In our previous article “Modern Conventional Strategies of Vaccines” we analyzed the strategies of a group of companies that adapted the classical vaccination approaches with more modern technologies. We now will investigate the latest strategies that use genetic modifications of the virus or elements of the virus. These are the Gene based vaccines and the Protein based vaccines that also use elements of the S protein (in red in window) as the main genetic vector for combating the pathogenic virus.
We have reproduced the drawing that illustrates the mechanisms of immune reaction following the administering of a SARS-CoV-2 vaccine.
Gene-based vaccines: Vaccines that use part of the coronavirus’s genetic code.
|DNA addition for the||mRNA|
|spike protein in plasmid||injection in cytoplasm|
|DNA Vaccines||RNA Vaccines|
Recently, a radically new approach to vaccination is emerging. A DNA vaccine involves the direct introduction of elements of the DNA sequence of a virus into the nucleus of the cell so that the cell, when reproducing, will present a foreign antigen on its surface and stimulate an immune response. Instead of delivering a whole virus in an attenuated or dead state into the body, one inserts a segment of the virus’ DNA in the nucleus of the cell. By this stratagem when the cell reproduces, its altered DNA will program modified genetic instructions to also build a protein contained in the virus This non self protein eventually will appear on the surface of one of the cell’s special MHC II class molecule, in a simplified peptide form and this in turn will engage the immune system to make antibodies against the virus. The method to alter the nucleus is the introduction into the cell of a plasmid, a small circular piece of DNA that can replicate independently from the host’s chromosomal DNA. (plasmids can be found in bacteria, yeast and plants but can be made synthetically in laboratories). A picture of a synthetic plasmid modified with the COVID -19 S protein is displayed on the left-hand side diagram. One of the main disadvantages of this approach is the difficulty in injecting the plasmid vaccine directly into the nucleus. So far, the only method of delivery are painful devices using electric shocks or gold microspheres into person’s skin. Although a few DNA vaccines have been approved for animals, none have been yet completed for humans.
mRNA vaccines ( Messenger RNA)
In a DNA vaccine, the cell is injected with the virus protein in its nucleus. In the process of cell reproduction, the altered DNA must then be transcribed in the nucleus into mRNA (messenger RNA) before moving to the cytoplasm and then present the antigen to the immune system. Researchers came up with a brilliant idea: what if instead of injecting the protein in the nucleus one could deliver messenger RNA into the cell’s cytoplasm instead of the nucleus, a much easier process of delivery as the outer membrane is much easier to pierce than the nucleus. To produce an mRNA vaccine, scientists produce a synthetic version of the mRNA that a virus uses to build its infectious proteins. For COVID-19 vaccine, the synthetic mRNA containing elements of the viral protein is delivered into the human body, whose cells read it as instructions to build the S protein, (the spike protein). As this protein is isolated from the other virus proteins, there is no danger for the virus to reform. The immune system then detects the non-self protein and starts to produce a defensive response against it. In addition to its easy delivery, it requires a much lighter dosage than in a DNA vaccine and therefore much larger volumes of production are possible and the cost per unit is much lower.
Rather than injecting the whole virus, it is possible to vaccinate a person with a single virus component. The pieces most commonly used are proteins from the surface of a virus. If a live virus enters the body, these surface proteins are easily recognized by the immune system. This approach is easier, faster, and safer because the virus protein can be produced in cell cultures.
By using proteins from the surface of the virus, it is possible to vaccinate a person without going through the complicated process of growing a dangerous virus. The roles of S protein in receptor binding and membrane fusion indicate that vaccines based on the S protein could induce antibodies to block virus binding and fusion or neutralize SARS-CoV-2 infection
Virus-Like Particle Vaccines
Some vaccines are particles that contain pieces of viral proteins. They cannot cause disease because they are not actual viruses, but they can still show the immune system what coronavirus proteins look like.
In early March, Medicago from Canada produced a Virus-Like Particle (VLP) of the coronavirus just 20 days after obtaining the SARS-CoV-2 genome sequence and quickly initiated pre-clinical testing. Medicago uses proprietary plant-based technology to develop protein-based therapeutics. Instead of traditional vaccine development, the company uses VLPs that mimic the shape and dimensions of a virus.
Yeast or other cells can be engineered to carry a virus’s gene and spew out viral proteins, which are then harvested and put into a vaccine. A coronavirus vaccine of this design would contain whole spike proteins or small pieces of the protein-based antigen together with an adjuvant to enhance the immune response. Adjuvants have been shown to create a stronger and longer- lasting immunity against infections than the vaccine alone. They can also improve the likelihood of delivering an effective vaccine that can be manufactured at scale
Novavax created the COVID-19 vaccine candidates using its proprietary recombinant protein nanoparticle technology platform to generate antigens derived from the coronavirus spike (S) protein. Novavax expects to utilize its proprietary Matrix-M adjuvant with its COVID-19 vaccine candidate to enhance immune responses.
Sanofi is using a similar technology, recombining particles of the S protein into the DNA of the baculovirus expression platform, the basis of Sanofi’s licensed recombinant influenza product in the US. It is using an adjuvant from GSK designed to reduce amount of vaccine protein required per dose.
It is hoped that one or several vaccines, whether using classical or the genetic approach will emerge soon. Meanwhile therapeutic strategies will become the focus of our attention in further articles.