Will they be worse?

Is it true that all the following vaccines are weaker than the previous ones

Polina Loseva, Ivan Shunin, N+1

At the beginning of December 2020, it seemed that 95 percent was the normal effectiveness for a coronavirus vaccine (although it's a pity that not all 100). Moderna BioNTech and Johnson & Johnson AstraZeneca continued to fall, but Pfizer and BioNTech set such a high bar that we sympathetically looked at Moderna and the Gamalea Center, which fell just a little short of it – 94.5 and 91.6. But in the reports of vaccines that received approval afterward, the numbers continued to fall: AstraZeneca – 70, Johnson & Johnson – 66. The further, the lower – and now American newspapers are calling the "dramatic" success of the Novavax development, which showed an efficiency of 90 percent (but this is only in the UK, in South Africa – 49%). What's happening?

When a researcher recruits volunteers for a clinical trial, he makes sure that they are as similar as possible to each other. If his subjects live in different countries and have a different set of chronic diseases and bad habits, it can be very difficult to combine the data obtained into one sample. But when we compare coronavirus vaccines, we often forget that they were tested in very different conditions.

On the needle

At the very beginning of the vaccine race, while all the developments were pushing through the trials in parallel, no one had any questions about how to organize these trials. Take two groups of people, administer a placebo to one and a drug to the other, release them "into the wild" and count the number of infected. And no one is offended: people from the placebo group do not get a chance to escape from infection – but they also do not suffer side effects unknown to doctors.

But as soon as at least one of the vaccines gets a license, the situation for all the others changes.

People who previously could have volunteered out of desperation – because they have no other way to protect themselves from a pandemic – can now get a shot of a proven vaccine. Then why sign up for clinical trials? You will get either a placebo, which obviously does not work, or a vaccine – possibly less effective than an already approved drug.

So those who managed to go to the test, there is a natural desire to quit the game – especially if they suspect that they were in the placebo group. We have already heard such stories: after the Mass vaccination with Sputnik V has begun in Russia, and the outflow of volunteers has begun not only from trials of other vaccines (for example, EpiVacCorona), but also from the placebo group of Sputnik itself.

Thus, developers who entered the stage of clinical trials later than competitors lose not only potential orders from states and media attention. It becomes very difficult for them to test their vaccines. The resource disappears, the raw materials for clinical trials are people.

Looking for a man

In world practice, there are several ways to restore justice and let those who are late show themselves. It is possible, for example, to test one vaccine in comparison with another: that is, to compare it not with zero (placebo), but with the effect of its predecessor. If in the case of covid everything was the same as with a cold or cancer, then this would most likely have happened – reports would appear in medical journals that "a new drug from covid turned out to be more/less effective than standard therapy."

But there is no "standard vaccine" in the case of covid yet. Even those developments that have received the green light from the regulator have been approved only provisionally – their clinical trials have not actually been completed yet. Researchers continue to monitor their volunteers and monitor the long-term effects of injections and the persistence of newfound immunity. Therefore, it is impossible to use a pre–approved vaccine as a control - this would mean building one clinical trial over another and losing the independence of evaluation.

Therefore, "late" vaccine creators often have to work with a smaller sample than they originally planned. Johnson & Johnson has 15 thousand people on average in the trials of subsequent vaccines (although the first protocols were about 60 thousand) versus more than 40 thousand at Pfizer/BioNTech or 3 thousand people at Vector versus a little over 30 thousand at the Gamalea Center.

In addition, it is possible to reduce the proportion of the placebo group in the sample or even abandon it altogether. This strategy was chosen by the developers of EpiVacCorona, who "agreed to a 25% placebo." The Russian Chumakov Center plans to follow the same path: in the third phase of their trials, which is due to begin in April 2021, the organizers plan to recruit only three thousand people (although they are thinking about increasing the sample to thirty thousand), and all of them, as the representative of the Chumakov Center told N+1, will receive the vaccine. The control group in this case will serve as the rest of the unvaccinated population – and this in Russia is still more than 90 percent.

