Moderna says its COVID-19 vaccine is 94.5% effective at preventing the respiratory disease, according to an early analysis of the ongoing 30,000-person Phase 3 trial. The results, announced Nov. 16, are significantly better than the biotech firm’s goal of at least 60% efficacy and well above the US Food and Drug Administration’s minimum of 50%.
The news came a week after Pfizer and BioNTech reported that their jointly developed vaccine was more than 90% effective in a preliminary analysis. Pfizer provided an update Nov. 18 specifying that its vaccine is 95% effective. The announcements from both trials bolster optimism that vaccines will be able to make a meaningful dent in the pandemic. “I am very hopeful and excited about it,” says Barton Haynes, director of the Human Vaccine Institute at Duke University’s Department of Medicine. “We’ve all been expecting that the percentage of protection would be lower.”
The numbers are “absolutely fabulous,” says Hildegund Ertl, a vaccine scientist at the Wistar Institute in Philadelphia. “But obviously you need to be a little bit cautious. You want a vaccine that works for at least a year, and we won’t have that data by the time the vaccine rolls out.”
The vaccines are not available yet. The FDA requires companies to amass data on a vaccine’s safety for at least 2 months after dosing is completed before they request an emergency use authorization (EUA). Pfizer says it will apply for an EUA in a matter of days, while Moderna says it will have the safety data in “the coming weeks.” Formal FDA approval of the vaccines requires at least 6 months of safety data.
Moderna’s vaccine, mRNA-1273, and the Pfizer-BioNTech vaccine, BNT162b2, are both based on messenger RNA, a new technology that until the pandemic had not been tested in large clinical studies. “This is really great news for the field and a great opportunity to show the world that mRNA vaccines are a viable new vaccine format,” says Norbert Pardi, an mRNA vaccine scientist at the University of Pennsylvania.
Both vaccines require two shots—Pfizer’s are administered 3 weeks apart and Moderna’s, 4 weeks apart. Each injection contains lipid nanoparticles filled with mRNA strands that encode genetic instructions for making the SARS-CoV-2 spike protein, which the virus uses to infect human cells. Once the vaccine is injected, our cells temporarily make these spike proteins to give our immune systems a chance to make antibodies that target the foreign substance. The intention is that those antibodies will stick around and prevent future infections of the coronavirus.
The preliminary results from Moderna and Pfizer suggest that the vaccines are working as planned. “It confirms that the spike protein is a very good strategy,” says Jason McLellan, a researcher at the University of Texas at Austin whose lab found a trickfor stabilizing the spike protein used in both Pfizer’s and Moderna’s vaccines.
An independent Data and Safety Monitoring Board reviewed Moderna’s data after 95 people tested positive for COVID-19. Only 5 people given the vaccine developed an infection, compared with 90 in the placebo group. “This is really fantastic for a respiratory virus vaccine,” Pardi says. Flu vaccines are often less than 50% effective, “and in a really good year the efficacy is 60%, and people are happy about it,” he adds.
In the update of its 43,000-person Phase 3 study, Pfizer said that 162 people in the placebo group and 8 given vaccine developed COVID-19.
The companies made the announcements by press release, and scientists don’t yet have data to vet independently, but some researchers say the move was justified. “We have a humanitarian crisis on our hands, so for companies to announce that they have over 90% efficacy is not a bad idea,” Ertl says. “It is also a good idea to keep the vaccine in people’s minds. We have to get people to accept these vaccines, otherwise they are useless.” Some researchers point out flaws in the trial design that might make the vaccines seem better than they are. Peter Doshi, an associate professor at the University of Maryland School of Pharmacy, has critiqued the vaccine trials for focusing on preventing any cases of COVID-19 rather than on preventing the severe cases that can lead to hospitalizations and death.
