The Vector Center’s “EpiVacCorona” vaccine is perhaps the most controversial of the three vaccines currently available or being prepared for release in Russia.
The government has allocated over 2 billion rubles to Vector for its production. Rospotrebnadzor has declared its 100% effectiveness, but according to the data from the group of clinical trial participants, the majority of them do not develop antibodies after it.
The Russian service of the BBC has investigated what this means and the peculiarities of the “EpiVacCorona” vaccine.
Participants in the third phase of the post-approval clinical trials of “EpiVacCorona” have addressed an open letter to the Ministry of Health, Rospotrebnadzor and “Vector”. They claim that in their sample more than 50% of participants who confirmed their participation in the study received negative antibody test results, although only 25% of participants were supposed to receive a placebo. According to the volunteers, even those who tested positive have very low titers. The letter was signed by 59 subjects.
According to information published in peer-reviewed journals, 53% of clinical trial participants (47 out of 89) had a negative antibody test, and four out of 15 participants in the public vaccination program had no detectable antibodies. Meanwhile, in November last year, Vector reported that volunteers developed antibodies in 100% of cases and cellular immunity in the majority.
During the meeting with volunteers at the center, it was noted that vaccination with peptide antigens provides a lower diversity of antibodies, but they have neutralizing properties. Vaccination does not guarantee protection against infection, but allows to reduce the viral load and avoid the development of severe disease, “Vector” added.
“Regarding the issue of a low titer: if it provides protection, it should be low. That is why you are voluntarily participating in this study to determine the protective level of the immune response,” said Alexander Ryzhikov, head of the Department of Zoonotic Infections and Influenza at the Vector Institute, during a meeting with volunteers.
We explain quickly, simply, and clearly what happened, why it matters, and what will happen next.
When asked by volunteers whether it would be better to work out all the details first and then test the vaccine in humans, the Vector Institute replied: “Research has shown that the vaccine protects animals against intranasal respiratory coronavirus infection. The results of the first phase of clinical trials have shown that the vaccine is safe for humans.
In a conversation with the BBC, he explained that he was one of the first to have an analysis for antibodies to the S protein on the Gamaleya Center test system – and he has them.
“Epivakkorona” is presented as a suitable vaccine for at-risk groups due to its mild or even absent side effects.
First, scientists have questions about the “Vector” test system, which the developers presented as the only one capable of detecting antibodies after vaccination with “EpiVacCorona”.
“This test system is not transparent, it is not known which specific protein – nucleocapsid (N) or spike (S) – the antibodies detect,” explains Olga Matveeva. “We believe that [this test] simultaneously detects antibodies to the spike protein peptides and the nucleocapsid protein, but antibodies to the nucleocapsid protein are primarily detected,” he says.
In the aforementioned papers, conclusions about which peptides should be taken in order to be “recognized” were made based on data from SARS-Cov-2 survivors, explained Margarita Romanenko, a candidate in biological sciences and a research fellow at the University of Minnesota’s Department of Surgery, in her presentation “Vaccines for Covid-19: Before Making a Choice.”
“Three peptides [in the vaccine] were chosen incorrectly, they are not the peptides that were published as epitopes for humans to generate immunity,” sums up a Russian-speaking molecular biologist from the University of Edinburgh, who asked not to be named.
At the same time, she says, the idea behind Vector’s vaccine – to create a vaccine using the nucleocapsid N protein as an immunogen – is a good one. The thing is, the N-protein is much more “conservative” and does not change, it is capable of stimulating a different type of immunity – cellular. Now there is a lot of talk about mutations and the fact that existing vaccines may not work with changes in the virus. Mutations occur specifically in the Spike S protein.
In other words, if the vaccine were effective, it would be less affected by coronavirus mutations. In a conversation with BBC, experts point out that reading the “Epivakkorona” patent, it can be seen that the antibody titers in rabbit vaccine research were two orders of magnitude higher against peptides and one order of magnitude higher against the full-size S protein than in humans. “Vector” admitted this problem in an interview with volunteers. They stated that it was “somewhat unexpected” for them when they started using the vaccine. “This situation continues to this day,” Vector reported. “The state is giving people, especially the weakest and most vulnerable, a vaccine that is likely to be ineffective. It seems scary to me,” says the molecular biologist, who holds a doctorate from the University of Edinburgh. “I don’t think anyone has malicious intent,” the scientist believes. “I think it’s unprofessionalism and an inability to rationally assess the situation.”
He believes that it is impossible to modify the EpiVacCorona” vaccine as it is, only a new one can be made. However, Matveeva believes there is room for improvement. “But even if more optimal peptides are selected, there is no guarantee that they will generate a high titer of neutralizing antibodies. The N-protein of the virus induces a strong T-cell immune response in people with Covid-19. However, we do not know if the N protein from the vaccine will do the same and if it will provide any benefit as an immunogen,” she notes.
