For all that scientists have done to tame the biological world, there are still things that lie outside the realm of human knowledge. The coronavirus was one such alarming reminder, when it emerged with murky origins in late 2019 and found naive, unwitting hosts in the human body. Even as science began to unravel many of the virus’s mysteries—how it spreads, how it tricks its way into cells, how it kills—a fundamental unknown about vaccines hung over the pandemic and our collective human fate: Vaccines can stop many, but not all, viruses. Could they stop this one? The answer, we now know, is yes. A resounding yes. Pfizer and Moderna have separately released preliminary data that suggest their vaccines are both more than 90 percent effective, far more than many scientists expected. Neither company has publicly shared the full scope of their data, but independent clinical-trial monitoring boards have reviewed the results, and the FDA will soon scrutinize the vaccines for emergency use authorization. Unless the data take an unexpected turn, initial doses should be available in December. The tasks that lie ahead—manufacturing vaccines at scale, distributing them via a cold or even ultracold chain, and persuading wary Americans to take them—are not trivial, but they are all within the realm of human knowledge. The most tenuous moment is over: The scientific uncertainty at the heart of COVID-19 vaccines is resolved. Vaccines work. And for that, we can breathe a collective sigh of relief. “It makes it now clear that vaccines will be our way out of this pandemic,” says Kanta Subbarao, a virologist at the Doherty Institute, who has studied emerging viruses. The invention of vaccines against a virus identified only 10 months ago is an extraordinary scientific achievement. They are the fastest vaccines ever developed, by a margin of years. From virtually the day Chinese scientists shared the genetic sequence of a new coronavirus in January, researchers began designing vaccines that might train the immune system to recognize the still-unnamed virus. They needed to identify a suitable piece of the virus to turn into a vaccine, and one promising target was the spike-shaped proteins that decorate the new virus’s outer shell. Pfizer and Moderna’s vaccines both rely on the spike protein, as do many vaccine candidates still in development. These initial successes suggest this strategy works; several more COVID-19 vaccines may soon cross the finish line. To vaccinate billions of people across the globe and bring the pandemic to a timely end, we will need all the vaccines we can get. But it is no accident or surprise that Moderna and Pfizer are first out of the gate. They both bet on a new and hitherto unproven idea of using mRNA, which has the long-promised advantage of speed. This idea has now survived a trial by pandemic and emerged likely triumphant. If mRNA vaccines help end the pandemic and restore normal life, they may also usher in a new era for vaccine development. The human immune system is awesome in its power, but an untrained one does not know how to aim its fire. That’s where vaccines come in. They present a harmless snapshot of a pathogen, a “wanted” poster, if you will, that primes the immune system to recognize the real virus when it comes along. Traditionally, this snapshot could be in the form of a weakened virus or an inactivated virus or a particularly distinctive viral molecule. But those approaches require vaccine makers to manufacture viruses and their molecules, which takes time and expertise. Both are lacking during a pandemic caused by a novel virus. mRNA vaccines offer a clever shortcut. We humans don’t need to intellectually work out how to make viruses; our bodies are already very, very good at incubating them. When the coronavirus infects us, it hijacks our cellular machinery, turning our cells into miniature factories that churn out infectious viruses. The mRNA vaccine makes this vulnerability into a strength. What if we can trick our own cells into making just one individually harmless, though very recognizable, viral protein? The coronavirus’s spike protein fits this description, and the instructions for making it can be encoded into genetic material called mRNA. Both vaccines, from Moderna and from Pfizer’s collaboration with the smaller German company BioNTech, package slightly modified spike-protein mRNA inside a tiny protective bubble of fat. Human cells take up this bubble and simply follow the directions to make spike protein. The cells then display these spike proteins, presenting them as strange baubles to the immune system. Recognizing these viral proteins as foreign, the immune system begins building an arsenal to prepare for the moment a virus bearing this spike protein appears. This overall process mimics the steps of infection better than some traditional vaccines, which suggests that mRNA vaccines may provoke a better immune response for certain diseases. When you inject vaccines made of inactivated viruses or viral pieces, they can’t get inside the cell, and the cell can’t present those viral pieces to the immune system. Those vaccines can still elicit proteins called antibodies, which neutralize the virus, but they have a harder time stimulating T cells, which make up another important part of the immune response. (Weakened viruses used in vaccines can get inside cells, but risk causing an actual infection if something goes awry. mRNA vaccines cannot cause infection because they do not contain the whole virus.) Moreover, inactivated viruses or viral pieces tend to disappear from the body within a day, but mRNA vaccines can continue to produce spike protein for two weeks, says Drew Weissman, an immunologist at the University of Pennsylvania, whose mRNA vaccine research has been licensed by both BioNTech and Moderna. The longer the spike protein is around, the better for an immune response. All of this is how mRNA vaccines should work in theory. But no one on Earth, until last week, knew whether mRNA vaccines actually do work in humans for COVID-19. Although scientists had prototyped other