In review, FDA stays neutral on the need for a Moderna booster

The Food and Drug Administration set the stage Tuesday for a new round of decisions on which Americans should get coronavirus booster shots, releasing a review of data suggesting that an additional half-dose of Moderna's vaccine at least six months after the second dose increased antibody levels. But the agency did not take a position on whether an additional shot was necessary.

An independent advisory panel of experts will examine the available data on both Moderna and Johnson & Johnson boosters in a two-day meeting later this week. Votes are scheduled on whether to recommend emergency authorization of boosters for both vaccines. While the panel's votes are not binding, the FDA typically follows them.

In documents released Tuesday, Moderna argued that a third injection is needed because the potency of its vaccine wanes over time, with levels of neutralizing antibodies falling six to eight months after a second dose. The company also cited "real world evidence of reduced effectiveness against the delta variant," although the FDA noted that the studies diverge on whether Moderna's protection weakened over time against symptomatic infection or against the delta variant.

The company did not argue that a booster was necessary to prevent severe disease or hospitalization but concentrated its arguments on preventing infection and mild to moderate disease.

Moderna said the mean antibody level of participants in its study was 1.8 times higher after the booster than it was after the second shot. In another measurement, the booster raised neutralizing antibodies at least fourfold in 87.9% of people compared to after the second dose, thus narrowly failing to meet the agency's requirement of 88.4%.

In a document that Johnson & Johnson submitted to the FDA before this week's meeting, the company argued that booster shots of its vaccine increased protection against COVID-19, including against severe forms of the disease, and increased the strength of the body's immune response against virus variants. Johnson & Johnson said that a booster shot could be administered as early as two months after the first dose but recommended doing so at least six months after, when it said recipients had been shown to have a more robust immune response.

Only 14.9 million Americans have received the Johnson & Johnson vaccine, compared to 103 million fully vaccinated with Pfizer-BioNTech's vaccine and 69 million with Moderna's.The advisory panel will vote on whether to recommend booster shots for Moderna on Thursday and for Johnson & Johnson on Friday after hearing from the companies, FDA scientists and the public.

A researcher will also present initial results from an ongoing National Institutes of Health study on how each of the three vaccines works as a booster shot, including whether using a different vaccine as a booster produces a better immune response against COVID-19.

In its data review of Moderna, the FDA noted that overall, the vaccines used in the United States "still afford protection against severe COVID-19 disease and death" here. The FDA summarized the evidence for a Moderna booster without taking a position, just as it did before the committee met last month to discuss whether to recommend a booster shot of the Pfizer-BioNTech vaccine.

The FDA and the Centers for Disease Control and Prevention decided to authorize boosters for many Pfizer-BioNTech vaccine recipients. Those eligible include people who are 65 or older, who live in long-term care facilities, who have underlying medical conditions or who are at higher risk of exposure to the virus because of their jobs or institutional settings. The last group includes health care workers, teachers and prisoners.

In the review released Tuesday, the FDA proposed that the outside experts consider essentially the same eligibility groups for Moderna recipients. People familiar with the deliberations said that federal officials may also ask the committee to consider broadening eligibility for boosters to include more middle-aged people.

Moderna said it compared using a full dose and a half-dose as a booster and found that a half-dose boosted antibody levels well with lower risks of adverse side effects. It also said that a half-dose "would result in a substantial increase in the worldwide supply" of its vaccine.

Several independent studies have tried to measure whether Moderna's potency wanes over time. One federally backed review looked at COVID cases in July and August among more than 15,000 volunteers in Moderna's clinical trial. One group had been fully vaccinated between July and October 2020; the second was vaccinated between December 2020 and March 2021.

Those who got vaccinated later had a 36% lower rate of infection. But Dr. Hana M. El Sahly, a professor of molecular virology at Baylor College of Medicine and one of the lead researchers, said that mild cases among younger volunteers accounted for much of the difference.

The study did not find a statistically significant difference in rates of severe COVID-19 — and there were only 19 such cases. Overall, El Sahly said, "the findings do not indicate that a booster is needed."

Another recent CDC study of nearly 3,700 patients in 21 different hospitals from March to August found that Moderna's vaccine held up best of the three vaccines.

The researchers said that Moderna was 93% effective against hospitalization from COVID-19, compared with 88% for Pfizer and 71% for Johnson & Johnson. Pfizer's efficacy dropped significantly after four months, to 77%, while Moderna's basically held steady, they said.

Given the dearth of data that a Moderna booster is needed to prevent severe disease, the committee may debate other potential goals, including making the nation's booster strategy more coherent, better protecting Moderna recipients against mild and moderate disease, and trying to disrupt transmission of the virus.

Dr. Peter Marks, the FDA's head vaccine regulator, argued for a uniform approach to boosters at a town hall earlier this month. He said the goal was to reach "a harmonized approach" for all three vaccines and to simplify booster recommendations for the general population.

At least 1.5 million Americans have already gotten an additional dose of Moderna, even though third shots are currently authorized only for recipients with immune deficiencies. Some appear to be finding friendly pharmacists willing to administer an extra shot, while others may be pretending to be unvaccinated.

More than one-tenth of the nation's vaccinated seniors have obtained booster shots, and at least 7 million people have gotten a third shot of Pfizer's vaccine, according to CDC data.

"We're in this very complicated situation right now: People are going into pharmacies or places where vaccines are available and saying, 'I want my third dose of Moderna, or I want my second dose of J&J," said Dr. H. Cody Meissner, an infectious disease expert at Tufts Medical Center who serves on the FDA panel. "I don't think anyone has much doubt that we will need a booster dose for these vaccines. What we don't know is, how urgent is the need?"

The advisory committee is also likely to consider whether Moderna's protection against severe disease and hospitalization may eventually weaken. Booster proponents argue that Moderna's potency is declining much like Pfizer's, which is based on the same technology, only more slowly because its initial dosage is significantly stronger than Pfizer's and the interval between the first two shots is a week longer.

"The fundamental issue is, what are we trying to do?" said El Sahly. "Both Moderna and Pfizer seem to have waned when it comes to mild to moderate disease, especially with the delta variant. So if that's the goal, a booster is needed."

"If we want to prevent only severe disease that lands people in the hospital," she said, "that's a different mathematics."

The FDA has yet to release its review of Johnson & Johnson's booster data. But in its application for a booster authorization, the company supplied details from two studies.

In a study it announced in August, the company gave a second shot of the vaccine to 17 volunteers six months after the first. In these subjects, Johnson & Johnson reported, the levels of antibodies against the coronavirus rose twelve times higher than after the initial dose. Researchers did not determine exactly how much protection that boost provided against COVID-19.The second study, which Johnson & Johnson reported last month, indicated that a booster can indeed improve protection. In November 2020, the company launched a clinical trial with 32,000 volunteers, this time giving a second dose of the vaccine two months after the first.

The company announced that in the portion of the trial that took place in the United States, the efficacy rose to 94%. Worldwide, the increase was more modest, at 75% — around the same efficacy reported for a single dose in the U.S. over the winter. Against severe to critical COVID-19, two shots had an efficacy of 100%.