Highlights
- ZyCoV-D belongs to an entirely new class of vaccines.
- The DNA-based jab against COVID-19 was developed in India by Zydus Cadila, based in Ahmedabad.
- It has been given emergency use authorisation (EUA) in the subcontinent.
- Approval was granted following late-stage clinical trials involving more than 28,000 participants.
- It’s the first-ever DNA-based vaccine against SARS-CoV-2 authorised for human use in the world.
DNA is the blueprint of life. Our genes, made up of DNA, determine how cells reproduce. Genes define heredity. What’s fascinating is that some genes have also proven to act as “instructions” to make molecules, such as proteins.
That, in a nutshell, is the idea behind DNA-based vaccines. Until today, no other DNA vaccine has been approved anywhere — except ZyCoV-D, developed in India and now authorised by drug regulators in the sub-continent. About a dozen other vaccine candidates using the plasmid DNA platform are on trial in different parts of the world. But the approval of ZyCoV-D signals a breakthrough in medical science, a "new wave" in vaccinology.
What we know so far:
What is a DNA vaccine?
A DNA vaccine uses a copy of a genetic sequence from a part (i.e. outer or spike-protein) of a pathogen (virus or bacteria) to stimulate the body’s immune system. More specifically, it known as “plasmid DNA vaccine”.
Is there an approved DNA vaccine?
Yes. ZyCoV-D was developed by Indian pharmaceutical company Zydus Cadila, based in Ahmedabad, with support from India’s Biotechnology Industry Research Assistance Council (BIRAC). It was approved by India’s drug regulator on August 20, 2021.
ZyCoV-D is India’s second home-grown vaccine — the first being Covaxin, developed by Bharat Biotech jointly with the Indian Council of Medical Research (ICMR) and the National Institute of Virology (NIV).
What is the vaccine efficacy (VE) of ZyCoV-D?
67%, based on interim data analysis. VE is defined as "protection against symptomatic COVID-19". This efficacy is essentially against the now-dominant Delta variant (trials were conducted in India, where Delta was first reported).
67%
Efficacy of ZyCoV-D DNA vaccine against COVID-19, based on initial data analysis of clinical trialWhen was it approved?
Zydus Cadila applied for approval in July 2021. Following a month-long review, the Drug Controller General of India (DCGI) approved ZyCoV-D on August 20, 2021.
What is the dosage?
3 doses are required to achieve efficacy, according to Zydus Cadila.
What age group is ZyCoV-D approved for?
People aged 12 and older.
How much is it per shot?
Pricing has not been announced. Indian media reported Zydus expects $27.2 to $34 million (Rs200-250 crore) in monthly sales from ZyCoV-D.
What’s the vaccine efficacy rate based on?
The immunogenicity figure of 67% is based on initial data readout of the Phase 3 trial involving 28,000 volunteers: 21 symptomatic cases of COVID-19 were detected in the vaccinated group and 60 among people who received a placebo, Nature reported. Included in the trial were adolescents in the 12-18 age group.
28,000
Number of volunteers enrolled in the ZyCoV-D DNA vaccine trial conducted in IndiaIs the ZyCoV-D trial complete?
No. Full results of the late-stage trials (Phase III) are yet to be published. The full analysis will be submitted for publication “shortly”, Zydus Cadila told Indian media.
What is the vaccine production run rate of ZyCoV-D?
Zydus plans to make up to 120 million doses of ZyCoV-D per year. The company says the first doses will start to be administered in India this month (September).
India has so far given more than 570 million doses of three previously approved vaccines — Covishield, Covaxin and Sputnik V — with about 13% of adults now fully vaccinated, while 47% have received at least one shot since January.
Why does it have a low vaccine efficacy?
Vaccines developed using other platforms, particularly mRNA, had a comparatively higher initial VE, upwards of 90%. Those were developed and trialled before new variants emerged.
ZyCoV-D’s 67% efficacy, on the other hand, was recorded from trials in the midst of a Delta-dominant pandemic in India. The variant has shown an immune-escape capability, thus reducing VE of other vaccines from their initially high levels. The most significant fact is that ZyCoV-D is a DNA vaccine, say scientists.
How does a DNA vaccine work?
Dr Paul Offit, the co-inventor of a rotavirus vaccine, explained in a video published December 2, 2020:
“The way this strategy (DNA vaccine) works is you take a small gene from the virus, the gene that codes for this so-called SARS-CoV-2 spike protein…It’s the protein responsible for attaching the virus to (human) cells. If you can make antibodies to that protein that attaches the virus to cells then, presumably, you can prevent the virus from attaching to cells. Or said another way, you can prevent the virus from infecting you.”
