The purpose of vaccination is to achieve longer-term protection against a disease. The idea behind the genetic vaccines favored for the fight against SARS-CoV-2 is that the body virtually produces the virus itself, and then forms antigens that prevent the disease if it comes into contact with the virus itself. In the course of SARS-CoV-2 diseases, the decline to “normality” should only be possible with a vaccine.
In medicine, a virus is a biological structure that can consist of nucleic acids (DNA or RNA), proteins and possibly a viral envelope. Viruses do not have their own metabolism and therefore require host cells to reproduce. They are therefore usually not referred to as living beings. 1
Coronaviruses belong to the family of RNA viruses, which infect both animals and humans and can cause respiratory diseases in humans in particular.2 RNA viruses are a disparate group of viruses that have a genome of RNA (Ribonucleic acid) as a common structural element. In addition to RNA viruses, there are also DNA viruses whose genome is present in the form of DNA (Deoxyribonucleic acid). 3
Vaccination is intended to prepare the body to detect pathogens and to respond to them with its own immune system. The administration of a vaccine is said to result in the formation of antibodies.
When developing a vaccine against SARS-CoV-2, various concepts are followed:
- virus-based vaccines
- vector vaccines
- protein-based vaccines
- gene-based RNA and DNA vaccines
In the hope of containing SARS-CoV2, research is currently being carried out on 291 vaccines, 68 of which are in clinical phases (as of January 8, 2021).4
These vaccines contain an isolated SARS-CoV-2 pathogen, either in a severely weakened or inactivated form. It is a weakened version of the pathogen, so it usually triggers an immune response without getting sick. However, live vaccines can lead to diseases in people with weak immune systems
In the development of inactivated virus vaccines, the genetic material of the viruses is destroyed. This makes them safer and more stable than toned down vaccines. People with weakened immune systems can tolerate them better.
The immune response may be weaker and less long-lasting with inactivated vaccines, so refresher doses may be required.
This method of virus-based vaccines is based on well-established technologies.5 They are known, for example, from conventional flu vaccinations.
In this completely new procedure, which has never been tested in human vaccinations, other viruses, such as measles, mumps or adenoviruses (highly contagious types of pathogens that cause a variety of diseases), are attenuated and genetically manipulated with fragments of the genetic material of SARS-CoV-2. They are called vector viruses because they serve only as carriers. The body’s own cells are to take up the genetic information and develop immunity against SARS-CoV-2.6
There are two types of viral vectors. One can still reproduce in the body’s own cells and the other can no longer because important genes are deactivated.7
However, the effect of the vaccine may be reduced if the affected individuals have already been exposed to the viral vector (e.g. measles), because an immune response against it may be triggered. In addition, such “anti-vector immunity” makes it difficult to administer a second dose of the vaccine.
If there is a strong immune response to the vaccine vector, there may eventually be increased infection in vaccinated individuals. This leads to safety risks. 8
However, the Robert Koch Institute does not express any concerns about the safety of vector-based vaccines. The replicable vector viruses would only multiply in the body for a limited time and would be controlled by the immune system. Also, no genetic information from the vectors would be incorporated into human DNA. After the degradation of the genetic information transferred by the vector viruses, no further production of the antigen would take place.9
With regard to SARS-CoV-2, spike proteins or envelope proteins or fragments of them are to be used to inject them directly into the body. So far, this vaccination method has only been shown to protect against infection in monkeys. Studies with humans do not yet exist. To achieve the targeted effect, these vaccines might need to be given in multiple doses
Another method is to administer empty viral envelopes designed to mimic the structure of the Coronavirus. They are noninfectious because they contain no genetic material. However, the production is difficult.10
Gene-based RNA and DNA vaccines
Nucleic acid is a chemical collective name for DNA and RNA.
DNA stores the genetic information, RNA is involved in the transfer and conversion of this information. DNA and RNA are mainly located in the cell nucleus and they are acids, therefore the name nucleic acids.
