4

Equitable Scientific Collaborations, Partnerships, and Coordination on the Global Scale

The second panel of the workshop focused on global aspects of the COVID-19 response in terms of successful coordination, areas to address and improve upon, production of research, equitable distribution of research and development (R&D) and manufacturing capacity, and equitable access to research results. The panel was moderated by Carla Saenz, regional bioethics advisor at Pan American Health Organization, and Kent Kester, vice president of Translational Medicine at the International AIDS Vaccine Initiative. Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine, gave a plenary presentation on innovation and collaboration to address vaccine inequities and the threat of growing anti-vaccine activism. A panel of speakers with perspectives from the pharmaceutical industry, academia, nongovernmental organizations, and civil society followed the plenary presentation. James Anderson, executive director of global health at the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), outlined the work needed to achieve swift availability of vaccines, therapeutics, and diagnostics in future pandemics. Glenda Gray, president and chief executive officer at the South African Medical Research Council, discussed factors that affected South Africa and other low- and middle-income countries (LMICs) during the pandemic and the capacity building needed to increase preparedness. In-Kyu Yoon, director and global head of programmes and innovative technology at the Coalition for Epidemic Preparedness Innovations (CEPI), outlined the broad strategies that CEPI proposed in its 100 Days Mission to improve speed and global access in vaccine development and distribution. Walter Cotte, special representative of the secretary

general for COVID-19 at the International Federation of Red Cross and Red Crescent Societies (IFRC), reviewed the pandemic response efforts by IFRC and the changes needed to move forward. Daniel Bausch, senior advisor for global health security at FIND, discussed advances in diagnostics during the COVID-19 pandemic and next steps and challenges to improving the development of and access to future diagnostics.

TWIN PILLARS OF GLOBAL VACCINE PARTNERSHIPS: ADDRESSING ACCESS EQUITY AND HESITANCY

Hotez described efforts to achieve vaccine equity and the threats posed by anti-vaccine activism. He noted that in addition to his work at Baylor College of Medicine, he co-directs (with Dr. Maria Elena Bottazzi) the Texas Children’s Hospital Center for Vaccine Development (CVD), an academic nonprofit-private development partnership. CVD primarily develops vaccines for parasitic diseases—such as schistosomiasis, hookworm, Chagas disease, and leishmaniasis—but a decade ago, it began to make coronavirus vaccines. Coronaviruses fit withing CVD’s mission because, at the time, they were “orphaned,” that is, no longer prioritized for manufacturing by the pharmaceutical industry. Before the emergence of COVID-19, CVD made vaccines for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). When the SARS coronavirus 2 (SARS-CoV-2) sequence was published in January 2020, the organization pivoted its technology and approach to create a vaccine for SARS-CoV-2.

Antipoverty Vaccines

Parasitic diseases occur in low-income settings and exacerbate poverty through chronic and debilitating effects on child development, worker productivity, and reproductive health, particularly in women, said Hotez. For example, female genital schistosomiasis occurs when eggs from the waterborne parasite enter the body and reach the cervix, uterus, and lower genital tract. This disease causes pain and bleeding in 40 million women and girls in the African continent, many of whom also experience social stigma, marital discord, and depression. Although the condition is contracted by standing in water contaminated with the parasite in its larval stage, its symptoms—which can peak during adolescent years—leave teenage girls vulnerable to false accusations of sexual promiscuity by health care workers and others in the community. Hotez added that female genital schistosomiasis increases the risk of acquiring HIV by two- or three-fold and is a major co-factor in Africa’s HIV epidemic.

For these reasons, parasitic disease vaccines are sometimes referred to as “antipoverty vaccines” (Hotez, 2021a; Hotez and Ferris, 2006).

Hookworm and schistosomiasis are most prominent in Latin America, Africa, India, or Southeast Asia, whereas biotechnology and pharmaceutical commercial activity tends to target North America, Europe, and Japan (Hotez et al., 2010). Therefore, CVD’s scope extends beyond pioneering the science behind parasitic disease vaccines to creating a sustainable business model for preventing diseases of regional importance in low-income settings.

Hotez described CVD’s approach as specifically designed for compatibility with vaccine producers in LMICs. Approximately 40 LMICs have partnered to form the Developing Countries Vaccine Manufacturers Network (DCVMN) (Hayman and Pagliusi, 2020). Microbial fermentation using yeast is a common manufacturing approach deployed by this network. This fermentation process creates recombinant proteins in the hepatitis B vaccine, one of the most widely produced vaccines in LMICs including Bangladesh, Brazil, China, Cuba, India, Indonesia, Thailand, and Vietnam. CVD uses the tools and technologies that these vaccine producers already possess to build their capacity. So far, CVD has created recombinant protein-based vaccines for parasitic diseases, SARS, MERS, and COVID-19, said Hotez. CVD vaccines for schistosomiasis and hookworm infection are currently in phase II trials in Brazil, Gabon, and Uganda.

COVID-19 Vaccination Equity Initiatives

In early 2021, CVD started to receive phone calls from leaders in South Asia, Southeast Asia, and Africa who realized that the mRNA vaccines would not be available in their countries for some time and were therefore searching for alternate options. Hotez noted that COVID-19 vaccination is highly inconsistent across the globe—in general, LMICs have lower vaccination rates than high- and upper-middle-income countries (see Figure 4-1). In addition to the humanitarian tragedy of widespread disease, low regional vaccination rates have implications worldwide. For example, the Delta variant originated in the largely unvaccinated population in India; the Omicron variant and its subvariants originated in the unvaccinated population on the African continent. In turn, these variants fueled COVID-19 cases worldwide—a second cost of vaccine inequality, he emphasized.