Finally, the third way is to move the trial to a place where mass vaccination has not yet started. For example, to another country. But then success will greatly depend on the conditions: the epidemiological situation, the severity of restrictions and the vulnerability of the population to the virus may vary in countries. As a result, it can be very difficult to bring the data obtained in different branches of the test to a common denominator. This can be seen in the example of Johnson & Johnson: its effectiveness in the British branch of testing was almost twice as high as in the South African. And, strictly speaking, it is not so obvious who is to blame for this – the genetic characteristics of the population, the work of the local health system or the potentially more contagious version of the coronavirus – and what value of the effectiveness of the vaccine is considered final.

Being second means not only looking for a new polygon, but also risking getting lower quality data. Small samples, skewed towards the vaccine group and distributed trials expand the confidence interval of the final value of the vaccine effectiveness. For being late, they pay with the accuracy of the result.

Whose laurels

But the downward ladder of vaccine effectiveness does not mean that latecomers work worse than pioneers. Strictly speaking, even those who did not have to look for volunteers abroad tested their vaccines as if in another country.

For example, the trials of Pfizer/BioNTech vaccines or the Gamalea Center occurred in the summer and early autumn, a relative lull between the waves of the epidemic. Those who followed, like Johnson & Johnson, got the end of autumn and winter – and a surge in morbidity. This means that the risk of contracting coronavirus in the placebo group in these studies was much higher than in their colleagues from the first trials.

In addition, during the time that has passed between the summer and winter tests, the coronavirus itself has changed. New variants of SARS-CoV-2 have appeared in the world – and in some countries they have displaced their predecessor from the battlefield. Some of these new variants have turned out to be more contagious – and this also puts vaccine research in unequal conditions.

Finally, the numbers that usually end up in the headlines – 95 for Pfizer/BioNTech or 91.6 for Sputnik V – are not the only parameter by which these vaccines can be evaluated. Behind these values lies the effectiveness against COVID-19, that is, a guarantee that a vaccinated person will not receive such a diagnosis. But vaccines can also be compared by other criteria: for example, how effectively they prevent infection, including asymptomatic – and this value is likely to be lower. And in the case of preventing hospitalization or death from covid, the effectiveness will be even higher: in none of the vaccine trials, the data on which are published, none of the vaccinated died from coronavirus infection. Therefore, our verdict on which vaccine is "better" depends on the angle at which we look at them.

Past the stairs

In Russia, it is now possible to get vaccinated not only with Sputnik V: KoviVak was launched into mass production at the end of March, and EpiVacCorona recently reached the regions. But comparing these vaccines with their predecessors is even more difficult than looking for a winner among existing vaccines – because we don't really know anything about them.

In the context of a pandemic, as can be seen, regulators make decisions faster than scientific articles are published. Among all the vaccine developers on the planet, only Pfizer and BioNTech managed to publish the results of the third phase of their trials in a scientific journal before they received permission for mass vaccination. In other cases, ordinary people could not open the article and independently assess how high-quality the vaccine that the government offers them is, and how plausible the data on its effectiveness look.

In the USA, this problem is solved by the standard practice of the FDA: before approving a particular vaccine, experts post their own, independent analysis of the data provided to officials by the developer company. And although the creators of the latest vaccine approved in the USA – Johnson & Johnson – have not yet published the results of the third phase of trials in a scientific journal, preliminary data have long been on the FDA website. And anyone who doubts the effectiveness of this vaccine can get acquainted with these data and figure out where its 66 percent effectiveness came from.

There is no such practice in Russia, and until a new vaccine is published in a scientific journal, we can only take the regulators at their word. And if the developers of Sputnik ultimately took care of two detailed publications about the results of the tests, then the creators of EpiVacCorona at the time of the start of mass vaccination can only boast of the results of phase 1-2. And there is not a single publication on the account of the Chumakov Center about the work of its vaccine, and the third phase of testing is just beginning.

The testers of "EpiVacCorona" and "KOVIVAK" undoubtedly had to face the same difficulties as their foreign colleagues: the epidemiological situation is changing, mass vaccination is ruining plans, volunteers are becoming scarce. Therefore, when and if the results of their research appear in the public domain, they will probably not be as beautiful and unambiguous as the pioneering vaccines. But there is no such data. So, for now, these vaccines cannot claim an assessment and a place on the general ladder, wherever it leads.

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