What to do with J&J Booster data
Johnson & Johnson has submitted data from multiple clinical trials to support a second dose and a booster dose of the COVID-19 vaccine, but few of them have in fact been verified by the FDA, said agency staff in briefing materials released Wednesday.
The FDA Advisory Committee on Vaccines and Related Biologics (VRBPAC) will meet on October 15 to discuss whether the data supports the safety and efficacy of a booster dose of the Johnson & Johnson vaccine at least 2 months after the primary single-dose series, and whether the data support that “an interval of at least 6 months between the primary vaccination and the 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 given 2-3 months after the first and a booster dose given at least 6 months after the primary single dose series.
However, the FDA was only able to conduct an independent assessment of the immunogenicity of the 6-month booster dose in COV1001, with data available for 17 healthy adults aged 18 to 55 who received a dose. booster 6 months after the primary series of one dose. .
“The datasets were not submitted in sufficient time for the FDA to conduct an independent review to verify the sponsor’s analyzes,” FDA staff wrote. “Thus, the FDA’s assessment of the sponsor’s submission is based on a review of the sponsor-generated assays that the FDA has determined to be most relevant to the booster dose request.”
The test used to measure the immune response at 6 months after vaccination threw a wrench into the work, as FDA staff noted that it was an “unvalidated and unqualified” test, which means that the immune response of 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 developed measurable immune responses one month after the primary series, they again blamed the test. Six months later, 59% had a detectable response before the booster and 100% after the booster.
When measuring the immune response, Johnson & Johnson submitted a post-hoc analysis, which showed that the geometric mean titers ratios were “above the non-inferiority criteria recommended by the FDA (lower limit of CI at 95%> 0.67) ”. FDA staff added that the analysis included only 17 participants and the low sensitivity of the test could be confusing.
The study also included a descriptive analysis of the neutralizing antibody response against the Delta variant for the same 17 people. At 6 months after vaccination, 24% of participants had a detectable immune response, while 100% had done so after the booster, with a three-fold increase in GMT on day 28.
None of the other studies have been independently verified by FDA staff. Even COV3001, which was the initial basis for single-dose EUA, had prominent vaccine efficacy (VE) estimates, showing a decrease in efficacy against moderate to severe disease of 66.9%. in January to 56.3% in July, although VE against critical and critical illness “remained stable”.
However, FDA staff said it could be due to a drop in VE against circulating variants in some of the countries where the study was conducted. There was also insufficient data to determine the VE versus Delta.
COV3009 found that “there may be a benefit in a second dose given approximately 2 months after the primary dose,” but FDA staff noted that the confidence intervals around the efficacy estimates overlapped between this study and COV3001. They also pointed out a small sample of adults aged 60 and over, which “limits the ability to conclude an increase in efficacy after the second dose in this group.”
In study COV1001 with 2-3 month intervals, FDA staff noted that although there was at least a two-fold increase in neutralizing antibody response, the study attempted to compare the immune response between a younger cohort of adults aged 18 to 55 and an older cohort aged 65 and over. It was also difficult to compare this data with the 6-month data because of the test used, they added.
The COV2001 study found a “numerically higher immune response” when the second dose was given at a 3-month interval compared to a 2-month interval, but FDA staff said there was no demographic breakdown for older and younger cohorts, and “differences in the age of participants between the two groups may have an impact on the results.
FDA staff did not find any new safety issues in any of the studies, but could not independently verify any of the safety data. They noted more frequent tinnitus, thromboembolic events and seizures in the vaccine arm compared to placebo, and out of 19 vaccine-related adverse events, nine were possible thromboembolic events.
Overall, they did not note any new safety signals, but summed up their results with “no reliable conclusion can be drawn”.