March 29, 2024

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dead or alive (current)

Vaccine production at the Serum Institute of India in Pune

Photo: Agence France-Presse / Punit Barangby

Alpha, beta, gamma, delta … And now the designations of the Sars-CoV-2 virus mutations – super fast – have already reached the fifteenth letter of the Greek alphabet, omicron. The fact that the virus mutates is one of its main characteristics. This is the only way to adapt to changing propagation conditions; A quality – at very different speeds – possessed by all life on Earth, including humans. Only he doesn’t need it that much to survive.

Due to the completely imperfect transcription machinery when the virus replicates in its target cell, sometimes a faulty building block gets here and there into the genome. As some readers may remember from my biology class, the scheme by which proteins are built from amino acids is stored with the help of so-called nucleic acid bases. In total, the four bases A, C, G and U are available. A combination of three of these bases stands for one amino acid. If, for example, a G ends up at the second position in the GAU sequence after an incorrect transcription process, the glycine is incorporated in place of the original asparagine. Such was the case with the B1 mutant, which first appeared in Europe since Spring 2020, then around the world, and its Alpha successor to Omikron. Incorporating the “wrong” amino acid changes the structure of this protein – and therefore has a different effect.

If such a mutated virus were transmitted, it might be able to penetrate better into target cells or be more difficult to recognize by the immune system—and thus the virus would have the advantage of selection. Mutants that are degraded have little chance of being degraded and are therefore unobservable. By the way, against the spread of mutations and against the emergence of a new immune system activated by vaccination or surviving disease against the virus – and as before, a suitable mouth and nose mask and a distance!

In the case of Sars-CoV-2, a new, highly reproducible mutant with as few as ~100 changes in the genetic material of the 30,000 constructs of the virus has now been observed to appear almost anywhere in the world. Two months, which fortunately doesn’t always make much difference. The low efficacy of the vaccines developed against the original “Wuhan variant”, which has now been recorded, indicates changes in the surface proteins of the virus that can no longer also be captured by the antibodies produced by the vaccination. This is supported by the increasing number of “grafting breakouts” in the delta and omicron mutants. This rapid change must now be countered — with booster vaccines, and even better with modified vaccines that provide antibodies that attack the virus again.

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Keyword Vaccine. There are two main types of vaccines (vaccines): live and killed vaccines. Live vaccines are viruses that can reproduce but are no longer harmful. Examples include vaccinations against measles, mumps, and rubella or chickenpox. There is no (yet) one for Sars-CoV-2. All other types of vaccines are actually dead-end vaccines because the active ingredients in them can no longer multiply in the vaccinated person.

Three classes of dead vaccines

There are three classes of inactivated vaccines: (A) killed or inactivated pathogens (eg BBIBP-CorV from the People’s Republic of China), and (B) vaccines with parts of pathogens as surface proteins (eg Soberana-2 from Cuba, With in the meantime, 90 percent of Cubans have been successfully vaccinated, or the Vidprevtyn vaccine still not approved by the French pharmaceutical giant Sanofi) and the (C) vaccine that contains a blueprint of parts of the pathogen that stimulates the body to produce these parts and present them to a device immunity. These include new types of mRNA and vector vaccines from Biontech/Pfizer, Moderna or the Gameleya Institute (Sputnik V), which were presented in the “nd Times vaccinated.”

Many people focus their hopes on group B – vaccines produced by long-known processes. They hope these are less dangerous than those in which genetic information is injected into the body – albeit an entirely different species compared to the human type. In addition to skepticism about genetic engineering, there may also be hope for better tolerance. But where are these vaccines? The description of the structure and production of these vaccines below may give some understanding of the long time it took for development to gain approval.

Let’s stay with the example of a vaccine against SARS-CoV-2. Thanks to a highly advanced analysis technology, which operates according to the same principles as well-known polymerase chain reaction (PCR) tests, it is possible to track down mutants and decipher their scheme, especially a specific surface protein, the so-called spike protein (it is these “spurs” that coronaviruses owe their appearance) ). Now there are two ways to go: On the one hand, you can try to multiply the virus on a large scale in bioreactors, and then separate the viruses and break them down into their components. But even hitting is not easy. You need suitable long-lived cell cultures for this, because viruses are picky – Sars-CoV-2 can only enter human cells from the mucous membranes of the throat, nose and lungs. The operation of these bioreactors is very complex and therefore expensive due to the materials used and clean room technology.

