A year ago, the term ‘plasmid’ may have generated little interest among people. And nobody would have associated DNA with vaccines. But on July 1, 2021, this changed, even if momentarily, when Ahmedabad-based Zydus Cadila announced that it had applied for emergency use authorisation of its COVID-19 vaccine, ZyCoV-D, which is set to become the world’s first plasmid DNA vaccine for human use.
COVID-19 Vaccine Platforms
There are many platforms—new and old—that are currently being used to develop COVID-19 vaccines. These include viral vector, inactivated virus, RNA, DNA, sub-unit and protein-based vaccines. The currently licensed COVID-19 vaccines include RNA-based vaccines (Moderna and Pfizer-BioNTech); viral-vectored (Oxford-AstraZeneca; Sputnik) and inactivated virus-based (Covaxin) vaccines, among many others. As of now, no DNA-based vaccine has been licensed for human use, nor for any disease.
The RNA and DNA vaccines together are called genetic vaccines or nucleic acid-based vaccines. These vaccines deliver one or more of the SARS-CoV-2 genes into the human cells to provoke an immune response.
What is a DNA Vaccine and What is Plasmid DNA Approach?
DNA vaccines involve direct injection of a plasmid containing the DNA sequence encoding the antigen(s) against which an immune response is sought, into appropriate tissues.
Plasmids are circular pieces of DNA, which are found in many bacteria. These plasmids store and share genes, which are not essential for the bacterium but may play a role in its survival. One of the characteristics of plasmids is that they replicate independent of the main chromosomal DNA. Therefore, they can be a simple tool for transferring genes between cells. It is for this reason that plasmids are widely used in genetic engineering.
The plasmid DNA has the unique property of self-replication, a reason why it is used in different kinds of molecular genetic research, such as gene therapy, gene transfer and recombinant DNA technology. A very good analogy of plasmid is a computer flash/pen drive. Pen drive improves the functionality but is not essential for the functioning of a laptop or computer. And that is exactly what a plasmid is—useful but not essential.
How Do DNA Vaccines Work?
One of the first steps in developing a DNA vaccine is identifying the antigenic section in virus, following which the DNA encoding of the antigen is chemically synthesized. Thereafter, it is inserted into an identified bacterial plasmid with the help of specific enzymes. Then, multiple copies of the plasmid are produced within giant vats of rapidly dividing bacteria, followed by isolation and purification. This material, after the standardized process, becomes the vaccine material.
The plasmid DNA, which carries an identified sequence of spike protein of the SARS-CoV-2, enters the host cell and then its nucleus, instructing the cell to make the messenger RNA. (Essentially, it is engaging human cells to do a task which they do not do on a routine.) Thereafter, the messenger RNA will carry the sequence to where protein is synthesized. The genetic material needs to be read by human cell’s protein-making machinery. Once protein is synthesized (which mimics the spike protein), these need to appear on the surface of human cells. It is at this stage the host immune system gets activated and starts producing antibodies and mounts a cell-based immune response.
What is Plug and Play Technology in Vaccines?
The plug and play technology here means that the antigenic part of SARS-CoV-2 can be identified and easily packaged as plasmid to modify the vaccine, if need be. Both plasmid DNA and RNA vaccines work on this science. The advantage: the vaccine material can be easily adapted to deal with the mutations in the virus and emerging variants.
Advantages of DNA Vaccines
The technology for producing DNA vaccines is simple and rapid. They offer a number of potential advantages over traditional approaches that include stimulation of both B and T cell responses. There are no live components; therefore, there is no risk of vaccine- triggered disease. The DNA molecule (in comparison of RNA) is stable, has a long shelf life, and does not require a strict cold chain for distribution. RNA vaccines, in contrast, need to be stored at low or ultra-low temperature. The plasmid DNA platform provides ease of manufacturing with minimal bio-safety requirements. DNA and RNA vaccines are considered cost-effective, and it is relatively easy to manufacture them at large scale.
However, there are known challenges as well. DNA vaccines find it harder to get inside the cell and be accepted by the cell’s protein-making system. Developing a plasmid DNA vaccine is considered slightly more complicated compared to an RNA vaccine, which can be synthesized in a laboratory.
The Status of ZyCoV-D Vaccine
On July 1, Zydus Cadila reported the interim findings of its plasmid DNA-based COVID-19 vaccine. The manufacturer reported that Phase-3 clinical trials of the vaccine were carried out on 28,000 volunteers at 50 different trial sites across India. Of them, around 1,000 participants were in the 12-18 age group. The vaccine is being developed in partnership with the Department of Biotechnology and the Indian Council of Medical Research, Government of India.
The interim analysis has found the three-dose vaccine showing a 66.6 per cent efficacy, with 4-week interval between each dose. (Although the manufacturer has reported that a two-dose schedule, 3mg per dose, is equally effective). Zydus Cadila has applied to the Indian Drug regulator—the Central Drugs Standard Control Organization (CDSCO)—and sought emergency use authorization of the vaccine for 12 year olds and above. The vaccine can be stored at 2-8 degrees Celsius and at 25 degrees Celsius for up to three months. Once approved, it will be an intra-dermal (between skin and muscles) vaccine administered through a specialized needle-free injector. The currently licensed COVID-19 vaccines are administered intra-muscularly.
First Vaccine for Teenagers?
The subject expert committee (SEC) under CDSCO is yet to take a decision on the plasmid DNA-based vaccine developed by Zydus Cadila. However, if and when it is approved for emergency use authorization, it may become the world’s first DNA vaccine for human use. It is already the first Indian vaccine to have completed clinical trials in the 12-17 age group and could well become the first vaccine in India to be licensed for adolescents. Once approved, the vaccine is likely to be available in the next 6-8 weeks.
Vaccines have reignited everyone’s interest in science. Vaccine development on newer platforms is challenging as well as exciting. Even a year ago, who would have thought that ‘plasmid’ would become a near-household term in India!
Disclaimer:Dr Chandrakant Lahariya is a vaccines, public policy and health systems expert. He writes a column ‘HealthHacks’ for News18, which appears every alternate Saturday. He tweets at @DrLahariya. Views expressed are personal.
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