It is interesting that Anna Popova, who has headed Rospotrebnadzor since 2013, is listed as one of the authors of the “EpiVacCorona” patent. “Vector” is an institution subordinate to Rospotrebnadzor, and Rospotrebnadzor is an agency responsible for supervising the production of vaccines and their compliance with all necessary standards. This could be considered a conflict of interest. The Russian service of the BBC has sent a request to Rospotrebnadzor and is waiting for a response.
In addition to humoral immunity, cellular immunity develops in response to the virus and serves as an equally important element of the body’s defense. It is also able to attack infected cells and destroy the virus, but in a different way. The cellular response kills the cells that produce the virus. T-cells recognize foreign antigens, destroy cells invaded by viruses or bacteria, and help other members of the immune system fight the enemy. Cells of this type of immunity are divided into “helpers” and “killers” – the former recognize antigens and enhance the immune response, the latter kill the pathogen. There are also memory cells that remember the pathogen so that it is easier for the organism to fight a known virus or bacteria in the future. T cells have receptors that respond to invasion. With their help, the T cell begins to divide, and “helpers” activate other cells to fight the pathogen, while “killers” kill it. T cells are often found in people who have recovered, even in the absence of antibodies. This part of the immune system is able to recognize infections and provide strong protection against them. “Sometimes, even in the absence of antibodies, a person can fight an infection with a cellular response alone,” says Olga Matveeva. However, peptide vaccines tend to induce a weaker cellular immune response, she explains. Peptide vaccines usually stimulate the production of protective antibodies. And if there is a strong T-cell response to the N-protein after immunization with a peptide vaccine, antibodies against the N-protein are usually produced as well,” Matveeva notes. “They are not necessary to fight the infection, but their formation can be considered as an indicator of the overall immune response to the vaccine, including the T-cell response, which is particularly valuable,” she explains.
However, as mentioned above, most study participants do not have antibodies. Cell immunity tests are practically unavailable in Russia. Moscow residents have two options to take such a test. It is possible to do this free of charge in polyclinics within the framework of the study “Assessment of the intensity of cellular and humoral immunity to the causative agent of Covid-19 among residents of Moscow”. Initially, participants were even given their results, but in December the media found out that they had stopped doing this. “We sent out the results, but people had a lot of questions about what it meant. People began to draw ambiguous conclusions that cannot yet be drawn from these results. So there was an order not to release the results for now. Scientific centers are only analyzing the general data set without highlighting individuals,” Business FM reported at the time on the hotline. Also in Moscow has appeared a test of cellular immunity produced by the company Generium, its cost is 18,700 rubles.
Even if a person who has recovered from the virus or has been vaccinated receives the results of a T-cell immunity test, it is difficult to interpret the data correctly. The results only indicate whether there is evidence of such immunity. There are tests available that provide more detailed data. Only a specialist, and not every specialist, can provide further interpretation. Determining the level of antibodies is a simpler and more understandable way to assess whether there is protection against the pathogen. However, according to experts, there are many nuances to this process.
On Tuesday, February 2, the members of the volunteer initiative group met with Alexander Ryzhikov, the head of the Department of Zoonotic Infections and Influenza at the “Vector” Institute, and Marina Bogryantseva, the representative of the quality management and the head of the Department of Biological and Technological Control. The volunteers prepared and coordinated the protocol of the meeting with Rospotrebnadzor for almost a week. In “Vector” they answered some of the claims, but some questions remained unclear.
Volunteers who participated in the “Vector” meeting. From left to right: Denis Lagutkin, Andrey Krinitsky, Anna Nebratenko, Mikhail Kachalin, Natalia Cherepanova, Alexey Ganza. Materials from the first and second phases of the research have been submitted to peer-reviewed medical publications, according to Vector. They are currently under review. “We expect the publication to appear by mid-February,” Ryzhikov said.
