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Johnson & Johnson submitted data from several clinical trials in support of both a second dose and booster dose of COVID-19 vaccine, but little of it was actually verified by the FDA, agency staff said in .

The FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) will meet on October 15 to discuss whether data support safety and effectiveness of a booster dose of Johnson & Johnson vaccine at least 2 months after the single-dose primary series, and whether data support that "an interval of at least 6 months between the primary vaccination and booster dose may result in a more robust booster response," FDA staff said.

Johnson & Johnson submitted safety and immunogenicity data from four clinical trials to support an amendment to their emergency use authorization (EUA) for a second dose of vaccine administered 2-3 months after the first, and a booster dose administered at least 6 months after the primary one-dose series.

However, the FDA only was able to conduct an independent assessment of the immunogenicity of the 6-month booster dose in , with data available for 17 healthy adults ages 18-55 who received a booster dose 6 months after the one-dose primary series.

"Datasets were not submitted in sufficient time for FDA to conduct an independent review to verify the Sponsor's analyses," FDA staff wrote. "Thus, FDA's assessment of the Sponsor's submission is based on a review of Sponsor-generated analyses that FDA determined to be most relevant to the request for use of a booster dose."

The assay used to measure immune response at 6 months following vaccination threw a wrench into the works, as FDA staff noted it was a "non-validated and non-qualified" assay, meaning that immune response from a booster at 6 months could not be compared to that at 2-3 months from the other studies, they said.

While FDA staff noted that only 12% of participants mounted measurable immune responses at one month following the primary series, they again blamed the assay. Six months later, 59% had a detectable response prior to the booster and 100% did following the booster.

When measuring immune response, Johnson & Johnson submitted a post-hoc analysis, which showed that geometric mean titer ratios were "above the FDA-recommended non-inferiority criteria (lower bound of 95% CI >0.67)." FDA staff added the analysis only included 17 participants and low sensitivity of the assay might be a confounder.

The study also included a descriptive analysis of neutralizing antibody response against the Delta variant for the same 17 people. At 6 months post-vaccination, 24% of participants had a detectable immune response, while 100% did following the booster, with a three-fold GMT increase at day 28.

None of the other studies were independently verified by FDA staff. Even , which was the initial basis of the single-dose EUA, featured top-line vaccine efficacy (VE) estimates, showing a decline in efficacy against moderate to severe disease from 66.9% in January to 56.3% in July, though VE against severe and critical disease "remained stable."

However, FDA staff said this could be due to a decline in VE against variants circulating in certain countries where the study was conducted. There was also insufficient data to determine VE against Delta.

found that "there may be a benefit in a second dose administered approximately 2 months after the primary dose," but FDA staff noted that confidence intervals around efficacy estimates overlapped between this study and COV3001. They also pointed to a small sample of adults age 60 and up, which "limits the ability to conclude about an increase in efficacy after the second dose in this group."

In Study COV1001 with 2- or 3-month intervals, FDA staff noted that while there was at least a two-fold increase in neutralizing antibody response, the study attempted to compare immune response between a younger cohort of adults ages 18-55 and an older cohort of ages 65 and up. It was also difficult to compare these data with the 6-month data due to the assay used, they added.

Study COV2001 found a "numerically higher immune response" when the second dose was given at the 3-month interval versus the 2-month interval, but FDA staff said there was no demographic breakdown for the older and younger cohorts, and "differences in age of participants between the two groups may impact the results."

FDA staff found no new safety concerns in any of the studies, but were unable to independently verify any of the safety data. They noted more frequent tinnitus, thromboembolic events, and seizures in the vaccine arm versus placebo, and out of 19 vaccine-related adverse events, nine were possible thromboembolic events.

Overall, they noted no new safety signals, but summed up their findings with, "no reliable conclusions can be drawn."

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