Scientist Uğur Şahin: "It is important to show the immune system as many of these mutated positions as possible now, so that it learns and also recognizes subsequent variants."

Scientist Uğur Şahin: "It is important to show the immune system as many of these mutated positions as possible now, so that it learns and also recognizes subsequent variants."

Foto:

Ramon Haindl / DER SPIEGEL

Interview with BioNTech Founder Uğur Şahin "The Virus Continues to Mutate at a High Speed"

We were fortunate that Omicron turned out to be as mild as it has been, says BioNTech co-founder Uğur Şahin. In an interview, he says he expects that his company's adapted vaccine will be available in September, just in time for the first Oktoberfest to take place in Germany since the pandemic.
Interview Conducted by Thomas Schulz

DER SPIEGEL: Mr. Şahin, at the beginning of the year, you worked as fast as possible to develop an adapted vaccine for the Omicron variant of the coronavirus and produced many millions of doses. This special booster, though, still hasn’t been approved. Should you have saved yourself the trouble?

Şahin: I still think that adapted vaccines make a lot of sense. The target structure of the vaccine, the spike protein, differs significantly in the Omicron variant from the wild type. On the one hand, our data has shown that a booster with an adapted vaccine produces significantly more antibodies against Omicron than the wild-type vaccine. The immune system is thus better able to ward off the variant. On the other, we must not forget that Omicron is already a partial escape variant. At some point, we could have a variant that doesn’t react at all to the antibodies in the original vaccine. We need to get ahead of it now.

DER SPIEGEL 35/2022

The article you are reading originally appeared in German in issue 35/2022 (August 26th, 2022) of DER SPIEGEL.

SPIEGEL International

DER SPIEGEL: How does an Omicron booster help?

Şahin: Omicron has a lot of mutations in the spike protein, so only some areas are still recognized by the antibodies of someone vaccinated with the wild-type vaccine. The virus continues to mutate at a high speed. It is difficult to predict when all the relevant positions will be mutated and thus no longer recognized by the wild-type vaccine. But it is likely to be sooner rather than later. It is thus important to show the immune system as many of these mutated positions as possible now, so that it learns and also recognizes subsequent variants.

"We can deliver in a very timely manner."

DER SPIEGEL: If the scientific benefits are as clear as you say, then why have finished doses been sitting in freezers for months waiting for approval?

Şahin: This is the first time that an adapted vaccine has been approved. The regulatory authorities wanted to see a whole range of additional clinical data. Things like whether an adapted vaccine should be based on Omicron only or on both Omicron and the wild type. Such a clinical trial takes four to five months.

DER SPIEGEL: It sounds like there was no longer any pressure once Omicron turned out to be less dangerous.

Şahin: A key factor was that the vaccine currently in use also significantly reduces mortality and reduces hospitalization in Omicron cases. The time required to develop an adapted vaccine could be bridged with boosters of the current vaccine.

DER SPIEGEL: Did it also take longer because the adaptation process for BioNTech was more difficult than previously thought?

Şahin: No, that went really fast and is no longer much of a challenge for us technologically. We produced the first doses for clinical trials in six weeks and started them in January. We make the spike protein sequences for potentially relevant variants in the lab every week and have run this process for hundreds of versions. We can also adapt production very quickly.

DER SPIEGEL: German Health Minister Karl Lauterbach announced that he expects the Omicron booster to be approved next week. Could you deliver immediately then?

Şahin: Delivery is logistically complex and requires a few days of preparation. But we could deliver very promptly, hopefully in early September. It should also be stated that we have made two different versions. One is based on the Omicron subtype BA.1. For that one, we have submitted all the necessary data to the European authority EMA for approval. The other vaccine is based on the BA.5 subtype, which is currently dominant in the EU, and we are currently submitting the final documents. Then it can go quickly on that, too. It depends on how rapidly the EMA conducts its review.

DER SPIEGEL: So, you anticipate that we will have to wait a few weeks rather than months for the more current BA.5 vaccine?

Şahin: Yes.

The original BioNTech vaccine

The original BioNTech vaccine

Foto:

Robert Michael / dpa

DER SPIEGEL: Which means that two different Omicron boosters are arriving at almost the same time. It’s a bit confusing. Which one should people get?

Şahin: Basically, there isn’t a huge difference between the two vaccines. Both have been shown in studies to produce a clearly superior antibody response to Omicron compared to the original vaccine. At the same time, we have clear indications that a BA.5 vaccine is just more effective against BA.5. However, there are also opinions that a variant could appear in a few months that is closer to BA.1 again.

DER SPIEGEL: That is a very diplomatic answer. The U.S. Food and Drug Administration (FDA) has made things simpler and clearly specified: In the U.S., we only want the BA.5 booster. Do you have a clear preference personally?

Şahin: Yes, I am in favor of always staying as close as possible to the dominant strain. This is how it is done with the flu. And we are able to reduce production times to less than three months with mRNA technology.

DER SPIEGEL: Starting in mid-September, Munich will host a big party that has the potential to become a massive super-spreader event. Millions of people will be crowded tightly together in the beer tents at Oktoberfest. Some virologists have thus called on visitors to be sure to get a booster shot beforehand. Will the BA.5 vaccine be available in time?

