A few months ago nobody would have expected that there would be a vaccine against the coronavirus by the end of 2020, less than 12 months after the outbreak of the Covid 19 pandemic. Never before has a vaccine been developed, tested, approved and inoculated so quickly – especially since it is a vaccine against a completely new type of pathogen. Otherwise, it takes years, sometimes decades – or it doesn’t work at all, as with the HIV pandemic.

Three vaccines against Covid-19 have now been approved in the EU and more will follow soon. But the extraordinary nature of this fact has long been forgotten. Now there is a dispute about what is not going according to the plans and contracts that were created at a time when no one could yet know whether and which vaccine candidate would work and how it could be produced.

That too few vaccine doses would initially be available for everyone was and is as clear as it is trivial. And that would also have been the case if the EU had ordered a few weeks earlier and more and companies with more government support had started building more production capacities even earlier. Because the expansion of capacities has limits.

Retrofitting and compulsory licensing certainly do not solve the problem

At the vaccination summit of the federal and state governments, it is still being discussed how more vaccine could be obtained. There were many proposals from the parties beforehand. SPD parliamentary group manager Carsten Schneider, for example, had the idea that pharmaceutical companies might simply “convert” their production facilities, from birth control pills to vaccines, for example. Achim Kessler from the Left is calling for “compulsory licensing” so that those companies can also produce corona vaccines that have not developed the technology and therefore usually cannot. FDP boss Christian Lindner in turn wants a “crisis production”, whatever that means.

Beyond the green table, however, the reality is different. “The idea,” says Florian von der Mülbe from Curevac, “that a pharmaceutical company, even if it already produces its own vaccines, could switch to a different, new technology, that’s something… simple.” It’s just not easy , explains the co-founder and head of production of the Tübingen biotech company, which, like Biontech and Moderna, is developing an RNA-based vaccine. Although the results of the final testing and approval of the Curevac vaccine are not expected until the second quarter, the company is already producing millions of vaccine doses.

“It’s a very complex process,” says von der Mülbe, and it usually takes at least 12 to 18 months to establish the necessary techniques and processes at a new location or in another company. With Wacker, one of several cooperation partners, von der Mülbe now wants to do it within four to five months. “But it also takes this time”, not only to get the necessary reactors for production and the purification equipment for the vaccines up and running, but also to be able to guarantee quality and safety. “This also includes approvals from the authorities, which process this very quickly these days, but there are no abbreviations.”

DNA as a template, millions of copies of RNA

As complex as the details are, the principle behind the manufacture of RNA vaccines is as simple – almost as easy as copying in the office. A piece of DNA, the gene that contains the instructions for the “sting” of the coronavirus, the S protein, serves as a template. On the basis of this template, an enzyme, the RNA polymerase, creates an RNA copy of the DNA assembly instructions, and then one more and one to billions of RNA copies are available, which then only contain the information about the S protein. These RNA molecules are purified, for example from the DNA templates, and then “packaged” in a means of transport that is supposed to facilitate their way into the cells in the body of the vaccinated person: lipid nanoparticles. These tiny fat droplets, millionths of a millimeter in size, carry the RNA molecules inside.

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Once injected, they fuse with the cell membranes in the body and the RNA enters the cell. There the assembly instructions are read and the prickly protein of Sars-CoV-2 is produced. The body’s defenses react to this and build up immunity in the form of antibodies and T cells against any virus that has such a prickly protein. The body of the vaccinated person builds its own vaccine, so to speak.

As early as 2006, Curevac was the first biotech company to raise this production process, which previously only worked on a laboratory scale, to “GMP level” – the “Good Manufacturing Practice” standard that every drug production must meet so that people can use the product may be treated. Curevac, Biontech and Moderna also optimized the production volume before the pandemic began. These are “still not smoking chimneys, but we can now produce millions of vaccine doses in a short time,” says von der Mülbe. In order to increase capacities, the process is now being “multiplied”, ie distributed in the form of a network to various partners such as Wacker. “We are well on schedule.”

Adaptable to mutants within four to six weeks

According to von der Mülbe, the “peculiarity of RNA technology” comes into play when the vaccines have to be adapted to new virus mutants – such as the South African vaccines against which, according to initial research results, the previous vaccines only offer reduced protection. You just have to change the assembly instructions, the sequence of the RNA a little. That goes “very quickly”. An adapted vaccine could go into production within four to six weeks. “You can’t do that with any other technology.”

