Researchers are working on vaccines against the new omicron variants. But by the time they have gone through the approval process, it could be too late, says Biontech boss Ugur Sahin. He proposes an acceleration. Top virologist Kekulé, on the other hand, thinks: safety comes before speed.
While heat-stricken Europe is dozing off the approaching “summer wave” of new corona infections, Ugur Sahin suddenly rings the alarm bell: If the complex approval procedures are not simplified now, the Biontech boss told the “Financial Times”, the updated vaccines will be be late in the fall.
He is therefore calling for mRNA vaccines tailored to new variants to be approved in the future without clinical studies, i.e. only on the basis of laboratory data and animal experiments. Thus, adaptation to BA.4, BA.5 and other omicron subvariants would take about three months, even with the fast mRNA technologies employed by Biontech and Moderna. If the regulatory authorities then demanded clinical studies on safety and effectiveness, another four months passed.
Alexander Kekulé is Director of the Institute for Medical Microbiology at the University of Halle. As a member of the Protection Commission, he has long advised the federal government on pandemic planning and disease control.
According to Sahin, a “flexible system” would be needed instead, as is practiced with influenza – flu vaccines are adapted every year to the prevailing virus types without the need for renewed approval. According to the Mainz vaccine researcher, the side effects of future mRNA vaccines would not differ from those of the Covid vaccines currently in use or the prototypes directed against the earlier omicron variant BA.1.
“The clock is ticking,” warns Sahin. The decision to simplify the approval process must therefore be made as quickly as possible. That is responsible, because after all you only want to “exchange a few amino acids of the spike protein”.
The reason for the dramatic appeal are the new omicron subvariants BA.4, BA.5 and BA.2.12.1, which are causing new waves of infection in Europe and the USA. They have adapted so perfectly to the human immune system that they can infect recovered, quadruple vaccinated and even quadruple vaccinated with additional omicron breakthrough infection. On the other hand, everything indicates that the infections are currently much easier than in previous waves of the pandemic. Omicron and its subvariants mainly replicate in the nasopharynx, while the earlier virus variants attacked the lungs and internal organs.
The currently available mRNA vaccines from Biontech and Moderna, which were developed against the original virus type from Wuhan, hardly protect against infection in BA.4 and BA.5, but they do surprisingly well against severe courses. In South Africa, where the BA.4/BA.5 wave has already passed, a two-dose primary series reduced the risk of hospitalization by 87 percent.
An additional boost causes the blood level of the so-called neutralizing antibodies, which can eliminate the virus right at the beginning of an infection, to rise again significantly. It can therefore be assumed that those who have been vaccinated three times have even better protection against serious illnesses if they become infected with BA.4 or BA.5. The protective effect against fatal courses is usually a few percent higher. !function(){var t=window.addEventListener?”addEventListener”:”attachEvent”;(0,window[t])(“attachEvent”==t?”onmessage”:”message”,function(t){if (“string”==typeof t.data
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It is epidemiologically incomprehensible that the Biontech boss is now pushing for a – further – simplification of emergency approval. The most likely scenario for the autumn, which the Federal Government’s Corona Expert Council now agrees, is a renewed wave of the BA.5 type currently predominant in Germany, or another Omicron sub-variant.
However, adapted vaccines would hardly prevent infections – that would be even less to be expected with the omicron mutants specializing in the upper respiratory tract than with their predecessors. It is questionable whether vaccines directed against future variants protect against severe and fatal courses better than the triple vaccinations currently available and can only be found out with the help of clinical studies – which pharmaceutical manager Sahin would like to do without at the moment.
In view of the already low mortality rate from omicron infections, an overload of the intensive care units is not to be expected even if we use the existing vaccines again in autumn to boost people at high risk.
The excitement of the Biontech boss should therefore primarily have entrepreneurial reasons. Competitor Moderna relied early on on a combination of the Wuhan vaccine and a component adapted against Omicron, presented the first results of clinical studies at the beginning of June and shortly thereafter applied for the rolling review approval process to be initiated at the European Medicines Agency.
According to the company, several million of the bivalent vaccine have already been produced, and delivery is scheduled to begin in August. In mid-May, Federal Minister of Health Lauterbach announced that the federal government had provided 830 million euros for the bivalent Moderna vaccine.
For the monovalent Omikron vaccine from Biontech/Pfizer, on the other hand, things have not been looking good for a long time. Initially, the development was delayed, reportedly because the prototype was not sufficiently protective. Then several studies showed that a previous infection with the omicron subvariant BA.1 hardly protects against a later infection with the currently widespread subvariants (BA.4, BA.5, BA.2.12.1). Since Biontech has developed its monovalent omicron vaccine against BA.1, it is highly unlikely that it will provide adequate protection against the variants currently circulating or similar variants expected in the fall.