mRNA vaccines before the pandemic, the technology was still new. None had been put through the paces of a large clinical trial. And the human immune system is notoriously complicated and unpredictable. Immunology is, as my colleague Ed Yong has written, where intuition goes to die. Vaccines can even make diseases more severe, rather than less. The data from these large clinical trials from Pfizer/BioNTech and Moderna are the first, real-world proof that mRNA vaccines protect against disease as expected. The hope, in the many years when mRNA vaccine research flew under the radar, was that the technology would deliver results quickly in a pandemic. And now it has. “What a relief,” says Barney Graham, a virologist at the National Institutes of Health, who helped design the spike protein for the Moderna vaccine. “You can make thousands of decisions, and thousands of things have to go right for this to actually come out and work. You’re just worried that you have made some wrong turns along the way.” For Graham, this vaccine is a culmination of years of such decisions, long predating the discovery of the coronavirus that causes COVID-19. He and his collaborators had homed in on the importance of spike protein in another virus, called respiratory syncytial virus, and figured out how to make the protein more stable and thus suitable for vaccines. This modification appears in both Pfizer/BioNTech’s and Moderna’s vaccines, as well as other leading vaccine candidates. The spectacular efficacy of these vaccines, should the preliminary data hold, likely also has to do with the choice of spike protein as vaccine target. On one hand, scientists were prepared for the spike protein, thanks to research like Graham’s. On the other hand, the coronavirus’s spike protein offered an opening. Three separate components of the immune system—antibodies, helper cells, and killer T cells—all respond to the spike protein, which isn’t the case with most viruses. In this, we were lucky. “It’s the three punches,” says Alessandro Sette. Working with Shane Crotty, his fellow immunologist at the La Jolla Institute, Sette found that COVID-19 patients whose immune systems can marshal all three responses against the spike protein tend to fare the best. The fact that most people can recover from COVID-19 was always encouraging news; it meant a vaccine simply needed to jump-start the immune system, which could then take on the virus itself. But no definitive piece of evidence existed that proved COVID-19 vaccines would be a slam dunk. “There’s nothing like a Phase 3 clinical trial,” Crotty says. “You don’t know what’s gonna happen with a vaccine until it happens, because the virus is complicated and the immune system is complicated.” Experts anticipate that the ongoing trials will clarify still-unanswered questions about the COVID-19 vaccines. For example, Ruth Karron, the director of the Center for Immunization Research at Johns Hopkins University, asks, does the vaccine prevent only a patient’s symptoms? Or does it keep them from spreading the virus? How long will immunity last? How well does it protect the elderly, many of whom have a weaker response to the flu vaccine? So far, Pfizer has noted that its vaccine seems to protect the elderly just as well, which is good news because they are especially vulnerable to COVID-19. Several more vaccines using the spike protein are in clinical trials too. They rely on a suite of different vaccine technologies, including weakened viruses, inactivated viruses, viral proteins, and another fairly new concept called DNA vaccines. Never before have companies tested so many different types of vaccines against the same virus, which might end up revealing something new about vaccines in general. You now have the same spike protein delivered in many different ways, Sette points out. How will the vaccines behave differently? Will they each stimulate different parts of the immune system? And which parts are best for protecting against the coronavirus? The pandemic is an opportunity to compare different types of vaccines head-on. If the two mRNA vaccines continue to be as good as they initially seem, their success will likely crack open a whole new world of mRNA vaccines. Scientists are already testing them against currently un-vaccinable viruses such as Zika and cytomegalovirus and trying to make improved versions of existing vaccines, such as for the flu. Another possibility lies in personalized mRNA vaccines that can stimulate the immune system to fight cancer. But the next few months will be a test of one potential downside of mRNA vaccines: their extreme fragility. mRNA is an inherently unstable molecule, which is why it needs that protective bubble of fat, called a lipid nanoparticle. But the lipid nanoparticle itself is exquisitely sensitive to temperature. For longer-term storage, Pfizer/BioNTech’s vaccine has to be stored at –70 degrees Celsius and Moderna’s at –20 Celsius, though they can be kept at higher temperatures for a shorter amount of time. Pfizer/BioNTech and Moderna have said they can collectively supply enough doses for 22.5 million people in the United States by the end of the year. Distributing the limited vaccines fairly and smoothly will be a massive political and logistical challenge, especially as it begins during a bitter transition of power in Washington. The vaccine is a scientific triumph, but the past eight months have made clear how much pandemic preparedness is not only about scientific research. Ensuring adequate supplies of tests and personal protective equipment, providing economic relief, and communicating the known risks of COVID-19 transmission are all well within the realm of human knowledge, yet the U.S. government has failed at all of that. The vaccine by itself cannot slow the dangerous trajectory of COVID-19 hospitalizations this fall or save the many people who may die by Christmas. But it can give us hope that the pandemic will end. Every infection we prevent now—through masking and social distancing—is an infection that can, eventually, be prevented forever through vaccines. Source