Development and Deployment of Corbevax

Hotez and his colleagues at CVD applied the yeast recombinant protein and fermentation approach that was successful for SARS and MERS to COVID-19. The organization transferred the technology, the production cell bank, and the technical expertise for production scaling to vaccine producers in LMICs. A vaccine producer in India, Biological E. Limited,

has since scaled the technology to produce Corbevax, a COVID-19 vaccine that has been administered to 75 million adolescents for their primary COVID-19 immunizations and 10–15 million adults as boosters. The administration of nearly 100 million doses of vaccine produced within an LMIC provides proof of concept that an alternative path to increasing vaccine access is viable, said Hotez. Although large multinational pharmaceutical companies perform important work and provide vaccines for Gavi, the Vaccine Alliance (Gavi), he continued, they are not the sole means of vaccine production. Vaccine producers in LMICs can be empowered to manufacture new vaccines locally through strategic partnerships.

In a summary of the engineering and cloning strategy used to create COVID-19 vaccines, Hotez noted that the recombinant spike protein was modified to prevent additional glycosylation and oligomerization during fermentation and manufacturing. This modified protein yielded a similar structure and immune response as the native viral protein (Chen et al., 2021). With the belief that all people should have ready access to vaccine technology, CVD shares all step-by-step processes for manufacturing its vaccines in the public domain via scientific papers in the National Library of Medicine’s PubMed database. To further enable reproduction of the processes, CVD provides the production cell bank and early scale-up assistance (Lee et al., 2021). The scale-up is performed in CVD labs, with scientists from other organizations invited to observe in person or virtually. Hotez also highlighted a partnership between CVD and the Emory University National Primate Research Center, through which researchers demonstrated that the COVID-19 vaccine stopped virus replication in the lungs and other

tissues with minimal evidence of lung pathology compared to controls (Rincon-Arevalo et al., 2021).

Throughout 2020 and most of 2021, CVD received calls from ministers of health and ministers of science in Asia and Africa, said Hotez. To date, CVD has provided the production cell banks and technical expertise to multiple vaccine producers, including (1) Biological E, a vaccine producer in India making Corbevax; (2) BioFarma, a vaccine producer in Indonesia making IndoVac; and (3) Incepta Pharmaceuticals in Bangladesh (Chen et al., 2021, 2022; Hotez and Bottazzi, 2022; Lee et al., 2021; Pollet et al., 2021, 2022). CVD grants ownership of technology to the producers, who then work with the World Health Organization (WHO) and national regulatory authorities to take necessary steps before administering vaccines to the public.

For example, the Drugs Controller General of India, which heads India’s regulatory authority, provided guidance on conducting clinical trials of Corbevax, including a superiority study comparing it to Covisheld, an AstraZeneca vaccine made by the Serum Institute of India, Hotez stated (Thuluva et al., 2022b). Corbevax was found superior to Covishield in the level of virus-neutralizing antibodies against the original lineage and viral variants, cellular responses, and durability of immune responses (Thuluva et al., 2022c). A trial also indicated that Corbevax is safe and immunogenic in children (Thuluva et al., 2022a). Administration of Corbevax in adolescents aged 12–14 years began on March 15, 2022, and 75 million teenagers had received the vaccine by year-end 2022. Corbevax has since been approved as an adult booster, with more than 10 million doses already administered to adults.

A similar process occurred in Indonesia, where religious dietary considerations came into play, said Hotez. Microbial fermentation in yeast is a vegan technology. In order to address dietary concerns in countries with large Muslim populations, the Indonesian government collaborated with clergy to have Corbevax certified as a halal vaccine. With that certification secured, scaling is now occurring to produce 120 million doses for Indonesia and other Muslim majority countries.

CVD is developing a vaccine for the Omicron BA.5 variant to provide additional boosting to children and adults. Initial studies have shown favorable immunogenicity results and have indicated that the vaccine may also offer cross-protection against recent subvariants of concern XBB, BQ.1 and BQ.1.1. Hotez noted that this vaccine may offer a higher level of protective immunity than the vaccines in use in China (Hotez, 2022b). As the world ponders the possibility of moving past the COVID-19 pandemic, WHO has released an immunization agenda for 2030 and an implementation framework to offer strategies for the coming decade (WHO, 2020b, 2021).

Vaccine Hesitancy and Anti-Vaccine Activism

Several social and environmental factors are driving disease rates, including poverty, war, political instability, urbanization, deforestation, climate change, and anti-science sentiments (Hotez, 2021b). Unfortunately, efforts to vaccinate the world’s children are losing ground, Hotez stated. After the formation of Gavi, childhood vaccination rates improved for two decades. However, child vaccination rates have recently declined, with the number of children immunized globally decreasing from 86 percent in 2019 to 81 percent in 2021 (Rachlin et al., 2022; WHO, 2022a)—the first decrease in this indicator in over two decades. The decrease in unvaccinated children is due in part to the social disruption caused by the COVID-19 pandemic, though anti-vaccine activism may also be at play, he added. Hotez explained that anti-science perspectives fuel anti-vaccine sentiment, and he outlined three versions of the anti-vaccine ecosystem. The first version began more than 20 years ago with false assertions that vaccines cause autism. A political movement then developed over the past decade, and now a global anti-vaccine sentiment is driving down vaccination rates. Hotez maintained that vaccine hesitancy has become a new aspect of vaccine inequality.

