Janssen’s Single-Dose COVID-19 Vaccine Under FDA Review

The expert’s advising the US Food and Drug Administration (FDA) will have a lot to chew over this Friday when they meet to discuss the phase 3 trial data for Janssen Ad26.COV2.S, the drug company’s candidate for a coronavirus 2019 (COVID-19) vaccine. The FDA’s Vaccines and Related Biologic Products Advisory Committee (VRBPAC) will review Janssen’s evidence that the one-shot adenovirus prophylaxis provided 66.1% efficacy (95% CI, 55.0 – 74.8) in preventing COVID-19 versus placebo ≥28 days after administration. The findings are the most extensively reported outcomes of an adenovirus vaccine candidate for the pandemic, and the first to highlight efficacy with a single-dose product.

The Vaccine

Janssen Ad26.COV2.S is an intramuscular injection vaccine consisting of a replication-incompetent recombinant adenovirus type 26 (Ad26) vector which expresses the SARS-CoV-2 spike (S) protein.

Per the FDA, the product additionally includes inactive ingredients citric acid monohydrate, trisodium citrate dihydrate, ethanol, 2-hydroxypropylβ-cyclodextrin (HBCD), polysorbate 80, sodium chloride, sodium hydroxide, and hydrochloric acid.

Stored at 2-8 degrees Celsius, the vaccine is provided in a five-dose vial and administered at 0.5 mL per person.

The Ad26 platform is prominent in use with Ebola vaccines, and is being used for investigative prevention of Zika virus, filovirus, HIV, HPV, malaria, and respiratory syncytial virus (RSV) in other vaccine forms.

Since December 2020, the Ad26 platform has been used in vaccines administered to nearly 200,000 real-world and clinical trial participants, and has been associated with an overall “acceptable clinical safety profile,” the FDA wrote.

The Trial

Ad26.COV2.S is currently being investigated in 5 randomized, double-blind, placebo-controlled clinical trials. The data supporting Janssen’s EUA application comes from Study 30001, a phase 3 efficacy and safety study comparing the vaccine candidate to placebo in preventing COVID-19 among 40,000 adult participants.

Included in the EUA review will be blinded safety data from Study 3009, a phase 3 efficacy and safety trial observed a two-dose regimen of Ad26.COV2.S that began in November 2020 but is yet to provide usable outcomes.

In Study 3001, 40,000 adults were randomized 1:1 to either intramuscular vaccine injection or placebo. Investigators sought co-primary endpoints of single-dose vaccine efficacy in preventing centrally confirmed, moderate to severe COVID-19 occurring at 2 time periods:

≥14 days after vaccination

≥28 days after vaccination, among participants without evidence of prior SARS-CoV-2 infection at baseline

Population

The trial population was required to have at least 30% of all participants aged ≥60 years old at baseline, and a maximum of 20% participants aged 18-40 years old, to assure observations could be made on older, greater-risk populations.

Median follow-up duration for participants in both efficacy and safety assessments was 8 weeks post-vaccination, the FDA’s equivalent to the mandated two-month minimum for COVID-19 vaccine EUA consideration. Janssen’s full analysis set included 29,111 (63%) participants who reached the eight-week mark.

The international study population was comprised of 46.7% (n = 18,356) Americans, 40.6% (15,981) residents of Latin America, and 12.7% (4984) residents of South Africa.

Mean participant age was 51.1 years old, with participants aged ≥60 representing 34.6% of the population. A majority of patients were male (55.5%) and White (62.1%). Black or African American (17.2%) and American Indian or Alaska Native (8.3%) comprised the next most represented races. At least 1 comorbidity indicative of increased COVID-19 severity risk was present in 40.8% of all participants.

Efficacy

In the first primary endpoint of Ad.26.COV2.S prevention of COVID-19 ≥14 days after vaccination, investigators observed 116 cases among vaccinated participants versus 348 in the placebo arm, indicating a 66.9% vaccine efficacy across all participant age groups (95% CI, 59.0 – 73.4). Among participants ≥60 years old, the efficacy was 76.3% (95% CI, 61.6 – 86.0).

In the secondary endpoint of COVID-19 prevention ≥28 days after vaccination among those with no SARS-CoV-2 history, investigators observed just 66 cases among vaccinated participants versus 193 in the placebo arm, indicating a vaccine efficacy of 66.1%. There were no statistically significant differences among younger and older participants in this outcome.

“The majority of COVID-19 cases were among participants in the United States, South Africa, and Brazil,” investigators wrote. “Study participants with comorbidities were not over-represented among COVID-19 cases as compared to the overall study population.”

In subgroup analyses assessing the vaccine’s efficacy in differing regions, investigators observed an efficacy of 74.4% (95% CI, 65.0 – 81.6) at ≥14 days and 72.0% (95% CI, 58.2 – 81.7) at ≥28 days in American participants.

Results among South African residents were 52.0% (95% CI, 30.3 – 67.4) and 64% (95% CI, 41.2 – 78.7) at the respective endpoints. Among Latin America residents, results were 64.7% (95% CI, 54.1 – 73.0) and 61.0% (95% CI, 46.9 – 71.8), respectively.

In preventing severe or critical COVID-19, Ad.26.COV2.S was associated with 76.7% efficacy at ≥14 days, and 85.4% at ≥28 days.

“In a post hoc analysis of all COVID-19 related hospitalizations starting 14 days after vaccination, including non-centrally confirmed cases, there were 2 cases in the vaccine group (with no cases after 28 days) compared with 29 cases in the placebo group (with 16 cases after 28 days),” investigators wrote. “As of February 5, 2021, there were 7 COVID-19 related deaths in the study in the placebo group and no COVID-19 related deaths in the vaccine group.”

Safety

Among 43,783 participants eligible for safety analysis, investigators observed no specific safety concerns that would warrant assessment prior to an EUA.

Common solicited adverse reactions associated with the vaccine included injection site pain (48.6%), headache (38.9%), fatigue (38.2%), and myalgia (33.2%)—a majority of which were mild and moderate in severity.

Investigators observed a “numerical imbalance” in non-serious urticaria events among vaccinated participants (n = 5) versus placebo (n = 1) within 7 days post-vaccination, as well as imbalances in thromboembolic events (15 vs 10) and tinnitus (6 vs 0). However, data was not considered sufficient enough to determine a causal relationship between the vaccine and these outcomes.

“There was more frequent, generally mild to moderate reactogenicity in participants 18 to 59 years of age compared to older participants,” investigators wrote. “There were no specific safety concerns identified in subgroup analyses by age, race, ethnicity, medical comorbidities, or prior SARS-CoV-2 infection.”

VRBPAC Meeting

On Friday morning, the FDA will convene for its third public expert panel hearing on the validity and benefit of a COVID-19 vaccine candidate up for EUA consideration.

The VRBPAC will provide recommendations, based on the above evidence and other submitted details on Ad.26.COV2.S, whether its benefits outweigh its risk in active immunization to prevent COVID-19 in persons aged ≥18 years old.

In December 2020, the VRBPAC gave supporting votes to Pfizer-BioNTech’s BNT162b2 and Moderna’s mRNA-1273 in separate meetings. The pair of two-dose mRNA-platform vaccines are currently the only authorized products in the US, having received emergency authorization shortly after their respective VRBPAC signoffs.

If VRBPAC support and emergency authorization comes at the end of this week, Janssen Pharmaceuticals anticipates to have approximately 4 million doses of Ad.26.COV2.S ready to ship in the US next week.

This article originally appeared in Contagion®.