An advisory panel on Thursday recommended that the Food and Drug Administration issue an emergency use authorization for a Covid-19 vaccine developed by Moderna, all but guaranteeing the agency will do so.
The authorization, expected on Friday, will mark the second Covid-19 vaccine cleared by the agency — and amount to one more step toward curbing a pandemic that has infected an estimated 17 million people and killed more than 300,000 in the United States.
Both Moderna’s vaccine and the one developed by Pfizer and its partner BioNTech, which was granted an EUA last week, use messenger RNA to instruct the body’s cells to produce copies of the spike protein found on the exterior of the SARS-CoV-2, the virus that causes Covid-19. Those vaccine-induced proteins teach the immune system to recognize the coronavirus as an invader and attack it when an immunized person is exposed to the virus.
Clinical trials showed both vaccines were highly effective, about 94% or 95% in fact, though both trigger side effects in a portion of people vaccinated.
STAT live-blogged the meeting of the advisory panel, known as the Vaccines and Related Biological Products Advisory Committee. An archive is below.
We have results
4:59 p.m. The question: Based on the totality of scientific evidence available, do the benefits of the Moderna Covid-19 vaccine outweigh its risks for use in individuals 18 years of age and older?
The panel’s answer: 20 votes in favor and one abstention.
The vote comes as little surprise considering the tenor of the day’s discussion, where panelists repeatedly endorsed Moderna’s data and reserved their questions for matters of the future, namely the long-term results of the vaccine and the company’s plan for unblinding its ongoing Phase 3 study.
“I think this is a really opportune time to move science forward, and I would say that the evidence — which has been studied in great detail — on this vaccine highly outweighs any issues that we’ve seen,” said Hayley Gans, an infectious disease specialist at Stanford University’s Lucile Packard Children’s Hospital.
There was some debate as to whether the wording of the voting question was too broad, with Tufts University infectious disease expert Cody Meissner asking for it to be amended to make clear that the debate was over an emergency use authorization rather than a full FDA approval. After a brief back-and-forth about the meaning of various words and the role of FDA advisers, most of the group came around on accepting — and voting yes to — the question as initially written.
“The answer to that question is clearly yes,” said Paul Offit, a virologist at Children’s Hospital of Philadelphia. “The question is never when do you know everything. It’s when do you know enough.”
Michael Kurilla of the National Institutes of Health, the lone abstention, said he remained ill at ease with the wording of the question.
The panel’s assent sets the stage for an emergency use authorization for Moderna’s vaccine, which could arrive as soon as Friday. A nationwide rollout would follow in the coming days, mirroring Operation Warp Speed’s distribution of the Pfizer and BioNTech vaccine earlier this week.
One footnote for the record: The panel’s opinion on Moderna’s vaccine is numerically more positive than its vote on Pfizer’s vaccine last week, which totaled 17 in favor, four opposed, and one abstaining. But that has more to do with procedure than preference. Pfizer requested an emergency use for people over the age of 16, despite having a small amount of data on the vaccine’s benefits for those under 18, which was off-putting to a few panelists. By contrast, Moderna’s application covered only those over 18, so there was no dissent about teenage vaccination.
— Damian Garde
4:50 p.m.: After a very long day, members of VRBPAC almost voted to recommend that the FDA issue an emergency use authorization for the wrong vaccine.
When members were asked to vote, the ballot before them on the screen asked if an EUA should be issued for the Pfizer-BioNTech vaccine, which was given an EUA last week.
“This is the wrong vote,” one of the members called out. A second vote was conducted.
— Helen Branswell
Another safety signal?
2:58 p.m.: Something a bit unexpected to add to the possible Covid vaccine side effects watch list: facial swelling in people who have had dermal fillers.
Rachel Zhang, an FDA medical officer who is presenting the agency’s analysis of the Moderna data to VRBPAC, reported that two people developed facial swelling after vaccination; both had a prior history of getting cosmetic injections of dermal fillers in their cheeks.
One person had undergone the procedure two weeks before being vaccinated; the second had most recently had dermal fillers injected about six months before being vaccinated.
A third person in the vaccine arm of the Moderna trial developed lip angioedema — swelling — about two days after vaccination. This person had received prior dermal filler injections in the lip, Zhang said.
“Interestingly, that subject reported a similar reaction after a previous influenza vaccine,” she noted.