Vaccines and Autism

The first version of anti-vaccine activism involved nuanced misconceptions and shifting narratives, said Hotez. A pattern developed in which an assertion that a certain vaccine caused autism would arise, the scientific community would debunk that assertion, and a new narrative would arise about a different vaccine or condition. The 1998 publication that falsely claimed that the measles, mumps, and rubella (MMR) vaccine caused autism was eventually retracted after revelations that the findings were invalid (Godlee et al., 2011). Scientific evidence has since shown that children who receive the MMR vaccine are not more likely to be diagnosed with autism, and children on the autism spectrum were no more likely to have received the MMR vaccine than children not on the autism spectrum. Hotez believed that the controversy should have ended there. However, anti-vaccine groups started to monetize their viewpoints on the internet, growing in influence and shifting the narrative regarding other purported dangers of vaccines. Shifting theories that vaccines were harmful targeted the thimerosal preservative used in vaccines, vaccine dose spacing, aluminum adjuvant in vaccines, and a false link between human papillomavirus vaccine and infertility or autoimmunity. He noted that these false assertions have been reapplied to COVID-19 vaccines.

Hotez shared that he has a personal connection to autism, because one of his four adult children has autism and intellectual disabilities. He wrote

a book, Vaccines Did Not Cause Rachel’s Autism, which explains the science behind vaccines and that no link exists between vaccines and autism, and offers a description of autism and it beginnings in early fetal brain development via the action of autism-related genes and epigenetics (Hotez, 2021c). Hotez’s institution, the Baylor College of Medicine, conducted whole exome sequencing on his daughter and identified the gene related to Rachel’s autism, one involved in neuronal communication. Approximately 100 autism-related genes have been identified; most are involved in neuronal communication and many are specifically involved in neuronal cytoskeleton such as in Rachel’s case, he explained. He added that his efforts to dispel misinformation about vaccines have made Hotez a target, and some anti-vaccine groups have referred to Hotez as the “OG villain,” that is, the “original gangster villain.”¹

Association of Anti-vaccine Sentiment with Political Movement

In the 2010s, fear of a link between autism and vaccinations led to an increase of unvaccinated children in Southern California (Ingraham, 2015). Measles is often the first breakthrough infection seen in populations with decreasing vaccination rates, said Hotez. A large measles epidemic broke out in California, and the state legislature responded by ending vaccine exemptions. He supported this measure as an appropriate one. However, backlash followed that centered on a concept of “health freedom,” which gained traction in the Republican Tea Party. Growth of this political movement was particularly evident in Texas, where anti-vaccine political action committees funded anti-vaccine activities and even some candidates who ran on anti-vaccine platforms. Under the banner of “health freedom,” non-medical vaccine exemptions have increased significantly, with nearly 100,000 school-aged children not receiving one or more vaccinations between 2021–2022 (Texas Department of State Health Services, 2022). This number does not account for the 300,000 children who are home-schooled in Texas. Hotez added that the “health freedom” movement has grown during the COVID-19 pandemic.²

Anti-vaccine activists have held events in front of the Texas capitol building. At some of these events, speakers have compared vaccine recommendations to the human rights violations committed during the Holocaust and have worn handmade Holocaust-era yellow stars on their clothing

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¹ “OG” is a slang term applied to something that is an original or to someone who is the originator of a concept or product. More information on this term can be found at https://www.merriam-webster.com/dictionary/OG (accessed March 11, 2023).

² While the early anti-vaccine movement was associated with liberal-leaning communities, the current promotion and activism are largely led by right-leaning figures. See https://www.mcgill.ca/oss/article/covid-19-pseudoscience/anti-vaccine-movement-2020 (accessed April 30, 2023).

(Dolsten, 2019). As a Jewish scientist, Hotez was particularly struck by the movement’s misappropriation of the Holocaust and incorporation of antisemitism into anti-vaccine messaging. In an article published in October 2022 on the “great Texas COVID tragedy,” Hotez discussed the cost of this anti-vaccine movement, attributing the high COVID-19 death rate in Texas—2–3 times higher than that of nations with similar populations and economies—to low vaccination rates (Hotez, 2022a). He explained that Texas experienced a small rise in cases when COVID-19 first broke out in the United States, followed by a large wave of cases associated with the original SARS-CoV-2 virus lineage that peaked in summer 2020. Waves of cases accumulated with the emergence of variants, with peaks in January 2021 (the Alpha variant), September 2021 (the Delta variant), and January 2022 (the Omicron variants). On May 1, 2021, the Biden administration announced that all adults were eligible to receive a COVID-19 vaccine, which by then was widely available. In Australia and Canada, the availability of vaccines ended high death rates despite the Delta and Omicron variants. However, high death rates continued in Texas. Many Texans refused vaccination in support of the concept of “health freedom.” Hotez suggested that almost half of the 90,000 deaths that occurred in Texas during the Delta and early Omicron waves could have been prevented by vaccination (Hotez, 2022a). Similar dynamics played out across the United States, particularly in the Southern states and the Western Mountain region. Hotez estimated that approximately 200,000 Americans died because they refused the vaccine after it became widely available.

The politization of vaccination becomes evident when tracking U.S. COVID-19 death rates by county political affiliation, Hotez described (Pew Research Center, 2022).³ An analysis conducted by the health data analyst Charles Gaba and reproduced by The New York Times, National Public Radio, and other outlets found that after COVID-19 vaccines became widely available in the United States, death rates became correlated with political conservatism (Gaba, 2021). Specifically, there was an inverse correlation between the percentage of people within a county that voted Republican and the county’s vaccination rate and COVID-19 death rate. He added that at the Conservative Political Action Conference in Dallas, Texas, in July 2021, government efforts to vaccinate the public were compared to government efforts to “take away guns and bibles.” At about the same time, a politician referred to Hotez and professionals who administer vaccines as “medical brown shirts,” a Nazi paramilitary analogy. The conference and other far-right venues featured narratives that COVID-19 vaccines were a threat to personal freedom. Hotez stated that popular hosts on

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³ For more information on the effects of COVID-19 on polarization and inequities in the United States, see https://doi.org/10.1016/S0140-6736(23)00461-0 (accessed June 12, 2023).

conservative-leaning news channels have repeatedly featured anti-vaccine content that falsely discredits the effectiveness and safety of vaccines. Social science researchers at ETH Zurich, a large federal university of technology in Switzerland, found that higher viewership of Fox News is associated with lower vaccination rates, whereas no effect was found for viewership of other major television news networks (Pinna et al., 2022).

