麻豆传媒

NEW ORLEANS -- Experience so far with Merck & Co.'s officially investigational Ebola vaccine, rVSVΔG-ZEBOV-GP, suggests it's been effective in quelling the Democratic Republic of the Congo's (DRC) stubbornly ongoing outbreak. Or not.

Merck's Jakub Simon, MD, MS, addressing a session at the American Society of Tropical Medicine's (ASTMH) annual meeting here, showed two charts tracking Ebola during this past spring's outbreak in the DRC's Equateur province and the subsequent one now raging in the North Kivu and Ituri provinces. In both, health workers on the ground have been using the Merck vaccine in a so-called ring vaccination strategy to contain the epidemic. Although not yet formally approved for marketing, the vaccine has been cleared for emergency use.

In Equateur, immediately after vaccination began with the Merck product, the outbreak petered out.

But the experience in North Kivu and Ituri has been quite different. Although new cases dropped significantly after vaccination began in early August, they never approached zero, and 2 months later they rocketed back to the level seen before vaccinations began. (They have since dropped again.)

Simon suggested that the widely reported difficulties faced by health workers in North Kivu and Ituri have made the ring vaccination less effective. Armed rebels have been active in the two provinces, killing dozens of villagers and preventing aid teams from reaching some areas.

He said World Health Organization (WHO) officials have told him they think the vaccine is effective. But the reality is that no one can yet be sure to what extent the vaccination campaign, versus other public health efforts, helped end the Equateur outbreak, or how much it might be helping in North Kivu and Ituri given the roller-coaster numbers.

At the same time, another presentation at ASTMH following Simon's gave the vaccine some limited support.

Katie Ewer, PhD, of the University of Oxford's Jenner Institute in England, reported findings from her lab on rVSVΔG-ZEBOV-GP and two vaccine combinations that use different products. Her data confirmed that Merck's vaccine does induce strong immune responses in clinical trial settings -- but not as durably as the other approaches, which combine two different vaccine types, both of which differ from Merck's.

The Merck product uses a vesicular stomatitis virus (VSV) engineered to express Ebola virus antigens. The two combinations on which Ewer reported include vaccine candidates based on engineered adenoviruses followed by boosters using a modified vaccinia virus -- all engineered, like the Merck product, to display Ebola virus antigens.

Ewer's bottom line: the two-punch vaccine combinations provoked anti-Ebola immune responses that were at least as strong as that from the Merck product, and were longer-lasting when study participants were re-examined 24-36 months later. Notably, however, these were data from healthy volunteers in phase I trials.

Study Details

Most of Simon's presentation at ASTMH centered on lab data regarding the rVSVΔG-ZEBOV-GP vaccine. The most recent involved immune responses with different production batches of the vaccine, intended to show that Merck's manufacturing process is consistent and reliable. That appears to have been achieved, as chart after chart showed virtually identical results with each of four lots tested.

The more interesting part came at the end, when he showed timelines of Ebola cases during the DRC's 2018 outbreaks (daily in Equateur, weekly for North Kivu and Ituri).

In Equateur, over about 3 weeks prior to initiation of ring vaccination, there were from one to five new cases almost every day. The day after vaccination began on May 21, there were none. Nor the next day, nor the day after. In fact only two more cases were seen in the province after May 21.

The North Kivu/Ituri outbreak has proved far worse. It began just as the Equateur outbreak was subsiding, with a case here or there until mid-July, when the weekly new-case count began hitting double digits. It topped out at nearly 40 the week ending Aug. 6, when vaccination began. At that point it dropped to the 5-10 range for several weeks, before soaring again to more than 30 the week ending Oct. 1. More recently, according to the WHO (who provided all these data), it has returned to the 5-10 range per week.

Simon told the ASTMH audience that Merck never expected the vaccine to have 100% efficacy. "Few vaccines do," he said. "We expect a few breakthrough cases."

With regard to future steps leading to formal approvals, he said Merck was pulling together the data from all the trials (12 in total). He didn't give a timeline for the company's regulatory applications, but said the company now has all the clinical data it intends to submit.

Ewer's talk centered on single-dose rVSVΔG-ZEBOV-GP; an adenovirus-based candidate called ChAd3 EBO Z followed by the engineered vaccinia product MVA BN-Filo; and AdHu26.ZEBOV, also using an adenovirus carrier, followed by MVA BN-Filo.

Mean antibody titers evaluated 2-3 years after dosing were similar among the three regimens, and the percentage of patients found to be seropositive for Ebola antibodies appeared to favor the Merck product (75% versus 54%/57% for the combinations).

But Ewer said the more clinically significant ELISPOT assay for cell-based responsiveness clearly favored the two-dose adenovirus-vaccinia combination approach:

• AdHu26.ZEBOV/MVA BN-Filo: 92%
• ChAd3 EBO Z/MVA BN-Filo: 100%
• rVSVΔG-ZEBOV-GP: 63%

"Booster doses substantially expand the effector CD8+ T cell response," she concluded.

For clinical application, Ewer said durable vaccine effectiveness is probably most important for healthcare workers in at-risk areas, who may expect repeated Ebola exposures, although it will matter too for ordinary residents of those areas.

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