The selection of peptides, about which scientists had questions, was justified in “Vector” because they were based on “the most conservative (linear – BBC) and least cross-reactive to human protein epitopes (sites in the virus that the immune system can “hook onto” – BBC), while having potential protectiveness”. No special algorithms were used to select the most immunogenic epitopes, Ryzhikov noted. “The answer to this question surprised me very much, as I expected to hear that “Vector” used some kind of proprietary predictive algorithm. But it seems that no algorithms were used at all, and what principle was actually behind the selection of the sites is completely unclear,” writes Denis Lagutkin, a molecular biologist and member of the volunteer group, in his Facebook post. The statement that conservative (linear) epitopes were selected seems “strange” to Lagutkin because of their “obviously weak immunogenicity and questionable steric accessibility (possibility for antibodies to bind to the epitope – BBC). During the period of peptide design at Vector, only two mutations in the spike protein were described, he explains, and Vector was not involved in the prediction of coronavirus mutation variants. Assumptions about possible mutations were made based on other coronaviruses. “External algorithms for selecting the most immunogenic epitopes were not used because the most immunogenic epitopes are often subject to mutations, allowing the virus to evade the immune response,” Ryzhikov said at the meeting. “We deliberately avoided inducing a response to regions that could stimulate the emergence of new mutations, allowing the virus to evade the immune response,” he said. “Immunodominant (three-dimensional) epitopes, unlike linear ones, are actually subject to change,” says Olga Matveeva. And linear ones do not change. Ryzhikov is right, she notes. But the volunteers still have very few antibodies, or none at all. “No immunologist can tell you how protection can occur in this case,” Matveeva says. Vector’s use of only one specific test system to detect antibodies was explained by the fact that the sensitivity of commercially available tests may not be sufficient to detect those antibodies that target specific fragments contained in the EpiVacCorona” composition. “Vector” did not provide an answer to the question of which specific proteins the test system is directed against.
In “Vector” it was noted that it is possible to shorten the research period to three months – that is, the participants will be “unblinded” and it will become clear who received the vaccine and who received the placebo. A decision on this will be made by the Ministry of Health after studying the interim report, which will be submitted after the 42nd day of the study. “There is no clarity about the deadlines for submitting this report,” Krinitsky comments. “It is logical to consider each person individually in terms of their deadlines,” he says.
“In “Vector”, study participants were allowed to be revaccinated. “We do not prohibit revaccination, but it is necessary to consider how the immune system works during immunization, for example, with vector vaccines, peptide vaccines or infection. As for timing, we recommend waiting at least three months between vaccinations,” Ryzhikov said. According to Andrey Krinitsky, the volunteers are generally satisfied with the meeting and hope that “this is not a coincidence, but a new trend for both the government and citizens – direct interactive dialogue”. But the most important question, according to Krinitsky, is still unanswered. “The vaccine’s protective properties have been tested in animals. Is there protection for humans, and what antibody titer is sufficient for them? The answer to this question is being investigated in the third phase of clinical trials, and we are conducting an independent experiment,” he said in an interview with the BBC. “Some of the information gathered by the participants in the trials turned out to be new information for “Vector” and is now being investigated separately,” he said. “Communication with Vector is ongoing,” Krinitsky noted.
The vaccine “EpiVacCorona” of the scientific center Vector was registered in Russia on October 13, 2020. This is the second vaccine against corona viruses registered in the country after “Sputnik V”. “Epivaccorona” consists of three different fragments of the SARS-CoV-2 coronavirus S protein attached to a carrier protein. These fragments are called peptides, which is why the vaccine is called a peptide vaccine. The carrier protein consists of fragments of the nucleocapsid protein that surrounds the RNA of the coronavirus. This viral nucleocapsid protein is synthesized using Escherichia coli bacteria. The vaccine formulation is enhanced with an adjuvant, the role of which is aluminum hydroxide.
The patent for this vaccine describes seven peptides of the spike protein and several potential carrier proteins. It is not known which three peptides were ultimately included in the development of Vector”. Like “Sputnik,” this vaccine requires two injections 21 days apart, but in the case of “EpiVacCorona,” the second dose – the booster – is identical to the first. “EpiVacCorona” is already being administered as part of the civilian vaccination program. According to data collected from research volunteers, limited batches of the vaccine are being delivered to regions, but the specific regions and rules for obtaining the vaccine need to be clarified in each individual region and clinic. The third phase of “post-registration” clinical trials of this vaccine began on December 1 last year. It is being conducted in nine medical organizations in Moscow, the Moscow region, Kazan, Tyumen, Kaliningrad, and the Novosibirsk region (on volunteers over the age of 60). According to Rospotrebnadzor, the recruitment of volunteers has already been completed. The sample size in the “Epivakkorona” study is much smaller than in the “Sputnik V” studies – only three thousand people, of whom 2250 were to receive the vaccine and 750 – the placebo. For comparison, the “Sputnik” trials have recruited 31 thousand people (vaccine developers say they want to increase this number to 40 thousand). According to Rospotrebnadzor, such a small sample was collected “in order to quickly start post-registration studies” and the issue of additional recruitment of volunteers “will be considered taking into account the results obtained”. The action “Epivakkorona” was separately studied on 150 volunteers over the age of 60. On February 4, Rospotrebnadzor announced the completion of this study. The number of offers should remain: Russia’s consumer watchdog Rospotrebnadzor has announced that elderly volunteers tolerated the vaccine well, with no significant adverse reactions reported. “For the most part, people either complained or did not complain about minor discomfort at the injection site,” said Tatyana Nepomnyashchikh, acting deputy general director for scientific and methodological work and international cooperation at the State Research Center of Virology and Biotechnology “Vector”.