One of the biggest headlines of recent days has been the announcement made by Pfizer, a U.S.-based company, and BioNTech, Germany, that BNT162b2, a COVID-19 vaccine they are developing, has proved to be 90% effective in its Phase 3 clinical trial. The news was met with big excitement all over the world. However, the Pfizer-BioNTech vaccine is based on a new platform, which is still understudied. According to protocol, its trial will be complete only in 2022. IQ talked to Larisa Popovich, Director of the HSE Institute for Health Economics, about the differences between the U.S.-German and the Russian Sputnik V vaccines, and about the chances of beating COVID-19 with massive immunization in the upcoming months.
Director of the HSE Institute for
PhD in Biology
One of the popular concerns today as regards to the new COVID-19 vaccine is the opportunity for its massive and effective use while its storage temperature must be no higher than -70˚C, and this makes transportation of the vaccine much more difficult. What can you say about this?
This can hardly be a topic for discussion. Any vaccine has rather strict conditions of storage and transportation. This is necessary to preserve the drug’s viability.
Do you mean that the -70˚C storage temperature for the vaccine is standard?
Cold chain maintenance is standard practice for many vaccines. Temperatures may differ, and the lower they are, the more complicated it is to use the vaccine. If we compare the vaccines, obviously, it is much harder to provide conditions for -70˚C than for -18˚C, which is the temperature needed for the Russian Sputnik V vaccine. In any case, the storage and transportation conditions still limit the opportunity for wide geographical distribution of vaccination, mainly due to insufficient technology. Future development should focus on increasing the drugs’ stability under more natural temperatures.
The Pfizer and BioNTech’s vaccine is being widely discussed today. What are the prospects for alternatives in the near future? Many countries started their development at the same time. What is going on?
Let me go into some more detail. As of today, 47 vaccines have passed at least two trial phases, including several Russian ones. Eight vaccines are completing the third stage, including Sputnik V. 144. And there are more vaccines that are in the preclinical trial stage.
And all this has been done in less than a year. What is the standard vaccine trial process?
Any vaccine, as any other biologically active agent, should go through several stages of research. First, researchers use computer software or chemical experiments to look for the most interesting options, which show promise of become candidates for medicines or vaccines. There may be several thousands of promising options. Then, the preclinical trials start – first, on small animals, then on big ones. Normally, preclinical trials of medicines and vaccines take about two years. And as a result, there are usually several (in the best case scenario) candidates left.
After that, the first phase of clinical trial starts, which is aimed at determining the safety profile in humans. About a dozen healthy volunteers get the medicine. Then, several dozen or even hundreds of people, including those with the disease, participate in the second phase of the trial. They are divided into those who get the candidate drug, and those who get a placebo. Then, the results are compared. This phase studies the drug’s effectiveness in disease therapy.
In vaccine trials, phase 2 and phase 3 are often combined, in which case not 100, but about 10,000 participants are enrolled. They get a vaccine, which is known to be safe, in order to understand whether they get infected or not when they are exposed to the pathogen.
These are all very subtle issues, which undergo a compulsory ethical evaluation. Clearly, vaccine trials do not include forced infection of humans (though this approach has been used in some cases), and this approach has definitely not been used in the case of COVID-19. That’s why a prolonged period of observation is needed: people may be exposed to the virus not tomorrow, nor the day after tomorrow. Nobody knows when it might happen. Clinical trials are usually held among the demographics that are more likely to be exposed to the pathogen and get infected—for example, on medics.
What trial stage is the Russian vaccine undergoing today?
Sputnik V is in Phase 3 of the clinical trial until the end of December. According to the protocol, 40,000 people in different Russian regions and other countries are participating in the trial.
What are the differences between the Pfizer/BioNTech vaccine and Sputnik V?
These vaccines are based on completely different platforms. In order to understand this, we have to look at what vaccine platforms are there.
And how many platforms are there? What are their essential differences?
There are about six key types of vaccine platforms. First, there is the platform that consists of a live, but attenuated (weakened), virus. The poliomyelitis vaccine is an example of this, and it is believed that a live virus leads to stronger immunity. There are no live virus-based vaccines in clinical trials against COVID-19.
There are vaccines based on inactivated (killed) viruses. A COVID-19 vaccine on such a platform is being developed, for example, in China, by several institutions at the same time—Sinovac, as well as institutes in Wuhan and Beijing. A total of six vaccines are undergoing Phase 2 and 3 clinical trials in China today, including those on other platforms.
The third type of a vaccine platform is the so-called viral vector—when a virus that is safe for humans is taken—for example, adenovirus,—and a part of the coronavirus genome is added to it, which serves as an antigen and induces an immune response. A vaccine on this platform, with the use of adenovirus serotype 5, is being developed by the University of Oxford together with AstraZeneca. They are going to enter Phase 3 of clinical trials in four weeks. The same adenovirus platform is also being used by Chinese developers.
So neither the Russian vaccine nor the Pfizer/BioNTech vaccine is based on any of these three platforms?
The Gamaleya Research Institute of Epidemiology and Microbiology also uses a viral vector as a platform. But the Sputnik V vaccine is unique in this regard—it has a double platform. While the British and Chinese researchers are using adenovirus serotype 5, the Russian vaccine additionally includes adenovirus serotype 26. This double-vector vaccine induces a stronger immune response than a single-vector one.
What are the features of a stronger immune response and why is it induced in the body?
An immune response may start with the formation of antibodies – fragments of protein that detect and ‘highlight’ the virus, like torches, so that it is visible for the immune system. Then, bigger cells come and eat this virus. Antibodies are formed by the body individually each time, from ‘materials at hand’.