[Welche Virusmutanten kursieren, welche Mutationen machen sie mehr oder weniger gefährlich? Wirken die Impfstoffe noch gegen sie? Unser FAQ zu den Sars-CoV-2-Varianten beantwortet wichtige Fragen.]

With the second fastest corona vaccine technology, the so-called “vector vaccine” from Astrazeneca, it inevitably takes longer. Here, too, the instructions for the prickly protein can be easily edited and inserted into the “vector”, a modified adenovirus from chimpanzees. But then cell cultures must first be infected with these vectors, the cells must grow, fermenters with these cells must be inoculated – a process that takes months rather than weeks. This also applies to the vaccine from Johnson & Johnson, which is also grown in cell cultures. “The process of RNA synthesis is cell-free, we don’t have to use cell lines and can get started right away,” says von der Mülbe.

Is it possible to use an abbreviation for examination and admission?

The time seems to be right to start developing customized vaccines. Although the vaccine manufacturers are still keeping a low profile in this regard, the Paul Ehrlich Institute (PEI) has “already initiated such developments and is aware that vaccine adaptations are being designed,” said Klaus Cichutek, head of the PEI, to the Tagesspiegel.

The “changeover time would ideally be chosen early,” says Cichutek, so that “strong losses in the effectiveness of the vaccines with regard to the circulating Sars-CoV-2 variants can be avoided.” It should be borne in mind that “the manufacturing capacities currently available for the approved vaccines are fully utilized, then have to be switched over to new productions accordingly. “

In the end, however, these new, adapted vaccines also have to be approved again. Do you then have to go through the entire month-long test procedure again? “In many respects, the approval can be based on the documents of the original vaccine that have already been assessed,” said Cichutek to Tagesspiegel. With the rolling review process, in which the companies can proceed with tests while the authorities are still checking some documents, and the rapid evaluations and decisions by the responsible bodies of the European Commission, the approved vaccines already have “very short approval times” has been achieved.

More about corona mutants:

Cichutek refers to the “European level”, i.e. the EMA, where there are “first discussions about the regulatory requirements”. One possibility would be “immunobridging”, a “clinical trial with a limited number of subjects,” says Cichutek. If one observes an immune reaction in this small group of vaccinated people that is comparable to the previous, effective vaccines, one can with a certain probability “ensure an adequate immune response against the spike protein variants contained in the respective vaccine product”.

But in addition, the vaccine quality must “of course be ensured again by evidence of consistent manufacture, specifications and experimental tests,” said Cichutek. In any case, “the time required for a limited clinical trial must be observed in order to determine the effectiveness as well as the tolerance and safety with a follow-up period of six weeks for the vaccinated.”

However, the question of whether there will then be a vaccine mix against all virus variants or whether further vaccinations against the mutants will be necessary in addition to the previous one is open. “Both are possible: Either you vaccinate against a virus mutant and later again against another, or you make mixtures right away,” says von der Mülbe. “We are examining various options. What is clear, however, is that it is in principle possible to mix different RNAs with RNA technology. “Such RNA cocktails have already been tested, including on humans, even if not yet against Covid-19.

More RNA, more protection

A cocktail of vaccine components against several virus variants is only one of several possibilities. For example, those who were already vaccinated against the original Sars-CoV-2 could be vaccinated against one of the new variants during the second vaccination with another vaccine, so that they are then protected against both. Anyone who has already received the second vaccination, or will be vaccinated with the single vaccine from Johnson & Johnson shortly, could be immunized against variants with one or more booster vaccinations.

A problem with vaccination cocktails could be that they contain several active ingredients, for example more RNA molecules, and experience has shown that more vaccination side effects can be expected at higher concentrations per vaccination dose. “These are questions that we have to deal with,” says von der Mülbe. “Ultimately, the tests have to show that.” So far, the side effects are minor and justifiable. If you want to take action against three variants in a vaccine, the RNA concentrations could triple: at Moderna to around 300 micrograms and at Biontech to 90 micrograms. “In our case, that would add up to 36 micrograms,” says von der Mülbe.

How compatible this is in each case, and whether it is even necessary to add the quantities in this way or whether less is sufficient, cannot yet be said. “The necessary amount”, says PEI boss Cichutek, “has to be chosen in such a way that acceptable tolerability and safety and effectiveness are guaranteed”. It should be remembered that the effectiveness of the current vaccines against the new variants is “not zero”, but “only needs to be supplemented”. The ideal composition to protect against virus mutants can initially also be determined in animal experiments. Florian von der Mülbe is convinced that RNA vaccines offer “the best opportunities to react to the germination of new virus mutants”.