Recipients of the Johnson & Johnson coronavirus vaccine may need a booster shot – and while they could benefit from a second dose of the original vaccine, they may derive even greater protection if the boost comes from a different vaccine technology, according to data that emerged Wednesday.

The documents include an FDA review of Johnson & Johnson’s tests of a second dose of its own vaccine and a separate preprint study that tested mixing booster doses from different companies. The data could provide a road map for the 15 million people who received the Johnson & Johnson vaccine in the United States, many of whom have felt left out because the vast majority of U.S. vaccine recipients received messenger RNA vaccines from Pfizer-BioNTech or Moderna.

The Food and Drug Administration review of company data appeared to acknowledge the potential benefit of a booster dose of the Johnson & Johnson vaccine, although the agency did not have time to complete an independent analysis of the company’s data as it typically does.

An expert advisory panel will meet Friday to consider the Johnson & Johnson booster and a National Institutes of Health study in which recipients of all three coronavirus vaccines received boosters from different companies.

That preprint study found that a second shot using a messenger RNA vaccine – Moderna – triggered the biggest boost of virus-neutralizing antibodies in Johnson & Johnson recipients, resulting in a 76-fold increase in antibody levels. A Pfizer booster increased antibody levels 35-fold. A matching Johnson & Johnson booster triggered only a fourfold increase.

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From the dawn of the vaccine campaign, many experts said they believed the one-shot Johnson & Johnson regimen would ultimately require a second shot, and the documents released Wednesday pave the way for a panel of experts who advise the FDA to discuss Friday the timing, necessity and safety of a booster dose – and whether they should stick to the same shot.

There are limitations to the NIH study, which was small, with short-term follow-up. The study measured antibody levels, which are easier to evaluate than other parts of the immune system, but did not review whether someone got infected. The Moderna dose tested in the trial was twice what Moderna is seeking authorization for as a booster.

“This is a small piece of the big picture,” said John Beigel, associate director for clinical research in the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, who worked on the study. Beigel said the main finding is that it appears booster doses can be used interchangeably and safely, regardless of what the primary vaccination was.

Beigel said there are other parts of the immune response that have yet to be measured after the boost, and recipients need to be followed to see what happens to those antibody levels.

“I would be hesitant to say one is better than the other. Our study was never designed to do that,” Beigel said.

The data will leave the FDA’s advisory committee with a bigger question: What is the role of a booster of Johnson & Johnson’s vaccine in a country with enough supply of messenger RNA vaccines?

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“If there’s one [booster] dose, should you get the one with the highest antibody? I’d probably say either of the two mRNA vaccines,” said Kathryn M. Edwards, professor of pediatrics in the division of infectious diseases at Vanderbilt University School of Medicine. “I think many people may choose to get the immunogenic booster.”

Johnson & Johnson’s initial advantage was largely logistical – the potential for a speedy vaccination campaign that could help end the pandemic, even though a single shot offered slightly less individual protection than the messenger RNA vaccines. It offered particularly strong protection against severe disease.

In a statement, Johnson & Johnson spokesman Jake Sargent said the results “complement” the other data “confirming the strong and long-lasting protection of the Johnson & Johnson single-shot COVID-19 vaccine, as well as Phase 3 data showing protection against COVID-19 increases when a booster shot of the vaccine is administered.”

The FDA review focused only on data submitted by the company, which exclusively tested a second shot of its own vaccine.

“Although not independently confirmed by FDA from datasets, summaries of the data suggest there may be a benefit in a second dose administered approximately 2 months after the primary dose,” FDA staff wrote in assessing data of a second dose of Johnson & Johnson.

There were shortcomings of the agency’s review of the Johnson & Johnson booster data. Typically, agency scientists do their own independent review of data, but much of the data was not submitted in time, meaning large parts depend on the company’s analysis.

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Johnson & Johnson is seeking authorization of a booster dose at six months or later after the initial shot for people 18 and older. The company says the extra dose could be given as early as two months after the first shot.

The safety and efficacy of a booster are reviewed in the documents Johnson & Johnson submitted to the FDA. The submission includes results from four clinical trials that tested booster doses two to three months after the first dose or six months after the initial shot.

Longer follow-up of the initial 40,000-person trial that showed the vaccine was effective found that it was 56% effective overall against illness, including moderate and severe disease – lower than the initial estimate.

One study that tested two doses 56 days apart found that two doses were 75% effective against illness, and 100% effective against severe disease.

Two other studies measured the immune response after a booster. Those studies suggested that giving a booster after six months drove antibody levels higher than if given at a shorter interval. But limitations in the test used to do the analysis mean FDA staff deemed that the immune responses shouldn’t be directly compared.

One of the discussion questions the FDA has laid out for the expert panel is whether a second shot should be authorized at two months, or with at least a six-month gap.

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The FDA’s reviews of booster doses of messenger RNA vaccines have not taken a position on whether boosters were needed. A Pfizer-BioNTech booster dose was authorized for a select population despite that. The expert committee is expected to vote on Moderna’s booster Thursday.

In contrast, the review of the Johnson & Johnson vaccine suggests the agency sees a clearer need for another dose, even as data remain limited.

The agency noted that overall, the data suggest the Johnson & Johnson vaccine still protects against the worst outcomes – severe disease or death – but pointed out that the initial protection was less than other available vaccines in the United States.

“The highest effectiveness estimates (including for more severe COVID-19 disease) across clinical trials and real-world effectiveness studies . . . are consistently less than the highest effectiveness estimates for the mRNA COVID-19 vaccines,” reviewers wrote.

Kathleen M. Neuzil, director of the Center for Vaccine Development at the University of Maryland School of Medicine, said all the vaccines are protective against severe illness and death, and the Johnson & Johnson vaccine’s protection has held up well, suggesting that parts of the immune system other than antibodies are contributing to its protection.

“This is a small study, it absolutely points in the direction of . . . saying the mRNA boosts are better,” Neuzil said. “We’re going to learn a lot more in the next two days.”