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These Russian-made doses of the Sputnik V COVID-19 vaccine can’t be imported yet into Brazil because a regulatory agency there believes they contain infectious common cold viruses.

Andrey Rudakov/Bloomberg via Getty Images

Is Russia’s COVID-19 vaccine safe? Brazil’s veto of Sputnik V sparks lawsuit threat and confusion

Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.

A confusing and unusually nasty fight broke out this week over the safety of a Russian COVID-19 vaccine known as Sputnik V after a Brazilian health agency declined on Monday to authorize its import because of quality and safety concerns. The stakes escalated yesterday when the Twitter account officially associated with the vaccine said “Sputnik V is undertaking a legal defamation proceeding” against Brazil’s regulators.

In an online press conference several hours later, the Brazilian Health Regulatory Agency (Anvisa) defended its decision, maintaining that documentation from some of the Russian facilities making Sputnik V shows that one of its two doses contains adenoviruses capable of replication, a potential danger to vaccine recipients. The vaccine uses two different adenoviruses, which cause the common cold, to deliver the gene for the spike protein of SARS-CoV-2, the virus that causes COVD-19. Both are supposed to be stripped of a key gene that allows them to replicate.

The Monday announcement left many scientists and media outlets believing Anvisa had directly tested Sputnik V for replicating adenoviruses, which would be unusual for a regulatory agency. But Anvisa has since clarified—it had not and was relying on information provided by the Gamaleya National Center of Epidemiology and Microbiology, the Moscow-based developer of the vaccine.

“The data we evaluated shows the presence of replicating virus,” Gustavo Mendes, general manager of medicines and biological products at Anvisa, said at the press conference. Anvisa would not accept the vaccine, he said, without further studies to indicate it is safe.

Gamaleya said in a statement on its website that Anvisa’s allegations “have no scientific grounds and cannot be treated seriously.” The research institute added that “no replication-competent adenoviruses (RCA) were ever found in any of the Sputnik V vaccine batches” and said a four-stage purification process prevents contamination.

The furor comes as Brazil, which has one of the highest burdens of COVID-19 in the world, is desperately trying to expand its vaccination campaign. The country has vaccinated just 14% of its people with a first dose and governors from some states hoped to bolster that effort by grouping together to buy 30 million doses of Sputnik V.

The spat has bewildered and divided outside observers, in Brazil and elsewhere. Some scientists have used social media to decry the apparent contamination and some have denounced the aggressive response by Sputnik V’s backers, who were already under fire for releasing little data on the vaccine’s safety record. On Wednesday, an agency of the European Union also issued a report criticizing Russia’s promotional effort for Sputnik V for providing disinformation.

Other scientists, however, have questioned whether Anvisa appropriately interpreted the information provided by Sputnik V’s makers, and whether the media has too readily accepted the agency’s claim that the vaccine is contaminated. The stakes are high because Sputnik V has been authorized for use in more than 60 countries, although neither the World Health Organization nor the European Medicines Agency has yet authorized it. “We need this vaccine. It’s cheap. It’s effective. It’s easy to store and transport,” says Hildegund Ertl, an adenovirus vaccine scientist at the Wistar Institute. “If the press could just take a deep breath before they rush to conclusions it would really help us all.”

One of the scientists who criticized Sputnik V this week on Twitter said she is keeping an open mind. “I will be glad to correct myself in public should the data be shared,” says Angela Rasmussen, a virologist at the Vaccine and Infectious Disease Organization at the University of Saskatchewan. (Her Twitter thread about Anvisa’s decision got a response from Sputnik V’s account that read “please do not spread fake news.”)

Viruses reborn?

The Anvisa review of Sputnik V was triggered because the Brazilian governors needed the agency’s sign-off to import the vaccine. Although complaints about Russia’s lack of transparency with Sputnik V data have simmered for months, many public health officials and scientists worldwide had been reassured when The Lancet recently published results from nearly 20,000 people in a clinical trial. The study showed the vaccine was safe and had an efficacy of 91.6% at preventing symptomatic COVID-19.

Both of the adenoviruses that make up Sputnik V, known as Ad5 and Ad26, are churned out by cultured human cells called HEK293 cells. The adenoviruses ferry the coronavirus spike gene to the vaccine recipient’s cells, which then make spike, prompting an immune response. In order to stop the adenoviruses from replicating once inside their human host, the vaccinemaker removed a gene they need for reproduction, called E1. The viruses can copy themselves in HEK293 cells, which are engineered to have a stand-in E1 gene, but they are not supposed to be able to replicate once they are separated from the human cells and packaged in the final vaccine product.

