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EpiVacCorona’s race to the finish line Meduza speaks to the developer and manufacturer about concerns surrounding Russia’s latest coronavirus vaccine

Source: Meduza

The “EpiVacCorona” coronavirus vaccine, developed by the Novosibirsk-based Vector Institute, is now rolling out in regions across Russia, and roughly half a million doses should be distributed by the end of the month. Scientists first registered EpiVacCorona back in October 2020. In early March 2021, Russia’s consumer protection agency Rospotrebnadzor approved the vaccine for persons older than 60, though the drug was made available sooner to many people, even before the end of clinical trials (just as health officials allowed with “Sputnik V,” the country’s first registered coronavirus vaccine). To learn more about Russia’s latest weapon against COVID-19, Meduza journalists Svetlana Reiter and Alexander Ershov spoke to EpiVacCorona developer Alexander Ryzhikov and Vector Institute deputy general director Tatiana Nepomnyashchikh. Why have participants in the drug’s clinical trials tested so low in antibodies? And what’s the evidence that the vaccine actually works?

Before you continue reading: On Monday, March 22, several participants in EpiVacCorona’s ongoing clinical study signed an open letter by three scientists urging Russian Health Minister Mikhail Murashko to order a study of EpiVacCorona’s efficacy to be conducted without Rospotrebnadzor’s involvement. According to the letter, an independent laboratory established that not a single person in their review who was vaccinated with EpiVacCorona developed the neutralizing antibodies that protect patients against COVID-19. This information contradicts the statements offered by Alexander Ryzhikov and Tatiana Nepomnyashchikh. Meduza’s reporters were unaware of these concerns when they spoke to EpiVacCorona’s creators, but the absence of peer-reviewed, scientific publications about the vaccine mean it’s possible that the drug lacks immunogenicity. In light of the independent inquiry’s findings, an independent study of EpiVacCorona appears to be absolutely necessary.

Trial issues

The scientists who developed EpiVacCorona acknowledge that there are serious concerns about the vaccine’s efficacy study. In particular, the clinical trials involve a relatively small sample size (just 3,000 volunteers — 10 times fewer people than in Sputnik V’s trials) and an even smaller control group. “In particular, similar samples are used in clinical trials for vaccines against seasonal diseases. We believe this [number of participants] will be sufficient to determine the vaccine’s epidemiological efficacy,” Vector Institute deputy general director Tatiana Nepomnyashchikh told Meduza.

EpiVacCorona’s late-phase clinical trials began in mid-November 2020, but the ethics of a study that deliberately leaves participants unprotected with placebos are different now that proven alternative vaccines are available to Russians. The Vector Institute hasn’t changed the experiment’s design, however, declining to switch to a “blinded crossover” design, wherein all participants would return for an additional two shots (the vaccine for the placebo group and saline shots for the vaccine group). Scientists also could have started using one of Russia’s other vaccines instead of a placebo. Nepomnyashchikh says any changes in the clinical trials require government approval, and health regulators already compromised by allowing researchers to reduce the size of the trials’ control group from 50 percent to 25 percent, she told Meduza.

A nationwide decline in coronavirus infections may also distort the study’s results. The research is still ongoing, but these conditions risk findings that don’t actually establish EpiVacCorona’s effectiveness against COVID-19. Meanwhile, the vaccine is registered with the government and available for use outside the efficacy study.

Tackling the genome and manufacturing immunity

EpiVacCorona is a “peptide vaccine,” consisting of artificially synthesized short fragments of viral proteins (peptides), through which the immune system learns and subsequently recognizes and neutralizes the virus. The drug was designed to create “three lines of defense” inside patients against the coronavirus, EpiVacCorona developer Alexander Ryzhikov told Meduza. Using peptides, the vaccine first blocks the virus’s spike 1 protein receptor-binding domain (S1-RBD). Second, it blocks the fusion of the viral envelope and the cell membrane, preventing the viral genome’s penetration into the cell. Finally, if these measures fail and a cell still becomes infected, antibodies hone in and destroy the compromised cells through a process known as antibody-dependent cellular cytotoxicity.

To create EpiVacCorona, scientists targeted the most “conservative” parts of the coronavirus genome (the pieces of the virus that are less prone to rapid changes), which theoretically reduces the danger posed by new variants of the virus. The approach carries its own risks, however, namely that the antibodies gained from the vaccine will be ineffective against the coronavirus because not every part of the S protein is immunologically important. EpiVacCorona uses peptides and the coronavirus’s nucleocapsid (N) protein as antigens to trigger an immune response, though new research shows that patients with antibodies to the N protein and not the S1-RBD fail to exhibit virus-neutralizing antibodies. In other words, the presence of antibodies against the N protein alone may not confer immunity against reinfection.

“You’ve got to understand how a peptide vaccine works,” says Tatiana Nepomnyashchikh. “It forms immunity subtly and elegantly, causing the production of antibodies literally with pinpoint accuracy for precisely the most important regions of the coronavirus’s S protein, without causing the production of antibodies that aren’t especially needed to protect the body. […] There should be balanced immunity and the antibodies should be protective, first and foremost. Our vaccine forms protective antibodies.”

Researchers tested EpiVacCorona’s effect on antibody production by immunizing animals and then infecting them with the coronavirus. The results of these experiments were satisfying, say the vaccine’s developers, though some observers question these conclusions. These same experiments are forbidden in humans, so scientists instead measure the presence of neutralizing antibodies in patients. EpiVacCorona’s creators say clinical volunteers show no fewer neutralizing antibodies than patients who have recovered from COVID-19.

An absence of published data

So far, however, researchers have released no corroborating data to the public — not in patents filed for the vaccine or in any other sources. Additionally, their claims about EpiVacCorona’s efficacy contradict the findings of an independent laboratory that analyzed blood samples from clinical-trial volunteers and found no neutralizing antibodies. Tatiana Nepomnyashchikh told Meduza that EpiVacCorona’s design as a peptide vaccine is unique and requires special testing to check for coronavirus antibodies. 

Developers say an article detailing their findings is forthcoming in a peer-reviewed scientific journal. To avoid influencing the journal’s decision to publish the research, the vaccine’s creators aren’t saying where the text will appear. The Vector Institute has declined to publish any unreviewed, “preprint” research (though Pfizer, for example, went ahead and disclosed its preprint data on its vaccine’s efficacy against new coronavirus variants, citing the public’s urgent need for the information). Russia’s Health Ministry is also ignoring legal requirements that compel medication developers awaiting registration to publish the trial results submitted for regulatory review.

Tatiana Nepomnyashchikh told Meduza that she contracted COVID-19 before she could be vaccinated with EpiVacCorona, but she plans to get the shot once her antibody levels fall again. Alexander Ryzhikov says he is one of the first people on the planet to be vaccinated with EpiVacCorona. He told Meduza that he’s tested his own antibody levels and is pleased with the results.