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Differences in corona vaccines

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A wide variety of vaccine candidates against COVID-19 based on different approaches are being examined and developed around the world. How do these vaccines work, how are they made, and are they safe?

Infectious diseases such as diphtheria and poliomyelitis (poliomyelitis) have been almost completely displaced in Germany and many other countries through the development and use of vaccines. Smallpox, poliovirus type 2 and rinderpest have been eradicated worldwide. Every year, the Paul Ehrlich Institute (PEI) publishes the data from the vaccine monitoring system from the previous year in the bulletin on drug safety. It shows that serious vaccination complications are rare and that vaccines are generally very well tolerated and safe.

Despite everything, the rapid development of the potential corona vaccines is leading to uncertainty among the population and also in specialist circles, especially since the gene-based vaccines are approaches that have not yet been approved. Is there something to the uncertainty?

How do the different representatives work and how are they made? We get to the bottom of these questions here.

The most promising candidates in corona vaccine development include the novel mRNA, DNA (messenger or messenger ribonucleic acid or deoxyrib nucleic acid) and vector vaccines, but other types of vaccines are also in clinical trials.

The different approaches to vaccine development are based on the following strategies:

Although there is not yet an approved representative for gene-based vaccines, RNA and DNA vaccines offer in a pandemic situation a big advantage: Since these two platforms do not require bioreactor culture techniques such as those required for an inactivated vaccine, they can be quickly produced in the laboratory. The development process can thus be accelerated in the event of a pandemic. So it's not surprising that most strategies are currently using these new technologies.

Gene based vaccines

Gene based vaccines (also called nucleic acid vaccines) use genetic material - either RNA or DNA - to instruct cells to make the antigen. In the case of COVID-19, this is usually the viral spike protein. Once the genetic material gets into human cells, it uses the cells' protein factories to make the antigen that triggers an immune response.

The advantages such vaccines are that they are easy to manufacture and therefore cheaper. Since the antigen is produced in our own cells and in large quantities, the immune response should be strong.

A disadvantage however, is that as yet no DNA or RNA vaccines have been approved for human use. Long-term data are therefore missing. In addition, RNA vaccines must be stored in extremely cold temperatures of at least -70 ° C. This could prove difficult for countries without dedicated refrigeration equipment, especially for low and middle income countries.

Manufacturing

Once a pathogen's genome has been sequenced, it is relatively quick and easy to develop a vaccine against one of its proteins. For example, Moderna's RNA vaccine against COVID-19 was entered into clinical trials within two months of sequencing the SARS-CoV-2 genome. This speed is especially important when emerging epidemic, pandemic, or rapidly mutating pathogens emerge.

Both DNA and RNA vaccines are relatively easy to make, but the manufacturing process is slightly different between them. As soon as the DNA coding for the antigen has been chemically synthesized, it is inserted into a bacterial plasmid with the help of specific enzymes - a relatively simple process. Multiple copies of the plasmid are then made in huge containers of rapidly dividing bacteria before they are isolated and purified.

RNA vaccines are easier to synthesize because it can be done in the laboratory without the need for bacteria or cells. In either case, vaccines for different antigens could be manufactured in the same facilities, further reducing costs. This is not possible with most conventional vaccines.

RNA vaccines

RNA vaccines such as BNT162 (BioNTech / Fosun / Pfizer) and mRNA-1273 (Moderna / NIAID) usually consist of single-stranded messenger ribonucleic acid (mRNA), which contains the genetic information for the structure of a protein. In the cytosol, this is then bound by ribosomes and the formation of a polypeptide is catalyzed. To facilitate absorption into the cytosol, the RNA in vaccines can be packaged in liposomes or lipid nanoparticles (LNP), for example.

Self-replicating or self-amplifying RNA (saRNA) are also used, as in BNT162c2. These code both for the corresponding antigen (in this case the spike protein) and for proteins that enable the replication of RNA vaccines, so that the vaccine dose can be reduced. sa-RNA vaccines are derived from alphaviruses (positive-strand RNA viruses without segmentation).

The alphaviral genome is divided into two open reading frames (ORFs): the first ORF codes for proteins for the RNA-dependent RNA polymerase (replicase) and the second ORF codes for structural proteins. In sa-RNA vaccine constructs, the ORF, which codes for viral structural proteins, is replaced by an antigen of choice, while the viral replicase remains an integral part of the vaccine and drives the intracellular amplification of the RNA after immunization.

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RNA-based vaccines are generally considered to be very safe. Because the manufacturing process of mRNA does not require any toxic chemicals or cell cultures that could be contaminated with viruses. The short production time for mRNA also offers few options for introducing contaminating microorganisms.

