At times over the past year and a half, messenger RNA (mRNA) vaccines have seemed almost like magic. Although the underlying technology was decades in the making, the shots themselves burst onto the scene with eye-watering speed. Less than 12 months after scientists discovered COVID-19, Pfizer-BioNTech and Moderna had each developed mRNA vaccines that were more than 90 percent effective. In countries that could buy large numbers of doses, case counts fell dramatically as inoculations rose. That is why, in our article in Foreign Affairs last spring, we referred to the creation and delivery of these mRNA vaccines as a “medical miracle.”
But over the last few weeks, the emergence of the supertransmissible Omicron variant has shown that even seeming miracles have limits. Although researchers are still racing to figure out just how effective mRNA shots (and all shots) are at preventing illness from Omicron, initial research suggests that the falloff is significant. One study found that two doses of the Pfizer-BioNTech vaccine are 30 percent effective at preventing infection, and a third dose given as a booster increased the effectiveness to 75 percent. (The vaccines still maintain very strong protection against severe illness and death.) Caseloads are rising again across Europe and the United States, and epidemiologists warn that large swaths of the world may soon be inundated with devastating new waves of COVID-19.
In the face of a mutating virus, can mRNA vaccines continue to work wonders? The answer depends on whether governments, manufacturers, and scientists improve on their prior efforts. To maximize the technology’s potential, these actors must make investments that enable vaccine doses (including variant-adapted ones, if needed) to be mass produced; easily stored; evaluated for safety and efficacy; and quickly distributed, particularly to countries that have not yet had adequate access. They also will need to ensure that poor states can rapidly vaccinate their residents, because high vaccination coverage limits opportunities for the virus to further mutate. And they will have to develop new vaccines capable of offering broader and longer protection against the variants of today and tomorrow.
But there is reason to hope that mRNA can continue to lead the way. These vaccines are astoundingly agile and effective, and nearly all actors—be they countries, manufacturers, or scientists—are already trying to capitalize on this impressive technology to create doses that are more durable and easily distributable. These shots can help the world meet the goal put forward by the Coalition for Epidemic Preparedness Innovations (where we work) and adopted by the G-7 of developing pandemic vaccines in as little as 100 days. This aim might seem impossibly ambitious, but so did putting a man on the moon, and the stakes of controlling pandemics are even higher. The COVID-19 virus may be around forever. Messenger RNA shots could help ensure that this pandemic’s future and the course of whatever pandemic comes next don’t repeat the past.
FIRST RESPONDERS
Since their approval for emergency use just over a year ago, mRNA vaccines have shown that they have many of the qualities needed in a rapid-response shot. They are quick to make, they are safe, they elicit a strong immune response, and they don’t require a lengthy gap between first and second doses. They are also “boostable,” and scientists believe they can be adapted swiftly when worrying new mutants, such as Delta or Omicron, emerge.
But the last year has also shown that mRNA technology has drawbacks, some of which stem from the mRNA construct itself. Messenger RNA directs the body to make key parts of COVID-19’s spike protein—the tool the virus uses to latch onto and invade cells. This allows the body to learn how to fight off the virus without having to contend with an actual infection. Yet the mRNA molecule and the lipid nanoparticle required to deliver the vaccine can trigger an immune response in addition to the reaction that helps the body develop protective antibodies. This helps explain why many people experience short-lived but unpleasant side effects after receiving these vaccines.
The mRNA construct can also make the vaccines difficult to distribute. The lipid nanoparticle—essentially a fat globule in which the mRNA molecules are encased—is highly sensitive to temperature and friction, making it quite fragile. The pandemic gave scientists an opportunity to learn a lot about mRNA vaccines, and stability testing has shown that current mRNA vaccines can be stored somewhat longer than initially thought, even at normal refrigeration temperatures. Future innovations, such as drying mRNA molecules in the presence of stabilizing additives, have the potential to improve storage conditions even further. But for now, shipment and long-term preservation still require ultracold temperatures, posing logistical challenges in some countries.
The last year has also shown that mRNA technology has drawbacks.
The novelty and complexity of these vaccines has led to production inequities. Currently, the vast majority of mRNA manufacturing sites are located in North America and the European Union. A few manufacturers in Asia can make mRNA doses, but all of them are in China and India. That means almost every mRNA vaccine destined for the developing world must be painstakingly shipped across long distances. In addition, components of these (and other) vaccines are sourced from around the world; Pfizer-BioNTech estimates that 28 border crossings are involved in making, filling, finishing, and distributing its doses. Many of those crossings are subject to customs and supply chain delays. Although there are now multiple efforts underway to build factories in less wealthy nations, neither Pfizer-BioNTech nor Moderna have shared their technological know-how. And even if additional factories could be waved into existence, manufacturing any vaccine takes trained people, quality control systems, and regulatory processes that ensure doses meet quality and safety standards. Manufacturing mRNA vaccines may be technically quick and flexible, but it is not simple.
