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The novel coronavirus—SARS-CoV-2—exploded onto the world stage about a year and a half ago, infecting hundreds of millions of people, killing millions, and causing immense social and economic disruption. But just under a year after the deadly virus emerged in China, governments were able to authorize the use of vaccines against COVID-19, the disease caused by the virus. Vaccines that rely on messenger RNA, or mRNA, were among the first across the finish line, progressing from the genetic sequencing of the virus to human trials in less than three months. Last December, the U.S. Food and Drug Administration (FDA) granted emergency-use authorization to an mRNA vaccine produced via a partnership between the U.S. company Pfizer and the German firm BioNTech and to another developed by the U.S. company Moderna, after clinical trials demonstrated that both were about 95 percent effective in preventing COVID-19. The public marveled at the speed of the vaccines’ development, but in truth, these vaccines—and the breakthroughs in their underlying technology—were more than a decade in the making. They represent an astonishing scientific and public health achievement.
Technology based on mRNA is transforming how the world confronts current and future pandemic threats. Messenger RNA is a molecule that shuttles genetic information contained in a cell’s DNA from its nucleus to its plasma, where it is then translated into proteins. Scientists have long dreamed of harnessing this mRNA in such a way that it could be injected into humans, triggering cells to produce specific proteins for therapeutic or preventive purposes. The mRNA vaccines developed for COVID-19 work by instructing the human body to produce the so-called spike protein located on the virus’s surface (but not the virus itself), which then triggers an immune response that creates antibodies capable of fending off the coronavirus that causes COVID-19.
These vaccines don’t just offer a way out of the current pandemic. Messenger RNA technology could also give researchers ways to fight off future COVID-19-like outbreaks and prepare for a hypothetical “Disease X”—a still unknown pathogen that will prove to be at least as contagious as SARS-CoV-2 but could lead to an even more lethal pandemic. What is more, mRNA could help create better routine vaccines, such as more efficacious flu shots. But vaccine technology is only as good as the infrastructure around it. None of the potential of mRNA technology will be truly realized unless international institutions, national governments, and private companies work collectively to ensure that the resources and capacity exist to take full advantage of this medical miracle.
A series of breakthroughs over the past 60 years made mRNA vaccines possible, beginning with the discovery of DNA in the 1950s and the subsequent unraveling of how the genetic code works. Early attempts to harness mRNA were unsuccessful, largely because mRNA is relatively unstable. But scientists made a breakthrough in the last decade. Using nanotechnology, they placed mRNA into a small lipid particle—essentially, a tiny bubble of fatty acids—and crafted a version of that nanoparticle that could safely be injected into humans. And through innovations in synthetic biology, they found ways to rapidly manufacture mRNA-based vaccines.
These scientific and technological advances coincided with greater public interest in devising vaccines against future pandemic pathogens. Following the H1N1 influenza pandemic in 2009, the U.S. government, among others, pledged to speed the development of vaccines and make more versatile vaccine platforms that could swap out one pathogen for another using the same underlying technology. This resolve drew researchers to mRNA-based platforms. Unlike conventional vaccines, mRNA vaccines do not require strains of a virus to be grown in either eggs or cell culture; they rely instead on a dependable and quicker process of chemical synthesis.
At the same time, mRNA technology won further financial and institutional backing from U.S. government agencies and other investors. In 2017, a group of governments and philanthropic organizations, including the Wellcome Trust and the Bill & Melinda Gates Foundation, launched the Coalition for Epidemic Preparedness Innovations, where we work, to support the development of vaccines against pathogens that could cause epidemics or pandemics, including Disease X. Guided by a list of pathogens with epidemic potential compiled by the World Health Organization (WHO), CEPI selected the MERS virus, a coronavirus that first appeared in 2012, as one of its priority pathogens, allocating around $125 million to support the development of vaccines against it. That investment paid off following the emergence of the COVID-19 pandemic. Scientists and vaccine developers were able to rapidly respond to the new threat by drawing on prior work on coronavirus vaccines, such as those for MERS, and on earlier research on mRNA and other vaccine technologies.
Researchers released the genetic sequence of SARS-CoV-2 in January 2020, roughly two weeks after the outbreak was first reported to the WHO. That sparked a furious scramble to develop vaccines. Unsurprisingly, mRNA vaccine candidates were among the first to enter human trials, with the Moderna vaccine reaching that stage in March and the Pfizer-BioNTech one in May. In late July, the two mRNA candidates began Phase 3 trials involving tens of thousands of participants; by November, results showed that they were both extraordinarily effective. The entire process took roughly 300 days—an incredibly quick turnaround in the development of a vaccine.
