Infectious Diseases Outbreaks in the 21st Century

The public often gains insights from popular media, Feinberg stated, noting the films Outbreak and Contagion as examples of outbreak narratives (Petersen, 1995; Soderbergh, 2011). He remarked that Outbreak featured an unrealistic plot resolution via an ambiguous scientific development—it was unclear whether the end product was a vaccine or an antibody—that became widely available almost immediately after discovery. Although more scientifically rigorous, the plot of Contagion also contained unrealistic elements, that is, that a vaccine was quickly made available and ultimately saves the world, and that an anti-vaccination character successfully promoted an ineffective homeopathic treatment as a cure. After the events in recent years, however, he now considers the anti-vaccination character to be perhaps the most accurate aspect of the film's depiction of an infectious diseases pandemic. The COVID-19 pandemic demonstrated the power of public perception and the importance of educating the public about the vaccine process and their role in its success, he stated.

The various infectious disease threats that have emerged in the 21st century have led to both insightful lessons and deleterious outcomes, said Feinberg. The outbreaks of severe acute respiratory virus and Middle East respiratory syndrome highlighted a lack of serious preparedness efforts. The response to the H1N1 outbreak highlighted tension between the public and private sectors, intensified by nationalistic sentiments, that resulted in debate over ownership of biological samples such as viral strains. Starting in 2014, the Ebola outbreak was influential in changing the approach to infectious diseases, he noted. And now, the COVID-19 pandemic has provided the most substantial learning opportunity in addressing infectious diseases to date in this century; inability or unwillingness to capitalize on that learning would constitute a failure, he said.

Multisectoral Alignment and Integration in Vaccine Development

Feinberg distinguished between emerging epidemic threats and pandemics. Whereas the latter affect everyone worldwide—COVID-19 as a prime example—epidemics such as Ebola or Lassa fever tend to be geographically localized, and the appropriate responses vary depending on the pathogen. He explained that private-sector companies are the traditional source of vaccine innovation, but epidemics are an unattractive space for the private sector, because of the small markets involved, limited resourcing, lack of return on investment, and other barriers attributed to nationalism. The scientific complexity of vaccine development typically requires concerted research and development efforts. However, private-sector companies, which are for-profit, face investment risk when pursuing vaccine innovation. These dynamics often result in reactive vaccine research. He recalled his own experience in realizing the extent of his limited understanding of these other aspects of vaccine development as an academic researcher when he moved into the private sector.

Vaccine development depends on an end-to-end view from discovery to implementation, but current models for vaccine development are not structured to achieve desired outcomes, said Feinberg. He noted that an ideal model for vaccine development facilitates bidirectional flow of information so that researchers can understand the goal of the vaccine development project, the target population for this vaccine, and the preferences of this target population in order to successfully translate science and research into positive outcomes for vaccination and disease prevention. End-to-end product development is challenging even within a single company in which all employees share the same incentives, he stated. In efforts that involve multiple stakeholders, sectors, funders, and populations, maintaining an end-to-end perspective can be extremely challenging. Participants in a multisectoral initiative may not share the same goals and perspectives, which can create gaps in the pathway from discovery to implementation. However, the scale of preparedness needed for infectious disease threats is too large for one sector to handle alone and inevitably requires multisectoral engagement, he emphasized. Feinberg contended that both the public and private sectors are obligated to contribute to solutions, and understanding the dynamics of product development is needed to generate results as quickly and effectively as possible. He highlighted a quote from Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota: “The only real expertise in the world to make these vaccines in a quantity and a safety environment is in the private sector. If the private sector isn't fully engaged and involved, it's a show stopper” (Branswell, 2018). Feinberg stated that an ultimate solution would engage the private sector in a motivating and sustainable way.

