Sputnik-V: A Russian con job on its COVID-19 vaccine

Yesterday, the news was dominated by what I consider to be one of the worst ideas ever. Russian President Dictator Vladimir Putin announced the approval of a new vaccine for COVID-19. In a not-very-subtle admission of the purpose of approving this vaccine, the Russians dubbed the vaccine “Sputnik-V,” after the surprise launch of the first space satellite by the Soviet Union in 1957 during the Cold War, which panicked the US, a panic sometimes referred to as the Sputnik crisis. In the wake of Sputnik, there was a period of fear and anxiety about a perceived gap in science and technology between the US and its Cold War superpower rival.

As CNN reported yesterday:

Russian President Vladimir Putin announced the approval of a coronavirus vaccine for use on Tuesday, claiming it as a “world first,” amid continued concern and unanswered questions over its safety and effectiveness. “

A vaccine against coronavirus has been registered for the first time in the world this morning,” Putin said on state TV. “I know that it works quite effectively, it forms a stable immunity.”

Putin added that one of his daughters had already taken it; he said she had a slightly higher temperature after each dose, but that: “Now she feels well.”

While it’s nice that Putin’s daughter didn’t suffer any adverse effects from the experimental vaccine other than what sounds like mild fevers, none of this obviates the obvious conclusion that this is pure propaganda, and an amazingly irresponsible bit of propaganda, to boot. Why irresponsible? Because:

Russia has released no scientific data on its testing and CNN is unable to verify the vaccine’s claimed safety or effectiveness.

Despite this, Russian officials have told CNN that at least 20 countries and some US companies have expressed interest in the vaccine.

I’ll discuss more about what is known (and, far more, what is unknown) about this Russian Sputnik-V vaccine in a moment. First, let me just reiterate my position (as if anyone here has any doubt about what it is). As hard as it is to believe, it was two and a half months ago when I first expressed my alarm at President Trump’s initiative to fast track a coronavirus vaccine that had been dubbed “Operation Warp Speed.” At the time, I commented primarily on the Moderna vaccine, which I viewed as an interesting example among the many COVID-19 vaccine candidates being tested because it is not a typical attenuated live virus vaccine or a vaccine consisting of key peptide antigens to provoke an immune response. Instead, it consists of messenger RNA (mRNA). For those not familiar with the biology, the DNA in your genome is translated into mRNA, which is then used as a template for the ribosomes to produce protein according to the nucleotide sequence of the mRNA. Of course, the process is a lot more complicated than that. For many genes, there are longer mRNA precursors that are cut up and then spliced together to form the final mRNA, but this description is correct, at least as far as the essence of the process goes: DNA to mRNA to protein. The Moderna vaccine uses mRNA, which is taken up by cells and turned into proteins, in order to provoke an immune response. It’s an interesting technique, although mRNA is notoriously difficult to work with because, unlike DNA, it is very unstable and breaks down easily. Personally, I was uneasy about the promotion of a vaccine based on a technique that had never resulted in an approved human vaccine before. Could it work? Sure. But it was risky.

The Russian vaccine similarly uses a technique that, while not as novel as an mRNA vaccine, is not widely used to make vaccines. Instead of using mRNA, the Russian vaccine uses an approach similar to other COVID-19 vaccines currently being developed:

Researchers at the Moscow-based Gamaleya Research Institute of Epidemiology and Microbiology, part of the Russian Health Ministry, developed the two-part vaccine. Both parts start with viruses that cause the common cold. Those viruses, adenovirus 5 and adenovirus 26, were each engineered to make the coronavirus’ spike protein. That protein helps the coronavirus latch on to cells and infect them. Since it is on the surface of the virus, it’s also a target for antibodies against the virus.

This approach is similar to other coronavirus vaccines in the works. The University of Oxford working with AstraZeneca uses a chimpanzee adenovirus. And a vaccine devised by China-based CanSino Biologics Inc. is based on adenovirus 5. Johnson & Johnson uses adenovirus 26 for its vaccine. Those vaccines have gone through initial safety tests where participants made antibodies against the virus and didn’t have any serious side effects (SN: 7/21/20).

So, instead of using mRNA, this approach uses a common virus as a vector, adenovirus. This is basically gene therapy as a vaccine. There are basically two approaches to using adenoviral vectors to produce proteins in humans. The first is to use what’s called a replication-defective adenovirus. Such adenoviruses are engineered to remove certain genes essential for replication, and usually the gene of interest (in this case, coronavirus spike protein) is inserted in place of those genes. This is almost certainly how the Russians engineered their vaccine, as it’s the approach used for most attempts at . Replication-competent adenoviral vectors are, as the name implies, capable of replicating in human cells normally. In general, replication-competent adenovirus vectors are used for what is referred to as oncolytic cancer therapy. Such viruses are generally engineered to replicate preferentially in cancer cells compared to normal cells and destroy the cancer cells by doing what adenoviruses do best: Replicating and then lysing (bursting) the cancer cells, thus killing them.