In all three cases, the swelling was localized and resolved itself after treatment with antihistamines or steroids. Zhang said the FDA team did a literature review and found earlier reports where people with dermal filler injections reacted with temporary swelling to vaccinations.
“We’re planning to note this in the prescribing information.”
— Helen Branswell
An important footnote
2:40 p.m.: Both the Moderna and Pfizer vaccines seem to prevent severe Covid-19, in addition to symptomatic infection. At the Pfizer panel, there was a lot of discussion about the one patient in the vaccine group who was marked as having severe disease, compared to the nine who didn’t.
Moderna has more severe cases — 30 — in the study, and all were up until now in the placebo group. But the FDA revealed that there is one potential severe case, not adjudicated, that occurred in a patient who received the vaccine. It’s a good reminder that we don’t know for sure that the vaccine’s ability to prevent severe disease is 100% based on the data we have.
— Matthew Herper
There’s a lot more Moderna data coming
2 p.m.: We know that, for all the vaccine clinical trials, more data are being collected after the study is officially done. For Moderna’s study, that seems to be a lot. The primary analysis of Moderna’s study included 196 cases of symptomatic Covid-19.
In responding to a question at the FDA panel about whether placebo-receiving participants should remain blinded, Jacqueline Miller, a Moderna senior vice president, said there are 450 more cases of disease that are going through the adjudication process, meaning that researchers are double-checking that everything is recorded properly before the data are analyzed. That would triple the number of cases in the study. She also said that one patient, who received placebo, had died from severe Covid-19.
— Matthew Herper
The elephant returns
1:35 p.m.: Earlier today Moderna executives told the panel that the company has done 12 Phase 1 and Phase 2 trials of mRNA vaccines for eight other pathogens over the years; those trials enrolled about 17,000 participants in total. The other experimental vaccines use the same vaccine platform and similar ingredients to Moderna’s Covid-19 vaccine.
Mark Sawyer, a professor of clinical pediatrics at the University of California San Diego, asked whether Moderna had gone back through the data of those earlier trials to see if there had been any reports of anaphylaxis among the participants.
Moderna did a rapid review of those data, Jacqueline Miller, vice president for infectious diseases development, told the committee. There was one report of anaphylaxis — in a woman with a soy allergy. She developed anaphylaxis more than two months after being vaccinated. Anaphylaxis triggered by vaccination has rapid onset, so this case is likely not linked to vaccine receipt.
Tal Zaks, Moderna’s chief medical officer, noted that the lipid nanoparticles used in the Moderna vaccine are not identical to the lipid nanoparticles in the Pfizer vaccine, and he would not assume that they would have the same potential to cause allergic reactions or other side effects. Lipid nanoparticles are used in the vaccines to encase the mRNA and protect it from being degraded before it can enter cells and trigger an immune response.
— Helen Branswell
The panel has some unanswerable questions
11:45 a.m.: Does Moderna’s vaccine prevent viral transmission in addition to symptomatic disease? Has the virus figured out how to get around it? And what happened with the 11 volunteers who got Covid-19 despite getting vaccinated?
The answer to those questions, posed by the panelists after Moderna’s exhaustive presentation on safety and efficacy, is pretty simple: No one knows yet. Jacqueline Miller, head of Moderna’s infectious disease unit, said the company is still collecting and analyzing key data, which is unlikely to be ready until next month.
To panelist Paul Offit, a virologist at Children’s Hospital of Philadelphia, those 11 so-called breakthrough cases of Covid-19 are particularly key. If it turns out those patients had demonstrably lower levels of neutralizing antibodies than vaccinated patients who didn’t get Covid-19, that could help establish a baseline immune response needed to protect against infection. As it stands, no one is certain just what kind of antibody levels are needed to prevent Covid-19.
Similarly, as University of Pittsburgh School of Medicine virologist Patrick Moore pointed out, those 11 volunteers could be instrumental in understanding how SARS-CoV-2 might mutate. If their viruses turn out to be genetically different from others in the study, it might suggest that SARS-CoV-2 can evolve to get around vaccination, which would be alarming.
But they’ll have to wait, Miller said, as Moderna has yet to do the swabbing, serology, and sequencing necessary to answer those vital questions.
— Damian Garde
Moderna investigator argues for giving more placebo patients the vaccine, sooner
Lindsey Baden, a researcher at Brigham and Women’s Hospital and one of the lead investigators in the Moderna vaccine study, presented Moderna’s plan for giving placebo patients vaccine. His comments implied that many of the FDA’s desires would not be reasonable.
