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Pivotal Trial Data Supports Viral Vector Vaccine against SARS-CoV-2

Final analysis of phase 3, placebo-controlled trial confirms efficacy and safety of single-dose adenoviral vector vaccine against COVID-19.

The final analysis of data from the placebo-controlled trial that was pivotal to emergency authorization of the Janssen single-dose adenoviral vector vaccine against COVID-19 confirms that more than half of recipients were protected against developing moderate to severe-critical illness for 6 months or longer.

The analysis determined that the vaccine afforded overall protection for 52.9% of recipients against developing moderate to severe-critical COVID-19, with differing levels of protection for specific variants.There was greater protection evidenced against the efficacy measures of severe-critical illness (74.6%), medical intervention including hospitalizations (75.6%), or death (82.8%).

Utilizing Kaplan-Meier cumulative incidence curves, the investigators determined that vaccine efficacy persisted through approximately 6 to 7 months after administration. The reduction in efficacy following that period was attributed, in part, to emergence of more resistant variants toward the end of the trial.

"Overall, our findings indicate that a single dose of Ad26.COV2.S provided protection against severe disease and hospitalizations, which could be important in regions requiring mass vaccination or in populations with poor adherence to two-dose prime regimens," indicated lead author Jerald Sadoff, MD, Janssen Vaccines and Prevention, Leiden, the Netherlands, and colleagues of the ENSEMBLE Study Group.

The multinational phase 3 trial began enrollment in September 2020, with data cutoff for final analysis in July 2021. A total of 43,788 participants were randomized 1:1 to receive the vaccine or placebo, and 39,185 who were seronegative for SARS-CV-2 at baseline were included in the per-protocol analysis population. Median follow-up was 121 days (range 1-284); and 91.3% of the vaccine group and 22.8% of the placebo group had follow-up of at least 2 and 6 months, respectively.

As new variants emerged in different locales during the study, analysis revealed differences in levels of protection. For example, vaccine efficacy was 70.2% (95% CI 59.1-76.8) against moderate to severe-critical COVID-19 caused by the alpha variant; 51.9% (19.1-72.2) against beta,and 36.5% (14.1-53.3) against the gamma variant.

The vaccine safety profile was derived from a subpopulation of 3356 in the vaccine group and 3380 receiving placebo. Overall, more solicited adverse events occurred in the vaccine group than with placebo during the 7 days after administration. Grade 3 or higher solicited local adverse events were rare among vaccine recipients (1.3% of those who were seropositive and 2.3% among seronegative vaccine recipients). The investigators reported that the vaccine was associated with generally mild-to moderate adverse events, and no new safety concerns were identified.

Sadoff and colleagues noted that the study provided limited or no data on the delta and omicron variants, and suggested that these will need to come from studies involving real-world evidence.

The investigators described one such study in South African health care workers during the emergence of the omicron variant in which the vaccine demonstrated 85% efficacy against hospitalization, when a booster was used 6 to 9 months after the single priming dose. The utility of a booster for the single dose regimen was also discussed in reference to evidence of omicron breakthrough despite primary vaccination.

"The recently noted incidence of breakthrough infections with the omicron variant in vaccine-primed persons, regardless of the primary vaccine regimen, suggests that a booster may be required for all primary vaccine regimens," Sadoff and colleagues opined.