Russia’s Covid-19 vaccine Sputnik V is plagued by a number of red flags and question marks surrounding its clinical trials and results. (Photo: scitetechdaily.com / Wikipedia)

The South African medical regulator has received an application for the Russian vaccine called Sputnik V. However, a decision on approval has not yet been made.

In the first of this four-part series, we will take a closer look at the existing data for Sputnik V – and also the gaps in it.

Sputnik V or Gam-Covid-Vac was developed by the Gamaleya Research Institute of Epidemiology and Microbiology. The Gamaleya Institute is under the Ministry of Health of the Russian government.

The Sputnik vaccine became the world’s first registered Covid vaccine on August 11, 2020 – even before the publication of study results.

The vaccine uses two different types adenoviruses, a type of virus that causes colds. This adenovirus acts as a vector or carrier (like a Trojan horse) that introduces a harmless form of another virus into your body (in this case, SARS-CoV-2, the virus that causes Covid-19). This type of vaccine is known as a viral vector.

Viral vector vaccines work differently than mRNA vaccines, like Pfizer’s vaccines (our vaccine introduction uses this injection) and Moderna. These recordings use man-made pieces of genetic material to convey instructions to your cells. However, virus vector shots like Sputnik use a different virus to get DNA into the body.

In Sputnik’s case, people get two vaccinations 21 days apart. The first stab uses adenovirus 26 (this is the same adenovirus used in the Johnson & Johnson stab) and the second, adenovirus 5, as a vector.

The use of these types of cold viruses in vaccines has been in HIV vaccines tested. The difference between Sputnik and other two-dose Covid vaccinations is that the two doses use different forms of adenovirus, rather than using the same virus in both shots, as the AstraZeneca vaccination does.

It however, there is some concern about the use of the adenovirus 5 vector used in the second dose of the Sputnik vaccine. At least one study has shown that it can increase a person’s risk of contracting HIV.

A vector can’t replicate in your body, so it won’t make you sick. It penetrates your cells and provides the instructions that are encoded in the DNA it contains.

These genes carry the code for the spike protein that sits on the surface of the SARS-CoV-2 virus. Your cells then translate this code and start building spike proteins.

The appearance of the spike proteins, which cannot harm you, sends out a warning signal to the immune system. Your body’s defenses then react by sending in battle cells to destroy the foreign invader (in this case the spike proteins).

These cells remember and mark the spike protein as a harmful object. This way, if it does happen again, for example if it is infected with the actual coronavirus, your immune system will be prepared and ready to kill the virus immediately.

Before a vaccine is approved for use, it goes through several phases of testing to determine whether it is safe and effective (in this case for disease prevention). Every step of the way, more information about the jab is gathered that can help fine-tune its use – such as the dosage required or the correct time interval between shots.

Before testing drugs (such as vaccines) on humans , scientists must first conduct laboratory and animal tests to determine whether it is safe to use in humans. These studies are called “preclinical” research.

They’re usually small studies, but they’re critical. Preclinical results are used to determine, for example, which dose levels are toxic and which are safe.

Preclinical results also help researchers refine the set of rules they will use for the future study, called the study protocol. In addition, this information sets out exactly how the research is being conducted and what the scientists are trying to find out.

Once this early data is collected, studies can move on to human clinical trials. These attempts take place in stages that gradually increase. Phase 1 (the starting point) tests safety and dosage and typically involves between 20 and 100 people. The next step is phase 2, which involves several hundred people and begins tracking efficacy and side effects.

The final phase is phase 3, the largest study with thousands of participants. If successful, the results of this phase are used by the manufacturers to apply for regulatory approval and start marketing the intervention (e.g. a vaccine). Only around a quarter of the products make it from phase 1 to phase 3.

Under Covid, it has become common practice to combine study phases in order to accelerate the research process and achieve results more quickly without compromising the safety of the intervention. Clinical trials usually take several years to produce results, but with Covid this has been condensed into a few months under pandemic conditions.

The drive to reach the finish line faster means that Covid vaccine trials are much larger than usual carried out involving tens of thousands of people. This larger sample size helps reduce the time frame for trials. The more people involved in a study, the easier it is to infect enough people to get a statistically significant result on the effectiveness of a vaccine.

The Gamaleya Institute has not published the preclinical data for its vaccine – nor the protocol that they followed for the study. You skipped straight to the results.

Hilda Bastian is a founding member of the Cochrane Collaboration, which specializes in reviewing and evaluating research on health interventions. She also runs the Absolutely Maybe blog about drugs for Plos, an academic journal.

Bastian says, “[The researchers] kept reporting data during the process and then [the process stopped] and they said ‘we have enough numbers’ but we didn’t know what the rules were for deciding when there was enough data. “

The Gamaleya Institute published a paper on a common phase 1 and phase 1 and joint paper in The Lancet in September 2020 2 study of the vaccine.

The study was carried out in two Russian hospitals and included only 38 people in each phase of the study, consisting of men and women between the ages of 18 and 60.

“Almost everything, what could be wrong with one early trial was wrong with this particular one, ”argues Bastian.

The study was not blinded, which usually meant that the doctors, study participants, and participants knew who was getting the actual vaccine and who a placebo or received a dummy drug. Studies are usually blinded so that neither group of doctors is treated differently, as this can skew the results of the study in a way that is difficult to correct.

