‘A virologist is always betting on the virus’

Scientists behind Russia’s ‘third vaccine’ explain why they believe in their product (despite publishing zero articles about it) and why they support mandatory vaccinations in Moscow

In June, Russians started receiving the CoviVac vaccine, the third COVID-19 vaccine registered in the country, which was developed by researchers at the Chumakov Research Center. CoviVac uses tried-and-true vaccine technology — it consists of an inactivated (“dead”) virus and an immune stimulant. At the moment, doses are still hard to come by, but manufacturers promise to put a million doses into circulation by the end of June — and five to six million by the end of the year. To learn more about CoviVac, Meduza correspondents Svetlana Reiter and Alexander Yershov spoke to several Chumakov Research Center employees: Deputy Director for Quality and Innovation Alexandra Sinyugina, Deputy Director for Regulatory Issues Yekaterina Korduban, Innovative Biotechnical Medications Department Head Ilya Gordeichuk, and Department of Current and Newly Emerging Infections with Pandemic Potential Lyubov Kozlovskaya. Why did it take so long for CoviVac to reach the market? How does it differ from other COVID-19 vaccines? How sure are we that the virus in the vaccine is really “dead” and can’t hurt people? And why do its developers think mandatory vaccinations are a good idea?

“This isn’t a business”

To hear Ilya Gordeichuk tell it, vaccine developers aren’t a competitive bunch. Gordeichuk, head of the Innovative Biotechnical Medications Department at the Chumakov Research Center, is one of the researchers behind Russia’s CoviVac vaccine, which, despite having been registered by the government back in October of 2020, is still undergoing clinical trials. Gordeichuk and his colleagues at the Chumakov are about to begin the third phase of CoviVac’s clinical trials — while around 20 million Russians have already received the Gamaleya Institute’s Sputnik V vaccine.

“We don’t have competitors — this isn’t a business,” Gordeichuk told Meduza. “Our dear colleagues and friends work at the Gamaleya Institute. We don’t use speed as a metric.”

The researchers did, however, start working almost immediately in the early days of the pandemic. “As soon as the first cases started to appear in Kommunarka, employees started going to the Center’s director and saying they wanted to work on something to help,” said Yekaterina Korduban, Deputy Director for Regulatory Issues at the Chumakov Center. “And beginning practically from when the first patients appeared in Kommunarka, virologist Lyuba Kozlovskaya and her colleague Anastasia Pinyayeva spent days and nights in Kommunarka, collecting samples from patients and trying to isolate the virus.”

“After they managed to cultivate samples of the virus, which is the basis of any vaccine, they came to our managers and said, look, we have an active substance that could be the start of a vaccine. We can go ahead and try,” said Alexandra Sinyugina, deputy director for regulatory issues at the Chumakov Center.

The fact that CoviVac is still undergoing trials months after Sputnik entered the market doesn’t necessarily mean that Sputnik’s developers took shortcuts, either. In fact, researchers at the Gamaleya Institute had something of a head start because they had already been working on a vaccine against MERS, which is also caused by a coronavirus.

“As a result, they had everything ready. To develop genetic vaccines or vector vaccines, for example, you only need lab animals susceptible to the virus in the late stages, when you’re testing effectiveness. You don’t need cell cultures susceptible to the virus in the creation stage, either,” Gordeichuk told Meduza.

At the same time, he maintains that competition between developers is the wrong way to think about vaccines. “When we work on vaccine development, we’re trying to create a safe and effective vaccine — it doesn’t matter what our colleagues are doing,” said Gordeichuk. “Moreover, it’s our belief that as a result, at some point down the line, it might be optimal to use different types of vaccines for second doses.”

Lyubov Kozlovskaya, head of the Department of Current and Newly Emerging Infections with Pandemic Potential at the Chumakov Center, agreed that having a variety of vaccines on the market is a good thing.