It’s long been known that Ad5 can on rare occasions acquire the E1 gene from the HEK293 cells, converting what is supposed to be a crippled virus into an RCA. Although adenoviruses typically cause mild colds, they can rarely kill people, and immunocompromised people who receive a vaccine that inadvertently contains RCAs could be at particular risk.

Vaccinemakers and others have developed tests to check for replicating adenoviruses in their products. Anvisa said that although the standard worldwide has been zero tolerance for the presence of replicating adenovirus in the vaccine, Gamaleya established an acceptable limit of 5000 replication-capable virus particles per vaccine dose. The Russian quality control documents displayed by Anvisa during the press conference state the batches tested had “less than 100” replication-capable particles per dose.

During yesterday’s press conference, Mendes also showed video of parts of an online meeting in March between officials from Anvisa and the vaccine’s developer. In one of the clips, Anvisa officials ask Gamaleya representatives why they had not changed their production methods once they “had detected the RCA occurrence in your production.” The Gamaleya representatives responded that they were aware of the risk, but that changing the process “would take too much time.”

Mendes noted that Anvisa has analyzed the quality control documentation on other adenovirus-based COVID-19 vaccines, such as those made by AstraZeneca and Johnson & Johnson, and found no evidence of replication-competent viruses in those companies’ final products.

Immunologist Jorge Kalil, a vaccine expert at the Federal University of São Paulo, São Paulo, and member of the Data and Safety Monitoring Board at the U.S. National Institutes of Health, disagrees with Anvisa’s interpretation. He believes Russian quality-control documents are actually referring to the sensitivity of the testing. “When the Russians say ‘less than 100 parts per dose’ they are not saying if there are replicant viruses [in the dose] or not,” he contends. “What they are saying is that if there are viruses, they are [there] in less than 100 parts per dose.”

Mendes told Science this is not the case and that if it were, Gamaleya would have reported “no detection.” One way or the other, Anvisa won’t tolerate replicating virus in the vaccine and needs more assurance there is none. “The limit for us is zero,” agency President, Antonio Barras said during the press conference.

Other quality concerns

Anvisa also reported a long list of other issues with the vaccine that it wants the Russians to address. Those include the lack of detailed information on the 63 cases of adverse events and four deaths reported during the clinical trial. (The Lancet paper on Sputnik V’s efficacy trial reported no serious adverse events or deaths were deemed to be related to vaccination.)

The Brazilian agency also complains that during an inspection trip to Russia in April its technicians were only allowed to visit three of seven manufacturing sites—and were not allowed to visit Gamaleya’s quality-control center. As a result, “It is not possible to verify the existence of standards within the … facilities,” according to an Anvisa report published Monday with the veto announcement.

“So, the word that sums up the visit to Russia is frustration,” Anvisa Director Alex Machado Campos said during the Monday discussion on the import vote, according to a video of the event.

Mendes yesterday said these issues alone, even without the possible presence of the replicating adenovirus, “would be enough to reject” the import request. It was the totality of the deficiencies that led to Anvisa’s decision, he says.

Unnecessary turmoil

The outcome has dismayed many in Brazil, who were hoping Sputnik V would help them blunt the nation’s out-of-control epidemic. Brazil’s former science minister, Sergio Rezende, who is part of the scientific board supporting the state governors who requested the vaccine, says he was surprised by how Anvisa presented information on Monday. He was among those who believed Anvisa said it had directly tested Sputnik V for replicating adenoviruses. “Most people don’t know that Anvisa does not have a laboratory, so this is very serious because Anvisa is an agency that has credibility,” Rezende says.

He still doubts the agency's decision, even after the press conference. “Anvisa did not clarify anything,” he says, noting that the governors have sent new technical documentation from Gamaleya to Anvisa and that they may appeal Anvisa’s decision to Brazil’s Supreme Court.

Immunologist Ricardo Gazzinelli, president of the Brazilian Immunology Society, calls the political fight around Anvisa’s decision “an unnecessary turmoil.” He believes all the vaccine concerns listed by the regulatory agency are basic and easily addressed. “Sputnik should have responded to [Anvisa’s considerations] instead of starting a fight.”

Anvisa officials say Sputnik V’s makers have not sought a meeting to address the agency’s concerns and that if Gamaleya clarifies the issues raised by the regulatory agency, the import ban can still be reversed. “We have made demands and we are waiting for the response,” Mendes says. “Sputnik V is not out of the question” for use in Brazil, he says.