Anti-vaccine and anti-science aggression is costing people their lives, said Hotez, and the effects of this agenda in the United States are playing out globally (Hotez, 2022c). Anti-vaccine content generated by political conservatives in the United States is being exported to LMICs in Africa. The anti-vaccine rhetoric is not limited to television hosts; it is being espoused by members of the U.S. Congress, and a partisan divide in vaccine narratives is clear, noted Hotez. He described this dynamic as uncomfortable for scientists to contend with, because scientists and physicians are trained to avoid discussing issues in terms of politics. Yet, the U.S. Department of Health and Human Services is focusing efforts to address anti-vaccine messaging on social media—which is providing a platform for anti-vaccine content—rather than on the people generating the content, Hotez stated. He remarked that the health sector should call upon the expertise of political and social scientists in navigating these matters.

PANEL REFLECTIONS

A panel composed of speakers from the pharmaceutical industry, academia, nongovernmental organizations, and civil society provided brief presentations on the COVID-19 response efforts and challenges in their areas.

Industry Perspective

Anderson discussed factors that influence the speed of pandemic responsiveness within the pharmaceutical industry. He stated the critical need for the global society to build new infrastructure to prepare against future pandemics. Strategies proven to work well can be built upon while areas in need of improvement are addressed. Maximizing the speed with which safe and effective vaccines, treatments, diagnostics, and other interventions can be developed and delivered increases the capacity to contain an outbreak before it becomes a global pandemic. To that end, the pharmaceutical industry supports the 100 Days Mission proposed by CEPI and backed by the Group of Seven (G7) governments (CEPI, 2022; International Pandemic Preparedness Partnership, 2021). Acknowledging that the target of developing safe and effective vaccines for any virus within 100 days is ambitious, he believes that this goal should be pursued by all stakeholders.

Anderson highlighted three factors connected to the concept of speed that have emerged during the pandemic: pathogen sharing, collaborations, and equitable distribution of treatments. Pathogen sharing enables research to begin. When a virus sequence is widely available, research can be initiated around the globe. Although the sequences for SARS-CoV-2 were made publicly available quickly, some scientists have questioned whether the initial sequences and those of subsequent variants could have been released sooner. The Global Initiative on Sharing All Influenza Data (GISAID) public database, which published most of the SARS-CoV-2 sequences, could be built upon to increase speed. In addition, overly bureaucratic systems can encumber the pathogen sharing process, and efforts to streamline these systems can hasten pathogen sharing. Anderson emphasized that during the pandemic, collaborations of an unprecedented scale and scope have formed between the public and private sectors and between competing companies large and small. More than 400 manufacturing and production agreements for COVID-19 vaccines and 150 agreements for therapeutics have been established. However, equitable distribution and access to these resources have not been achieved. To address the inequities evident during the COVID-19 pandemic, the biopharmaceutical industry has collectively proposed the Berlin Declaration.⁴ Under this proposal, manufacturers would allocate a portion of real-time production of vaccines, therapeutics, and diagnostics for priority populations in LMICs. Formally supported by DCVMN, this proposal aims to provide LMICs with early access to vaccines and treatments during future pandemics. Anderson stated that inability to achieve speed in the delivery of lifesaving products during a future global health crisis would constitute a failure.

Academic Perspective

Gray outlined lessons learned from the COVID-19 pandemic from her medical research perspective and role as leader of a major research council in an LMIC setting. South Africa was the only country on the continent to monitor excess deaths that occurred during the pandemic. The nation determined that more than 300,000 South Africans died of COVID-19, constituting one of the highest fatality rates in the world. South Africa has the largest population of people with HIV worldwide and also carries a substantial tuberculosis (TB) burden. Given that long-term effects of COVID-19 were not immediately understood, the potential risks of

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⁴ More information about the Berlin Declaration is available at https://www.ifpma.org/resource-centre/berlin-declaration-biopharmaceutical-industry-vision-for-equitable-access-in-pandemics/ (accessed January 26, 2023).

comorbidity with HIV or TB were of particular concern as COVID-19 cases began to rise in South Africa.

Importance of Surveillance

Gray emphasized the importance of surveillance in future pandemic preparedness. Investment in research to understand the genetic mechanisms of treatment resistance for HIV and TB was pivoted to genomic surveillance of SARS-CoV-2, enabling early identification of locations of concern. South Africa is also utilizing wastewater surveillance for monitoring SARS-CoV-2, measles, and other pathogens. Gray envisioned future investment in scaling up vital statistics and wastewater surveillance to serve as an early warning system. As the Omicron variant emerged, hospital surveillance helped to track cases that led to hospitalizations or deaths and to determine mortality risk factors and predictors. Software investment enabled SARS-CoV-2 genotyping using sequence data. Gray highlighted that South Africa exported its software to 11 countries in Africa and 29 countries worldwide to support automatic variant identification.

Local Diagnostic Capacity

National investment in diagnostics proved important to South Africa’s pandemic response, said Gray. As COVID-19 emerged, the nation went into lockdown, closing borders and airports. Diagnostics were required to enable safe travel. Early in the pandemic, South Africa did not have access to polymerase chain reaction (PCR) diagnostics, because these testing resources were diverted to high-income countries. Thus, the country developed systems to manufacture diagnostics locally. South Africa cultured the SARS-CoV-2 virus for validation testing to develop its own diagnostic platform and technology. The nation not only ensured that point-of-care testing was available for South Africans, but also exported diagnostics to 26 countries.