Şahin: That is out of our hands. However, BA.1 should be available by then.

DER SPIEGEL: Are there any findings from your studies on whether a minimum interval should be observed from the last vaccination with the wild-type vaccine?

Şahin: We haven’t looked into that specifically. In principle, however, in our studies we had an interval of six to eight months from the last vaccination. Individuals who had not previously had an Omicron infection could also benefit from an Omicron-adapted vaccination with a shorter interval. I can imagine that the EMA or the STIKO will make a recommendation on this.

DER SPIEGEL: Will the Omicron booster be approved for children?

Şahin: To begin with, we have applied for approval from the age of 12. For younger children, with are in contact with the authorities about what data they require for approval. I can’t give a date here yet.

"We have developed an early warning system that uses artificial intelligence to constantly analyze the evolution of the virus."

DER SPIEGEL: In the past two years, science has learned a lot about the virus. Can this knowledge be used to better predict its further evolution and new variants?

Şahin: We have indeed made progress. We have developed an early warning system that uses artificial intelligence to constantly analyze the evolution of the virus. As part of the process, we look at tens of thousands of sequences from the spike protein of new variants every month. For example, we identified the risk posed by variants BA.4/5 very early on.

DER SPIEGEL: Can you explain a bit more about how this early warning tool works?

Şahin: We first calculate whether and to what extent newly identified spike protein sequences can bypass current vaccine protection. We are also using new computer-based algorithms to see how fit these spike proteins are.

DER SPIEGEL: What do you mean by "fit”?

Şahin: How effectively the spike protein can dock to the host cell, increasing contagiousness. We map this precisely, calculate for each sequence how much it increases in frequency over the observation period, and produce a weekly Top 100 list of variants to watch. With this step, we can better identify which virus developments could become problematic. For all variants on this list, we also create the matching DNA plasmids.

DER SPIEGEL: Why are they so important?

Şahin: The plasmids are the template for the mRNA production, a kind of copying process. If we have these in stock, we can shorten the production time for a new potential vaccine by another two to four weeks.

Vaccine syringes

Vaccine syringes

Foto: Jens Schlueter / Getty Images

DER SPIEGEL: What are you seeing right now? Are we just going to see new subtypes of Omicron from now on? Or is a new, potentially dominant variant lurking on the horizon?

Şahin: Omicron currently accounts for 99.8 percent of the pathogens, and it is constantly mutating. We also saw this type of evolution with new sublineages of Delta, but it is much more pronounced with Omicron. The variant will thus not be easy to supplant. An unsolved problem is the second evolutionary mechanism: highly mutated variants appearing seemingly out of nowhere. We can’t predict them because the virus practically reinvents itself.

DER SPIEGEL: Just as Omicron did originally.

Şahin: Right. There is a hypothesis that such sudden, highly mutated variants develop in people with compromised immune systems. There, they can gradually optimize themselves over a period of several months, largely undisturbed, until they possess a completely new set of escape mutations that can trigger a new pandemic locally or even globally.

DER SPIEGEL: In other words, we will have to be prepared for an annual booster vaccination for the dominant variant in each case? Or will there soon be a new generation of vaccines that covers a broad spectrum of variants and lasts longer?

Şahin: We are testing different approaches for our next-generation vaccines. Improved spike designs, for one. So far, I am not as enthusiastic about this as other researchers because, in my view, the approach underestimates the evolutionary capacity of the SARS-CoV-2 pathogen. I am more excited about approaches for the other defense mechanisms of the immune system: the T cells.

"There are a number of studies showing that people have gotten rid of the virus even without measurable neutralizing antibodies, sometimes even asymptomatically."

DER SPIEGEL: The vaccine is mainly aimed at generating neutralizing antibodies against the virus. The body’s own T cells are normally the second line of defense in humans. Can this mechanism be optimized?

Şahin: There are a number of studies showing that people have gotten rid of the virus even without measurable neutralizing antibodies, sometimes even asymptomatically. T cells apparently manage the job of eliminating the virus on their own in these cases. We are actively researching this. The goal is a universal T-cell vaccine that targets non-mutating regions of the virus and will protect against disease of all severities, regardless of the viral variants circulating in the future.

DER SPIEGEL: Will future approval processes also become shorter?

Şahin: That is important, yes. We not only need improved vaccines, but also the processes to be able to respond more quickly. When dangerous variants appear out of season, for example. In our discussions with the authorities, we can see that progress is being made.

DER SPIEGEL: The process would then be similar to the flu vaccine, where adaptation to the currently circulating variant doesn’t have to be accompanied by a clinical trial and reapproved each time?

Şahin: I would be surprised if we don’t have an internationally agreed solution by next year at the latest, similar to the flu vaccine. We can’t afford anything else. We were doubly fortunate with Omicron because it is not a full escape variant and the existing vaccine could provide booster vaccine protection. And because Omicron leads to milder disease than Delta. We shouldn’t bet on that happening again.

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