Furthermore, the theoretical risk of infection or integration of the vector into the DNA of the host cell for mRNA appears to be very low, since the mRNA does not come close to the DNA which is located in the cell nucleus. In principle, DNA insertion is not possible in this way. The enzyme reverse transcriptase, which humans do not have and which converts the single-stranded RNA into double-stranded DNA, would also be required for the incorporation. A few viruses, such as the HI virus or HBV, use reverse transcriptase to transcribe their genome into DNA.

Potential safety concerns primarily include local and systemic inflammation, biodistribution and persistence of the expressed immunogen, stimulation of autoreactive antibodies, and possible toxic effects of non-native nucleotides and components of the delivery system. A potential problem could be that some mRNA-based vaccine platforms induce potent type I interferon responses that are associated not only with inflammation, but possibly also with autoimmunity.

Another potential safety issue could arise from the presence of extracellular RNA during mRNA vaccination. It has been shown that extracellular naked RNA increases the permeability of tightly packed endothelial cells and thus can contribute to the formation of edema.

Another study showed that extracellular RNA promotes blood clotting and pathological thrombus formation. Preclinical studies of RNA vaccines against SARS and MERS have raised concerns about the exacerbation of lung disease from infection-enhancing antibodies.

DNA vaccines

DNA vaccines consist of a piece of DNA inserted into a bacterial plasmid that codes for the antigen and is taken up and read in the target cell after the vaccine has been injected. A DNA vaccine that is currently being developed for corona vaccines is, for example, INO-4800 (Inovio Pharmaceuticals). The plasmid is a circular piece of DNA used by a bacterium to store and share genes. Plasmids can replicate independently of the main chromosomal DNA and provide a simple tool for transferring genes between cells. For this reason, they are already an established system in the field of genetic engineering.

DNA plasmids carrying the antigen are usually injected into muscle, but getting them into human cells is a key challenge. This is an essential step because the machinery that translates the antigen into protein resides in the cells. Various technologies are being developed to support this process - for example, electroporation, in which short electrical pulses are used to create temporary pores in the patient's cell membranes, or the encapsulation of DNA in nanoparticles that are designed to fuse with the cell membrane.

As soon as the DNA or RNA is in the cell and produces antigens, these are displayed on its surface, where they can be recognized by the immune system and trigger a reaction. This response includes killer T cells that seek and destroy infected cells, as well as antibody-producing B cells and helper T cells that aid in antibody production.

However, the immunogenicity of the DNA vaccines is comparatively low, so that according to the current status, repetitions of the immunization would be necessary and the long-term effects would not be sufficiently guaranteed. Research includes DNA vaccines against influenza, AIDS, hepatitis B and hepatitis C, rabies, human T-cell leukemia and cervical cancer. So far, however, DNA vaccines have only been approved for use in veterinary medicine

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A potential security risk could be the accidental integration of plasmid DNA into the host's genome. This integration could lead to a hypothetical activation of oncogenes or a deactivation of anti-carcinogenic DNA sequences, as well as causing autoimmune diseases. This risk is mutagenic: the integration could activate proto-oncogenes or deactivate tumor suppressor genes.

Furthermore, DNA vaccines usually require strong adjuvants so that they can trigger an effective immune response.

Vector vaccines

Vector vaccines such as AZD1222 (AstraZeneca / University of Oxford) or Ad5-nCoV (CanSino Biological inc./ Beijing Institute of Biotechnology) differ from nucleic acid vaccines in that they use a carrier virus which contains the genetic material for a vaccine antigen. Through the vector, for example the modified vaccinia virus Ankara (MVA), the adenovirus serotype 26 or the genetically engineered vesicular stomatitis virus (rVSV), genetic material is smuggled into the body cells.

The virus acts as a delivery system. As with nucleic acid vaccines, the body is instructed to produce the antigen from the instructions and to trigger an immune response. A distinction is made between replicating viral vectors and non-replicating viral vectors:

  • Replicating vector vaccines also produce new virus particles in the cells they infect and then infect new cells, which also make the vaccine antigen.
  • Non-replicating vector vaccines cannot produce new virus particles. They only produce the vaccine antigen.

One approved vector vaccine is the Ebola vaccine Ervebo (rVSV-ZEBOV), which received European approval from the European Commission at the end of 2019. The COVID-19 viral vector vaccines under development use non-replicating viral vectors.

Adenovirus (Ad) vectors have shown promise in animal models and are currently being used in numerous clinical studies, especially in cancer therapy. Here, the vector in the form of recombinant viruses, recombinant DNA or recombinant mRNA codes for a tumor-specific antigen.

Manufacturing

Traditionally, viral vectors have been grown in cells that are bound to a substrate, rather than free-floating cells - but this is difficult to do on a large scale. A disadvantage of the vector viral vaccines is therefore their scalability. Suspension cell lines are currently being developed that can be used to grow viral vectors in large bioreactors. The assembly of the vector vaccine is also a complex process, involving several steps and components, each of which increases the risk of contamination. Therefore, extensive testing is required after each step, which increases costs.

