Here’s one way to get mass participation in your experimental vaccine clinical trials: Don’t call it experimental, and don’t call it a trial.
Russian President Vladimir Putin made headlines Tuesday by announcing that the country had developed and registered the world’s first coronavirus vaccine. In a televised video conference with government ministers, he said the new Gam-Covid-Vac Lyo, developed by Russian scientists at Moscow’s Gamaleya Institute of Epidemiology and Microbiology, was so safe and effective that his daughter and a top government official have already taken it. In touting the new drug, he insisted it had passed “all needed checks” despite the fact it hasn’t undergone phase 3 trials—a fact that has horrified vaccine experts in the U.S. who are trying to parse the science from the PR spin.
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“Until it has been tested in randomized clinical trials in tens of thousands of patients and the results are carefully reviewed by regulators, there is no ‘Russia vaccine,’” Dr. Henry I. Miller, PRI Senior Fellow and founding former director of the FDA's Office of Biotechnology, wrote in a direct message to The Daily Beast. “There's only a candidate vaccine.”
That said, a candidate is a candidate. Gamaleya has been churning out immunological research since 1891, and they may even have the advantage of the Russian state’s vaccine espionage efforts on their side — but without proper testing, it’s a roll of the dice.
What’s Your Vector, Vladimir? The Gamaleya vaccine is based on a viral vector—or a vehicle—that delivers genetic information to the human immune system to help it fend off the novel coronavirus.
In this case, that vehicle is a common cold virus called the adenovirus, and tucked inside it are genetic instructions, or RNA, for the formation of antibodies to prevent the coronavirus’ signature spiky proteins from taking hold.
This adenovirus vector approach is so cutting-edge, it was only just approved for the first time on July 1 of this year by Europe’s regulatory body for an Ebola virus vaccine, and while no adenovirus-vectored vaccines have yet made it to market, there are several in trials— including leading U.S. and Chinese coronavirus vaccine candidates: Johnson & Johnson, AstraZeneca, and CanSino are each working with altered, harmless adenovirus strains as delivery mechanisms for RNA.
CanSino Biologics in China, which announced its phase 3 trial in Saudi Arabia on August 9, uses adenovirus strain Ad5 as its vector. In late June, after promising phase 2 trials, the Chinese military approved it for early use. And Johnson & Johnson, which plans to launch Phase 3 trial in September, uses Ad26 as its key ingredient —the same strain it used in its experimental Ebola vaccine.
Gamaleya uses a combination of both—Ad5 and Ad26.
Rushed and Reckless: Naor Bar-Zeev, an associate professor at Johns Hopkins Bloomberg School of Public Health and the deputy director of the International Vaccine Access Center, believes the science behind Russia’s vaccine may be promising. In a recent paper in The Lancet, published alongside the “promising” results and “reassuring” safety findings of two other candidates that use the adenovirus vector approach, he called the technology innovative, efficient, and full of potential.
“But when things are urgent,” Bar-Zeev writes, “we must proceed cautiously.” And Russia’s approach demonstrates a terrifying lack of caution.
Limited information is available about their phase 1 and 2 trials, and few to none of the results have been peer-reviewed or published. Their plan appears to be to replace phase 3 trials with administering the supposedly approved shot to “tens of thousands” of people in the coming weeks, including teachers and health-care workers, and then asking them to “document how they are feeling,” while simultaneously putting 30 million doses into production.
Phase 3 trials are a critical step in establishing a vaccine’s efficacy and safety before securing regulatory approval. Without phase 3 results to share, Bar-Zeev told the Daily Beast, two critical questions are left unanswered: Does the vaccine work? And a question that has become even more make-or-break as sentiments of vaccine skepticism grow more widespread: Can the vaccine itself do harm?
“Safety is always an issue, but it's definitely an issue now,” Bar-Zeev said. “Number one, because there's reasons to be concerned about safety biologically, and number two, because we're in an environment where safety is a massive concern for the public, and if we don't address that concern with integrity, honesty, transparency and respect for the public's concerns, then we will only prevent people from accepting the vaccine, and we have the potential, if we're arrogant about it, to do the public harm.”
It’s Not So Simple: As to the basic question of efficacy, it may be close to impossible to know, at this early stage, whether Russia’s vaccine works.
“We need to know if there is efficacy in subgroups,” Bar-Zeev said. “I really want to know that this vaccine works in African Americans. I really want to know if it works in Latin populations. I want to know that it works in the elderly. Ideally, I'd like to know that it works in diabetics or people with obesity,” groups in which many vaccines tend to be less effective, and groups that are inherently more vulnerable to coronavirus symptoms and fatality.
The more specifics you add to the inquiry, he said, the larger an effective trial needs to be.
According to Bar-Zeev, previous clinical trials of adenovirus-vectored vaccines have yielded “less than exciting results in the performance.” In past trials for adenovirus-vectored flu and rabies vaccines, he said, “the phase 2 trials and the animal studies looked good, and then it didn't translate to very high efficacy in the human phase 3 trials. And that yet may be the case—where we may be super excited about the phase 2, and be slightly disappointed with the phase 3.”
He added that one drawback of adenovirus vectors is that it is possible for a person to have pre-existing immunity to the vector. “It depends on which adenovirus you use. If you use a vector that I've encountered in my life previously, I might be immune to the vaccine—kind of vaccinated against the vaccine.”
This is why AstraZeneca’s candidate, developed by scientists at Oxford University, which recently launched its own large-scale phase 3 trials, uses a chimpanzee adenovirus, ChAdOx1, which would theoretically solve for the possibility of existing human immunity.
Gamaleya’s dual-adenovirus approach may do the same, but without a formal Gam-Covid-Vac Lyo phase 3 trial, there will be no way to know.
But, Bar-Zeev added, “Hopefully we won’t be disappointed. This is a race where we want more than one winner. We want as many winners as possible.”
