FDA Questions Reliability of Data Backing J & J’s Bid for Boosters

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The US Food and Drug Administration (FDA) said Johnson & Johnson may have to put its thumb on the scale when making its case to an advisory panel on Friday to market boosters for its single-dose vaccine.

Johnson & Johnson, together with its partner Janssen, has asked the FDA to authorize a second dose to boost the effectiveness of their one-shot vaccine. 

These second doses could be considered as soon as 2 to 3 months after the first dose for all Americans over 18 years of age.

A panel of advisors to the FDA will meet Friday to discuss whether data provided by the company supports an amendment to the vaccine’s emergency use authorization (EUA).

But the FDA, in a briefing document released today in advance of the meeting, questions some of the data used by Johnson & Johnson and Janssen to support their request for boosters.

In total, Johnson & Johnson and Janssen presented data from four different studies that tested a second shot of their vaccine at the same doses as the original when given as part of the primary series, 2 to 3 months after a first dose, or as a booster shot, 6 months after a first dose.

Overall, updated data from the original clinical trial of the single-dose vaccine suggest that it remains very effective against severe illness and death in the United States, though its effectiveness against infection does appear to have fallen over time from roughly 72% to 42%. 

The FDA notes that some of that decrease may be due to the emergence of variants in the countries where the vaccine is being studied, and is not necessarily explained by waning immunity. The agency notes that studies conducted in the United States show little decrease in vaccine efficacy over time.

“No Reliable Conclusions”

In the briefing document published ahead of the meeting, the FDA questioned the drug company’s methods, saying that, while results of its 6-month booster study met its recommended criteria, the results come from a small study of just 17 healthy adults ages 18 to 55. 

The agency notes that the study wasn’t originally designed to measure differences in immune response after a primary and secondary dose; that was done after the study was already under way, making the results subject to bias. 

The FDA also notes that the results appear to have been affected by the use of a less sensitive test to measure neutralizing antibody levels in vaccine recipients. 

In the original vaccine trial of the Johnson & Johnson shot, study volunteers had a good response to the vaccine a few weeks after they got the shot. But in the booster trial, the FDA notes, only 12% of study participants developed a measurable immune response a month after their first shot. After 6 months, 59% of study participants had a measurable response. 

That wasn’t a problem with the vaccine, the agency states, but with the test used to measure the antibodies, which appears to have been less sensitive than the antibody tests used to measure response in study volunteers in the original trial. They note that the new test has not yet been validated or qualified.

That less sensitive test appears to have made the booster dose look more effective, as antibodies after the booster were compared with antibodies after the primary dose. After the booster dose, 100% of people in the study developed measurable antibodies to the SARS-CoV-2 virus.

“No reliable conclusions can be drawn,” the FDA wrote in its summary of the 6-month booster dose data.

At the same time, no safety signals were identified in the results. The most commonly reported side effect after a booster was a sore arm, followed by headache, fatigue, and nausea.

The agency notes that Janssen has a larger study under way that should provide more information about how well booster doses work after 6 months, but said that data wasn’t yet available.

Two other small groups, with 25 participants in each study, were given second doses of the Johnson & Johnson vaccine 2 and 3 months after their first. The first group consisted of study volunteers ages 18 to 55. The second group was of volunteers over age 65. 

These groups, which were given the more sensitive antibody test, each saw sizeable jumps in levels of neutralizing antibodies after their second doses. These increases faded over time, but were still higher than after their first dose after 6 months.

The FDA notes that a larger study, where participants were given a second dose 2 months after their first, suggests that people may see increases in protection after a booster, but noted that the windows of uncertainty for these results overlap, so it’s not clear how much more benefit they might get compared with the original shot.

Reassuringly, the larger studies presented to the agency did not point to safety problems with boosters.

The FDA reviewers also noted that there were big data gaps related to the Johnson & Johnson vaccine. 

For example, information is still lacking on use of the vaccine in pregnant or breastfeeding women, in frail or elderly patients, and in children. The agency also noted that there’s little information about how well it works or how safe it is when combined with other vaccines.

The advisory committee is expected to vote on Friday on expanding the EUA for the Johnson & Johnson vaccine’s second dose. 

The FDA is not bound by the committee’s recommendations, but typically follows them.

Mix and Match

The panel will also discuss early data from a government-run clinical trial called Mix and Match that is doing just that — giving boosters to study participants with vaccines that are the same and different from the ones they originally received.

In a draft of the study published ahead of peer review on Wednesday, the results showed that people got higher levels of neutralizing antibodies and were more likely to mount strong immune responses against COVID-19 when they were boosted with a different vaccine than the one they originally got. 

Participants boosted with the same kind of vaccine they first received saw a 4- to 20-fold increase in antibody levels, while those who got a different shot saw a 6- to 76-fold increase. No safety concerns were identified in the first month following the second dose.

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