He said that the results from the Pfizer and Moderna studies “are not lost” on study participants. “It’s important we carefully consider the volunteer’s viewpoints,” he said. “Without them, clinical research cannot function.” He said that volunteers, many of them health care workers who might be eligible for the Pfizer/BioNTech vaccine, are already voting with their feet and dropping out of the study. He pointed out that patients were enrolled in the Moderna study precisely because they were at high risk for Covid-19 and its complications.
Baden said that he was a co-author on a paper proposing the double-blind crossover study proposed by Stanford’s Steven Goodman earlier in the day. But he said it’s too late to put that design in place.
“The problem is it’s impractical at this point in time, in my view, and if we lose our volunteers, then the ability to learn anything further will be substantially impaired,” Baden said.
— Matthew Herper
Moderna reveals plan to give placebo patients vaccine
11:05 a.m.: Moderna unveiled a plan to offer volunteers who received placebo in its clinical trial the vaccine. It appears this plan would switch volunteers more quickly than the one described by Pfizer and BioNTech last week for their Covid-19 vaccine.
But the FDA and the advisory panel continued to express resistance about offering volunteers the vaccine too soon. Companies have said that they feel an ethical obligation to deliver vaccine to placebo recipients; the FDA and experts at its advisory panel have debated whether this obligation even exists. Instead, they argue, offering vaccine to volunteers receiving placebo limits the quality of the data about the vaccine’s long-term efficacy and side effects.
Pfizer and BioNTech plan to offer placebo volunteers the vaccine as it would otherwise become available to them based on recommendations from the Centers for Disease Control and Prevention and local authorities, a plan informed by pressure from the FDA not to offer the vaccine too early to those volunteers. In contrast, the Moderna plan seems to begin offering vaccine to any trial participants who request it, although all of the wording around that plan is not entirely clear.
Steven Goodman, a guest speaker and Stanford’s associate dean of clinical and translational research, made a case for a different clinical trial design, in which all volunteers in Moderna’s clinical trial would be called in for two more shots. Placebo recipients would get the vaccine, and vaccine volunteers would receive the placebo. This would allow for the collection of more data, in particular about how durable the benefits of the vaccines are.
Eric Rubin, the editor of the New England Journal of Medicine and a VRBPAC panelist, endorsed the idea. “This is the way these trials should have been designed,” he said. But last week, representatives from Pfizer described that change, which would involve every volunteer in a 44,000-person study, as impractical. Moderna, which conducted a 30,000-person study, is likely to agree.
In a letter sent to participants in its trial, Moderna advises them that all of them will be reconsented, and then continues: “If you find out that you received placebo, we plan to offer you the opportunity to receive the mRNA-1273 vaccine and to continue to be followed in the study. We hope to start offering the vaccine within approximately 1-2 weeks after EUA is granted for mRNA-1273.”
The letter contains no details suggesting that volunteers might have to wait after this process begins.
The FDA briefing documents also discussed Moderna’s plans: “Moderna expects that participants, including approximately 25% who are healthcare workers, may request unblinding to receive mRNA-1273 or another vaccine potentially available under EUA external to the trial.”
The documents continue that Moderna “is evaluating the opportunity to amend the protocol to proactively reconsent participants who received placebo to be offered mRNA-1273 vaccination and to remain in the trial, enabling ModernaTX to continue to collect the relevant safety and effectiveness data over the entire two years of follow-up while increasing the likelihood of retaining participants on trial.”
Tal Zaks, Moderna’s chief medical officer, argued that volunteers who received placebo would not be “jumping the line” when they received the vaccine, because they would be receiving shots designated for clinical trials, not commercial use.
This appears to be one area where the rush to start late-stage studies of vaccines led to poor planning on the part of regulators and, potentially, Operation Warp Speed. In his presentation, Goodman suggested that it is problematic for all of the companies studying vaccines to have different plans for what happens when the placebo recipients want to get a vaccine. That, however, appears to be exactly what is happening.
— Matthew Herper
Addressing the elephant in the room
9:55 a.m.: The anaphylaxis issue came up quickly in today’s discussion. Doran Fink, deputy director of FDA’s division of vaccines and related products applications, raised the now two cases of allergic reactions — one of which was anaphylaxis — in health workers in Alaska on Wednesday. They followed reports of two cases of anaphylaxis in the United Kingdom last week. All of these cases were after receipt of the Pfizer vaccine.