Beyond partner involvement, the establishment of end-to-end product development programs would entail changes to funding mechanisms, said Feinberg. Current funding mechanisms—including government grants, donor funding, and government support initiatives for organizations such as the Coalition for Epidemic Preparedness Innovations (CEPI)—are typically tailored to a specific program and product. Thus, these traditional grant and donor funding mechanisms are ill-suited for making at-risk investments in advance of an identified infectious disease threat, he remarked. Furthermore, lack of alignment in priorities between public- and private-sector stakeholders can result in tensions, if not overt hostilities. Working efficiently and effectively toward a common goal would involve developing an understanding of how best to align stakeholders. The private sector is a powerful component in this equation, but its connection to the goal is tenuous, he stated. Private-sector willingness to engage in R&D programs targeting diseases that disproportionately impact low-income countries can be constrained by concerns about opportunity costs and distraction from core programs. The sizable profits made by Pfizer, BioNTech, and Moderna may give the impression that vaccine development is an attractive commercial opportunity, but these are outliers, noted Feinberg, and the goal of profit generation will not create a successful solution. Therefore, financial profit cannot serve as the only motivation in engaging the private sector; needed is a method of engagement that secures private-sector commitment and accesses its expertise and insights without overburdening it, he maintained.

Scientific and Technological Prerequisites for a Shift Toward Preparedness

Ironically, the success of developing the rVSV-ZEBOV vaccine motivated Feinberg to resign from Merck to pursue more collaborative work with multiple stakeholders. He shared that the infectious disease field analyzed the Ebola response to better prepare for future outbreaks; yet, many of the lessons gleaned were not heeded and are now being discussed once again in the context of the COVID-19 pandemic (Commission on a Global Health Risk Framework for the Future and National Academy of Medicine, 2016; Moon et al., 2015; Plotkin et al., 2015; Wellcome Trust and Center for Infectious Disease Research and Policy, 2015; WHO, 2015a). Nonetheless, some initiatives did proceed, including the creation of CEPI in 2017 (Røttingen et al., 2017). Feinberg remarked that some people have an unrealistic expectation that CEPI can independently address vaccine needs for all emerging infectious diseases, but placing responsibility on just a single organization is not viable solution.

Feinberg outlined the scientific and technological components of CEPI's 100 Day Mission (CEPI, 2022):

1.

Preexisting prototype vaccines for representative pathogens across multiple virus families

2.

Global clinical trial infrastructure and readiness

3.

Earlier biomarkers of robust immune response and protection

4.

Global capacity for rapid manufacture and validation of experimental vaccines

5.

Global capabilities for early characterization of pathogens and outbreaks

The plan also specifies that innovation is needed in the areas of (1) leveraging preexisting insights about pathogens and platforms, (2) constructing the vaccine development model, (3) operationalizing excellence to accelerate development and manufacturing, (4) promoting collaboration among stakeholders, and (5) enabling continuous generation and review of evidence to support rapid approval.

Though each of these components are reasonable, achieving the 100 Day Mission will involve answering additional questions, said Feinberg. These questions center on who will lead the effort, make decisions, fund the effort, execute programs, assume risk for development and liability, manufacture the vaccine, and serve as product sponsor for regulatory approval. The vaccine products will ultimately require licensing by regulatory authorities around the world, prequalification by WHO, and procurement by United Nations agencies for use in low- and middle-income countries (LMICs). Furthermore, decisions have yet to be made regarding who will decide distribution priorities and who will be accountable for achieving equitable and sustainable access. Feinberg stated that realizing the 100 Day Mission will require a wide range of public- and private-sector partners to align on such determinations in advance of the emergence of an outbreak.

The Threat of Complacency

Feinberg noted that the tendency to wait until a crisis begins to take needed action was captured in an analogy made in April 2022 by Jon Cohen, author and science journalist:

How can science help us prevent the next pandemic? I think we can do a whole lot better in rapid response and there are a lot of clever ideas I'm excited about, yet I feel like we've kicked back into that lackadaisical mode. We have a lull now. In surfing, when there's a lull in between the big set waves, that's when you paddle out. But we tend to paddle out when the waves are crashing. We wait for crisis. (Cohen, 2022)

Feinberg remarked that all stakeholders act to address a crisis when it is occurring, but their level of engagement wanes as the threat wanes. He added that this dynamic happened with Zika and Ebola, and has already begun to happen with COVID-19.

