Health regulators in Brazil say that doses of Russia’s Sputnik V COVID-19 vaccine contain a cold-causing virus capable of replicating in human cells.
The unintended presence of the virus in the vaccine can “lead to infections in humans and can cause damage and death, especially in people with low immunity and respiratory problems, among other health problems,” Brazil’s Health Regulatory Agency, Anvisa, said Wednesday in a translated statement.
Russia has unequivocally denied the claim, lobbed legal threats at Anvisa, and accused the respected regulators of being politically motivated to reject the vaccine.
Still, Brazil’s findings raise serious questions about the quality and safety of the vaccine, which is now being used in many countries. The findings also support concerns of Slovak regulators, who said earlier this month that batches of Sputnik V they received did not “have the same characteristics and properties” as the Sputnik V vaccine that was described in a peer-reviewed publication and found to be 91.6 percent effective.
Moreover, quality-control issues weren’t the end of Anvisa’s concerns. In an overall evaluation of the Russian vaccine, Brazil’s regulators found its safety and efficacy were based on insufficient, limited, and sometimes faulty data and analyses. “Flaws… were identified in all stages of clinical studies,” Anvisa said. The agency also reported that its inspectors who traveled to Russia to assess the vaccine’s production were barred from vaccine facilities at Gamaleya Institute, which developed Sputnik V.
In a vote late Monday, Anvisa’s five directors unanimously denied the importation and use of the Sputnik V vaccine in Brazil. Prior to the decision, 14 states and two municipalities had requested imports of the vaccine, Anvisa said.
Brazil is currently being ravaged by the pandemic coronavirus, including a more-transmissible variant, P.1, which may evade some immune responses. The latest surge of infections peaked late last month at over 100,000 new cases in a single day. In turn, deaths peaked at over 4,000 a day in early April. New daily case counts have now fallen to a seven-day average of around 57,000 cases, which is still very high. To date, more than 14.5 million people have been infected in the country of around 211 million. Nearly 400,000 people have died.
“I express here with sincerity that we are doing everything we can to ensure that vaccines for COVID-19 reach the people of this nation and that they meet the standards of quality, safety, and efficacy,” Anvisa Director Meiruze Freitas said in a translated statement. “When [Brazilians’] arms are offered, they need to have confidence in the work of Anvisa’s public servants.”
For now, no Brazilians will be rolling up their sleeves for Sputnik, given the regulator’s concerns. Freitas expressed hope that Russian vaccine developers would be open to Anvisa’s critique and take the necessary steps to address problems “because millions of people need access to safe and effective vaccines,” she said.
But that appears unlikely. In a press release, the Russian Direct Investment Fund (RDIF), which financially backed the development of Sputnik V, called Brazil’s criticisms and vote “political.”
“These allegations have no scientific basis and cannot be taken seriously in the scientific community and among international regulators,” the RDIF said.
The official Twitter account for the Sputnik vaccine, thought to be run by the RDIF, took things a step further, calling Anvisa’s assessment “fake news.” On Thursday, the account tweeted that “Sputnik V is undertaking a legal defamation proceeding in Brazil against Anvisa for knowingly spreading false and inaccurate information.”
The virus that regulators in Brazil say is contaminating Sputnik V is a replication-competent adenovirus. Sputnik V is supposed to contain adenoviruses, but only ones that are engineered so that they cannot replicate in human cells.
Adenoviruses are extremely common viruses and typically cause only mild infections, such as colds, diarrhea, and pink eye. Over the years, researchers have found adenoviruses to be useful delivery systems for therapies—once the viruses have been tweaked to render them completely harmless. This is done by simply deleting a few genes. Non-replicating adenoviruses are often used for vaccines and gene therapies. And several other COVID-19 vaccines use non-replicating adenoviruses, including vaccines by Johnson & Johnson and AstraZeneca.
Adenovirus-based vaccines work by having the engineered adenovirus deliver to human cells snippets of genetic code from an enemy germ. In the case of the COVID-19 vaccines, the adenoviruses deliver the code for SARS-CoV-2’s spike protein. When a shot goes in an arm, the adenoviruses in the vaccine break into and infect human cells, delivering the code for the spike in the process. But then, the non-replicating viruses hit an engineering wall, at which point they can’t use the cell to make copies of themselves. Normally, those viruses would turn the cell into a virus clone factory, and the clones would go on to infect more cells. Instead, the non-replicating adenoviruses in the vaccine essentially stall out. The human cells are left to decode the SARS-CoV-2 spike sequence and have the immune system use the sequence for target practice.
By design, Sputnik V uses two adenoviruses, with a different virus given in each of the vaccine’s two doses. The first shot is a spike-loaded adenovirus type 26 (Ad26), an adenovirus first identified in children’s stool. The second shot uses adenovirus type 5 (Ad5), which causes colds and has been used extensively in biomedical research. While other adenovirus-based COVID-19 vaccines use only one type of adenovirus, there’s good reason to use the mix.
Because adenoviruses are extremely common, many people already have immune responses to them. Thus, a potential pitfall for using adenoviruses as a vaccine delivery system is that a person’s immune system may end up responding more to the adenovirus itself than the vaccine’s genetic payload—i.e. the spike protein. There is, in fact, evidence to suggest that pre-existing adenovirus immunity can make a vaccine less effective. To try to skirt this problem, Russian vaccine developers used the two different adenoviruses so that the vaccine won’t amplify the same pre-existing adenovirus immune responses after each dose. (AstraZeneca’s vaccine, by contrast, uses a modified version of chimpanzee adenovirus that doesn’t normally circulate in humans—another strategy for dodging the problem of pre-existing adenovirus immunity.)
Troubling replication limit
But doubling up the adenovirus might have boosted the risks for Russian vaccine developers. Brazil’s regulators say they reviewed data indicating that there was replication-competent adenovirus (RCA) in every evaluated batch of the second Ad5-based dose of Sputnik V.
In a 21-page report from Anvisa, the regulator wrote (translated from Portuguese on page 8), “Although international guidelines have established that replicating viruses should not be present in the vaccines, the [Sputnik V developers] set the limit of 1×103 [1,000] RCA per dose of 1×1011 [100 billion] viral particles, which is considerably above the limits allowed in the guidance of the American FDA” for gene therapies.
The US Food and Drug Administration’s guidance for gene therapies states that the agency recommends “a maximum level of 1 RCA in 3×1010 [30 billion] viral particles.” That would allow for no more than about 3.33 RCA in 100 billion viral particles, not 1,000.
In another report, Anvisa wrote (again translated): “It is noteworthy that the replicating adenovirus was detected in all batches presented for component II [Ad5-based second dose] of the vaccine and not evaluated in component I [Ad26-based first doses].”
The data was enough to worry the regulators, who had a string of questions after seeing it, including: “How long can replicating viruses remain in the human body? In what organs and tissues can they be found? Can they cause any damage to tissues and organs? Can this replicating virus be transmitted to other people? What does it mean in terms of safety for those who receive the vaccine? [Is there] increased risk of adverse events?”
Russia touts that “the safety and efficacy of Sputnik V has been confirmed by 61 regulators in countries where the vaccine has been authorized.” However, Brazil’s regulators said that of the 51 countries it contacted, only 14 were using the vaccine, and most of those countries did not have a tradition of vigilant drug-safety monitoring.