Messenger RNA vaccines represent an astonishing scientific and public health achievement.
Subsequently, multiple countries have licensed and authorized both mRNA vaccines, and at the time of this writing, 44 million people have completed a full immunization, with two doses, in the United States (around 13 percent of the population). Approximately 60 percent of the entire population of Israel has received at least one dose of the Pfizer-BioNTech vaccine, and early data indicate an epidemiologically significant reduction in both COVID-19 illness and the transmission of the virus.
Despite this good news, challenges remain for the first generation of mRNA vaccines. Both the COVID-19 pathogen and the vaccines are new, and researchers do not yet fully understand the nature of the immunity produced by either natural infection or vaccination; it is unclear, for example, how long the immunity that prevents COVID-19 lasts. The vaccines also produce some side effects (sore arm, fever, chills, fatigue, and muscle aches) that, although short-lived, make some people hesitant to get the shots. The capacity to manufacture these mRNA vaccines is still limited, and they require cold storage—at extremely low temperatures in the case of the Pfizer-BioNTech vaccine—both of which cause logistical headaches in devising mass vaccination campaigns.
Most concerning, new SARS-CoV-2 variants emerged late last year in Brazil, South Africa, the United Kingdom, and elsewhere. These new virus variants are more transmissible and have quickly spread around the world. Researchers are trying to determine whether they are also more lethal and whether they render existing vaccines less effective in real-world settings, as laboratory studies suggest. Scientists must prepare for the likelihood that new variants of the virus will require new or adapted vaccines. Like other vaccine producers, mRNA vaccine developers have begun to ready their platforms to respond to these new strains; Moderna, Pfizer, and BioNTech are already creating booster shots for their vaccines, in the event that they are needed. This represents a further test of how quickly a new mRNA vaccine can be developed and manufactured.
The emergence of variants of the virus means that scientists and vaccine manufacturers must work more quickly to devise new vaccines. When CEPI launched, it hoped to radically shorten the time it takes to develop vaccines, moving from the genetic sequencing of a virus to clinical trials within 16 weeks. But such a timeline is too slow for highly transmissible and lethal diseases. The initial COVID-19 outbreak in a Chinese province became a full-fledged pandemic in less than 12 weeks. CEPI’s view is that to combat newly emerging variants of concern, governments and companies should aspire to make a vaccine within 100 days, and the United Kingdom urged other G-7 countries in February to adopt this goal.
But even with sophisticated technology, governments will struggle to develop vaccines quickly without first hurdling some logistical challenges. They need to ensure that the goods necessary to make vaccines at a large scale are readily available. Currently, many of the raw materials and critical components required to make a vaccine against a new strain—including filters, tubes, and the lipids to make nanoparticles—are in very short supply. Ramping up raw material and manufacturing capacity will demand further financing. There is no global entity responsible for this task, and relying solely on market forces would likely exacerbate the emerging inequalities in vaccine access between wealthy and low- and middle-income countries.
As they address these challenges, vaccine manufacturers can fine-tune the vaccine production process to make it faster and more efficient. When it comes to tackling SARS-CoV-2 variants, vaccine developers and the relevant regulatory bodies should agree to a streamlined approach for clinical trials that uses evidence about the performance of already authorized COVID-19 vaccines (to avoid needless repetition) and ensures that vaccines are safe and effective but avoids redoing lengthy Phase 3 trials. The goal of having a platform in which one pathogen can be swapped out for another is becoming closer to reality with the technological advances that have risen to the challenge of the current crisis. Already, the FDA and the European Medicines Agency have issued initial regulatory guidance on how to quickly adapt COVID-19 vaccines to new variant strains.
Experts at CEPI now believe that a vaccine against an entirely new pathogen—not just a new variant of the virus that causes COVID-19—also needs to be produced in 100 days to adequately respond to a future epidemic with pandemic potential. Given the devastation brought about by COVID-19, a year is simply too long to wait for a vaccine. Vaccines using mRNA technology have proved to be effective and quick to develop; they will inevitably play a major role in fighting future pandemics.