The United States and other national governments made substantial investment in the 2014–2016 Ebola epidemic response, said Feinberg. However, as the Ebola outbreak waned and the threat of Zika emerged, the U.S. government and other governments repurposed funds from Ebola research toward Zika research (Scott, 2016). This reallocation resulted in an unfinished agenda because researchers working to address Ebola were no longer funded. After the outbreak of Ebola Zaire in 2014 and the demonstration of efficacy of the rVSV-ZEBOV vaccine, CEPI and WHO initially prioritized continuing Ebola preparedness efforts to develop and stockpile vaccines to address other filoviruses, including the Sudan ebolavirus and Marburg virus, and to potentially develop thermal stable vaccines and combination vaccines. However, the reallocation of funding led to a de-prioritization of these plans, and they were never realized. In June 2022, an outbreak of Marburg virus occurred in Ghana, and no vaccine was available. Fortunately, the Marburg virus outbreak was contained. However, another outbreak of the Sudan ebolavirus that began in Uganda in September 2022 remains ongoing as of December 2022. Because no vaccine with demonstrated efficacy is available for this virus, a rush of research activity is under way to move candidates through trials (Branswell, 2022). Feinberg contended that if the plans that were made 5–6 years ago had been carried through, a vaccine would have been available to deploy immediately when the Sudan ebolavirus outbreak emerged; instead, efforts to develop this vaccine are taking place during a crisis once again. He noted that as of December 2022, the outbreak is waning and will hopefully be controlled. Thus, the Sudan ebolavirus vaccines may not be tested for efficacy in the context of an outbreak, but development should continue so that preparedness is improved before the next outbreak.

The cost of complacency is also seen in scientific innovation, said Feinberg. Waning government support and declining vaccine utilization will stifle ongoing R&D efforts to develop vaccines that are more efficacious, have broader coverage for variants of concern, are more durable, and are better tolerated, he maintained. The work to develop COVID-19 vaccines is not over, given the need for vaccines that have longer term immunity and potentially block infection and transmission, he stated. Despite interest generated by a COVID-19 nasal vaccine, no funding has been allocated to develop it (Topol and Iwasaki, 2022). In addition, complacency costs are manifest in the access agenda. As of December 2022, worldwide access to COVID-19 vaccines continues to vary widely, and the number of doses administered daily—including boosters—has decreased substantially (Our World in Data, 2022a, 2022b). Feinberg added that a recent article in The Washington Post even reported on the potential to discontinue the COVID-19 Vaccines Global Access (COVAX) initiative (Parker, 2022). Although he has heard that this reporting is inaccurate, the problem of declining vaccination rates and issues of access inequity continue, and complacency threatens resolution of these issues.

Optimization of Partnership Models

Current partnership models (1) rely on the decisions of individual private-sector companies regarding whether they will engage in the partnership, (2) do not feature a method to identify and prioritize the most promising technologies to pursue, and (3) are not a viable solution for accelerating product development and achieving equitable access, said Feinberg. He shared his preference for a more strategic public-private partnership model that features not only engagement between the public and private sectors, but also collaborative work within the private sector. Global threats affect everyone, and therefore it is in the interest of everyone to pool resources, he maintained. A global compact is a possible mechanism for overcoming nationalistic tendencies, and WHO is holding discussions regarding the creation of a pandemic treaty. Although local manufacturing of diagnostics, therapeutics, and vaccines is a potential solution to addressing accessibility, Feinberg stated his doubt about this solution's viability and sustainability and added that it may be used by some stakeholders as a way to sidestep some of the more challenging issues. Alternatively, a fit-for-purpose solution could be designed to ensure equitable, affordable global access. He suggested the development of a “science of partnerships” field of study, which would focus on understanding the factors involved in the successes and failures of scientific partnerships to generate optimal solutions and maximize effectiveness.

