Mutations: This is how vaccines for gene variants should be approved

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All vaccine manufacturers are currently concerned with how corona vaccines can remain effective against gene variants that are currently in circulation and those that will appear in the future. Studies have shown that certain gene variants reduce the effectiveness of the vaccines – especially with gene variant B.1.351, which was first discovered in South Africa. She showed reduced efficacy in vaccines from Biontech and Pfizer as well as from Moderna, AstraZeneca and Janssen.

The problem is: it could be followed by others. Experts emphasize that the likelihood of new mutations increases when there is a high infection rate – which could then escape the body’s immune response as a result of a vaccination or an experienced Covid 19 disease. So researchers need to prepare to adapt their vaccines to new mutations.

Some already do. Moderna has just announced that it has delivered a new version of its vaccine, adapted to B.1.351, to the National Institutes of Health in the United States. A clinical study should include a few hundred participants and begin “very soon”, according to Moderna boss Stephane Bancel.

The conventional approval process takes far too long

But how should these adapted or new corona vaccines then be approved? The fact that the coronavirus is genetically changing so quickly also poses new questions to regulatory authorities worldwide. The FDA, for example, has considered how the conventional approval process can be accelerated. Because actually each vaccine would have to prove its safety again one after the other in a phase 1 study before the dosage is tested in phase 2 and the effectiveness in the last major phase 3. However, this process takes about a year – far too long in view of the speed with which new gene variants develop and spread around the world.

This week the FDA presented a new guideline, the so-called “Guidance for Industry”, which is intended specifically for the development of vaccines adapted to gene variants, but also for antibody preparations, corona tests and drugs. Accordingly, the FDA will not require a complete new approval for adapted vaccines. All the manufacturer has to do is show that the vaccine produces an antibody response similar to that of the original vaccine.

The vaccine adapted to the mutations, like the flu vaccine, which is updated every year, is to be tested on a few people and in only one age group. On the one hand, people are included who have already been vaccinated with the original vaccine – to see whether the adapted vaccine can strengthen the immune response like a booster. On the other hand, the vaccine should also be tested on people who have not yet been vaccinated. The FDA assumes that the manufacturing information is identical in both processes.

The European Medicines Agency (EMA) also wants to establish fast-track procedures

Because even this process can take several months, there are also considerations to dispense with clinical tests altogether if necessary. Then approval would be possible within about six weeks. Six weeks is the approximate time frame that it takes to adapt mRNA vaccines to new gene variants in the laboratory – for example, as from Moderna and Biontech / Pfizer. Another six weeks would then be needed for production.

In response to the expected new virus variants, the European Medicines Agency (EMA) has also announced that it will enforce a fast-track procedure for vaccines that have already been approved and are only being adapted. Klaus Cichutek, President of the Paul Ehrlich Institute, said at a briefing by the Science Media Center that there were already talks with the European Commission.

The Commission’s proposal is that vaccine manufacturers do not have to submit a new license, but get their approval via a so-called type II variation. The EMA understands this to mean a change in the vaccine with possible effects on the quality, safety or effectiveness, but not on its strength or route of administration. The manufacturing process has to be essentially the same, according to Cituchek.

In this case, vaccine manufacturers would only need formal approval from the EMA. Smaller studies would also suffice for this. These should show that the converted active ingredient is about as effective against variants as the original against the original strain. “That can then be done in a few weeks,” said the PEI President. At the moment, he cannot say when a decision will be made on this possible approval route.

“We don’t want to make a vaccine against a mutant that doesn’t neutralize the wild type sufficiently.”

This may also be due to the fact that vaccine manufacturers – with the exception of Moderna – still rely on their approved vaccines, even when used against the gene variants. The time to change that, said Klaus Cichutek, would have come from his point of view if there was a sharp drop in the effectiveness of current vaccines.

Ugur Sahin, Chairman of the Board and CEO of Biontech, said at the briefing that so far there are only a few variants where the protection from the vaccination is probably lower. Biontech and Pfizer have already tested a total of 25 gene variants. This includes variant B.1351, which was first discovered in South Africa. “So far we have no real world data on this,” says Sahin, “but in the laboratory the vaccination also offers sufficient protection against this variant, albeit reduced by a factor of 3.”

So far there is no fixed answer as to when and how vaccine manufacturers should react to the mutants. “The situation is still a bit confusing,” says the researcher. At the moment, scientists are still in the process of developing an understanding of the virus, which is very important: why people got sick despite being vaccinated, how pregnant women tolerate the vaccine, children or people with immunosuppression.

“We also don’t want to make a vaccine against a mutant that doesn’t neutralize the wild type sufficiently.” In his opinion, another option is a vaccine boost: a third vaccination to strengthen the immune response, which Biontech and Pfizer are already using Is tested. Variant adaptation, says Sahin, is basically a new science. New approval regulations are appropriate for this. There is still no process to bring a new vaccine onto the market. It is true that one has the example with the flu vaccines, which are also adjusted annually. The question is, however, how much deviation is allowed from the originally approved vaccine. So it’s not about the “whether”. It’s about the “how”.


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