Developing new mRNA vaccines might not take that much time, but they still need to be tested, and they can be delivered only as fast as they can be manufactured and distributed. Once a vaccine is manufactured, it must be shipped, often across the world, to be put in its final form and vialed. Since most mRNA vaccine manufacturing occurs in wealthy countries, various built-in delays slow the vaccines’ arrival to poorer countries. Pandemic preparedness efforts must therefore include the innovation needed to craft and deploy transportable, modular manufacturing systems that can be used to fabricate such vaccines and also carry out the final “fill and finish” steps of the process. New technologies hold promise in that regard, as evidenced by a joint project between the German biotechnology firm CureVac and Tesla Grohmann Automation, an automotive manufacturing company owned by Elon Musk, with the aim to build mobile mRNA vaccine production units that could eventually be shipped to the site of an outbreak and rapidly make targeted vaccines locally.
Messenger RNA vaccines have revolutionary global health potential beyond combating pandemics. Take, for example, influenza, an infection of the respiratory tract that kills between 12,000 and 61,000 Americans annually and, like COVID-19, disproportionately affects certain sectors of the population, especially older adults. Every year, experts and manufacturers attempt to predict the strains of the influenza virus that will most likely be circulating in the subsequent flu season. It then takes roughly six months for them to formulate, manufacture, and release a vaccine. But occasionally, the circulating influenza viruses evolve between the time that vaccine makers get started working with the season’s vaccine strains and the time they begin to produce the vaccines, with the process of manufacturing too far along to make another change. When such a vaccine mismatch occurs, populations receive a reduced benefit from the flu shot, often resulting in a more severe and deadly flu season.
That risk of a mismatch can potentially be mitigated with mRNA manufacturing. A new seasonal influenza vaccine could, at least in theory, be produced in large quantities in weeks rather than months. That speed would give researchers more time to decide the composition of the seasonal vaccine, resulting in a better match between the flu shot and the circulating influenza strains. The technology might also open up new opportunities to develop vaccines against other constantly changing viruses, such as norovirus, which causes acute gastrointestinal illness.
Messenger RNA technology could also address the suboptimal performance of certain existing vaccines. For example, mRNA vaccines might offer a safer way to inoculate immunocompromised people and pregnant women, who are often advised to avoid traditional vaccines that contain attenuated versions of the viruses they target. And judging from the success of the Moderna and Pfizer-BioNTech vaccines in protecting older people from COVID-19, other mRNA vaccines might prove to work well for older people, who tend to have less robust immune systems.
Scientists are only just beginning to unlock the full potential of mRNA vaccines. To ensure that more people can have access to them, researchers need to find ways to make mRNA vaccines less expensive by, for example, making essential goods more readily available and making production processes more efficient. And to overcome the understandable wariness with which many people view this new technology, additional evidence from clinical research and from the vaccines’ performance in real life after they have been approved should be made public to clearly demonstrate their levels of safety and effectiveness.
The vaccine rollout during this pandemic has been hampered by a lack of financing and resources, limiting the early, necessary purchases of raw materials and investments in manufacturing capacity. Being prepared for the future will require not just honing the development of vaccines but also ensuring the ready availability of financing. The launch of a vaccine-financing commission recently formed under the auspices of the G-20 is a promising start and a sign that governments recognize the need for collective action.
One final fundamental challenge remains. Scientists can develop a vaccine only when they have detected a new pathogen and determined its gene sequence. This requires a better, faster system of surveillance and international data sharing—and a good precedent already exists for building one. Since 1952, the WHO’s Global Influenza Surveillance and Response System has continuously monitored circulating influenza viruses across the globe and released recommendations on the composition of influenza vaccines twice a year. This coordinated monitoring and decision-making effort has worked well and could readily form the basis for monitoring newly emerging variants of SARS-CoV-2 and other pathogens, as well. Such a system would work only with close communication and collaboration among international institutions such as the WHO, private vaccine developers, national regulatory authorities, and the global scientific community. The COVAX Facility, which seeks to distribute COVID-19 vaccines more broadly to people in low-income countries, is a good example of such a collective enterprise, as it is chaired by CEPI, the WHO, and the public-private partnership Gavi, the Vaccine Alliance.
A new era in vaccinology has arrived. The year 2020 will be remembered not only for the pandemic but also for the fact that it witnessed the culmination of nearly a decade’s worth of technological breakthroughs in a mere 12 months. The world will emerge from the pandemic with a new arsenal of vaccine technologies at its disposal, with mRNA at the forefront. These successes in dark times provide much-needed grounds for optimism that in the future, societies will be able to respond much more rapidly, effectively, and equitably to emerging pandemic threats.
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