Next-Gen vaccines and what they have in store for us
By: Manas Joshi
Tags: Rna, Vaccines, Synthetic Biology, Immunology, Dna

As the situation surrounding the COVID-19 pandemic mounts, attempts at finding a vaccine have intensified. The WHO lists about 180 COVID vaccines being developed around the world. Some use traditional methods, while others have their sites set on newer technologies that have never been tried before.

What is a vaccine?

Vaccines are substances that prepare the immune system to fight a pathogen(known as active acquired immunity). They mimic different molecules present on the pathogen without infecting the body with the actual pathogen. The result is that the body has a “memory” of the infection without actually getting it.

Traditional vaccines

Traditional vaccines do so by using by either using non-virulent varieties of the pathogen(known as “attenuated vaccines”), inactivated pathogens that have been destroyed (inactivated vaccines), using related microorganisms that do not cause the disease in humans(“Jennerian” vaccines), inactivated toxic compounds released by a pathogen(toxoids) or by mimicking the surface polysaccharides of the pathogen(conjugate vaccine).

However, these methods, while being very useful, also have a few drawbacks. To circumvent these, several innovative vaccines are also in development.

DNA & RNA Vaccines

There are many types of biomolecules present in the living cell. Some of them are deoxyribonucleic acids(DNA), ribonucleic acids(RNA), proteins, carbohydrates, etc. In these molecules, DNA is more stable than other biomolecules in the cell. Due to its inertness, cells use DNA to store their genetic information. This property of DNA gives rise to the idea of using DNA as a material to make vaccines. These types of vaccines are called DNA vaccines.

DNA vaccines

The plasmid is a small, circular, and extrachromosomal DNA present mostly in the bacteria. They may be found as single or multiple copies and may carry half a dozen to several hundred genes. While making plasmids synthetically, replacing some of the DNA by a sequence of base pairs that code for a protein present on the disease-causing agent’s external surface, we produce a potential vaccine. The synthesis of plasmid DNA (pDNA) with a gene of interest follows its insertion in the person’s body.

There are two ways to insert pDNA in the human body. Intradermal delivery of vaccines means that the layer under the skin is the site of delivery of the pDNA vaccine. Gene guns facilitate intradermal delivery of pDNA vaccines. A Gene gun is a device used to deliver exogenous DNA, RNA, or protein to cells. On the other hand, intramuscular delivery of vaccines is the insertion of pDNA vaccines in a person’s muscle cells. If this method is assisted by electroporation, the DNA quickly passes through the membranes of the cell. Electroporation is a technique in which an electrical field is applied to cells to increase the cell membrane’s permeability, allowing chemicals, drugs, or DNA to be introduced into the cell. This method improves the efficacy of the vaccine. The following table lists differences in the intradermal and intramuscular methods of delivery of vaccines:

The plasmid enters the nucleus and integrates with the DNA of the cell. The central dogma of molecular biology occurs in the cells. Post translation, corresponding proteins are expressed on the cell membrane of the cells to trigger immune responses. The lymphocytes(one of the subtypes of a white blood cell in a vertebrate’s immune system), especially T cells, recognize these structures and develop immunity against those foreign structures. The plasmid DNA vaccine is thus successful in creating immunity against the causative agent. DNA vaccination had emerged as an attractive immunotherapeutic approach due to its simplicity, stability, and safety.

Drawbacks of the DNA vaccine

The body has a natural mechanism to prevent autoimmunity, i.e., the system of immune responses of an organism against its own healthy cells and tissues. As a consequence, the lymphocytes fail to develop sufficient immunity against causative agents. The mechanism of central and peripheral immune tolerance makes the DNA vaccine inefficient. Central tolerance, also known as negative selection, eliminates any developing lymphocytes(one of the subtypes of a white blood cell in a vertebrate’s immune system) that are reactive to themselves(known as “Autoreactive Lymphocytes”). Through the elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack the host. When autoreactive lymphocytes escape the central tolerance and spread to the rest of the body, peripheral tolerance ensures that they are deleted or become anergic (functionally unresponsive to antigen). Naked DNA does not easily spread from cell to cell in vivo(within the body). Destruction of naked DNA can occur while delivering it. Also, it is difficult to transfer it to other surrounding cells.

Researchers are, thus, trying to find better options than DNA vaccines.

mRNA vaccines

Our cells have biomolecules called messenger ribonucleic acid(mRNA), present mainly in the cell’s cytoplasm. According to the central dogma of molecular biology, DNA information is converted to mRNA and, ultimately, to proteins that perform various functions. In the DNA vaccines, DNA is used to store information about the protein expressed to build immunity against the disease-causing agent. mRNA vaccines skip the step of converting DNA to mRNA (i.e., translation) and directly store the required information into an mRNA molecule.

The main component of the mRNA vaccine is the mRNA molecule. The purpose of making the vaccine is to help cells make proteins that will stimulate the immune system to build immunity against disease. The mRNA molecule is made synthetically according to the sequence of amino acids(building blocks) required to make the antigen protein expressed by the cell on its membrane.

Some vectors help in the delivery of this mRNA molecule. One of the methods used is the delivery of mRNA encapsulated in lipid nanoparticles. The lipids are a group of non-polar biomolecules. the lipid nanoparticles help deliver the mRNA in the cell’s cytosol.

The cytosol has many ribosomes. These make proteins(antigen) using the mRNA template. Expression of these antigens on the cell membrane stimulates the immune system to build immunity against the disease.

Advantages of mRNA vaccines

Production of mRNA vaccines is flexible and highly scalable. Translation of mRNA occurs in the cytosol of the cell itself. RNA does not integrate itself into the host genome, and the RNA strand in the vaccine degrades once the protein generates. As a result, the cell’s genome is not perturbed and prevents the cell from adverse effects due to the DNA strand’s addition in the genome. mRNA vaccines can be produced more rapidly in the laboratory in a process that can be standardized, improving their responsiveness to emerging outbreaks.

Conclusion

Now, we know about the DNA vaccine as well as the mRNA vaccine. Along with these, there are many types of vaccines. Both have their pros and cons. The choice of the vaccine solely depends on the purpose, cost, efficiency, safety, and many other factors.