They are composed of so-called nucleotides, each of which consists of a phosphoric acid, a sugar and a base. These nucleotides combine to form the familiar double strands of DNA.11
Nucleic acids (DNA and RNA), are particularly crucial in the storage and processing of genetic information. In this vaccination method, nucleic acids containing genetic information of the desired antigen are administered. The body’s cells absorb this information via the corresponding proteins and the body begins to produce virus fragments. This is how immunity is supposed to be developed.12
The gene-based vaccines are simple and thus cheap to produce, so a large number of vaccine dosages can be produced within a few weeks. The immune response is said to be strong because the body produces the antigen itself.
No DNA or RNA vaccines have yet been approved for human use. Long-term data on efficacy and tolerability are lacking. In addition, RNA vaccines must be stored and transported at extremely low temperatures of about -70°C.13
RNA or mRNA vaccines (messenger RNA) contain gene segments of SARS-CoV-2 in the form of mRNA. After administration, viral proteins are produced in the body’s cells, which are intended to stimulate antibody formation against SARS-CoV-2. Thus, an immune response is to be generated. These proteins are called antigens.
The mRNA is coated with lipid substances (lipids = water-insoluble natural substances, such as fats) to enable absorption by the body’s cells. This creates so-called mRNA lipid nanoparticles. The genetic information on the mRNA is read out in the cells and converted into proteins. This process also occurs in the same way in body cells with the cell’s own mRNA.
The Robert Koch Institute points out that the mRNA of the RNA vaccines would be broken down by the cells after a short time. It is not converted into DNA and has no effect on human DNA. After the degradation of the mRNA, no further production of the antigen would take place.14
The manufacturing process of mRNA does not require toxic chemicals or cell cultures, which is why the RNA-based vaccines are generally considered safe. The short production time for mRNA also means that there are only a few options for introducing contaminating (contaminated) 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.15
However, there are potential safety concerns, e.g. local and systemic inflammation, the stimulation of autoreactive antibodies or possible toxic effects of non-endogenous nucleotides (additional building blocks for RNA) and components of the vaccine.
Another problem could be that some mRNA-based vaccines produce strong type-I interferon reactions that have been linked not only to inflammation, but possibly also to autoimmunity
Interferons are proteins that are produced in cells and trigger immunological reactions.16
Another safety issue could arise from the presence of extracellular (outside the cell) RNA during mRNA vaccination, which can contribute to the formation of edema. It can also stimulate blood clotting and thrombosis.
Preclinical studies of RNA vaccines against SARS and MERS have raised concerns about the aggravation of lung disease from infection-enhancing antibodies.17
In DNA vaccines, a piece of DNA containing genetic information for the antigen is inserted into a bacterial plasmid, which is taken up and read in the body cell after the vaccine has been administered.
Plasmids are small circular DNA molecules that i.a. found in bacteria and used to store and share genes. They can replicate independently of the main DNA and provide a simple tool for transferring genes between cells. That is why they are already an established system in the field of genetic engineering.
The difficult part of the process is getting the DNA plasmids, containing the antigen information, into the human body cell. This is important because the system that translates the antigen into proteins is in the cells. One type of technology to support this process is short electrical current pulses (electroporation). These are used to create small, short-term openings in the cell membrane.
When the antigen information is in the cell and antigens are produced, they are displayed on its surface, where they can be recognized by the immune system and trigger a response that helps antibody production. However, the immune response capability of the DNA vaccines is comparatively low. Therefore, according to the current status, repetitions of the immunization would be necessary and the long-term effect would not be sufficiently guaranteed.
So far, DNA vaccines have only been approved in veterinary medicine.
Accidental integration of plasmid DNA (through the injected DNA plasmids) into the genome (genetic material) of the patient could represent a possible safety risk. This could lead to a possible activation of oncogenes (cancer genes) or a deactivation of anti-carcinogenic (cancer-inhibiting) DNA sequences. It can also cause autoimmune diseases.
In addition, DNA vaccines usually require strong auxiliary substances (adjuvants) so that an effective immune response can be triggered.18
The original language of this article is German. The English and French versions are translations.