Nanobodies made in llamas and alpacas in order to fight covid

The start of vaccination campaigns against covid-19 in many countries suggests that, within a reasonable interval of time, infection curves will begin to fall significantly. Even so, there are several factors that indicate that alternative medical strategies are needed. On the one hand, according to epidemiologists, SARS-CoV-2 is here to stay, which means that it is likely to become a seasonal virus that will have to be fought locally from time to time. On the other hand, a large part of the world's population still does not have access to vaccines and may not have access to them for some time to come, which means that, in order to reactivate the world economy, it will be necessary to have drugs available to treat travelers who become infected in a timely manner.

Finally, the possibility of random mutations allowing the virus to escape the protective effect of vaccines, although reasonably low, is not zero. For all these reasons, alternative medical strategies are needed. Paul-Albert Koening and his collaborators, some thirty scientists from various research centers in Germany, Sweden and the USA, have just presented in the Science journal the development of molecules called nanobodies that can easily inactivate the infective capacity of this virus. To obtain them, they have used animals that are rarely used in scientific research: alpacas and llamas.

Versatile proteins

Alpacas and llamas belong to the zoological group of camelids, along with dromedaries, camels and vicuñas. Like all mammals, they have a complex immune system that allows them to defend themselves against viruses and bacteria. However, they have a special feature: unlike our own, they generate proteins called nanobodies that can be particularly versatile, not only to fight the coronavirus directly in infected individuals, but also to reduce the possibility of mutation, which will make vaccination campaigns more effective.

One of the elements of the immune system are antibodies. They are very fat proteins, with the appearance of a Y, capable of recognizing and binding to foreign elements that can cause disease. One of their peculiarities is that the shape of the upper ends of the Y is extremely variable, which allows them to recognize a virtually infinite range of infectious agents and to bind in a specific way. It is like the complementarity between a key and the lock it opens. Naturally there are immune system cells, a type of lymphocyte, that produce them and generate all the necessary variability.

When an antibody binds specifically to a virus, it serves as a marker for other cells of the immune system to destroy it and, on many occasions, also to inactivate it. In the latter case, they normally bind to the area of the virus that allows it to enter the cells it infects, so that it cannot reproduce and the progression of the disease is halted. Different strategies based on the use of antibodies have been designed to block the viruses from infecting any cells, but often the virus recognition zone is hidden in very narrow areas of its surface. And sometimes antibodies, which, as mentioned above, are very large molecules, do not have access. Moreover, they are very expensive to generate in the laboratory.

This is where the nanobodies generated by Koening and his collaborators may have a very important role to play. These molecules, which camelids make naturally, correspond precisely to the upper Y-ends of the antibody. That is, they are also extremely variable and capable of recognizing very specifically any infectious agent and blocking it. But they are much smaller, which allows them to bind to areas of the virus that may be hidden from conventional antibodies.

These researchers have immunized a llama and an alpaca with fragments of SARS-CoV-2 and isolated the most effective antibodies. They then selected those that, in addition to blocking the virus, do not generate any rejection when administered to a person. Finally, once selected, they have joined them in pairs, so that they not only recognize specifically one of the areas on the surface of the virus that allows it to infect human cells, but two simultaneously, which increases their effectiveness.

The advantages of this medical strategy are diverse. On the one hand, they can reach corners of the virus where a conventional antibody would not. In addition, being much smaller molecules than an antibody, they can be produced much more quickly and economically in the laboratory. Their size also makes them more stable, allowing them to be administered not only with an injection but also with an aerosol spray. And because they inactivate viruses before they infect cells and do so through sites that the human immune system cannot access, they are much less likely to accumulate mutations that decrease the efficiency of vaccines. Although they are still in the experimental phase, according to the authors of the study, they represent a very promising way of combating covid-19.

David Bueno is director of the UB-EDU1ST Chair of Neuroeducation.