A new model for accelerating global health innovation is needed, said Feinberg. Private and public partners should be aligned such that subject matter professionals are proactively engaged, work collaboratively, share risks and responsibilities, and achieve clarity around roles and responsibilities for the most effective program execution possible, he described. Numerous stakeholders include innovators such as pharmaceutical companies, philanthropists, not-for-profit product development partnerships, government funders, government researchers (e.g., NIH), normative agencies (e.g., WHO), procurement and delivery agencies, access advocates, academic researchers, regulatory authorities, and national governments. Alignment across all these various and essential partners to maximize preparedness, response, and effectiveness is a challenge, he noted, particularly given that not all stakeholders share the same goals.

Applying Lessons from COVID-19 Research and Development to Future Epidemics

Feinberg summarized the lessons from the COVID-19 response that could be applied to future pandemics:

• Optimizing partnerships and collaboration
• Continuing scientific innovation for preparedness and response
• Defining optimally effective and sustainable approaches to ensure prompt and equitable access
• Performing needed work during “peace time” across the spectrum of necessary activities, ranging from continued scientific innovation to effective ongoing public education and engagement
• Pursuing a global collaboration framework that counters nationalistic tendencies

He stated that now is the time to act, and that the actions taken affect real people, particularly those living in settings disproportionately affected by disease. Feinberg shared a photo of a 6-year-old girl living in a Liberian community heavily affected by Ebola in the 2014–2016 outbreak, who, upon hearing the news of the ring vaccination trial results in Guinea, made a sign proclaiming, “Thank you Science!” This young girl serves as an example of the real life that could benefit from improved preparedness efforts.

Support for Private-Private Partnerships

Timothy Burgess, Professor, Department of Preventive Medicine and Biostatistics, Uniformed Services University, asked Feinberg to expound upon what might be required to facilitate private-private partnerships. Feinberg replied that his experience in academia, government, industry, and a not-for-profit organization has provided him with multiple perspectives. He stated that companies within the industry should be asked to hold discussions about how best to approach these partnerships. Antitrust issues are important to keep in mind but can be addressed to enable partnerships. An appetite for this type of collaboration is present in the private sector, he remarked, and acceptance and support from the public sector could help to translate this appetite to action. Public health preparedness is a viable model for collaboration between private-sector entities, but it must be welcomed and supported. For instance, during his time at Merck, the company engaged in an endeavor with multiple entities to ensure the availability of affordable antiretroviral therapy in low-income countries to replace the outdated and more toxic drugs commonly used. The initiative dissipated in the face of criticism from self-purported access advocates who were wary that private collaboration could only be harmful, he described. The climate disincentivized private collaboration, and serious discussion about approaches to make such collaboration feasible would benefit the preparedness effort, he maintained.

Advancing Research Partnerships

Saenz noted that tackling the challenges of infectious disease threats is incredibly complicated at the global level. She asked about actionable steps that can be taken now to advance research partnerships for the future. Feinberg shared his optimism that progress will occur on the research partnership front, and he acknowledged the value of this workshop in informing understanding of the aspects of response that should be built upon and expanded, as well as the ones that need improvement. He remarked that IAVI's diverse product portfolio would not exist in the absence of collaborative partnerships with stakeholders from governments, public-sector entities, and for-profit companies, and that the organization is modestly sized, yet able to perform exciting research. Scaling such efforts will involve learning about other organizations' perspectives, motivations, incentives and disincentives, limitations, and areas to which they can contribute, he stated. This knowledge can then be applied to the creation of a comprehensive solution for issues of vaccine R&D and access. Such a solution will require a shift away from siloed approaches and sustained momentum, he added.

African Pandemic Preparedness Organizations

An online participant asked which organizations are best able to represent the needs of LMICs in discussions regarding manufacturing capacity and pandemic preparedness. Feinberg replied that the answer varies by region. The creation of the Africa Centres for Disease Control and Prevention in 2016 has enabled the conduct of important work, he said. More recently established, the African Medicines Agency is building needed infrastructure. Feinberg emphasized that these organizations need support as well as inclusion in discussions, because their perspectives are often excluded.

