Curevac vaccine: the first RNA defeat against the Corona virus | Science

The power of new RNA-based vaccines has waned in recent days with the disappointing results of a new injection based on this technology. The German company Curevac acknowledged that its vaccine is only 47% effective and does not meet established expectations. The immune system has been of interest because it does not need freezers and can be affordable in many developing countries where vaccination against SARS-CoV-2 has just begun. But, for unknown reasons, it does not work.

If anything is proven in this pandemic, messenger RNA could have fought off viruses. It’s a strategy that big pharma ignored in its infancy. RNA was thought to be an ephemeral and fragile molecule that would not work as a medicine. The date changed this view as of December 2020. Two messenger RNA vaccines, one developed by the German company BioNTech in cooperation with the American company Pfizer, and the other by Moderna in cooperation with the public sector in the United States, showed efficacy greater than 94% and almost 100% their ability to prevent the death of infected people . So what happened to the corivac vaccine based on the same molecule?

There is a striking fact about the Curevac clinical trial. It was conducted in 10 countries in Europe and Latin America at a time when 13 different types of the virus were already circulating. Of the just over 130 infections recorded in this trial with 40,000 individuals, only one is the classic strain of MERS-CoV. Others were the most recent, including Delta, which originated in India – one of the most contagious and dangerous – as well as variants recently discovered in Peru and Colombia The clinical trial of Curevac is not yet finished, and the full results have not been published in any scientific journal . But preliminary data shows that the effectiveness of this vaccine is disappointing – and declines with age and if the patient becomes infected with the new strains.

“We were hoping for more robust results, and now we see it as very difficult to achieve high efficacy with such an unprecedented diversity of virus variants,” said Franz Werner Haas, the company’s CEO, in a press release.

These results are part of an intermediate analysis. The clinical trial is still ongoing, and the full details of effectiveness won’t be known until it’s finished, perhaps in a week or two. “It is possible that the efficacy data will vary upon completion of the study, and for example we will see that the vaccine works against some variants and not against others,” explains Antonio Portoles, a pharmacist at the Clinical Hospital of Madrid who is leading the part of the clinical trial at Curevac at that institution. “It is possible that 50% efficacy can be reached, but it is unlikely that efficacy levels of 94% will be reached by two other RNA vaccines,” he admits.

The German laboratory reported that it had already developed a second improved version of its vaccine, which is supposed to be able to defeat new forms of the Corona virus. But it is possible that the flaw is in the essence of the technology used.

An RNA vaccine is an encrypted message written in the universal language of life. The RNA language consists of four letters: A, C, U, G. The sequence of genetic letters found in RNA vaccines informs the cell: “From here you must follow my commands to translate this message.” It then includes the entire sequence of protein S, which the virus uses to enter human cells.

Injecting foreign RNA into our bodies is not an easy task: the immune system immediately takes over to destroy anything malignant. The great innovation that allowed the development of messenger RNA vaccines was precisely the introduction of a synthetic letter into this RNA sequence, pseudouridine, represented by the Greek letter Ψ (psi). In 2010, after years of rejection by both the public and private sectors, USA-based Hungarian scientist Katalin Kariko demonstrated that this simple change from one letter to another allowed for the injection of messenger RNA from outside without triggering an immune reaction. exacerbated. BioNTech, who hired her as director, and Moderna both use this patented, modified-RNA-based technology that the University of Pennsylvania sold at a bargain price years ago, because they “wanted fast money,” Carrico told EL PARENTS.

One of the biggest critics of Carriko’s role as the mother of RNA vaccines is Hans-Georg Ramense, an immunologist at the University of Tübigen (Germany) and co-founder of Curevac. His company builds on a discovery by colleague Ingmar Hoyer, whose doctoral thesis in 2000 showed that unmodified RNA could be fixed and used to make vaccines. Since then, the company has been trying to develop RNA vaccines against many diseases. Nothing has come to the market yet, but preliminary animal and human data for the covid-19 vaccine has been good. In December, Ramense told this newspaper that none of Carrico’s accomplishments were decisive. However, he admitted the inevitable: “Were it not for our 2000 study, neither Moderna nor BioNTech would have been founded, but they would have been faster to develop.”

“It is likely that unmodified RNA is part of the explanation for such disappointing results,” says Spanish virologist Isabel Sola. The unmodified RNA activates the immune system’s first line of defense, the innate line, which prevents cells from translating the RNA message contained in the vaccine. Here may be one explanation for the failure.

The researcher believes that there is a great lesson to be learned from these findings. “At one point we thought developing messenger RNA vaccines was really simple and fast, but the truth is that it takes a tremendous amount of work, over the years, and any small change in the sequence of the genetic message in RNA can make the molecule unstable or very aggressive on the immune system. “.

Immunologist África González, from the University of Vigo (Spain), believes that unmodified RNA may have played a role, but other factors are involved. The vaccine dose used by Curevac is 12 mcg, much lower than the combinations of Pfizer (30 mcg) and Moderna (100). He argues that it is possible that Curevac did not want to give more doses to avoid adverse reactions, and therefore the efficacy is very low.

There’s one last, small but perhaps essential detail: the vehicle that vaccines use to transfer RNA from the needle into human cells. These are lipocytes of microscopic size, the composition of which is very precise: they must remain intact until the inoculum adheres to the outside of the cells, and then open to release the messenger RNA inside. Curevac uses different fields, which are able to remain stable at lower temperatures than the other two vaccines. But it is possible that this ability adversely affected their ability to carry their protective payload. As the Anglo-Saxons say, the devil is in the details.