Fink said the FDA anticipates there will be more reports of allergic reactions to the vaccines, and they will be investigated when they occur.
“While the totality of data at this time continue to support vaccinations under the Pfizer EUA without new restrictions, these cases underscore the need to be vigilant during the early stage of the campaign,” he told the committee.
The FDA is working with Pfizer to update the fact sheet and prescribing information for their vaccine to highlight guidelines for post-vaccination monitoring and management of allergic reactions, stressing the need to be able to rapidly treat anaphylaxis if it occurs. Fink said the same will be done for the Moderna vaccine, if it is authorized for use under an EUA.
— Helen Branswell
6:30 a.m.: With one mRNA vaccine to prevent Covid-19 already being rolled out under an emergency use authorization in this country, a second vaccine that seems as effective will surely be approved.
And Moderna executives have chosen an easier path; the company’s EUA application asks only to be able to use the vaccine in people 18 and older. Pfizer applied for an EUA for people 16 and older, even though it had data from only 153 16- and 17-year olds. The paucity of that data caused consternation among some VRBPAC members; several voted against the recommendation based on that fact alone.
While Moderna will not face that issue, there will undoubtedly be questions about the side-effect profile of the vaccine. Documents released Tuesday by the FDA in advance of the meeting showed the Moderna vaccine appeared to be more reactogenic — that is, it was more likely to induce side effects — than the Pfizer vaccine. Nearly 16% of participants in the vaccine arm of Moderna’s Phase 3 clinical trial developed what is known as a grade 3 reaction — severe but not severe enough to be hospitalized.
There may be discussion about Bell’s palsy, a temporary facial paralysis, cases of which were reported in both the Pfizer and Moderna trials. Pfizer reported four cases of the condition among people in its vaccine arm, and none among its placebo recipients. Moderna saw three cases among people who received their vaccine, and one in the placebo arm. The National Institute of Neurological Disorders and Stroke estimates that about 40,000 Americans a year develop Bell’s palsy.
There may also be questions about anaphylaxis, a potentially life-threatening allergic reaction. On Wednesday a nurse in Alaska who had just been vaccinated with the Pfizer vaccine developed flushing, an elevated heart rate, and shortness of breath — signs of an allergic reaction. Last week, two British nurses with histories of severe allergies developed anaphylaxis after being vaccinated. VRBPAC member will likely want to know if Moderna saw any hint of allergic reactions among the trial participants it vaccinated.
On the plus side, people involved in the massive task of trying to vaccinate Americans will welcome the arrival of this vaccine. Its requirements for storage are less onerous than is the case for the Pfizer vaccine; whereas Pfizer’s must be stored at -94 Fahrenheit, which takes special freezers, the Moderna vaccine can be stored in regular freezers and, when thawed, in a refrigerator for up to 30 days. This vaccine will be much easier to use than the one that beat it to an EUA.
— Helen Branswell
6 a.m.: Good morning. The meeting starts at 9 a.m. EST with roll call, followed by a short presentation by the FDA. At 10:45 a.m., Moderna executives will make a detailed presentation on their vaccine.
But before that, at 10:05 a.m., Steven Goodman, associate dean of clinical and translational research at the Stanford University School of Medicine, will — as he did during the Pfizer VRBPAC meeting — talk about the implications of issuing EUAs for the ongoing effort to collect placebo-controlled data on the performance of Covid vaccines.
Pfizer, and now Moderna, have indicated they plan to unblind the participants in their trials when they have reached the point where they would be eligible to be vaccinated. For instance, any health workers in these trials are in the priority list currently being offered vaccine; the companies say they cannot ethically keep them in the dark about whether they received vaccine or placebo in the trial. Pfizer has already started informing some participants which arm they were in.
Last week Goodman presented an interesting but complicated idea for continuing the trials in a blinded fashion, suggesting all participants — 44,000 in the case of Pfizer, 30,000 in the case of Moderna — could be called in and given two more vaccinations. People who had first received placebo would get vaccine; those who received vaccine would receive saline shots. All would remain unaware of when they were vaccinated, but the impetus for participants to quit the trial to get vaccine would presumably dissipate.
Soon after, Pfizer senior vice president William Gruber put the kibosh on that idea, describing it as an enormous amount of work that was unlikely to have the desired effect. The company is clearly ignoring this suggestion.
Goodman’s session is scheduled for 40 minutes. Is another proposal about to be aired?
— Helen Branswell