First US Phase III trial of a COVID-19 vaccine begins

At 6:45 Monday morning in Savannah, Georgia, a volunteer was injected in a Phase III study of mRNA-1273, an experimental vaccine made by Moderna. Thus began the first final-stage study of a COVID-19 vaccine in the US. At 5:15 that afternoon, two other companies, Pfizer and BioNTech, announced that they had begun a late-stage study of their jointly developed COVID-19 vaccine, BNT162b2. The world could learn as early as October or November whether the vaccines are broadly safe and effective.

Developed through a partnership between the US National Institutes of Health and the biotech firm Moderna, mRNA-1273 is the first mRNA vaccine to begin late-stage studies of preventing infection by the novel coronavirus. While conventional vaccines typically use inactivated virus or pieces of a virus to train our immune cells to react to a pathogen, Moderna’s vaccine delivers the genetic instructions for building a key component of the virus.

The Phase III trial is expected to enroll roughly 30,000 people. Half will get two doses of the vaccine—to be effective, a booster is required—and the other half will receive two shots of a placebo.

During a press conference to discuss the trial launch, NIH director Francis Collins told reporters that so far 150,000 people had registered on a website meant to recruit volunteers for the trial. While the response is encouraging, Collins noted that “most of them don’t live in areas where the recruitment sites are active.”

If more people sign up in areas where the virus is spreading, the trial should be able to quickly get answers about the vaccine’s safety and efficacy. Based on both the ongoing rate of infection and the robust interest in the trial, the National Institute of Allergy and Infectious Diseases should have enough data to judge whether the vaccine works and is broadly safe by November or December, NIAID director Anthony Fauci told reporters.

If the results are positive, the next big question is how soon the vaccine can be approved and made available to the public. While the ultimate goal is full approval, Moderna CEO Stéphane Bancel said an Emergency Use Authorization (EUA) might be appropriate for a vulnerable subset of the population during the period when the US Food and Drug Administration is reviewing the application. An EUA allows government stockpiling and distribution of unapproved products during extreme circumstances, such as the current coronavirus pandemic.

Moderna is prepared to have hundreds of millions of doses of the vaccine available in 2021, Bancel said. Between its own site in Massachusetts and that of its contract manufacturing partner, Lonza, Moderna’s goal is to get to close to a billion doses of vaccine in 2021. “It’s not in the bag yet,” he said, but the firms are making progress.

The day before the trial began, Moderna announced receiving another big commitment from the US Biomedical Advanced Research and Development Authority, which has been supporting scale-up of COVID-19 vaccines. The new award increases the agency’s funding from $483 million to up to $955 million, reflecting a larger-than-anticipated Phase III study.

Like all of the COVID-19 vaccines in clinical development, mRNA-1273 is moving forward at a breathtaking pace. The Phase III study is launching just 6 months after scientists at NIAID first saw the genetic sequence of SARS-CoV-2, the virus that causes COVID-19.

However, the vaccine’s efficacy is far from assured. No mRNA vaccine or therapy has reached the market for any disease. And so far, the world has only seen data from a Phase I trial of mRNA-1273 that enrolled 45 healthy volunteers. The study’s primary goal was to ensure the vaccine was safe and to help guide the choice of a dose for the Phase III trial.

Researchers landed on 100 µg because it struck the best balance between safety and a robust immune response; all 15 people in that dosage arm of the study generated neutralizing antibodies—the kind that prevent SARS-CoV-2 from entering cells. While the result was encouraging, scientists cannot predict whether generating neutralizing antibodies is enough to prevent infection by the virus.

The second late-stage COVID-19 vaccine trial is also an mRNA vaccine, jointly developed by Pfizer and the German firm BioNTech. Half of the volunteers in the Phase II/III trial, which will enroll up to 30,000 people, will receive the experimental vaccine BNT162b2, while the other half will receive a placebo. If the vaccine proves effective, Pfizer says it could request regulatory approval for the vaccine, possibly through an EUA, as early as October.

The vaccine is one of four candidates that Pfizer and BioNTech designed and tested in Phase I studies. The companies have posted two pre-prints, which have not been peer-reviewed, outlining preliminary results from a different vaccine candidate, BNT162b1, but they have not published any data on BNT162b2 yet. Peer-reviewed data from Moderna’s Phase I study was recently published.

Like Moderna’s vaccine, Pfizer and BioNTech’s four vaccine candidates all focus on inducing immunity to part of the coronavirus called the spike protein. While Moderna only tested a vaccine that encodes instructions for making the full version of this large protein, Pfizer and BioNTech compared vaccines that encoded the full spike to ones that encoded just a fraction of the spike—a strategy that the firms said would enable easier manufacturing and might help the immune system focus on an important part of the protein called the receptor binding domain. Both vaccines induced similar levels of antibodies in Phase I studies, but the vaccine encoding the full spike protein, BNT162b2, created a better T cell response, according to the companies.

The primary goal of both the Moderna and Pfizer studies is to simply prove that the vaccines can prevent COVID-19. Both firms have set secondary goals of preventing severe COVID-19 and preventing SARS-CoV-2 infection entirely. Many immunologists say that preventing disease is a lower bar than entirely preventing viral infection.