Health-care workers rolled up their sleeves Monday, Dec. 14, for injections of the first COVID-19 vaccine authorized by the US Food and Drug Administration. It was a stunning debut for the world’s first messenger RNA (mRNA) vaccine, codeveloped by Pfizer and BioNTech. Scientists have been working on mRNA vaccine technology for more than 2 decades with the dream that it would one day be used for rapid vaccine development in pandemics.
That dream was realized Dec. 11, when the FDA permitted the vaccine to be used after analyzing the results of a 44,000-person clinical trial that showed it was 95% effective at preventing COVID-19. Two days later, the first FedEx and UPS trucks rolled out of Pfizer’s Portage, Michigan, manufacturing plant, where the vaccines were produced and loaded into crates filled with dry ice. The shots offered a hope of reprieve after the pandemic’s deadliest week in the US.
“It is really an amazing scientific achievement,” says Srilatha Edupuganti, an infectious disease physician at the Hope Clinic of Emory Vaccine Center. “I am very excited about this vaccine that is going to prevent disease and death.”
Daniel Hoft, director of the Saint Louis University Center for Vaccine Development and a member of the National Vaccine Advisory Committee, is also pleased with the news. “No one thought the first vaccines tested in Phase 3 could be so effective without major safety issues. So this is really a great event,” he says in an email.
Supply of the vaccine will be limited, and there will not be enough for everyone who wants it. In July, the US government paid $1.95 billion to preorder 100 million doses—enough to vaccinate 50 million people, since the vaccine requires two shots given 3 weeks apart. Pfizer expects that up to 25 million doses could be distributed in the US before the end of the year, with the rest delivered in the first few months of 2021.
Vaccinating the country—let alone the world—will require additional COVID-19 vaccines to succeed in trials and win FDA authorization. The US government recently increased its order of another mRNA vaccine, made by Moderna, to 200 million doses. As C&EN went to press, the FDA’s vaccine advisory committee, made up of infectious disease doctors and vaccine scientists, was convening to hear the latest data on that vaccine. The committee overwhelmingly voted in favor of using it in people 18 and over on the basis of positive preliminary results first disclosed in November, as well as more detailed results published Dec. 15 on the FDA’s website.
And depending on the outcomes of ongoing Phase 3 clinical trials, three more companies—AstraZeneca, Johnson & Johnson, and Novavax—might be ready to request authorization of their vaccines in the first few months of 2021.
Although the FDA worked at a remarkable speed to review data from Pfizer, the agency’s words and actions also indicate that its leaders largely resisted political pressure to unduly hasten authorization of the vaccine. Five other countries—Bahrain, Canada, Mexico, Saudi Arabia, and the UK—authorized the vaccine before the US.
The FDA green-lit the vaccine for use in people 16 and older via emergency use authorization (EUA), which requires 2 months of follow-up after clinical trial participants get their second shot. A formal FDA approval will require 6 months of follow-up. Pfizer plans to file a Biologics License Application for that formal approval in 2021.
Pfizer and BioNTech first announced a collaboration to make a vaccine for COVID-19 on March 17. Although the pair began working together on experimental flu vaccines in 2018, they had never run a large clinical trial to prove the efficacy of an mRNA vaccine. The first volunteers were injected in Germany in April and in the US in May. The Phase 3 study began in July, and the companies announced preliminary results of that trial to great acclaim in November.
A subsequent peer-reviewed paper showed that the vaccine was about 50% efficacious during the 3 weeks between the first and second shot and about 95% efficacious 7 days after the second shot—which is the primary data point Pfizer emphasized when seeking its EUA (N. Engl. J. Med. 2020, DOI: 10.1056/NEJMoa2034577).
That level of efficacy is “really remarkable,” Asuncion Mejias, an infectious disease doctor at the Center for Vaccines and Immunity at Nationwide Children’s Hospital, says in an email. A big question is how long that immunity conveyed by the vaccine will last. “We hope that the vaccine efficacy will remain that high,” she says, but herd immunity could be achieved “with vaccines with even a bit lower efficacy.”
Moderna’s vaccine was 94% effective at preventing COVID-19 2 days after the second shot in a trial of 30,000 people. While 30 people who got the placebo developed severe COVID-19, none who got the vaccine did.