All 11 people who developed severe COVID-19 in Moderna’s trial and 9 of the 10 with severe disease in Pfizer’s study were in the placebo group. But Doshi notes that the FDA’s criteria for severe disease could result in the counting of some people who would normally be considered to have mild cases. For example, someone in the trial with blood oxygen saturation below 93% would be defined as having a serious case, even though some people’s oxygen levels are in that range without infection. “We don’t have enough information to make a judgment at this point,” Doshi says.
Researchers also emphasize that it is too early to know how long these vaccines will remain effective. Moderna plans to follow the participants in its study for 2 years after their second shot and to measure the levels of certain markers of immunity—specifically, binding and neutralizing antibodies—in their blood six times during that period. “That’s going to be very important to see what the durability of this vaccine response is over time,” Haynes says. “The durability is going to determine how often folks need to be revaccinated, if at all.”
Pfizer reported data collected just 1 week after volunteers got their second shot, and Moderna reported data collected 2 weeks after the second shot. The immune responses to these vaccines “are near peak” at those time points, McLellan says. “It will be interesting to see how this changes over time.”
Moderna’s trial enrolled large numbers of people hardest hit by the pandemic and at the greatest risk of developing severe disease. Its trial included more than 7,000 people over 65; more than 5,000 under 65 who have chronic conditions like cardiac disease, diabetes, or obesity; and more than 11,000 people of color—including 6,000 Hispanic and 3,000 Black people. The vaccine has not been tested in pregnant women or children.
Pfizer said that around 42% of people in its trial—about 18,000—were from ethnically and racially diverse backgrounds. A similar percentage were 56–85 years old.
Although data so far suggest that the vaccines are safe, they are not without unpleasant side effects. Nearly 10% of participants in Moderna’s study experienced severe fatigue or muscle pain, while roughly 5% had severe headaches or joint pain. The available data suggest these symptoms—often seen across vaccines of all types—could seem relatively common once the vaccine is administered to hundreds of millions of people.
Pfizer reported fewer severe side effects in its trial, possibly because of its smaller vaccine dose of 30 μg, compared with Moderna’s 100 μg dose. Higher doses caused more side effects in small clinical studies earlier this year.
Moderna says that if mRNA-1273 is authorized for use, it could distribute about 20 million doses—enough for 10 million people—in the US by the end of the year and between 500 million and 1 billion doses worldwide in 2021. Pfizer anticipates distributing 50 million doses—enough for 25 million people—by the end of the year, with up to 1.3 billion doses next year. Although the vaccines are similar on the surface—both use lipid nanoparticles and mRNA encoding the spike protein—there could be subtle or large variations that the companies haven’t disclosed, Pardi says. “There are so many different ways to make mRNA, and the differences are important.” One key difference is the vaccines’ stability. Pfizer’s vaccine has to be transported and stored at about –70 °C. In contrast, Moderna’s vaccine requires just –20 °C for transportation and long-term storage of up to 6 months. The firm also recently disclosed that the vaccine would remain stable for up to 30 days at 2–8 °C and for up to 12 h at room temperature. “I did not expect that,” Pardi says. “It is great news and will solve a lot of potential issues.”
It’s not clear why Moderna’s vaccine has less stringent temperature requirements. Gaurav Sahay, a lipid nanoparticle scientist at Oregon State University, says the difference is likely related to one of three things: modifications that stabilize the fragile mRNA itself, the proprietary ionizable lipid that Moderna uses to encapsulate mRNA in the nanoparticles, or different cryopreservatives used to store the lipid nanoparticles for shipping.
While trials got underway, Moderna began manufacturing an unprecedented amount of mRNA in anticipation of future approval. The firm struck a partnership with Lonza to boost its manufacturing capacity for the vaccines and made deals with Catalent in the US and Laboratorios Farmaceuticos Rovi in Spain to fill and finish the vials, each of which will contain enough mRNA for 10 doses. According to Moderna’s R&D-day presentation in September, Catalent and Rovi will package those vials 10 per carton, with a dozen cartons per case and up to 192 cases per temperature-controlled delivery truck—a total of 230,400 doses.