“We don’t know what’s going to happen, six months from now. We don’t know, for example, who’s going to need booster shots, or how many of them we’ll need. We also don’t know whether people who were vaccinated a year ago are still protected today. We still have a lot of epidemiological data to collect. At some point, every single vaccine will either find its niche — it might have an advantage for people in some definite category, people in some specific situation, etcetera — or both vaccines will be interchangeable,” she told Meduza.

It took some coaxing, but Gordeichuk did eventually acknowledge that he likes the thought of people receiving their vaccine specifically. “We will be pleased if a lot of people get our vaccine!” he said. “And we also just want a lot of people to get vaccinated. It can be Sputnik or CoviVac, for God’s sake — just go and get vaccinated.”

“We have a million doses ready right now”

Because of extenuating circumstances — namely, the pandemic — the third phase of CoviVac’s clinical trials will look a bit unusual. Usually, at this stage of drug trials, the chance to receive a drug before it’s introduced to the market would incentivize people to volunteer, at the risk of receiving a placebo. With CoviVac, however, people can just go to a regular hospital and get the vaccine — and there won’t be a placebo group.

According to Sinyugina, this shouldn’t deter people; on the contrary, the researchers plan to begin a study involving 32,000 volunteers in the coming weeks.

“This isn’t just any trial; it’s a trial for an already-registered drug. Our vaccine is easy to use because it doesn’t have different components, it just has one single component. Two doses from the same line, from the same production,” she told Meduza.

She’s also confident of the vaccine’s safety. “We spent a year on all of the tests, all of the trials, to ensure the product we were putting on the market is completely safe. We tested its effectiveness, too — just not on a group as huge as the one we’ll be able to test it on now,” said Sinyugina.

The scale of this phase will allow them to determine the vaccine’s effectiveness more thoroughly in the absence of a placebo. “We compare [the volunteers] to an identical group of unvaccinated people from their population,” said Kozlovskaya.

So far, no articles about CoviVac have been published in scientific journals. According to Kozlovskaya, an article is currently under review “at one of the leading international journals,” but the public has heard that story before. The developers of EpiVacCorona, another Russian vaccine, said the same thing shortly before their article was published in Infection and Immunity, a publication controlled by Rospotrebnadzor, Russia’s consumer protection agency.

“Let’s put it this way: the article is undergoing review,” said Kozlovskaya. “We’re answering some final questions and hoping that it comes out soon. Because, in addition to the pre-clinical trials we conducted ourselves, we also connected with, let’s say, outside organizations, which conducted part of our pre-clinical trials for us.”

“Our first phase [of trials] is for safety,” said Korduban. “We ensured its safety. After that, we entered the second phase — immunogenicity. We did that phase in stages: 200 people in one group, 200 in another. We should receive the final report processed by the statisticians at the end of the week.”

CoviVac’s developers are still unsure whether their vaccine will be effective against the Delta variant, but they have obtained some samples of the strain and are currently doing tests.

“We’re currently working with several institutions, including Kommunarka and a few other hospitals, and collecting samples from patients with atypical disease courses,” said Kozlovskaya.

According to Sinyugina, production of the CoviVac vaccine will increase rapidly in the coming months.

“Right now, we have a million doses ready. They’ll enter circulation at the end of June. We’re planning to release around five or six million from our existing site by the end of the year. We’re waiting for some pretty heavy equipment, so to speak, which should arrive in July. Then we’ll be able to expand production to 60 million doses a year,” she told Meduza.

“Initially, we were all perfectionists”

When faced with vaccine skepticism, virologists often remind people that the viral part of the vaccine is inactivated, or “dead.” For many consumers, however, this isn’t much of a reassurance. After all, viruses are tiny and alien — how can scientists be sure they’re really dead?

According to Lyuba Kozlovskaya, there are tests for that. After adding a compound called beta-Propiolactone, which deactivates the virus, to the viral fluid, they put the virus back into the same culture they grew it in — only this time, nothing grows.

“We check this parameter about nine times,” said Yekaterina Korduban.

