Russian’s Sputnik V Controversy On Raw Data

Sputnik V, the Covid-19 vaccine developed by Moscow’s Gamaleya Research Institute, has suffered a sharp fall from grace since it was first announced. Once a front-runner in the race to develop a vaccine against SARS-CoV-2, Sputnik V has become shrouded in controversy, largely due to the Institute’s refusal to share important data on the drug.

Russia’s Federal Service for Surveillance in Healthcare approved Sputnik V for emergency use in August 2020, after it was tested on just 38 people and before the Phase III trial was completed. This set alarm bells ringing in the scientific community. A group of 37 scientists from around the globe signed an open letter in September that year, highlighting their suspicions about the vaccine’s early trial data.

In November, the Gamaleya Research Institute countered this with an impressive report of a 91.6% efficacy rate. This was based on interim analyses of Phase III data, however, the Institute failed to include the supporting raw data.

Despite the doubts and lack of data, the Russian vaccine has now been registered in 66 countries with a total population of over 3.2 billion people. Most of these are lower-middle-income nations with a high unmet need when it comes to access to vaccines.

Blocked by Brazil

Amongst these nations was Brazil, a country ravaged by a devastating second wave of Covid-19, with a native strain of concern and a vaccinated population of only around 16%.

In light of the controversy, lack of data and mounting concerns around Sputnik V’s quality and safety, the Brazilian Health Regulatory Agency (Anvisa) dropped its deal with Gamaleya Research Institute to import the vaccine in April.

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“The data we evaluated shows the presence of replicating virus,” Anvisa’s general manager of medicines and biological products Gustavo Mendes said at a press conference. He added that Anvisa would not accept the vaccine without further studies to demonstrate its safety.

The first and second doses of Sputnik V harness two different common cold-causing adenoviruses to deliver the gene for the spike protein of SARS-CoV-2, both of which are supposed to be engineered so that they cannot replicate. Anvisa says that documentation from some of the Russian facilities producing Sputnik V shows that one of its two doses contains adenoviruses that are ‘live’ and therefore capable of multiplying, which could be hazardous to vaccine recipients. Anvisa inspectors were also barred from entering Gamaleya’s quality control centre and some of the manufacturing sites when they visited Russia to examine the plants where Brazil-bound Sputnik doses were to be developed.

Brazil’s announcement that the deal had been dropped led to some scientists and journalists incorrectly believing that Anvisa had conducted tests on the Russian vaccine itself, which would have been unusual for a regulatory agency. It has since clarified that this is not the case.

Despite this, the Brazilian regulator’s shun of Sputnik V sparked the Twitter account officially associated with the vaccine to post: “Following the admission of Brazilian regulator Anvisa that it did not test Sputnik V vaccine, Sputnik V is undertaking a legal defamation proceeding in Brazil against Anvisa for knowingly spreading false and inaccurate information.”

The spat had left the scientific community and the media confused and divided. Gamaleya Institute deputy director Denis Logunov responded by saying: “The statements I have read in the press have nothing to do with reality” and that the adenovirus vector was not able to replicate.

Brazil’s drugs regulator wasn’t the first to raise concerns and block imports of Sputnik V. In the Czech Republic, the country’s medicines regulator SÚKL said on 29 April that it didn’t have enough data to decide whether to approve the drug. Slovakia also said it had concerns, claiming that Sputnik doses delivered to the country didn’t match those supplied elsewhere, but decided to approve the vaccine anyway.

Still no raw data

On 22 May, some of the same scientists who wrote the September open letter submitted another damning note reiterating their concerns, this time to the Lancet. The nine scientists and academics, hailing from Russia, the US, France, Italy and the Netherlands and led by Temple University’s Enrico Bucci, highlighted “data discrepancies,” “numerical inconsistencies” and “substandard reporting” of interim data in the published Sputnik V Phase III trial data, as well as “problematic data” in the Phase I/II results.

Gamaleya researchers came back with a defensive response letter published simultaneously in the same journal, pointing out that regulators in many countries had approved Sputnik V based on the data provided and that it had been dosed in almost four million people in Russia alone with no reports of any concerning side effects. They also noted that the Phase I/II and III data analysis in question was peer-reviewed prior to publication and said that their research “fully complies” with international clinical trial standards and that “the safety and immunogenicity of the Sputnik V vaccine has been confirmed in multiple studies.”

