J&J's single-dose COVID-19 vaccine gets backing from FDA staff ahead of panel meeting

Johnson & Johnson's COVID-19 vaccine candidate Ad26.COV2.S appeared safe in clinical trials and protected against SARS-CoV-2 infection starting at 14 days after vaccination, according to FDA briefing documents released Wednesday ahead of an advisory panel meeting set for February 26. Agency reviewers noted that efficacy findings were also "generally consistent" across subgroups, including by age and risk for severe COVID-19. Further, they noted that as Ad26.COV2.S is administered as a single dose, this could provide "operational benefits to mass vaccination campaigns."

Earlier this month, the company submitted a filing seeking FDA emergency-use authorisation (EUA) based on data from the Phase III ENSEMBLE trial conducted in the US, South Africa and Latin America with over 40,000 participants aged 18 years an older. Similar to what Johnson & Johnson had reported in late January, FDA staff said Ad26.COV2.S showed efficacy of 66.9% against moderate-to-severe/critical COVID-19 across all geographic areas in which the trial was conducted at least 14 days after the single-dose vaccination. The rate was 66.1% when considering cases at least 28 days after the vaccine was given. Regarding severe/critical COVID-19 occurring at least 14 days and 28 days after vaccination, efficacy rose to 76.7% and 85.4%, respectively, which also aligned with Johnson & Johnson's interim analysis.

Trend toward rising protection in older people

FDA reviewers noted that Ad26.COV2.S appeared less effective for the subgroup of participants aged ≥60 years with comorbidities, compared to the overall population, although they pointed to a trend of "increasing vaccine efficacy with narrower confidence intervals as numbers of cases included in the analysis increased." Meanwhile, results for some other subgroups in the study with small numbers of participants, such as those ≥75 years of age and certain racial groups, have "limited interpretability," FDA staff said, while there was not enough data to assess efficacy among those previously infected with SARS-CoV-2.

Agency staff also highlighted a post-hoc analysis of all COVID-19-related hospitalisations, and said there were two cases among vaccinated individuals starting 14 days after vaccination, and zero cases at the 28-day mark. By contrast, there were 29 cases in the placebo group after 14 days post-vaccination, and 16 cases after 28 days. Further, as of February 5, there were no deaths due to COVID-19 in the vaccinated arm of the study, compared with seven deaths in the placebo group.

Reviewers also indicated there is insufficient data at the moment to draw conclusions as to whether Johnson & Johnson's vaccine can prevent asymptomatic infection, nor is it possible to say if efficacy is sustained beyond two months given the limited length of follow-up. However, an analysis conducted in 2650 subjects found that 50 people in the vaccine group tested positive for the SARS-CoV-2 virus without having symptoms, compared to 18 who received the vaccine, representing a 65.5% reduction.

High efficacy against severe/critical illness across variants

Johnson & Johnson had previously reported that the vaccine's efficacy also varied by region, with the level of protection against moderate-to-severe COVID-19 28 days after vaccination being 72% in the US, dropping to 66% in Latin America and 57% in South Africa, where the highly transmissible B.1.3.5 strain was first detected. Vaccines from Pfizer and AstraZeneca have appeared to elicit less protection against this particular variant as well, with South Africa recently pausing rollout of AstraZeneca's shot and launching its national vaccination drive with Johnson & Johnson's candidate instead.

FDA reviewers suggested that while Ad26.COV2.S appeared less potent in the South African cohort of Johnson & Johnson's trial, where there was a predominance of the B.1.3.5 lineage during the study period, "vaccine efficacy against severe/critical COVID-19 was similarly high across the US, South Africa and Brazil." According to the briefing documents, Ad26.COV2.S was found to be 64% effective in South Africa at 28 days post-vaccination against moderate-to-severe/critical COVID-19 caused by the B.1.3.5 variant, but it reduced severe/critical illness there by 81.7%. Similarly, the vaccine's efficacy against severe/critical COVID-19 in the US was 85.9% at 28 days, and 87.6% in Brazil, where over two-thirds of cases have been sequenced, and nearly 70% of these were identified as variant of the P.2 lineage. Still, FDA staff said it is "critical" to continue evaluating the vaccine's effectiveness even after an EUA is issued as potential changes in virus infectivity and significant mutations to the S protein "limit the generalisability of the efficacy conclusions over time."

Commenting on the data, Paul Offit, a member of the FDA advisory committee, said "most encouraging to me were the data in South Africa." Offit added "that you could still get protection against medically attended illnesses - meaning hospitalisation, ICU admission and deaths from that vaccine against the South African strain, I thought that was really encouraging."

'No specific safety concerns'

The safety analysis through the January 22 data cut-off included 43,783 participants with two months of median follow-up. "The analysis supported a favourable safety profile with no specific safety concerns identified that would preclude issuance of an EUA," FDA reviewers said. The proportions of participants who had at least one serious adverse event was 0.4% in both the vaccine and placebo groups. The results showed that 15 thromboembolic events occurred in subjects given Ad26.COV2.S, versus 10 in the placebo group, while there were six case of tinnitus in the vaccine arm compared to none in those who received placebo. The FDA noted that it will recommend monitoring for thromboembolic events if Ad26.COV2.S is used in larger populations.

The regulator said there was one case of Guillain-Barré syndrome (GBS) and another of pericarditis that occurred among vaccine recipients, while reports of Bell's Palsy were "overall balanced" between the vaccine and placebo groups, with two cases occurring in each. FDA staff said they could not rule out that the vaccine may have contributed to the pericarditis case since no alternative etiology was determined, and while the events of facial paralysis and GBS are "unlikely related" to the vaccine, they could not definitively exclude a causal relationship there either.

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