“Why did we choose beta-Propiolactone? We expect it to change the protein structure less. It has more of an effect on nucleic acid, which changes and becomes unable to interact with anything. In addition, formalin, which was used in previous vaccines, takes 14 days, while beta-Propiolactone works in 24 hours. To me, the choice is obvious,” explains Kozlovskaya.

The technology used in CoviVac is remarkably similar to that of several other vaccines, including the Chinese vaccines Sinovac and Sinopharm, as well as the Indian vaccine Bharat. According to Kozlovskaya, however, that doesn’t necessarily mean trial results won’t differ.

“Sinovac and Sinopharm are closer to the Chinese strain — their strains don’t have the D614G mutation, for example. As a result, it’s possible that we have some differences, and we might get some different results — perhaps one will last longer in storage, or something like that. But it would be arrogant of us, in my view, to expect a better result than them,” she said.

COVID-19 vaccines have already garnered a reputation worldwide for having frequent side effects which, while rarely dangerous, can resemble symptoms of the live virus for a brief period. Perfectionists by nature, the Chumakov Center’s researchers are anticipating the fallout.

“We were used to making vaccines for children, and to us, any adverse reaction to our vaccine is a nightmare, a horror; it means someone will be in tears, all of that,” said Korduban. “Not only are we a scientific research institute, we’re also a production facility; that means we handle all of our side effect oversight independently. For 40 years, we’ve vaccinated everyone in Siberia, especially children, every year against tick-borne encephalitis; 80 percent of children who get bit by dogs, foxes, hedgehogs, and so on come to us to get our inactivated rabies vaccines. So we know we’re going to get a barrage of calls.”

“Direct, targeted calls,” Sinyugina added.

Nonetheless, the team is confident that its product is safe. Even before the first human volunteer had received CoviVac, Ilya Gordeichuk had no doubt the vaccine would be both safe and effective, thanks to the Chumakov’s Center in-house monkeys.

“The animals we use are born at our institute and live their whole lives there. They’re Callitrichids. They’re kept under controlled conditions for their entire lives. And because they’re small, it’s feasible to create decently comfortable conditions that observe all ethical standards. In addition, their immune response is similar to that of a human,” said Gordeichuk. “When we initially tested the vaccine’s safety on marmosets, and then when we tested immunogenicity, for me, personally, there was no question that there would be immunogenicity [in humans]. Of course, all preclinical researchers have a favorite saying: mice lie, and monkeys exaggerate. Still, all the animals had [sufficient] levels of neutralizing antibodies. The neutralization reaction specifically. It was stable over a long period.

Other vaccine researchers who use beta-Propiolactone have observed a “balding effect” — when deactivating the virus to make a vaccine, they also inadvertently stripped it of its characteristic “spikes,” which could adversely affect the immune system’s ability to recognize and respond to the live virus later on. According to the CoviVac researcher, however, they’ve made sure their vaccine doesn’t have this problem.

“Of course we looked at everything through an electron microscope,” said Gordeichuk. “We saw that the spikes were in place and everything, but functional testing is actually even more important than that. Before every vaccine batch is released, we test it on mice, and we observe neutralization every time.”

“We’re perfectionists, so we work very carefully to make sure our vaccine has a ‘hairy’ virus,” said Korduban. “But to a certain degree, it also doesn’t matter if a few of the virus’s spikes fall off,'' Kozlovskaya added. “The important thing is that most of them stay on, which ensures that the vaccine provokes a certain antibody response.”

“Nobody knows how many antibodies is enough”

At this point, it’s still uncertain whether and how often people will need to get COVID-19 vaccine booster shots. Because some of the volunteers in the CoviVac study had already had the virus, however, the researchers are able to make some educated guesses.

“They had very good seroconversion, the antibodies grew and didn’t decrease. Empirically, we can infer that booster shots will be just like they are for the flu — yearly,” said Kordugan.

“But it will definitely be based on epidemiological evidence, and not based on antibodies,” added Gordeichuk.