The FDA’s authorization of the Pfizer vaccine came a day after the agency’s vaccine advisory committee voted 17–4 in favor of authorizing it. Late in the 9 h meeting, some committee members objected to authorizing the vaccine for use in 16- and 17-year-olds. H. Cody Meissner, chief of pediatric infectious disease at Tufts University School of Medicine, said Pfizer’s data were insufficient to justify giving the vaccine to 16- and 17-year-olds. He requested, to no avail, that the FDA change its wording to authorize the vaccine in adults 18 and over. He abstained from the vote.
Most young people are unlikely to be first in line for the vaccine, however. The US Centers for Disease Control and Prevention said the first wave of vaccines should be given to health-care workers that treat patients and residents of long-term care facilities. The next wave will include other health-care workers, essential workers, and adults with medical conditions, such as cancer and diabetes, that put them at high risk for severe COVID-19.
Now that the vaccine is authorized, the difficult task of distributing and administering has begun. The doses must be shipped and stored at about –70 °C, and Pfizer is using dry ice and special containers to keep them cold. Upon arrival, the vaccine can be kept refrigerated at 2–8 °C for up to 5 days. Pfizer says it is banking on a just-in-time system with minimal intervals between manufacturing, shipping, and administering the vaccines.
Medical facilities have begun prioritizing vaccine administration to their staff members. “States are being asked to basically figure this out themselves. It is not coming from the federal level,” Edupuganti says. Although the government is making the vaccine available for free, states and medical facilities are left with the cost of administering it and keeping track of recipients, including ensuring that they return for their booster shot 3 weeks later.
Because such large quantities of an mRNA vaccine have never been made before, some delays in the production and rollout of the vaccines should be no surprise. Pfizer has already experienced a delay in producing enough raw material for its vaccine, which led it to cut its 2020 goal of 100 million doses to 50 million.
There are some lingering questions about for whom and how well Pfizer’s vaccine will work. The company doesn’t know if the vaccine is safe and effective for children under 16, for pregnant women, and for immunocompromised people. The company is planning additional studies with these groups.
And although the vaccine clearly protects against the disease, Pfizer is still collecting data on whether it also blunts the spread of infection. Until we know, Mejias says, it’s important for vaccinated people to follow measures like mask wearing and social distancing to prevent unintended spread of the virus.
Doctors will also need to watch for rare side effects that may be found only once the vaccine is given to millions of people, Edupuganti says. Two people in the UK with a history of severe allergies experienced anaphylaxis after getting the shot. The CDC recommends that doctors monitor everyone receiving the vaccine for 15 min and those with a history of anaphylaxis for 30 min.
People getting the Pfizer vaccine should anticipate side effects, including fatigue, headache, muscle pain, and chills. These reactions are within the range of side effects produced by existing vaccines, according to Edupuganti. “This COVID-19 vaccine is more reactogenic than a flu vaccine but less reactogenic than some vaccines, such as the shingles vaccine,” she says.
While Pfizer awaited the authorization of its vaccine Dec. 11, two other groups reported setbacks on their COVID-19 vaccines built on the more traditional recombinant protein technology. CSL Behring and the University of Queensland announced that they were abandoning their vaccine, while Sanofi and GlaxoSmithKline said their trial would be delayed.
Queensland researchers modified the coronavirus spike protein with amino acids derived from an HIV protein intended to boost immunity. Unexpectedly, vaccine recipients developed antibodies to HIV. Follow-up tests confirmed that they were not actually infected with HIV, but CSL and the Australian government decided to drop the vaccine rather than change existing HIV testing procedures.
The Sanofi-GSK vaccine produced good immune responses in people under 50 but not in those over 50, likely because the concentration of antigen—the spike protein—was not high enough, the companies say. Although the firms were planning to start a Phase 3 trial this month, they now plan to reformulate the vaccine and test it in a Phase 2b study starting in February. The original goal of having the vaccine authorized by the middle of 2021 has been pushed to the end of the year.
“This slows down clinical development of these vaccines, but they still can be optimized and contribute to worldwide vaccination plans to overcome the pandemic,” says Hoft at Saint Louis University.