That’s why, when a human becomes exposed to a new virus, new antibodies are formed from the existing ones. That’s why antibodies break down fast – usually, in three to five months after exposure to the infection.
But there is also the so-called cell immune response – when a bunch of immune system cells is formed – specialized lymphocytes that evolve in the thymus. Experts say that this kind of response is directly stimulated by adenovirus serotype 26, which is used in the Russian vaccine. This considerably speeds up and reinforces the development of acquired immunity to coronavirus infection.
The result is a sustainable and guaranteed antibody and cell immunity. This immunity can remain for quite a long time, probably, several years, but further studies will show the real duration. This is the Russian vaccine’s advantage as compared to the British and the Chinese ones, which are based on adenovirus serotype 5 only.
Speaking further about vaccine platforms, a single-vector vaccine based on adenovirus serotype 26 is also in the pipeline. This kind of vaccine is being developed, for example, by Janssen Pharmaceutica, a subsidiary of Johnson & Johnson, a pharma behemoth. They have also entered Phase 3 of the trial recently.
What are the features of the other three types of platforms, and which of them is used for the widely discussed Pfizer/BioNTech vaccine?
The fourth type of platforms is a protein fragment of the virus. A vaccine based on this platform is being developed in China, it is also in Phase 3 clinical trials.
The fifth platform type is based on implanting a harmless virus in the ring DNA molecule (plasmid) a fragment of coronavirus genetic material, which includes ‘instructions’ on creating a virus protein. This platform is produced in many countries, but they are all at preclinical or, at best, second phase of clinical trials. In WHO materials, researchers from Japan, China, India and Israel report using this platform.
And now, we have finally come to the sixth platform, on which the Pfizer/BioNTech vaccine is based. This is a new platform, completely unstudied and never-before used. It is based on matrix RNA – a fragment of the virus’s genetic material, which is introduced in the body. This platform is being used not only by Pfizer/BioNTech, but by another company from the U.S., as well as companies from China and Kazakhstan. The latter studies are at earlier stages.
Out of these six platforms, if we compare the adenovirus one, on which the Russian vaccine is based, and the mRNA platform, on which the Pfizer/BioNTech vaccine is based, what are the essential differences between these vaccines in terms of the prospects for their use?
First of all, we should keep in mind that the Gamaleya Research Institute, which is developing the Sputnik V vaccine, is a renowned institute with extensive experience in vaccine development. In coronavirus vaccine development, the Institute has taken the easiest path and used the platform it has been using for decades. Adenovirus-based vaccines have been studied since 1953. The Gamaleya Institute scholars have used them to create vaccines against Zika virus and Ebola virus, and are very well aware about how the adenovirus acts.
The Gamaleya Research Institute started to work on the new vaccine in February, as soon as they received the coronavirus genetic material. The Russian vaccine is built on a strong theoretical and practical basis, which has been developed for years. We clearly can’t say that the Russian vaccine has been developed in a rush, as it is sometimes presented in media.
The adenovirus platform is also used by many developers in western countries, since it is very well studied. And it is a good achievement that a Russian institute has made a vaccine on this platform so quickly, managing to combine two adenoviruses.
Now, if we look at Pfizer and BioNTech, they, unlike Russia, have only recently applied for the vaccine’s Emergency Use Authorization, EUA. But according to the protocol, its Phase 3 will be finished only in 2022 – exactly because absolutely no one knows what may happen in the distant future after the use of an RNA-based vaccine. The biggest problem of a vaccine based on mRNA technology is that it has never been used in approved vaccines before. The difference between BNT162b2 and Sputnik V is the factor of uncertainty. We do not know what effect it may have in the long-term perspective.
Is mass immunization in Russia and globally in 2021 a real prospect?
We can suppose so. Despite the more complicated storage conditions and problems due to uncertainty on the delayed consequences, it is known that the Pfizer/BioNTech vaccine manufacturing technology allows to quickly produce the drug in big volumes. So, if the countries choose to risk their population’s health with using a completely unknown product, they can get the vaccine quite soon.
The Russian vaccine trial should be complete, in accordance with protocol, by the end of 2020 – since Russia is using a well-known platform. There are good chances that thanks to the vaccine, the COVID-19 problem in Russia will largely be solved in spring.
Recently, there has been news that several medics who volunteered in the Sputnik V trials got infected with COVID-19. How could this happen?
We have to analyze what these doctors received – a placebo or the vaccine? We have to understand whether they received the full or the lower dose of the medicine. We have to understand the specifics of their disease progression – what form of the disease did they have? There is no vaccine that can provide a 100% protection for 100% of recipients. There are always people with weakened immunity who will get sick anyway, but will have a milder form of the disease. Comparing the number of those who got sick without the vaccine with the number of those who got sick after vaccination returns the vaccine efficiency parameter. The efficiency of Pfizer/BioNTech vaccine is 90%: this means that among vaccinated participants, there were ten times less those who got sick, than among those who were not vaccinated. As far as I know, the Russian vaccine has higher efficacy. But we will see, after all the trials are finished, when we can compare all the vaccines. Then, we will be able to talk about their efficacy and safety profiles.
Will people in Russia be able to choose the vaccine they are going to get?
In terms of the Pfizer/BioNTech vaccine, it is not easy, since it has not been trialled in Russia. According to Russian law, registration is only available for drugs that have passed multi-centre clinical trials, including centres in Russia. If this vaccine will not be trialled in Russia, it will not be registered. But let me remind you—Russia is also hosting trials of Chinese vaccines, as well as vaccines by Vektor Research Centre, and a few more research institutions are now launching clinical trials. So, there will definitely be a choice of vaccines in terms of different platforms.