Briefing documents released by the FDA related to the Vaccines and Related Products Advisory Committee meeting slated for Friday suggest that the COVID-19 vaccine from Johnson & Johnson (J&J) will sail smoothly to an emergency use authorization (EUA).

“A century ago, [J&J] played a leading role in combatting the 1918 flu pandemic,” said Richard Nettles, the Whitehouse Station, N.J.-based company’s vice president of medical affairs in testimony Feb. 23 before the House Energy and Commerce Subcommittee on Oversight. “Our history of confronting global health care challenges continues to the present day, including with the European approval of our Ebola vaccine last year,” he added, saying the company “brought this same approach to the COVID-19 pandemic.”

The FDA reviewed materials submitted by J&J unit Janssen Biotech Inc., including safety and efficacy data from an ongoing, multi-national phase III randomized, double-blind and placebo-controlled trial of a single dose (5x1010 vp) of the vaccine, called Ad26.COV2.S, in about 40,000 participants. Janssen’s EUA request followed a successful protocol-specified primary analysis that evaluated co-primary efficacy endpoints of molecularly confirmed, moderate to severe/critical COVID-19 with onset at least 14 and 28 days, respectively, after vaccination in participants without evidence of SARS-CoV-2 infection prior to their shots.

With a cutoff date of Jan. 22, 2021, the co-primary efficacy analysis took in 39,321 randomized (1:1) participants with a median follow-up time of two months post-vaccination. These subjects were included in the per-protocol efficacy analysis population. Vaccine efficacy (VE) against central laboratory-confirmed moderate to severe/critical COVID-19 across all geographic areas in which the trial was conducted was 66.9% (95% confidence interval [CI] 59.0, 73.4), when considering cases occurring at least 14 days after the injection and 66.1% (55.0, 74.8) when considering cases occurring at least 28 days post-shot.

For the vaccine and placebo groups, respectively, 116 and 348 COVID-19 cases turned at least 14 days after vaccination, and 66 and 193 at least 28 days later. Analyses of secondary endpoints showed VE against central laboratory confirmed and blind-adjudicated severe/critical COVID-19 occurring at least 14 days and at least 28 days after shots of 76.7% (54.6, 89.1) and 85.4% (54.2, 96.9), respectively. VE estimates for prevention of moderate to severe/critical COVID-19 and for prevention of severe/critical COVID-19 – including positive PCR results, still awaiting confirmation by the central laboratory – were similar (but with narrower CIs) to the VE estimates that included only centrally-confirmed cases, the agency noted.

In a post hoc analysis of all COVID-19 related hospitalizations starting 14 days after vaccination, including non-centrally confirmed cases, two surfaced in the vaccine group (with no cases after 28 days) compared with 29 cases in the placebo group (with 16 cases after 28 days). As of Feb. 5, 2021, researchers chalked seven COVID-19-related deaths in the study in the placebo group and none in the vaccine segment.

Two-dose regimen in hopper

Subgroups seemed to check out, too, including those determined by age, comorbidity, race and ethnicity. In these, VE “appears to be similar to [that of] the overall study population,” the FDA said. “A lower VE estimate was observed for the subgroup of participants 60 years of age and older with comorbidities compared with the overall population,” but with a trend toward increasing VE with narrower CIs as the numbers of cases included in the analysis increased (i.e., counting cases from 14 days rather than 28 days and including cases not yet centrally confirmed).

If the EUA is authorized for Ad26.COV2.S, J&J said it would submit a protocol amendment to its experiment called study 3001, also known as Ensemble, that would allow all participants who received placebo to receive the vaccine. Such a move “would effectively result in unblinding of participants and investigators,” regulators pointed out, but subjects who cross over from placebo “will be encouraged to remain in the study [for] up to two years after vaccination so that they may be followed for efficacy/effectiveness, safety, and immunogenicity.”

J&J’s vaccine already has begun to roll out in South Africa by way of research involving up to 500,000 health care workers – the first time Ad26.COV2.S has been used outside of clinical experiments. Earlier in February, officials in the country paused the use of London-based Astrazeneca plc’s vaccine, which apparently wasn’t working against the strain prevalent there. J&J’s shot, on the other hand, yielded about 57% efficacy in preventing moderate and severe COVID-19 infections in South African trials. Data show the J&J vaccine also does well against variants that have cropped up in Brazil.

