Viruses and pupae, the curious ingredients of a new recipe for the coronavirus vaccine

According to the World Health Organization, laboratories of 45 countries are already working to obtain a coronavirus vaccine . The past 20 of April, five of these proposals were already in clinical evaluation phase. Meanwhile, around a hundred continue their course, even in the previous stages. It is not a competition, because the objective is the same for everyone. However, it is logical that many research groups have joined this purpose.

A good vaccine must generate immunity against SARS-CoV-2 and be able to be administered in a safe way . But that is not all. It is also important that it can be obtained on a large scale with ease and, above all, while reducing costs as much as possible. If this is not achieved, the general access of the population can be very difficult, especially for countries with fewer resources, where the virus has broken in without hesitation, alien to the economy or social strata.

That is why the proposal of Algenex, a company based in Pozuelo de Alarcón (Madrid), is so interesting, in which they obtain proteins with the invaluable help of virus and pupae of butterflies .

Protein biofactories

The obtaining of proteins in the laboratory is a very important process in the field of the pharmaceutical industry.

They are available for therapeutic purposes, such as insulin , or for diagnostic purposes, such as the hCG used to prepare the pregnancy tests. Furthermore, proteins can be used in the manufacture of vaccines. Although initially they used to be formulated from an attenuated version of the pathogen itself that was to be prevented, over time other safer forms were found. This new stage is carried out by proteins , since those that trigger the body's defensive response can be used, so that immunity is generated without need to cause an infection.

Thanks to biotechnology, there are many ways to obtain these proteins in the laboratory. The use of microorganisms is common. For example, the insulin used by diabetics is usually obtained from bacteria E.coli . Complex organisms, such as genetically modified goats, can also be used to generate a specific protein in their milk.

But, without a doubt, if there are invaluable aid allies, whose use is spreading more and more in this industry, those are the insects .

Baculovirus to transport instructions

Obtaining protein from insects is a process in which a virus, called baculovirus , is also actively involved.

The family baculoviridae affects a wide range of insects, but is harmless to vertebrates . For this reason, they have been used for a long time to introduce a gene of interest into the DNA of insects. Genes contain the “code of instructions” so that an organism can synthesize a specific protein. We also know that viruses have the ability to “mix” their DNA with that of their host, so it can be used to carry those instructions to an organism that does not normally have them.

Since this baculovirus purpose was discovered, insect larvae have been inoculated with genetically modified virus strains to carry the gene necessary to encode a particular protein. This was done manually, while the larvae moved, so it was not exactly the best measure, if what you want is to obtain proteins quickly. It would be necessary to look for an alternative that meets the advantages of this procedure, but solving the errors. That is what Algenex has achieved.

In your case, the insect selected to obtain protein is the caterpillar of the cabbage ( Trichoplusia ni ), but they do not do it directly on the larvae, but on the pupae.

Its technology, dubbed CrisBio , optimizes the most useful phase of the metamorphosis of these insects. “A butterfly puts approximately 1. 000 eggs, from which they will hatch 1. 000 larvae ”, explains to Hypertextual the scientific director of Algenex, José Escribano . “From there they will go to chrysalis and, finally, back to butterfly.” The complete cycle lasts about nine weeks, but it is not necessary to wait all this time, since they continually have insects in different phases of the cycle, so that there are always pupae. But why pupae?

From larvae to pupae

“We started by inoculating larvae manually, as described in the scientific literature,” Escribano recalls. “Any manual process has limitations of personnel, space, repeatability, etc. For this reason, we have thought of a system that allows us to automate this technology. “

For this, in the last three years they have developed a series of robots , which are responsible for both handling insects and inoculation. “We verified that by inoculating the baculovirus in the chrysalis we obtained the same amount of protein per unit as if we did it in the larva”, adds the scientific director of Algenex. “This allows us that a hard and inert organism can be handled by machines, contrary to what would happen with the larva, which is hard and more difficult to handle.”

Another reason why this technology stands out is its security . “No animal component is used in the production process, and besides, the viruses we use do not infect mammals.” This means that, even if some accidental contamination is generated, it cannot cause disease.

Chrysalis and the coronavirus vaccine

A large part of the coronavirus vaccine options currently under investigation are based on a SARS-CoV-2 protein: the spicule. It is known that it acts as a “key” to the virus, allowing its entry into cells, but it is also the piece that the host's antibodies recognize, before initiating the immune response.

Until now, Algenex technology has been used to obtain proteins for veterinary use. Among these is a vaccine that is currently being evaluated by the European Medicines Agency for possible approval in the first half of 2021. However, they have also participated in the development of diagnostic kits for human diseases and plan to continue expanding in this area.

“There is only one difference between obtaining human or veterinary protein,” says Escribano. “Animals require a purification of 60%, while in humans it must exceed 90% ”.

Therefore, they have already started a protein production process to obtain a coronavirus vaccine. The objective of using this technology is precisely to obtain the desired drug as soon as possible and with an easy and cheap production process. “In three breeding cycles can be obtained 250 millions of pupae . If of each one can be obtained between 10 and 80 vaccine doses , imagine the amount that would be obtained in that time. ”

Such is the speed of the procedure that in just two months these scientists have already obtained the proteins to start testing their own vaccines. “We have a battery of four vaccine formulations, which we will test between June and July with animals and in the presence of different adjuvants .” This concept refers to those substances that are added to the vaccine to enhance its effect.

The future of the coronavirus vaccine

If all goes well, in November these scientists could already have a proposal for coronavirus vaccine for their passage to the clinical phases .

Taking into account that everything started on 15 March, it is understood that its technology is especially fast. Its speed is based both on the use of machines to inoculate the immobile pupae and on that of a cassette very efficient expression. These are “pieces” of DNA that are added together with the gene of interest, so that an extra quality is obtained, in addition to the synthesis of the protein sought. In this case, the insect cells are able to manufacture it with a productivity up to four times higher than normal.

Other great advantages of using pupae are that bioreactors are generated depending on the prevailing needs. “Other companies invest in large bioreactors, whose investment is lost if production stops,” Escribano says. “We generate bioreactors at will.”

It is true that in your case that container for obtaining protein is the chrysalis, which is only obtained when necessary. In addition, it is valid for any protein that you want to obtain, you just have to change the baculovirus .

“In these cases, simplification is important. The more sophisticated the process, the easier it is to fail. ”

In short, these scientists have taken advantage of the efficient reproduction of insects for a most necessary purpose. Therefore, it serves to remind us of two of the main actions that must be encouraged for a society to advance: looking at the environment around us and, above all, investing in science.

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