Vaccine Development Capability

Gray stated that lack of vaccine development capability—both in terms of funding and personnel bandwidth—led South Africa to rely on the U.S.-based COVID Prevention Network in order to execute vaccine trials. The lack of vaccine capability and vaccine access during the COVID-19 pandemic also prompted South Africa to partner with WHO to become a mRNA hub for vaccine technology development. Gray highlighted the importance of investments in basic science and clinical research. South Africa has established a solid laboratory and clinical research infrastructure

in collaboration with the U.S. National Institutes of Health and other entities. These investments enabled South Africa to quickly pivot to conducting COVID-19 vaccine trials and immunology and viral neutralization studies. She stated that continued investment in communicable disease research capacity in LMICs will add value to future response efforts. Moving forward, global vaccine procurement and establishment of a market for African vaccines will be important, and South Africa could serve as a regional player in vaccine development and supply to other countries, said Gray. The nation is exploring possibilities for developing localized R&D capabilities to generate the capacity to manufacture vaccines in the future, she added. Increasing development capacity also entails building a workforce skilled in biomanufacturing. To this end, South Africa has established partnerships to train a vaccine manufacturing workforce.

Vaccine Hesitancy

Finally, Gray emphasized the varied social science implications of the COVID-19 pandemic, which range from mental health issues to increased gender-based violence to lack of school access for children. Despite a history of wide vaccine acceptance, vaccine hesitancy has also affected South Africa. She stated that South Africa did not anticipate the levels of vaccine hesitancy seen in the pandemic; thus, efforts are needed to understand how false perceptions penetrate the populace and how to restore trust in Western medicine. South Africa and other LMICs face challenges in developing adequate pandemic preparedness programs, she added. Addressing these challenges would enable more comprehensive response efforts in the future that could potentially prevent the magnitude of mortality that COVID-19 caused in the nation.

Foundation Perspective on Vaccines

Yoon outlined strategies and planned paradigm shifts in CEPI’s 100 Days Mission. He reiterated that the unprecedented speed of the COVID-19 vaccines development is an achievement and that further accelerating the speed of vaccine development could dramatically decrease the number of deaths caused by future pandemics. This is the goal of the 100 Days Mission proposed by CEPI (CEPI, 2022). This effort involves a paradigm shift to a “front-loading” approach, in which the majority of research is completed during the preparedness stage, rather than initiating research in the response stage. One of the tenets of the 100 Days Mission is to create vaccine libraries. Yoon highlighted the work of Barney Graham, senior advisor for global health equity at Morehouse School of Medicine, in developing this concept. The libraries would consist of the knowledge

base, research-grade constructions and reagents, and selected clinical candidate vaccines developed against high-risk virus families. When novel viral threats emerge, these previously developed library materials could be adapted to the new virus, thereby preventing the loss of valuable time that is required to create a vaccine from scratch. He noted that this principle was demonstrated to some extent during the COVID-19 pandemic, as previous research conducted on SARS and MERS viruses was quickly applied to SARS-CoV-2. The 100 Days Mission seeks to replicate and improve the process of applying research on prior coronaviruses to COVID-19 vaccine development to extend to other virus families, said Yoon.

Shifting some vaccine development activities from the response stage to the preparedness stage requires technical and structural changes, Yoon explained. Certain baseline safety evaluations involving clinical trials and regulation can be performed before an outbreak occurs. In an emergency scenario, these pre-established safety data could then be combined with an ongoing review of real-world evidence of efficacy, thus accelerating the development process substantially. Yoon acknowledged that this paradigm requires a change in mindset, and achieving acceptance of this paradigm could be a challenge during inter-crisis periods, when an emergency is not present. Another major tenant of the 100 Days Mission is building global vaccine R&D and manufacturing capacity that is closer to where outbreaks occur and tools are therefore needed. Working with partners, CEPI seeks to create a globally distributed network of R&D and manufacturing capacity that enables rapid response to LMIC regions. The mission of CEPI’s 5-year strategy for 2022–2026—called CEPI 2.0—is to accelerate the development of vaccines and other biologic countermeasures against epidemic and pandemic threats so that they can be accessible to all people in need. Yoon emphasized that speed and global access are the pillars of CEPI’s strategy going forward.

Nongovernmental Organization Perspective on Diagnostics

Bausch discussed recent diagnostic innovations, the 100 Days Mission to speed the development of diagnostics, and the challenges facing the field of diagnostic development. A number of diagnostic successes were achieved during the COVID-19 pandemic. On April 3, 2020, 64 days after WHO declared COVID-19 to be a public health emergency, it granted an emergency use listing to the first COVID-19 PCR assay (International Pandemic Preparedness Partnership, 2021). On September 22, 2020—236 days after the public health emergency declaration—the first rapid diagnostic test (RDT) for COVID-19 was granted a WHO emergency use listing. Collaboration between academia and industry enabled the swift development of these diagnostics, he noted. High demand for these diagnostic

tests from governments led to increased manufacturing capacity and capabilities. Bausch also discussed challenges that accompanied the successes in diagnostics development. For instance, diagnostic developers were initially hindered by slow access to samples, lack of clear product requirements and target product profiles, and insufficient regulatory harmonization. Improving future responses to health emergencies will require addressing these challenges, added Bausch.

The proliferation of RDTs and PCR testing brought a new awareness of diagnostics to the general public, said Bausch. Many people can now identify lateral flow assay as the test in which a sample is dropped on the instrument and one or more lines appear. Although the public may not be as familiar with the science behind PCR, there is increased awareness that PCR testing is administered by a health professional and performed in a laboratory. Moreover, there is also greater public awareness that genomic sequencing enables identification of variants and their potential to harm. Bausch stated that the COVID-19 pandemic has presented an opportunity for a routinization of diagnostics that could potentially be game changing. Indeed, the diagnostic landscape is already shifting. Before the pandemic, the majority of diagnostic tests were performed by health providers. The advent of at-home RDTs for pathogens is one of many exciting innovations. Industry partners are now developing multiplex assays that can be used to detect a panel of seven to eight different respiratory pathogens at a low price point of a few dollars per test. Other innovations include tools utilizing wearable technology and artificial intelligence, he added.