Intellectual Property Rights

Jill Gay, chief technical officer at What Works Organization, remarked that the best vaccines are made by large pharmaceutical companies that need to protect their intellectual property. She asked how vaccines can be made available in LMICs without infringing on intellectual property rights. Feinberg noted that these rights are often presented as a barrier to access, but he does not view them as such. Intellectual property rights preserve the ability of owners to determine how their products will be used and are therefore not inherently a barrier to access; if companies want their products to be widely available, then the products could be widely available, he contended. Companies have specific concerns regarding property rights, such as compromises to quality that might affect markets in higher-income countries, product diversion, and counterfeiting. These are concerns for which solutions are possible, said Feinberg. He commented that Moderna, Pfizer, and BioNTech have not filed patents for COVID-19 vaccines in the African countries with least access to the vaccines, so intellectual property has not been established in those locations. The companies are loath to lose control of unique assets, and the context could be changed to enable them to feel secure in approaching those regions. The concern of a potential Moderna vaccine lookalike would be made irrelevant if the innovator granted lowest-income countries access to the technology. Feinberg stated his strong belief that solutions are possible for these issues, but their generation is hampered by a distrust stemming from 1960s-era conflict between sectors that prevents the initiation of dialogue. He remarked that distrust and antagonism constitute a greater barrier to access than intellectual property rights.

COVID-19 Vaccines Global Access Initiative

An online participant asked about the potential long-term effects that COVAX could have on vaccine contributions to LMICs. Feinberg replied that COVAX was established with the best intentions, but its design might inhibit its ability to accomplish its goals. How best to design a solution ensuring equitable, affordable access to vaccines is a guiding question. One possible solution is procurement, and the United Nations Children's Fund and Gavi, the Vaccine Alliance have supported the successful procurement of several vaccines, he remarked. Potential solutions for vaccines against diseases such as COVID-19 include local manufacturing and large-volume production of lower cost vaccines. He maintained that despite a concerted effort by COVAX employees, the initiative was not achieving its stated goals. He emphasized that COVAX was created in the middle of the COVID-19 pandemic, as an emergency response. A better solution should be designed now, in advance of future diseases, so that the world is prepared to meet the need for ready access to vaccines.

Vaccine Distribution

Noting that vaccine distribution has been a critical challenge during the COVID-19 pandemic, an online participant asked about actions that can be taken to facilitate distribution. Many geographic regions lack adequate infrastructure, technical training, and technical capacity for vaccine distribution and require support, Feinberg replied. In many countries, most vaccines are administered for pediatric diseases, which created issues when vaccinating the general population for COVID-19 became a priority. Technological innovations could simplify distribution. For instance, the Pfizer and Moderna COVID-19 vaccines must be transported and stored at low temperatures, which is a significant challenge in many low-income countries. Advancements in technology could result in thermostable vaccines or easier delivery routes. He again emphasized the importance of pursuing such activities now, so that a plan can be in place before the next pandemic.

Investment in Pandemic Science and Public Health Trial Infrastructure

Omer remarked that the emphasis on social and behavioral sciences should extend beyond a taskforce to include a focus on the science of behavior in outbreaks. Much of the work of containing outbreaks involves ground management, and local efforts—and in many cases, state efforts—played an important role in COVID-19 vaccination campaigns. However, scientific gaps in this area remain, and investment is needed to address them, he contended. Omer shared that approximately $150 million was appropriated in 2020 for preventing pandemic-related despondence, but no funds were allocated to research vaccine acceptance or behavior. Furthermore, the infrastructure and vocabulary for public health trials are lacking. Trials of masking effectiveness were underpowered, and infrastructure for large trials of public health measures is needed, he added.

Bernardo added that communities should be engaged and heard, and public health efforts should adjust to meet each community's unique needs. In addition, the robust body of research on health communication and changing health behaviors should be included in the body of evidence for combating COVID-19, she said.

Sustainability Considerations

Kester remarked that sustainability must be considered for any identified need (e.g., manufacturing, specific infrastructure). He noted that all past efforts by the U.S. government to establish facilities designed to respond to pandemics and related crises failed. Without plans for sustainability, infrastructure will be ineffective. For example, in addition to factory facilities, vaccine manufacturing requires ongoing quality control and trained personnel. He stated that as new infrastructure and systems are created, the logistics of sustainability must be addressed in tandem.