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One challenge with this vaccine approach is that humans may have previously been exposed to the virus vector and an immune response is triggered against it, which can reduce the effectiveness of the vaccine. Such "anti-vector immunity" also makes it difficult to give a second dose of the vaccine.

If there is a high pre-existing immune response to the vaccine vector, this may lead to an increased infection in vaccinated persons. Therefore, a vector-specific immune response (pre-existing or induced by immunization) can potentially affect safety. Since the genetic information for the pathogen-specific antigen is inserted into the genome of DNA viruses such as adenoviruses, viral integration mechanisms could lead to the uptake of DNA in the cell nucleus.

Protein Subunit Vaccines

Protein Subunit Vaccines (Subunit vaccines) use parts of the pathogen, often protein fragments, to trigger an immune response. This minimizes the risk of side effects, but it also means that the immune response may be weaker. Because of this, they often need adjuvants to boost the immune response. An example of a subunit vaccine that has already been approved is the hepatitis B vaccine.

A disadvantage of these vaccines is that the antigens used to trigger an immune response may lack molecular structures known as pathogen-associated molecular patterns (PAMPs), which are characteristic of a broad spectrum of microorganisms and allow the immune system to recognize their invasion. The absence of these patterns can lead to a weaker immune response. Since the antigens still do not infect cells, vaccines against subunits mainly only trigger antibody-mediated immune responses. This, in turn, means that the immune response may be weaker than other types of vaccines.

Manufacturing

All subunit vaccines are made using living organisms such as bacteria and yeast, which require substrates and strict hygiene standards to grow to avoid contamination with other organisms. This makes them more expensive to manufacture than chemically synthesized vaccines such as RNA vaccines. The exact method of manufacture depends on the type of subunit vaccine.

Protein subunit vaccines, such as the recombinant hepatitis B vaccine, are made by inserting the genetic code for the antigen into yeast cells, which are relatively easy to grow and can synthesize large amounts of protein. The yeast is grown in large fermentation tanks and then broken down so that the antigen can be harvested. This purified protein is then added to other vaccine components, e.g. B. Preservatives to keep it stable and adjuvants to boost the immune response - alum in this case.

In polysaccharide or conjugate vaccines, the polysaccharide is made by growing bacteria in industrial bioreactors before they are broken down and the polysaccharide is extracted from their cell walls. In the case of conjugate vaccines, the protein to which the polysaccharide is bound must also be produced by growing another type of bacteria in separate bioreactors. Once its proteins are harvested, they are chemically bound to the polysaccharide and then the remaining vaccine components are added.

Live attenuated vaccines and inactivated vaccines

Contain many approved vaccines Live attenuated vaccines and inactivated vaccines to trigger an immune response. They either contain the entire pathogen or only part of it. There are two main approaches:

Both types use well-established technologies. However, live vaccines can cause disease in people with weak immune systems and often require careful cold storage, making their use more difficult in resource-poor countries.

Because these vaccines are just weakened versions of natural pathogens, the immune system reacts like any other invader, mobilizing a range of defense mechanisms, including killer T cells and helper T cells and antibody-producing B cells (which target Target pathogens that lurk elsewhere in the body, such as in the blood).

This immune response continues until the virus is cleared from the body, which means that memory cells against the virus have enough time to develop. Because of this, live attenuated vaccines can produce an immune response almost as good as exposure to the real virus, but without getting sick.

Manufacturing

Different viruses require slightly different production processes, which means equipment and facilities are required for each individual vaccine. For example, the influenza virus is bred in fertilized chicken eggs - which themselves have to come from special sterile laying facilities. Poliovirus is grown in dishes of cells that require different handling, while bacterial-based vaccines are grown in huge bioreactors.

Growing live pathogens also mean strict precautions must be taken to prevent the virus from escaping and infecting vaccine facility workers. Once large numbers of viruses or bacteria have been grown, they need to be isolated, purified, and attenuated or inactivated, depending on the vaccine. Each of these steps requires special equipment, reagents, and rigorous procedures to avoid and check for contamination, which can add further cost.

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Because inactivated viral vaccines contain the disease-causing virus or parts of it, but the genetic material has been destroyed, they are considered to be safer and more stable than live attenuated vaccines and can be given to people with weakened immune systems. Although their genetic material has been destroyed, inactivated viruses usually contain many proteins that the immune system can respond to.

However, since they cannot infect cells, inactivated vaccines only stimulate antibody-mediated responses, and this response can be weaker and less long-lived. To overcome this problem, inactivated vaccines are often given with adjuvants and booster doses may be required.