SVB Leerink analyst Mani Foroohar said that, “while it is difficult to make apples to apples comparisons between efficacy [of the two cleared mRNA vaccines vs. J&J’s prospect] given differences in trial design, length of patient follow up, and the geographical distribution of SARS-CoV-2 variants at the time of each study, Ad26.COV2.S is an effective single-dose vaccine with advantages in distribution that will likely contribute to substantially lowering the COVID-19 curve once available.” In a Feb. 24 report, he predicted that “efficacy data will continue to evolve favorably further follow-up for this J&J candidate,” as well as for the other two vaccines.

Trefis analysts said in a Feb. 22 report that, although the headline numbers put J&J behind EUA-granted vaccines from Pfizer Inc. and Moderna Inc./Biontech SE, both with shots that are over 90% effective in the market, Ad26.COV2.S “remains very promising for a couple of reasons.” The single-dose option is especially attractive during a pandemic. Distribution could be “relatively seamless,” since the vaccine is expected to remain stable for at least three months at refrigerator-like temperatures, unlike some other vaccines – such as Pfizer’s – that require specialized freezers. Twenty-eight-day protection from hospitalization is another selling point. “Moreover, the efficacy figures actually compare quite favorably with some other vaccines,” in their view. “For example, the Astrazeneca COVID-19 vaccine posted an efficacy rate of roughly 62% with the standard two-dose regimen that is currently being used in the U.K.” – not bad, considering that annual flu vaccines are only about 40%-60% effective. J&J has started late-stage trials to evaluate a two-dose regimen, with recruitment expected to finish in March. “It’s possible that this dosing could offer better efficacy levels,” Trefis said.

Post-EUA safety surveillance

During a U.S. House committee meeting where Nettles testified, officials from Pfizer, Moderna, Astrazeneca, and Novavax Inc. talked about development and manufacture of their vaccines. All are studying efficacy against the dominant variants that have emerged and are developing boosters or next-generation products to tackle them.

Pfizer’s chief business officer John Young said his firm is “laser focused” on the variants, and can rapidly alter the mRNA sequence of its vaccine to address them. Meanwhile, in vitro studies with the current product have found no real-world evidence to indicate the vaccine works less well against the known variants. Pfizer execs hope to kick off a study of a booster in patients who have received two doses of the original shot, and they are talking with the FDA about an upgraded version should the need arise.

Moderna President Stephen Hoge said that changing his firm’s mRNA vaccine is a simple “copy and paste” process. The company had started work in that area, scaled up manufacturing, and begun tests to determine whether a booster is effective. John Trizzino, chief business officer at Novavax, explained how his company deploys nanoparticles with a modified version of the coronavirus spike protein to teach the body to respond – an approach that can be quickly modified for variants. Although Novavax has yet to submit an EUA request, researchers there are manipulating new constructs to fend off the variants and studying the potential for boosters or a bivalent approach.

Each of the firms is exploring the durability of its vaccine with an eye to nailing down the right time window for boosters, as well as trying to figure out whether vaccines significantly knock down transmission of the virus. Endpoints used in EUA trials were aimed at prevention of disease and easing severity. Ruud Dobber, president of Astrazeneca’s biopharmaceuticals unit, said preliminary data from one study showed a 67% drop in transmission with its candidate, but more work needs to be done.

The briefing documents for J&J’s vaccine did contain a few caveats. Wider use “may reveal additional, potentially less frequent and/or more serious adverse events not detected in the trial population,” the FDA said. “Active and passive safety surveillance will continue during the post-authorization period.” Also, the “risk of vaccine-enhanced disease over time, potentially associated with waning immunity, remains unknown and needs to be evaluated further” in the clinic as well as by way of observational studies that could be done after the EUA is granted.

All in, SVB Leerink’s Foroohar finds cause for optimism. “Though it remains premature to proclaim the beginning of the end for the pandemic, these data, along with EUAs and availability for several vaccine candidates, signal to us that we are perhaps at ‘the end of the beginning,’” he wrote.