The next step, which is to “harvest” the viruses and separate them into their protein components, is also difficult. On the one hand, it must be ensured that no accompanying materials from viruses or host cells reach the final product. Some things are difficult to grasp, and others act similar to the desired product so that they slip off easily during the cleaning process – on the other hand, proteins in particular are very sensitive and tend to bend or tangle, and are then used as a vaccine that is no longer suitable.

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Another method is to genetically engineer suitable proteins as vaccines (virus-specific antigens). This is the approach taken, for example, with the Soberana-2 and Vidprevtyn vaccines. Since the scheme is known thanks to the above analyzes, this information can be incorporated into established cell systems that are already used for many other purposes, then the so-called recombinant proteins are also obtained in bioreactors, which are in their amino acid sequence (primary structure) Identical spike protein match. Unfortunately, there are also significant technological hurdles to overcome here. Apart from the cleaning procedures, which are very similar to those used for virus extraction, care must also be taken to ensure that the spatial structure of the recombinant protein resembles the natural structure. To use an image: Imagine someone extending their fist to you: It’s hard to shake hands!

pitfalls in manufacturing

Finally, many proteins, including the spiky one, have to attach additional components such as sugar residues after the actual protein synthesis so that they are similar enough to the original protein. However, many of the cell cultures used to produce recombinant proteins cannot or only incompletely do this. This means that not every cell type is equally good at creating the correct structure. More tricks must be used in order to achieve the correct fold (structure). Or the dose of the vaccine may have to be increased – in the hope that the “right thing” will be included in sufficient quantities.

In protein synthesis, one of the advantages of mRNA vaccines plays a role: the synthesis and folding mechanisms used by the infectious virus are used to form the spike protein; No cleaning procedures are necessary, so it will not differ much from the surface protein of the virus – from the point of view of the biochemical protein, it cannot be bypassed.

Assuming all of these hurdles have been successfully overcome, the next step comes: the protein must be presented to the immune system in such an observable form, as if it were a natural virus protein. To do this, the protein often has to be chemically linked (conjugated) to another – in soberana with tetanus toxoid that sounds dangerous, but is actually harmless. Or it should be mixed with an immune booster (adjuvant), such as finely divided aluminum or silicone compounds or an oil-in-water emulsion as with Vidprevtyn. Finally, the optimal recipe (formula) for the entire mixture must be found, ensuring storage, transportation and subsequent pollination. Each of these steps can lead to obstacles that will delay the achievement of the goal.

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Above all, clinical studies that conclusively prove the efficacy and reliability of the vaccine are essential.

In addition to extensive knowledge, all this requires a great deal of physical and technical effort as well as the time in which the virus continues to mutate and change so that the antibodies formed after vaccination with a painstakingly manufactured vaccine cannot or just insufficiently recognize and fight. The low efficacy of previous vaccines, which became known in the meantime, certainly has a reason for this.

The immune process after vaccination is the same as after infection – with the difference that the immune system recognizes the vaccine, ie the protein of the conjugated, adsorbed or killed virus, as foreign and begins to form antibodies.

The strength, quality, and duration of protection against the virus depends not only on individual factors but also on how the vaccine is chosen ‘foresighted’ so that there is also great structural similarity to subsequent mutations. The conventionally manufactured inactivated vaccines used to date do nothing better than mRNA and vector vaccines.

It just depends on how well the protein antigen used – in the case of mRNA vaccines, the antigen scheme – matches the proteins of the current virus mutation. Because if the key is no longer suitable for the lock, it may be because the lock has been changed … although it is a little better with grafting: the now vaccinated “keys” still fit, they are only “hooks”. What makes Sars-CoV-2 even more challenging is that many mutants around the world now simultaneously determine the infection process, and these mutations continue to mutate. And so it is more likely that the vaccines will be modified and combined again, as with influenza, and a new vaccine is due. It would also be reasonable to inject different types of protein in a single vaccine dose into a future vaccine…

Theoretically, one could react faster to viral mutations with mRNA and vector vaccines, because proper mRNA synthesis is easier compared to the processes just described, and the vaccine could remain the same. But clinical studies are necessary here, too — and factors like economics play a role, as shown in “Week Two” on 4/5, December 21.