In the case of Sputnik V, however, there was no placebo group – so there was none Basic information with which the results of the study could be compared at the end. Instead, the researchers compared the two different formulations of the Sputnik V vaccine – one was a normal frozen version (as used in other vaccinations) of the two adenovirus shots and the other was a freeze-dried formulation (which must be mixed). on the website before it can be used).

The Sputnik study was not randomized either. Randomization is a key element of clinical research to ensure that study participants are non-biased and represent the general population. Randomization also helps to eliminate external factors that scientists call confounding variables that could potentially influence study results.

The participants in the small study were mostly young, white men of similar body weight. The few women (all young and white except for one Asian) were not divided equally into the two study phases. A variety of study participants is required to assess how well the vaccine works in different populations.

The dominance of young people in this study should be a cause for concern, says Bastian. “The first people to get [this vaccine] were old people, so they went into this phase 3 trial without ever really testing whether it was safe in people of all ages.”

Two months after its approval and widespread use in Russia, data from the Phase 3 clinical trials for the Sputnik-V vaccine were published in The Lancet in February.

The trial showed an efficacy of 91.6% in a group of over 40,000 adults (about half of whom received the Sputnik-V vaccine while the other half received a sham vaccine).

This brings the vaccine’s effectiveness closer to that of top mRNA candidates like Pfizer and Moderna as those of its other adenovirus counterparts, AstraZeneca and Johnson & Johnson.

At the start of the Phase 3 trials, there were already questions about the quality of the research by the Gamaleya team, says Bastian. This is because, up to this point, only data from the Phase 1/2 study, which was poorly designed (as it was an open-label study, there was no control group, and participants were not randomly selected, were shared).

Bastian says that the first study results put her on high alert: “This study asked the question ‘Can you do a real study?’ The basics?”

It has become very difficult Bastian explains that because the protocol has not yet been published at this late stage.

Protocols provide a guide or overview of the rules of the study and what exactly is being measured. Not to share this part of the research, would be like saying you hit a hole-in-one when no one knows what golf course you are playing on.

Studies should have systems in place to monitor people gen after they have received the vaccination. Gathering this information will help assess the safety of the vaccine and what symptoms people should look out for after vaccination.

This monitoring can be done in two ways: either actively or passively. With active monitoring, researchers would call in on all participants to record any symptoms they might have. Passive monitoring is a reporting system that encourages people to log the data themselves if they believe they have side effects from the vaccination.

The Sputnik-V study used an existing government electronic database in Moscow called United Medical Information and Analytical System to track possible adverse events. This system is used to log doctor’s appointments and also provides information on hospital admissions.

The problem with this approach is that there was no separate data acquisition system for the study and the paper neither explains the reliability nor recognizes possible limitations of the database used, says Bastian.

The study was carried out entirely in Russia – and in just one city. In itself this is not a problem, but if, for example, all test participants belong to the same race, it becomes difficult to generalize the results of the study.

At Sputnik V, the majority of the test participants were white. The lack of racial diversity plays a role in the results of clinical trials on Covid as we know the virus affects people differently and race is a factor in that experience.

Covid vaccine studies like those by Johnson & Johnson found held in multiple countries, while Moderna was conducted in one country (the United States).

But the Moderna study was conducted with a diverse group of participants from different age groups and from multiple ethnicities. Unfortunately, Sputnik didn’t get the same advantage.

In addition to the shortcomings of the study itself, the research community also criticized the “poor quality reporting” in the paper later published by The Lancet.

The critics of the Gamaleya Research Institute wrote to The Lancet and noted inexplicable changes in the data they considered “special”, including missing enrollment dates for 100 participants. They also warned that the number of participants in different age groups was insufficient to match the total number of participants reported in the study.

What exactly the researchers examined is also unclear as the main objective of the study appeared to be changing. First, the effectiveness of Sputnik V was assessed after one dose, but in the end the assessment was made after two doses.

The finding that Sputnik V is 91% effective depends on this change, but the reasons for it have been not published, argued critics.

These and other questions would be easier to understand and critically evaluate if the study protocol and individual patient files had been made available, but the Gamaleya Institute did not respond to the researchers’ request for access. “We invite the investigators once again to make the data on which their analyzes are based publicly available,” it says in their letter.

The institute replied, saying that the numerical errors were “simple typographical errors that were formal have been corrected “and that the minutes and the data set were submitted to The Lancet in accordance with international publishing standards.

Barry Schoub, Head of the South African Council of Ministers for Covid-19 Vaccines, argues, however, that the editors of journals with the provided Data can only do so much.

He explains, “I would more or less trust the high-citation journals like The Lancet… it’s one of the oldest medical journals. I think their scientific integrity is pretty good. ”DM / MC

This story was produced by the Bhekisisa Center for Health Journalism. Sign up for the newsletter.

“Information about Covid-19, vaccines, how to control the spread of the virus and possible treatments is constantly changing. According to Regulation 11 (5) (c) of the South African Civil Protection Act, it is forbidden to publish information through any medium. ” with the intent to deceive people about government measures to combat COVID-19. We therefore deactivate the comment area in this article in order to protect both the commenting member and ourselves from possible liability. Should you have any additional information that you think we should know? , please email [email protected] “

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