Janssen's product is a recombinant viral vector-based COVID-19 vaccine, and if it receives an EUA, it will become the first non-messenger RNA (mRNA) vaccine on the U.S. market. The safety and efficacy of the candidate were discussed in a February 26 meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC), which advises the FDA's Center for Biologics Evaluation and Research (CBER).

Committee members were specifically asked to address the following question:

"Based on the totality of scientific evidence available, do the benefits of the Janssen COVID-19 vaccine outweigh its risks for use in individuals 18 years of age and older?"

Unlike previously authorized vaccines, Janssen's candidate is a recombinant, replication-incompetent human adenovirus type 26 (Ad26) vector, constructed to encode a stabilized form of the SARS-CoV-2 spike protein. It delivers a transgene that encodes the spike protein with two proline mutations and a knockout of the furin cleavage site to lock the protein into its prefusion conformation. The vaccine was developed using the company's AdVac technology platform.

In the briefing documents, the company outlined the immunogenicity results from preclinical and phase I/IIA clinical trials. The vaccine elicited strong humoral (antibody) and cellular (CD4+ T cells, CD8+ T cells) immune responses. The CD8+ T-cell responses were predominantly T helper type 1 (Th1) CD4+ T-cell responses. The investigators also found that neutralizing and binding antibodies were maintained to at least day 85 days postvaccination.

In support of the EUA submission, the company and the FDA discussed the results of the COV3001 trial, an ongoing, multicenter, randomized, double-blind, placebo-controlled phase III study. A total of 464 cases of COVID-19 were accrued during the study period. Coprimary efficacy end points were molecularly confirmed moderate and severe COVID-19 cases at least 14 or 28 days after vaccination, cumulatively termed "symptomatic COVID-19."

Vaccine efficacy for the coprimary end points against confirmed symptomatic COVID-19 in participants who were seronegative at the time of vaccination was 66.9% when considering cases diagnosed at least 14 days after vaccination and 66.1% when considering cases diagnosed from at least 28 days after vaccination. These efficacy numbers average the number of cases from both moderate and severe COVID-19. Vaccine efficacy against just severe COVID-19 diagnosed at least 14 days after vaccination was 76.7% and increased to 85.4% at least 28 days after vaccination.

There were 19 total deaths in the trial of more than 40,000 individuals. Of those, only three were in the vaccinated group and none were considered related to the vaccine.

Regarding reactogenicity, the most common adverse events were headache, fatigue, myalgia, and vaccination site pain. These were of mostly mild or moderate severity and lasted only a few days. Furthermore, the company and FDA observed no difference in the number of serious adverse events between the vaccine and placebo groups.

Janssen conducted the clinical trial in selected countries where it is known that variants of the SARS-CoV-2 virus are emerging. These included Brazil, South Africa, and the U.S. No differences were observed in spike-specific antibody levels between participants in the various countries.

In the South African arm of the study, where the B.1.351 lineage of the virus was first observed, the vaccine efficacy in preventing severe disease was 81.7% at least 28 days after vaccination. In Brazil, where the P.2 lineage first emerged, vaccine efficacy was similar to that observed in the U.S.

Issues that remain

Based on discussions from previous committee meetings, Janssen noted that if it is granted an EUA, it intends to amend the phase III study design to facilitate crossover of placebo participants in all countries to receive one dose of the vaccine as quickly as possible. According to the company, offering the vaccine to placebo-group participants is an effective way to keep individuals in the trial and continue to gather data from them.

Some members of the VRBPAC committee expressed concern over a single-dose vaccine regimen, and the company is conducting a phase III clinical trial of the same vaccine candidate in a two-dose regimen. The company explained that it is moving forward with a single-dose vaccine to assist in an outbreak setting.

Dr. Johan Van Hoof, global therapeutic area head of vaccines at Janssen, and others on the Janssen team expressed that they believe the protection provided by a single dose of the vaccine will be sufficient. Whether there would be a benefit from a second dose would have to come from data, Van Hoof stated.

After deliberation, the committee voted on the potential benefits of the Janssen vaccine in preventing COVID-19 in individuals 18 years of age and older. With 22 votes in favor, the committee gave a favorable recommendation to the FDA for issuance of the EUA. As in the past, the agency is expected to make a final determination about the EUA within a number of days.

Final comments by committee members centered on the usefulness of the vaccine in a pandemic setting, which is supported by the evidence provided by Janssen. However, they did express their interest in reviewing more information as it becomes available to guide clinical use of the product.

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