Adenoviral vectors have a number of advantages, but several disadvantages as well. The virus is well-studied, and adenoviral vectors can be grown into high titer stable stocks without much difficulty. They also infect dividing and non-dividing cells. In general, as formulated now they are safe and well tolerated. Another advantage of adenoviral vectors is this:

Ads are strongly immunogenic and this has consequences not only for Ad infection outcomes and prevention, but also for the use of Ads as vectors for gene therapy, for vaccines, and for cancer gene therapy. The most important antigens are the three major capsid proteins, the hexon, penton base, and fiber. Most neutralizing antibodies are directed against the most abundant capsid protein, hexon, and especially against so-called hypervariable loops (i.e. regions that differ among serotypes) that are exposed on the surface of hexon [9, 10]. Ad-specific CD4+ T cells have been found among peripheral blood lymphocytes of almost all individuals of all ages. Most of the CD4+ T cell epitopes are in hexon [11]. Although less common, hexon-specific CD8+ T cell epitopes are present in healthy donors [11]. There is evidence that cytotoxic T lymphocytes (CTL) specific to hexon are protective against Ad infections in humans [12].

Ads and Ad vectors induce a strong innate immune response that has been studied extensively in mouse models [13]. Understanding and appreciating these strong innate and adaptive immune responses are likely relevant to assessing the use and safety of Ad vectors.

This is a problem that the Russians could conceivably have overcome by the use of two different strains of adenovirus:

Using two adenoviruses instead of one is unusual, but may help solve a potential problem, says Daniel Kuritzkes, a virologist and infectious diseases doctor at Brigham and Women’s Hospital in Boston. Because the body may develop antibodies to the virus carrying the spike protein, a booster shot with that same virus might be rendered useless. The two-step inoculation with different adenoviruses may sidestep that issue.

What this basically means is that Sputnik-V could work. It’s true that translating efficacy the efficacy of adenovirus-based vaccines from rodent models to primates and humans has thus far been mostly elusive. Indeed, even though adenovirus-based vaccines against COVID-19 are the frontrunners right now in the race to be the first to be approved, they have a rather checkered past for other diseases. The technology has been around for 30 years but has yet to result in an approved vaccine for humans, and:

Adenovirus vaccines might be grabbing the limelight amid the coronavirus pandemic, but they have a checkered past.

When scientists began creating adenoviral vectors in the 1980s, most worked with a particular kind of adenovirus called Ad5, which ubiquitously infects humans and causes the common cold. Researchers stripped Ad5 of the genes it needed to replicate and inserted those genes into genetically engineered cell lines. That ensured that the modified viruses could be grown only in these special cells in the lab. It also opened up space in the Ad5 genome for scientists to stitch in new genes of their choosing.

Many scientists hoped to use Ad5 to deliver a human gene that could correct rare genetic mutations—an approach called gene therapy. Those efforts came to a grinding halt in 1999 when a teenage boy with a rare genetic liver disease died after receiving an injection of an Ad5-based gene therapy, which had been designed in James Wilson’s lab at the University of Pennsylvania.

The large dose of 38 trillion viruses the patient was given sparked massive body-wide inflammation and sent his immune system into overdrive. After that, scientists mostly stopped using adenoviral vectors for gene therapy, in which the dose needs to be high to reach many cells of the body.

But vaccine developers viewed adenovirus-induced inflammation as an asset. “There is an expression out there that a failed gene therapy makes a good vaccine,” says Luk Vandenberghe, a viral vector expert at Harvard Medical School.

One attractive feature is that adenoviruses’ inflammatory effects mean developers don’t have to use adjuvants, molecules added to conventional vaccines to direct the immune system’s attention to the viral protein. The adenoviruses themselves drive the inflammation, which is kept under control by giving the vaccines at low doses.

Jesse Gelsinger’s death was a tragedy and a huge blow that set gene therapy back several years. Most likely it was the enormous dose of adenovirus vector that resulted in his death. Still, none of this changes the fact that, as yet, there are no adenovirus-based vaccines demonstrated to be sufficiently safe and effective to be approved for general use use.

