred, at which

point demand dramatically surged. Collaborations could develop joint purchase agreements with various global partners to provide vaccine developers with a commercial market. These collaborations would not take place at the scale required for the COVID-19 vaccine, but at a scale sufficient for creating a commercial market. Disbrow shared that before the mpox outbreak, the JYNNEOS vaccine was primarily purchased by the U.S. government and a limited number of other national governments for smallpox. The global community could work together to provide small procurements over a sustained period of time in order to provide manufacturers with a commercial basis for continued manufacturing.

Preparing for Acceptance of Public Health Actions

Kim commented that three disciplines have been discussed at the workshop as areas to address in pandemic preparedness: bench science, clinical science, and implementation science. He noted that a gap appears to exist between clinical science and implementation science, and a transition between the two would require effective communication. Kim highlighted the tenets of strong public health practice outlined earlier by Daskalakis—that is, good science, media engagement, and political will, the latter of which Kim rephrased as “committed leadership”—and asked how the public can be better prepared to accept public health actions for future epidemics. Daskalakis emphasized the importance of clear risk communication from public health, which includes acknowledgment that both the understanding of the risk and the guidance to mitigate it are evolving. This approach enables investigation in real time and reduces the element of surprise when guidance shifts.

Mpox response communication exemplifies this strategy, said Daskalakis. Initial guidance around behavior modification was released before detailed data on the outbreak were available, and the best practice recommendations became more nuanced as more data became available. This dynamic continued after vaccine became readily available, with the addition of recommended behavior changes for individuals while waiting for immunity to establish after vaccination. He stated that from the beginning of the mpox outbreak, communication clearly acknowledged that the information being shared was the best available at the time but could change as surveillance or research investigations yielded more data. Without being apologetic, professionals communicated the evolving nature of knowledge regarding the outbreak. This approach was particularly valuable when vaccination switched to intradermal administration, because the change was based on one clinical study and this was clearly communicated, said Daskalakis. He noted the imminent release of data indicating no difference in the subcutaneous and intradermal dosing in terms of performance (Payne et al., 2022a).

Political will, engagement, and science can change suddenly—particularly during an acute outbreak—and good risk communication can aid the public in navigating those changes.

Bhadelia added that data about the global polio eradication initiative indicate that understanding a community can strengthen vaccination efforts. Knowledge of what is important to a community can serve as a lever in engaging its members in combating infectious diseases. This finding, which played out in the 2018 Ebola outbreak, can inform crisis preparedness efforts. An important component in preparing a community to accept public health actions may be the health workers’ preparedness to engage with the community. Public health professionals can incorporate the lesson that understanding the varied issues a community faces can make the community more likely to accept interventions.

Data and Digital Literacy

Sheldon Jacobsen, computer science professor at the University of Illinois Urbana-Champaign, remarked that illiteracy of data understanding is common in the general population and that consideration should be given to how best to engage the entire population—not solely the highly educated—in matters related to data. Emanuel stated that an educated public that can understand some of the complexities of research is an important element to consider if public participation is desired in shaping the structure of research conducted and products developed. Bhadelia added that a component of digital literacy is understanding where to attain reliable information, given the myriad online sources.