Moderna, on the other hand, seems to have backed the right horse at the right time. The omicron component of his bivalent vaccine is also directed against BA.1 and would therefore be virtually ineffective on its own. But in combination with the spike protein of the original strain, the same thing happens as with the previous third vaccinations: the immune response unfolds a broader effect, a single bullet becomes a shot.
The bivalent vaccine protects better than the sum of its individual components. As Moderna announced on Wednesday, neutralizing antibodies against BA.4/BA.5 increase more than five-fold after a booster injection. The bar is probably set unattainably high for the monovalent competing product from Biontech. Some experts had doubted for a long time whether a vaccine directed only against omicron made sense. However, the federal government was advised differently and had initially only ordered the monovalent Biontech ampoules – which are likely to become slow sellers if the contracts cannot be terminated.
In the face of falling demand, share prices falling significantly from the highs and uncertain virus forecasts, a veritable marketing battle has broken out between the vaccine manufacturers. The response to Biontech’s call for no clinical trials followed immediately: “Fortunately, we don’t have to think about it,” Moderna President Stephen Hoge told the Financial Times, because the bivalent vaccine is effective against BA.4 and BA.5 and stands already available in August.
Three days later, last Saturday, Biontech surprised the experts with the first data on its own prototype, which is said to also contain two types of mRNA, one of which is directed against the Wuhan type and the other against BA.1. However, Biontech is unlikely to be able to catch up with its US competitor Moderna in time for the autumn wave – unless the regulatory authorities refrain from conducting clinical studies.
“How we live with the pandemic and what we can learn from it” by Alexander Kekulé
In the heat of such a battle, it is forgivable if a highly respected scientist like Ugur Sahin exceptionally slips out a doubly limping comparison. Firstly, the Sars-CoV-2 pandemic virus is in no way comparable to the pathogens of seasonal influenza, for which an annual adjustment of the vaccines is permitted without renewed clinical testing.
The proteins used for the influenza vaccines are components of influenza viruses that have been circulating for many decades. The virus and host have adapted to each other to such an extent that the excessive immune reaction that sometimes makes a Covid disease fatal does not occur. The rare but unusual side effects of the Covid vaccines – from myocardial inflammation to skin symptoms and microthrombosis – are also very likely to be due to an excessive immune response. Nobody knows how this overreaction is triggered and which parts of the spike protein are responsible for it.
The outer spines (spikes) of the omicron variant BA.5, which is predominant in Germany, have only twelve modified building blocks (amino acids) compared to BA.1, whose mRNA blueprint is contained in the new vaccines from Biontech and Moderna that are currently being clinically tested. However, this small difference has a powerful effect on the immune system, as it allows BA.5 to reinfect those recovered from BA.1 infection. It is therefore quite conceivable that the replacement of these “few amino acids” (Sahin) increases the rate of known side effects or causes new undesirable reactions.
Second, the mechanism of action of mRNA vaccines is not comparable to that of protein-based influenza vaccines. The injected mRNA is used by the body’s own cells as a template for the production of spike proteins, which stimulate the immune system to produce antibodies and defense cells directed against Sars-CoV-2. !function(){var t=window.addEventListener?”addEventListener”:”attachEvent”;(0,window[t])(“attachEvent”==t?”onmessage”:”message”,function(t){if (“string”==typeof t.data
In addition to this “adaptive immune response”, mRNA stimulates the immune system via a second mechanism, in contrast to the proteins contained in flu vaccines. The mRNA vaccines provoke the so-called “innate immune response” that cells normally use to defend themselves against virus attack (they confuse mRNA with the genetic material of viruses, which often also consists of RNA). How this innate immune response works depends on the three-dimensional structure of the mRNA used as a vaccine – and here even tiny changes can have a huge impact. However, these cannot be predicted without clinical studies because the innate immune response has so far only been researched to a limited extent.
Due to the first generation of Covid vaccines, the involuntary infection of the population and the less pathogenic effect of the omicron subvariants, the situation is “really no longer dramatic”, as Ugur Sahin himself stated in February. In view of the cooling off of the pandemic, vaccines, which, in contrast to medicines, are administered to healthy people, must once again be “safe before speed”.
Instead of demanding approval without clinical studies, Biontech should take the looming stage victory of the US competition in a sporting manner. The adaptation of the vaccines to the omicron variants is only an intermediate step on the way to a sustainable strategy against Sars-CoV-2. Only a universal vaccine that protects against all variants can keep the pandemic virus in check in the long term. And who will win the race here in the end is still completely open.