However, the Institute has still failed to present the raw data after numerous requests to quell concerns of data manipulation, something that has caused “serious concern” to Bucci and his co-authors.

The researchers also highlighted “very peculiar” results in the reporting of the vaccine’s efficacy across different age groups. Variation across the five age bands studied ranged between just 90% and 92.7%.

Gamaleya responded that: “The homogeneity of the values only confirms the fact that… the effectiveness of the vaccine does not differ between age groups.”

The researchers also said that the published results were unclear in terms of the testing regime used to detect Covid-19 among the trial participants, saying that: “the way cases of suspected Covid-19 were defined could have led to bias in PCR testing used to assess the number of confirmed Covid-19 cases, which is crucial for the efficacy determination.”

Sputnik V’s developers countered that in cases when it was suspected that a participant had contracted Covid-19, they: “were assessed according to Covid-19 diagnostic protocols, including PCR testing.”

Missing participants

Another issue mentioned in the open letter was the inconsistencies between the number of patients screened for the trial (35,963) and the number of patients randomised (21,977). The record for the trial claimed that 33,758 patients were enrolled. The letter authors said: “we would expect that this last figure should be equal to either the number of participants screened or randomised. Moreover, there is no information about what caused the exclusion of 13,986 participants, as per the trial profile.”

In response, Gamaleya’s Logunov said: “Some of the volunteers were screened and had not yet been randomised at the time of the snapshot, and others were excluded according to the exclusion criteria or did not meet the inclusion criteria.”

He also said that some “numerical inconsistencies were simple typing errors.”

The Gamaleya Institute did not publish any additional data in its response to the scientists’ claims. It stated that it will only make full data available upon the study’s completion and only if certain stakeholders approve, including what the opposing scientists described as “a so-called security department.”

The group has called on the editors at the Lancet to “clarify the consequences of further denying access to the data needed for assessing the results presented, should the authors still deny it.”

The scrutiny comes as Russia tries to get authorisation from the European Medicines Agency (EMA), whose inspectors have completed a “special ethics probe” into the vaccine’s clinical research. The results will only be published after all stages of the trials for Sputnik V are complete.

Highlighting the need for better transparency

In an opinion piece for STAT News, Transparency International head of global health programs Jonathan Cushing said: “The Sputnik V issue highlights why better clinical trial transparency is urgently needed, and not just for the Russian vaccine but for all Covid-19 vaccines.”

Transparency International conducted an analysis of the world’s 20 leading coronavirus vaccines and identified a total of 86 clinical trials on registry platforms as of March 2021. However, results have been announced for less than half of these.

Cushing says that of the trials with announced results, 41% of the reports provided no data analysis – only “headline information” via “carefully worded” press releases or conferences.

He states that the blame shouldn’t be entirely on the firms developing vaccines when it comes to not sharing all of their clinical trial data: “Rather, this issue reflects the lack of any real guidance on how, what, or when clinical trial data should be shared during health emergencies. Even in ‘normal’ times, there is no harmonized global policy on clinical trial transparency despite the best efforts of the World Health Organization and transparency advocates in promoting best practices.

“That said, a lack of coherent guidance does not excuse drug or vaccine developers from behaving in the most transparent manner possible.”

A politically-charged candidate

Named after the first man-made satellite launched into orbit in 1957 by the Soviet Union and described by Russia’s President Vladimir Putin as “reliable as a Kalashnikov assault rifle,” Sputnik V is being described as an agent of geopolitical motives by critics in and out of the country.

This is compounded by Russia’s aggressive touting of the Kremlin-backed, government-funded vaccine, alongside what many are saying is a widespread disinformation campaign aiming to undermine vaccines developed in Western countries. Sputnik V’s very active Twitter account has also accused the EMA of bias.

Until the data the world is waiting for is released and the EMA has completed their rolling review of the vaccine, it is hard to separate fact from fiction when it comes to Sputnik V. In the meantime, the vaccine is continuing to be approved in less concerned countries around the world.