The 100 Days Mission seeks to capitalize on the current potential for a sea change in diagnostics, therapeutics, and vaccines. Bausch noted that FIND is working closely with CEPI on the diagnostics component of the mission. Similar to the concept of creating vaccine libraries, the 100 Days Mission proposes developing novel diagnostic platforms and prototype diagnostic libraries for pathogens, starting with 10 priority pathogens. This approach can speed development, because even if the next epidemic or pandemic is not caused by one of the pathogens in this library, these prototypes can serve as a springboard to develop tests for the specific pathogen in question. There are many challenges to accomplishing this goal. In addition to scientific and technical challenges, operational challenges include access to biomaterials, technology transfer, regulatory harmonization, and others that need to be addressed, said Bausch. He added that establishing evidence-based policy, equitable access, and universal health coverage requires advocacy. Emphasizing the need for universal health coverage, Bausch stated that even the best diagnostics, therapeutics, and vaccines are useless if people cannot access them. The fragmented nature of the field of diagnostics presents another challenge, with myriad partners performing various activities. To address this issue, FIND is exploring the concept of

a diagnostics alliance. It would differ from Gavi or a global fund in that efforts would not be channeled through one partner. Rather, a convening power would bring together various entities to collaborate. He noted that WHO faces a potential conflict of interest with industry partners in this endeavor, but that it remains an important player.

Civil Society Perspective

Cotte outlined the pandemic response efforts carried out by IFRC and the changes needed to be better prepared for future health crises. IFRC is a network of 50 million volunteers and 700,000 employees worldwide who work toward the following goals: (1) people anticipate, respond to, and quickly recover from crisis; (2) people lead safe, healthy, and dignified lives and have opportunities to thrive; and (3) people mobilize for inclusive and peaceful communities. The COVID-19 pandemic presented an opportunity to create transformation and clear action in scaling and speeding up all response processes and in generating more absorption capacity. The operational priorities of IFRC’s COVID-19 response were to address socioeconomic impacts, sustain health and support sanitation and hygiene, and strengthen the capacity of national society auxiliaries. IFRC has advanced change management within its organization to become more connected with other stakeholders and to improve capacity to address the challenging effects of COVID-19. During the pandemic, IFRC reached 1.1 billion people via communication actions, community engagement, and hygiene promotion activities. The organization engaged with 170 million people in community preparedness measures and 130 million people in the water, sanitation, and hygiene (i.e., WASH) program that provides sanitation infrastructure and hygiene promotion.

Although much has been accomplished, more work remains, said Cotte. COVID-19 vaccination mechanisms faced numerous challenges that undermined equity and access, such that more than 90 countries have vaccination rates below 50 percent. The pandemic spotlighted essential workers’ critical role in fulfilling a duty of care and facilitating business continuity; their work requires resources and support that should be integrated with future response planning. The COVID-19 pandemic caused disruption to livelihoods and social interaction, and these challenges led to an increased need for mental health and psychosocial support. To address such issues, future efforts to support community recovery could center on restoring people’s livelihoods. He suggested that additional efforts should focus on achieving universal access to digital technology—enabling people to virtually interact and share information—and on expanding community-based capacity for mental health and psychosocial services. Cotte noted that during the pandemic, IFRC reached 13 million people with mental health support.

He added that the consequences of the COVID-19 pandemic have eclipsed other humanitarian needs that existed before 2020 or that stem from recent crises, such as the war in Ukraine.

Learnings from the COVID-19 pandemic and an analysis of the humanitarian debts it created can serve in improving and adapting systems for the future. Cotte emphasized that although the intensity of the COVID-19 emergency has waned, addressing the collateral damage from the pandemic is far from over. Referring to “humanitarian debts,” he entreated that society must address issues of exclusion and limited capacity that were exacerbated by the pandemic. One example is global vaccination levels: herd immunity for COVID-19 has not been achieved and waves of new variants are expected to continue, he cautioned. A transition from emergency response efforts into long-term programs and sustainable support can meet health, access, and health system capacity needs. Planning for future pandemics or other global crises necessitates a solution-oriented, collaborative approach in which networks carry out humanitarian joint ventures, said Cotte, and the development of a pandemic and global crisis playbook could aid in managing these programs. Investment in preparedness should include resources to improve absorption capacity,⁵ distribution, and action at the local level, he added.

DISCUSSION

Sustainable Pandemic Preparedness

Kester stated that scientific and political leadership can propel pandemic preparedness efforts, as demonstrated in various surge efforts such as Operation Warp Speed. Given the context of limited resources, funding existing in multiple pools, and a fragmented U.S. public health system, he asked how preparedness can be sustained at the national or global level. Gray replied that the COVID-19 pandemic demonstrated the importance of “decolonizing science” by investing in local science that seeks to answer questions relevant to the country and local communities. The value of a resilient health system was also made evident during the pandemic. Gray noted that the South African health system was fragile and unable to simultaneously respond to COVID-19 cases and continue TB and HIV diagnostic, treatment, and monitoring programs. Strengthening a health system’s resilience can increase its capacity to absorb the ramifications of a new pathogen while continuing ongoing care for people with chronic conditions. She acknowledged that LMICs face substantial challenges in

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⁵ Absorption capacity refers to the ability to utilize aid in a manner that maximizes efficiency of public spending and avoids induced adverse effects.

investing in science and strengthening health systems; however, resources allocated to developing and maintaining scientific capability and health capacity will enable countries to successfully pivot during times of crisis. Gray added that many countries face issues resulting in significant death and devastation on an ongoing basis, and an emergent health crisis only exacerbates these issues.

