'They've jumped the gun': scientists worry about Russia's Covid-19 vaccine

In 1977, Scott Halstead, a virologist at the University of Hawaii, was studying dengue fever when he noticed a now well-known but then unexpected feature of the disease.

Animals that had already been exposed to one of the four closely related viruses that cause dengue and produced antibodies to it, far from being protected against other versions, became sicker when infected a second time, and it was the antibodies produced by the first infection that were responsible, allowing the second infection to hitchhike into the body.

The effect was called antibody-dependent enhancement (ADE). The reason it matters today, in the midst of the coronavirus pandemic, is that unexpected glitches such as ADE are the kind of problems vaccine developers look for in phase-3 testing of vaccines – testing that has yet to be carried out on Russia’s newly approved Sputnik V vaccine.

In recent weeks, as announcements on the development of scores of vaccines around the world have come in rapid succession, the still poorly understood mechanisms of ADE have been thrust into the spotlight as scientists speculate on whether vaccine-produced antibodies could trigger this effect.

ADE “is a genuine concern”, Kevin Gilligan, a virologist and senior consultant with Biologics Consulting, told Nature Biotechnology in June. “Because if the gun is jumped and a vaccine is widely distributed that is disease-enhancing, that would be worse than actually not doing any vaccination at all.”

This week, following Russia’s announcement that it is pushing ahead with mass production of Sputnik V and mass inoculation , the fears expressed by the likes of Gilligan became a chorus, underlining the concerns among scientists that Russian researchers have jumped the gun.

Russia has described claims that the vaccine is unsafe as groundless, and on Wednesday vowed to roll it out in two weeks. But criticism has continued to build.

Among those mentioning ADE as a concern was Danny Altmann, a professor of immunology at Imperial College. He said part of the problem was that the work behind Russia’s vaccine development had been so opaque that no one really knows how safe or even how effective it will be.

“I don’t think the Russian researchers have done anything wrong, but I think they’ve jumped the gun,” he told the Guardian. “If we are talking about safety then you have to be looking at issues like ADE, which was a concern that scuppered some efforts to develop a Sars vaccine, where it exacerbated an asthma-like response in lungs.”

It is not just the potential for issues such as ADE that concerns people like Altmann, who is optimistic that the hunt for a vaccine for Covid-19 is not “intractable”. He said the ideal approach would have been to compare 150 or so different vaccine candidates transparently, using the same testing criteria, to ensure the world gets the best vaccine, not simply the first.

“No two of these candidates is going be alike in terms of safety, how effective they are or how cheap they are to produce,” he said. “The reason we’re crying out for transparency and peer review is because those factors are very serious. There have been too many debacles in this pandemic. This is not another occasion to blunder in. You want to line up the candidates side by side.”

The lack of effective testing throws up other issues. “I think there is enough general background data … to assume the [Russian] vaccine itself will be safe at the usual doses,” Ian Jones, a professor of virology at the University of Reading, said in a statement posted on the Science Media Centre website. “The bigger risk, however, is that the immunity generated is not sufficient to give protection, leading to continued virus spread even among immunised individuals.

“And although only a possibility, less than complete protection could provide a selection pressure that drives the virus to evade what antibody there is, creating strains that then evade all vaccine responses. In that sense, a poor vaccine is worse than no vaccine. Careful virus tracking will therefore need to accompany any early release.”

Even before Russia’s announcement, some were warning about accelerated vaccine development programmes in Russia and in the US. In an opinion piece for the New York Times, Natalie Dean, an assistant professor of biostatistics at the University of Florida, flagged up many of the same issues, adding that she would hesitate to take a vaccine that appeared to have been rushed through without proper testing.

“[The] benchmark [of phase-3 testing] is crucial because a weak vaccine might be worse than no vaccine at all,” she said. “We do not want people who are only slightly protected to behave as if they are invulnerable, which could exacerbate transmission. It is also costly to roll out a vaccine, diverting attention away from other efforts that we know work, like mask-wearing, and from testing better vaccines.”

The last thing phase-3 trials do is examine safety. Earlier trials do this too, but larger trials allow for rarer side effects to be detected. One such effect is a paradoxical phenomenon known as immune enhancement, in which a vaccinated person’s immune system overreacts to infection. Researchers can test for this by comparing the rates of disease severe enough to require hospitalisation across two groups.

“A clear signal that hospitalisation is higher among vaccinated participants would mark the end of a vaccine,” Dean said.