Data Modernization and Sharing

Christopher Braden, acting director of the National Center for Emerging and Zoonotic Infectious Diseases at CDC, highlighted the competitive tension between research on medical countermeasures and on non-medical mitigation interventions required for a pandemic response. The structure for determining funding priorities should not position these areas in direct competition, he maintained. He added that responsibility for pandemic response should be distributed across government, as well as across public leaders and the public themselves. Data modernization is another area in need of improvement, given the numerous electronic medical records vendors. The data challenges are compounded by various public health data systems across different states and counties. These data are needed for research and other aspects of response efforts, he said, and investment is required to develop an integrated method for sharing and analyzing data. Moreover, platforms for combining data in large databases would enable decision making by international collaborations guided by data. The development of science standards around data is a related area of need. Capacity in data architecture technology, especially in terms of cloud-based technology, enables advancement beyond the standalone, on-premises systems traditionally relied upon. The existing technical capability to bring together data should be leveraged for health data. Braden noted that policy can address data sharing agreements. Acknowledging that the capacity to gather and share data effectively varies widely within local and state public health agencies, Zahn commented that the ability to share data between the health care system and public health is even more limited.

Dynamics Hampering Sustainability and Preparedness Advancement

Gary Roselle, director of the National Infectious Diseases Service at the U.S. Department of Veterans Affairs (VA), remarked that sustainability is a challenge in Washington, D.C., because of the continuously changing priorities and political will. He emphasized that during the COVID-19 pandemic, public health workers faced aggression and threats of violence; this situation must be addressed, because a competent workforce cannot be retained under such working conditions. He commented on the complications involved in data reporting, even from one government agency to another. For example, the VA was initially reporting data to the CDC, then to an intermediary using a different transmission system, and then back to CDC's National Healthcare Safety Network. Roselle stated that workshops such as this one spotlight issues, and any advances made could be valuable. He stated that his optimism is constrained by a perpetual cycle in which preparedness efforts are not sustained. Given the loss of more than 1 million lives in the United States to COVID-19, one might expect demands for change, yet the public has a short memory, he remarked. Feinberg noted that a public health crisis on the scale of the COVID-19 pandemic has not been seen in generations. He added that if the scientific and public health community cannot make the case for preparedness to policymakers and government officials, then the political astuteness of scientists needs to evolve. Jon Heinrichs, global head of innovation and emerging sciences at Sanofi, stated that humankind will not realistically be fully prepared for the next pandemic, but that the current moment presents an opportunity for the world to become better prepared for a future pandemic than it was for COVID-19, because the will and number of people working on preparedness is greater than ever before. Noting that this work is dependent on funding, he highlighted the role of sustained investment in preparedness.

Collaborative International Focus

Thacker commented that COVID-19 highlighted the need for global collaboration, given the interplay of communication and social dynamics between nations. Disinformation mutates and moves from one part of the world to another and back again. The world is not separate, and these issues cannot be addressed in isolation; rather, all countries should work together to pursue solutions to these worldwide challenges. He noted the need for additional focus on communication and other forms of non-pharmaceutical interventions, such as the implementation of vaccination plans. Moreover, no current platform can bring together all the professionals who work on immunization, which extends beyond pediatricians to include multiple disciplines. A global effort to align the efforts of immunization advocates could address some of the issues raised at this workshop, he said.

Designating Leadership for Action Steps

Saenz recounted that PAHO held a series of regional dialogues on the research ethics challenges that arose during the COVID-19 pandemic in order to publish guidance on the topic (Pan American Health Organization, 2022). This process involved engaging regulators, researchers, and ethics committees from various countries. As problems were discussed and action items suggested, it became apparent that no progress would occur unless responsibility for each action item was specifically designated. She suggested that action items be broken down into actionable tasks, and a leader should be identified as responsible for overseeing each task. Burgess added that an action is unlikely to be taken, especially on a sustainable basis, unless a responsible party is designated.

Kester concluded the workshop by stating that any action items accomplished will constitute progress. He remarked that pandemic preparedness is a work in progress that will continually evolve.