Anderson stated that needed change will require actions from a multitude of stakeholders. Some of these actions involve one-time, lasting steps, such as making regulatory adjustments, said Anderson, while other efforts, such as the ones that Gray highlighted, will require ongoing investment. He added that stronger systems should be built to be sustainable, and all solutions should be assessed for sustainability before moving forward. Moreover, some strategies may have a beneficial short-term effect, but carry long-term risks. For example, Anderson believed that waiving intellectual property rights during a pandemic could affect long-term investment continuity. In addition, funds are currently available to build manufacturing facilities for vaccines and therapeutics in locations where this type of infrastructure does not exist. Distribution of manufacturing capability is desirable, but Anderson cautioned that if these new facilities do not have products or market demand to support their growth and sustainment, they could become obsolete. He stated that IFPMA is not opposed to these proposals’ objectives, but advocates for careful evaluation of strategies that may create systemic risks that could undermine the sustainability needed for an effective future system.

Hotez challenged the concept that multinational pharmaceutical companies are the only entities with the capability to develop vaccines. In his opinion, a model that provides incentive funding to large pharmaceutical companies and leaves LMICs reliant on them for products has been a catastrophic failure that resulted in an almost complete lack of mRNA vaccines in LMICs for the first 2 years of the COVID-19 pandemic. He emphasized that pharmaceutical companies perform valuable work, generate innovation, and provide many needed vaccines for Gavi. However, he contended that more balance could be introduced within this ecosystem, and achieving this balance involves efforts beyond building manufacturing sites. Vaccines are complicated biologicals, said Hotez, and processes for scaling production while ensuring quality control requires years of human capital development. Hotez believes that the process of generating human capital needs to start now. This human capital is necessary for both vaccine production and vaccine science and research, said Hotez, because vaccine manufacturing capacity ultimately involves academic scientists who understand vaccine science and can investigate different vaccine platforms. Universities can cultivate this type of human capital by building programs rooted in a culture of vaccine science. Distribution of vaccine manufacturing capacity ensures

that products of regional relevance are not overlooked. For instance, Hotez said he was once approached by the Director of WHO regarding the need for Buruli ulcer vaccine. Hotez stated that companies such as Merck, Pfizer, or GSK are unlikely to manufacture this region-specific vaccine, whereas a vaccine producer based in Africa is more likely to undertake the endeavor.

Regulatory capacity is another major challenge, Hotez stated. Currently, global approval for a vaccine can be granted by WHO—which entails a slow process—or by one of a group of regulators that have established stringent regulatory reciprocity, such as the European Medicines Agency, the U.S. Food and Drug Administration, or equivalent agencies in Canada, Japan, and Australia. No national regulatory authority in LMICs has been designated as a stringent regulatory authority. He remarked on how this dynamic excludes LMICs and creates reliance on high-income countries. Hotez highlighted India as an example of one country that would derive significant benefit from building the capacity to afford stringent regulatory status to additional agencies.

Hotez cautioned against focusing vaccine capacity-building efforts solely on mRNA technologies. Multiple platforms that deliver spike protein to the immune system (e.g., mRNA, recombinant protein, adenovirus vectors) are effective in preventing COVID-19. He remarked that the mRNA platform may not perform as well for vaccine targets that are more complicated than COVID-19. To illustrate this dynamic, he recalled his anticipation early in the pandemic that the vesicular stomatitis virus (VSV) vaccine technology from Merck would be a likely candidate for developing the COVID-19 vaccine, because it had been used to develop a single-dose vaccine effective against Ebola. However, the VSV platform did not replicate well when the SARS-CoV-2 spike protein was added, and it was outperformed by mRNA. Similarly, DNA vaccines, which have existed for decades, did not emerge as COVID-19 candidates. Although mRNA COVID-19 vaccines performed much better than many scientists expected, it remains difficult to predict how a platform will perform on future novel targets. The success of mRNA COVID-19 vaccines has led to discussions of building mRNA capacity in Africa and South Asia, but Hotez cautioned that other technologies should be included in capacity-building efforts.

Disinformation

Shah noted that disinformation is impeding pandemic response efforts. Hotez replied that the scientific community is doing too little to address the spread of disinformation, which the United Nations (UN) agencies are referring to as the “infodemic.” Disinformation does not appear on the internet without reason; it is targeted, anti-science aggression by political entities for authoritarian and political gain, he stated. Hotez contended that more than

200,000 Americans have lost their lives because of disinformation-fueled vaccine hesitancy; thus, anti-vaccine activism killed more people in the past year than gun violence, nuclear proliferation, cyberattacks, or global terrorism. The effects of this movement will be global, Hotez said, noting that U.S.-style anti-vaccine rhetoric is emerging against the introduction of the RTS,S/AS01 and R21/Matrix-M malaria vaccines. He maintained that anti-vaccine activism is a deadly force that has extended beyond the health system to the political realm, and its containment should therefore be addressed by a future G7 or G20 summit.

Kester asked how disinformation is propagated in sub-Saharan Africa, Southeast Asia, or other regions in comparison to the United States, whether the drivers are similar, and whether a tailored approach is needed. Citing research from Heidi Larson at the London School of Hygiene & Tropical Medicine,⁶ Hotez replied that national and regional differences are at play in terms of anti-vaccine propaganda, but the U.S. style of anti-vaccine activism—featuring rhetoric about “health freedom” and “medical freedom”—has recently spread to LMICs where this language was not previously used. Authoritarian regimes, such as those in Brazil and Hungary, have also adopted this terminology.