Finally, mRNA-induced antibodies—and hence protection against infection—appear to wane in six months to a year. This raises questions not just about whether recipients need a third dose but about whether a third dose will be sufficient. Given the uncertainties around declining immunity, it is unclear if mRNA vaccines will be the answer for the long-term management of endemic disease or whether they should be primarily regarded as a first line of defense.
What is clear is that whether by using mRNA technology or not, the world needs vaccines that provide both more durable protection and protection against a wider range of coronaviruses and their variants. The race to develop such a vaccine is on, and both the Coalition for Epidemic Preparedness Innovation and the National Institutes of Health have announced funding support for such efforts. Many of these approaches will involve mRNA, but not all will. For example, viral vector vaccines and recombinant protein vaccines have also been shown to be effective against COVID-19, and researchers are exploring ways to make them more quickly. Furthermore, growing evidence demonstrates that when people mix these vaccine platforms—for example, getting viral vector doses such as Johnson & Johnson’s shot followed by mRNA vaccines (the so-called heterologous vaccination regimen)—they may receive broader and more robust protection than if they stick to one type of product.
WINNING THE WAR
Whether these other platforms or combinations of vaccines will prove faster or better suited to handling COVID-19 remains to be seen; at the time of this writing, mRNA does the best job of generating very high antibody levels, at least in the short term. The international community should continue to develop other technologies. But it must find ways to help developing countries build up domestic manufacturing capacity for mRNA vaccines.
Some global institutions are working hard to help these states. The World Health Organization, for instance, has identified facilities to serve as “mRNA technology transfer hubs” in Africa and Latin America, and it is actively recruiting companies willing to make their technology available for the effort. Multiple international banking institutions have agreed to help finance such facilities. Messenger RNA manufacturers themselves, however, have proved less enthusiastic. Right now, Pfizer-BioNTech and Moderna are not willing to share their intellectual property, triggering a series of controversies about trade policy and intellectual property protection as well as calls by many countries for a waiver to the Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement. But the two companies have signaled an openness to building facilities of their own in poor countries, and several such projects are in the early stages of development, including in South Africa, Rwanda, and Senegal.
Production capacity is only part of the puzzle. To better protect the world against this virus, now is the time for manufacturers to explore and test the “plug and play” versatility of mRNA platforms by adapting them for possible use against new variants. Both Pfizer-BioNTech and Moderna have begun doing this by starting to develop Omicron-specific vaccines, which the EU and Germany expect will be ready for distribution in early 2022. Regulators are streamlining their approaches to COVID-19 vaccine authorization, including by borrowing from the process for approving annual flu shots.
The world needs new, more durable vaccines to avoid further waves of disease and death.
Whether this will all happen fast enough to have an impact on the Omicron wave remains to be seen, but either way, Omicron may not be the last serious COVID-19 variant. The virus is constantly changing, and even if regulators and developers can meet the ambitious 100-day timetable, the world needs new, more durable vaccines to avoid further waves of disease and death—and the social and economic disruptions they will cause. To that end, some mRNA developers are creating multivalent vaccines that present the spike proteins from several known SARS-CoV-2 variants. For example, Moderna’s bivalent vaccine construct contains the spike proteins from the original strain as well as the Beta variant, and it has been shown to elicit a strong immune response for each strain.
Similarly, manufacturers are trying to make vaccines based on a “consensus” SARS-CoV-2 spike protein. This approach would expose cells to genetically engineered spikes containing a selection of mutations that have been identified in different variants—mutations that might dodge existing immunity. The technique could therefore produce doses that protect against dangerous future variants. Other scientists have made vaccines that include portions of nonspike proteins that have not mutated significantly, which may be also effective at preventing disease from a range of variants.
Of course, such adaptions may be easier to imagine than to execute. Future research will have to prove that these second-generation vaccines are broadly protective in real life and that their immunity will last over time. Given the initial blockbuster results, it is easy to forget that mRNA vaccines are still an emerging technology. Scientists and manufactures must make vaccines that can stop future threats much quicker. Medical miracle or not, mRNA shots will need to be further refined—but they may well help the world meet the 100-day mission.