In fact, while antibody production is one of the immune responses triggered by vaccines, Kozlovskaya said there’s no point in keeping track of one’s antibody count to determine immunity.

“We want to discourage people from counting their antibodies because it’s not a good idea to try to interpret them yourself. Nobody knows how many antibodies is enough — and enough for what? For your own peace of mind? That’s all it would be for,” she said.

“We’re fully aware that there are different kinds of immune responses,” said Korduban. “Not everyone develops an antibody response. But in no way does that mean you aren’t protected.”

The researchers also emphasized that preventing infections entirely is not the way vaccines work. A vaccine’s job, according to Korduban, is “to make sure you don’t end up on a ventilator or in a coffin.”

“There’s no vaccine that’s giving us 100-percent effectiveness for all groups,” said Gordeichuk. “And there’s not going to be. The main issue is making sure that everyone gets vaccinated as quickly as possible.”

Given the way coronaviruses tend to mutate, time is of the essence, according to the team.

“We know that this is a coronavirus; well, there are other coronaviruses with similar proteins, and antibodies against them decrease, for example, faster than antibodies against yellow fever. In other words, antibodies against this virus decrease eventually, and if we take an extremely long time, five years, to vaccinate everyone, we’ll be handing the virus new variants. People who administer polio vaccinations are well aware that on India’s National Vaccine Day, 200 million vaccines are administered [to prevent this from happening].”

“Maria Ivanovna, what are you doing? Come get your shot!”

Russia’s COVID-19 vaccines are dismally unpopular among the Russian populace, leading Moscow and a number of other regions to institute mandatory vaccination policies in recent weeks. While public backlash has been fierce, the virologists at the Chumakov Center said unequivocally that mandatory vaccination is a good idea.

“If you keep track of expenditures from the hospital bed fund, you start to realize that, eventually, we’re going to run out of beds. And in a situation like that, you start making unpopular decisions. Given the situation, this decision is appropriate. Not because the vaccination campaign was moving too slowly and we didn’t like that, but because otherwise we’ll run out of beds, and people having their first heart attack won’t even make it to the ambulance,” said Ilya Gordeichuk. “In an epidemiological race, a virologist is always betting on the virus. As long as you give the virus a chance, it will adjust and adapt.”

The mandatory vaccination campaign also takes some of the pressure off of CoviVac manufacturers to sway public opinion — a difficult task, given that they still haven’t published a single scientific article. Nonetheless, Alexandra Sinyugina doesn’t believe publication in a prestigious journal would mean much to ordinary Russians.

“The mother of five who’s busy planting cucumbers with her butt in the air isn’t going to be reading scientific articles. She won’t understand anything in them. She has a third-grade education and a bunch of kids to take care of. She doesn’t care whether there’s a publication or not. But she will listen to her country doctor when he comes to her and says, ‘Hon, what are you doing? Come get your shot — we need to vaccinate everybody!’ That’s who she’ll believe.”

And it’s not difficult to understand why virologists and epidemiologists, whose main goal is to save as many lives as possible, would see public opinion as a relatively minor factor, given their experience working closely with patients. It’s clear from the scientists’ conversation with Meduza that the poliovirus, specifically, looms large in many of their minds.

“I’ve worked in a polio lab since 2013, and I’m responsible for polio surveillance at the WHO center,” said Kozlovskaya. “So my lab examines every case of Acute Flaccid Paralysis to see whether it was caused by polio, God forbid, or something else. I’ve seen the faces of mothers whose children got polio after they failed to vaccinate them. One mother looked me in the eyes and said, ‘Our grandmother is a doctor, and she said we didn’t need to vaccinate. What’s going to happen to him now?’ And her child has quadriparesis, he’s paralyzed for life. Two injections could have prevented it. And I don’t know what to tell the mother, but I do know that her child will be lying on his back for the rest of his life. And I don’t know what to do with that.”

Interview by Svetlana Reiter and Alexander Yershov

Abridged translation by Sam Breazeale