Transnational Health Systems

Shah asked about strategies to bring the global and domestic arenas together to elevate transnational health systems strengthening and achieve successful responses. Bausch remarked that the changing architecture for outbreak response over the past 2 years has shifted the established colonial model, in which high-income nations respond to crises and LMICs are relegated to receiving aid. Although an uncomfortable balance of accountability remains, a greater sense of ownership and sovereignty in decision making has been demonstrated in LMICs, he added. This shift raises questions about how to recast international health regulations to enable and broaden productive and accountable international discourse when crises strike. Although uncomfortable, this transition will ultimately be a positive development, said Bausch. Yoon added that the COVID-19 pandemic has shown the peril of relying exclusively on some high-income countries in an emergency situation, because each country faces pressure to serve its self-interests to some extent during a crisis. Thus, research and manufacturing capability must be distributed via a regional approach to achieve greater equity, he stated. In strengthening global collaborations, assumptions about

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⁶ Heidi Larson is the founder and director of the Vaccine Confidence Project. More information about her research can be found at https://www.researchgate.net/profile/Heidi-Larson (accessed March 29, 2023).

what is in other countries’ best interest should be avoided. The development of global efforts should feature an active shift from making assumptions about another country to eliciting perspectives from representatives of that country, said Yoon. Kester noted that numerous existing best practices should be tailored to the context of each country.

EXPANDING GLOBAL COLLABORATION, CAPACITY, AND ENGAGEMENT

A subsequent discussion featured speakers from both the first and second panels of the workshop. Kester asked the panelists to discuss methods to promote equitable scientific collaborations, partnerships, and coordination.

Bridging Between National- and Global-Scale Efforts

Yoon stated that R&D and manufacturing should be diversified beyond the high-income countries with which companies are more familiar. Global targeted outreach efforts should extend to partners and institutions that are typically excluded, he added. Cohen stated that global and domestic efforts should be part of one homogenous, collaborative effort. He added that consistent funding is needed, yet crisis funding typically has a “0 to 60 to 0” dynamic, in which large amounts of funds are made available for immediate response, but such funds are not available for preparedness efforts outside of the emergency situation. Graham remarked that pandemic preparedness must be addressed by the G20 summit and an accord should be established, similar to the Paris Climate Accords. At least a dozen large sequencing facilities should be established in biologically diverse areas around the globe, and a multidisciplinary vaccine development program is needed on each continent, he maintained. In addition, efforts are needed to help leaders in high-income countries understand that it is in their nations’ best interest to help LMICs solve regional problems before they become global problems. HIV was a regional problem in central Africa before it became a global pandemic. Investment in solving problems at the regional level—before they spread worldwide—should be a global priority, said Graham. Gray emphasized the need for (1) global collaboration in research and data sharing, (2) localization of R&D activities to build regional capacity for development of vaccines and diagnostics, and (3) social science research to better understand vaccine hesitancy and distrust of Western medicine.

Bolstering Manufacturing Speed and Capacity

The speed with which COVID-19 vaccines were developed was enabled by manufacturing decisions made at substantial financial risk, said Gruber.

Hastening manufacturing decisions avoids delays in clinical trials, but obtaining at-risk funding to support this effort is challenging. Historically, funding for manufacturing at scale tends to be difficult to secure until proof of concept is achieved, even in the case of products for major markets that hold appeal for large pharmaceutical companies. In the case of COVID-19 vaccines, Gruber noted that Pfizer’s chief executive officer Albert Bourla allocated hundreds of millions of dollars to fund vaccine development and manufacturing when only preclinical data were available. Shah emphasized the importance of investment in research and all that is required to bring products to market.

Gruber highlighted the need to create a workforce with the expertise to meet quality requirements and successfully navigate the regulatory process. Anderson stated that although the regulatory system increased its efforts to reduce delays, additional innovation could improve the process. Companies that developed a vaccine or therapeutic were required to navigate various registration processes in multiple countries. He added that the COVID-19 pandemic can serve as a driver for needed innovation to streamline regulatory processes.

Increasing Surveillance Capacity

Anderson remarked on the importance of surveillance and facilitating the immediate sharing of identified pathogens and genetic sequences via avenues that private researchers can access without navigating a heavy bureaucratic process. Increased clarity on which viral risks to prioritize could be achieved via global consensus efforts. He noted that WHO and CEPI are working on processes to build consensus, which should encourage multiple research groups to vote on prioritized risks while ensuring that no major gaps exist. Bausch highlighted the role of diagnostics and surveillance in informing the vaccine development process. Although not opposed to genomic surveillance, he believes that primary care is the key to effective surveillance because primary care providers are well-positioned to identify signals for outbreaks. The development of reasonably priced RDTs and multiplex diagnostics could widen and strengthen surveillance efforts. Bausch said that if the patient, health care provider, government, and ministry of health see the value in such diagnostics, then surveillance capacity could expand substantially.

Engaging Communities and Establishing Trust

Several panelists remarked on the need for increased transparency and community engagement. Cohen stated that investigators should participate directly and transparently with communities instead of relying on

intermediaries. In his work, each trial network has a community advisory board, and investigators meet with these boards repeatedly to develop community buy-in. Shah remarked that funds should be invested to establish systems able to administer the therapeutics or other products developed while maintaining public trust. In other words, investment should extend beyond vaccines to actual vaccination. Community members are not typically incorporated into the process; thus, community engagement is an area for improvement. Investment in creating public health systems capable of establishing truly healthy communities is needed worldwide, said Shah.

Hotez stated that a government agency task force should be established to combat anti-vaccine activism, which is not being adequately addressed by the health sector. The U.S. Department of Justice, Department of Commerce, and State Department should be involved in this effort because foreign actors such as Russia are using technology to spread disinformation in the United States and because vaccine hesitancy is a cause of inequality as great as any other, he contended. Hotez added that on a global level, the UN agencies should address anti-vaccine activism.