So theoretically Sputnik-V could work. But does it? The answer is simple: We have no idea! Not only have the Russians not published any of the data that they used to “approve” Sputnik-V, they haven’t done the phase 3 clinical trials necessary to demonstrate efficacy and safety. The whole thing has been quite shady. Yes, the Russians did register two clinical trials at ClinicalTrials.gov, NCT04437875 and NCT04436471. These were both open-label (unblinded), phase I clinical trials. These trials accrued 38 healthy volunteers each, for a total of 76 people having received the vaccine. This is all fine, as far as early human testing of a new vaccine goes. Phase I trials, however, are not designed to determine efficacy. They are designed to rule out major safety concerns and to determine dose, and all we know about the results of these phase 1 trials is this:

According to the vaccine’s Russian-language registration certificate, all 38 participants who received one or two doses of the vaccine had produced antibodies against SARS-CoV-2’s spike protein, including potent neutralizing antibodies that inactivate viral particles. These findings are similar to results of early-stage trials of other candidate vaccines. Side effects were also similar, such as fever, headache and skin irritation at the site of injection.

Again, so far, so good, but this is only a preliminary result that supports moving on to larger phase 2 trials (which usually involve a few hundred subjects). It in no way shows that the vaccine will work to prevent infection or that it will be safe when given to millions (or hundreds of millions) of people. Interestingly, First Deputy Defense Minister Ruslan Tsalikov said in an interview published in the Argumenty i Fakty newspaper that the Russian military has completed phase 2 trials of Sputnik-V, but, again, there are no data published anywhere.

Worse:

Since then, Russian officials have claimed that they would be moving the vaccine quickly into manufacturing. Mr. Putin’s announcement on Tuesday made it official. Yet the institute has never published its Phase 1 and 2 trial data.

At Mr. Putin’s announcement, Russia’s Minister of Health, Mikhail Murashko, declared that “all the volunteers developed high titers of antibodies to COVID-19. At the same time, none of them had serious complications of immunization.”

That is the sort of result you’d expect from a Phase 1 trial. It doesn’t tell you if the vaccine actually works.

“This is all beyond stupid,” said John Moore, a virologist at Weill Cornell Medical College in New York City. “Putin doesn’t have a vaccine, he’s just making a political statement.”

Vaccine expert Peter Hotez notes about Sputnik-V:

Hotez expects that the Gamaleya vaccine will elicit a decent immune response against SARS-CoV-2. “The technical feat of developing a COVID19 vaccine is not very complicated,” he says. “The hard part is producing these vaccines under quality umbrellas — quality control and quality assurance — and then assuring the vaccines are safe and actually work to protect against COVID19 in large phase III clinical trials.”

Exactly. Not only do we not have any publications in the peer-reviewed scientific literature about the results of the two phase 1 trials of Sputnik-V registered at ClinicalTrials.gov by the Russians and have no information other than a translation of the Russian registration certificate, but we have no phase 3 trials. Who knows if Sputnik-V works or not? Certainly not us, and certainly not the Russians. Even more shady, it’s been primarily the Russian elite, such as Vladimir Putin’s daughter and others, who were given access to the vaccine:

Scores of Russia’s business and political elite have been given early access to an experimental vaccine against Covid-19, according to people familiar with the effort, as the country races to be among the first to develop an inoculation.

Top executives at companies including aluminum giant United Co. Rusal, as well as billionaire tycoons and government officials began getting shots developed by the state-run Gamaleya Institute in Moscow as early as April, the people said. They declined to be identified as the information isn’t public.

Oligarchs gonna oligarch, I guess. Even more…interesting, Vladimir Putin hasn’t taken the Sputnik-V vaccine himself:

Asked on a conference call with reporters on Monday if President Vladimir Putin had taken it, Peskov said: “It probably wouldn’t be a good idea to use an uncertified vaccine on the head of state,” adding that he wasn’t aware of other officials trying it.

In fairness, the article I’m quoting is from July, and that was weeks before this announcement. However, the article also noted that it was not clear how participants in the Sputnik-V clinical trials were selected. The whole process has been, unsurprisingly, very opaque. There’s also a lot less to this announcement than meets the eye. As noted in Science, the certificate issued by Russia for the Sputnik-V vaccine allows the vaccine to be given to “a small number of citizens from vulnerable groups,” including medical staff and the elderly. However, the certificate also stipulates that the vaccine cannot be used widely until January 1, 2021, presumably after larger clinical trials have been completed.

Bottom line, I’m with blog bud and fellow defender of vaccines Skeptical Raptor. The Russian announcement of Sputnik-V is propaganda. It’s smoke and mirrors. It’s a con job designed to make it look as though Russia was the first to develop a coronavirus vaccine that’s safe and effective. One could hardly make a more obvious contrast with the original Sputnik, which involved a real feat of science and technology fused with engineering. Of course, there is always an outside chance that Russia got very, very lucky and that Sputnik-V will actually turn out to be safe and effective at preventing COVID-19 infection in phase 3 trials, but that would just be luck. In the meantime, there is now the very real risk that Russia has just handed the antivaccine movement its best weapon in a very long time.

As for me, I’m as pro-vaccine as they come, but I will not accept a COVID-19 vaccine for myself or my family until it has undergone phase 3 clinical trials demonstrating safety and efficacy.