The way the DNA vaccine works is: now this is just a small gene that codes for that spike protein. You inoculate it into people, that gene then enters the nucleus where it's then initially transcribed to messenger RNA, which then is translated to a protein. That protein is the SARS-CoV-2 spike protein, which is then excreted from the cell, and then you make antibodies to that protein. So in other words, your body makes the SARS-CoV-2 spike protein, and then your body makes antibodies to that protein.”
In short, when you get a DNA shot for COVID-19, it uses the replication mechanism in your own cells to make the spike protein.
Does the DNA vaccine create the entire SARS-CoV-2 virus?
No. The DNA vaccine encodes only a specific spike protein of SARS-CoV-2 — not the virus’ entire genome. When the immune system recognises the target protein gene as being foreign to the body, it triggers an immune response.
How is the DNA vaccine different from other vaccines?
Vaccines differ in a number of ways: their composition and how they trigger an immune response. Most of the anti-COVID vaccines approved today are made of the following:
- Inactivated: Whole inactivated or “killed” virus is used.
- Weakened: A part of the virus (“attenuated”) is used.
- Messenger RNA: a single-stranded RNA molecule codes and creates the SARS-CoV-2 spike protein copies in the recipient’s body without causing disease.
- DNA: Injects genetically-engineered plasmids that trigger body cells to produce the same spike protein and trigger an immune response.
How is a DNA vaccine different from a mRNA vaccine?
The crucial thing with DNA shots are the plasmids — and therein lies the key challenge. For plasmids to work, they have to make it all the way to the cell nucleus, unlike mRNA vaccines, which just need to get to the cytoplasm, Shahid Jameel, a virologist at Ashoka University in Sonipat, India, told the journal Nature.
As with the mRNA and attenuated (live-virus) vaccines, the body’s immune system recognises and mounts defences against self-generated S-protein molecules coded by the DNA shot. In case of a subsequent infection, the body’s inner defences have developed an army of antibodies.
• The nucleus is inside a fully enclosed nuclear membrane and contains most of the cell's genetic material.
• Some of the components of the nucleus: nuclear envelope, nuclear lamina, nucleolus, chromosomes, nucleoplasm — they all work for the nucleus to accomplish all of its functions.
How is ZyCoV-D administered?
By “deposition” under the skin. It’s also called a “needle-free” vaccine. The DNA is administered using a “gene gun” pressed against the skin, which creates a fine, high-pressure stream of fluid that punctures the surface.
Why are DNA vaccines being used only now?
Investigations into the use of DNA as a vaccine platform tarted more than 60 years ago. In 1960, Dr. Yoichiro Ito, a Japanese scientist, first reported the property of DNA to get “transfected” to mammalian cells in vivo (in a living organism). In 1993, the first DNA vaccine — applied to poultry — was directed against avian influenza virus (AIV). DNA vaccines had been approved for use in animals, such as horses, too.
However, until recently, they have not demonstrated robust immune response in human trials. In recent months, vaccines have undergone “warp-speed” development as governments funded the trials due to the pandemic-driven urgency. The ease of enrolment of thousands of subjects, thanks to the internet, has also helped accelerate trials.
What are the advantages of DNA vaccines?
DNA vaccines offer a number of benefits, including:
- Speed of manufacturing: DNA shots can be made is a relatively shorter amount of time — replicating huge amounts of a gene is much easier than making proteins or growing up bacteria or viruses.
- Faster response against variants: Speed is king when it comes to making a vaccine specifically meant for variants/strains of a virus (or bacteria) that are constantly mutating and changing.
- Easier logistics: Since DNA is a very stable molecule and does not need super-cooling during storage and transport, the logistics for its is much easier and cheaper compared to other vaccines (especially mRNA ones).
- Affordable: DNA vaccines may be relatively more affordable to make – it is relatively easy to make and purify large amounts of DNA.
- Less risky: Making DNA vaccines poses no risk to those who make them — conventional vaccines (i.e. inactivated or attenuated) require literally growing the infectious bacteria or virus in huge bio-safe facilities — and this carries a risk (albeit very small) to those who work making vaccine.
• A “gene gun” is quite versatile, as the device can transform almost any type of cell.
What are the disadvantages of DNA vaccines?
- Experimental stage: Initial attempts to create DNA vaccines have not worked – they have not had a big enough impact on the immune system.
- Unproven in real world: Before India’s approval of Cadila Healthcare’s ZyCoV-D vaccine, no DNA vaccine has been licensed for use in humans (though dozens of DNA vaccines are now in clinical trials) –
1) Experimental stage: Initial attempts to create DNA vaccines have not worked – they have not had a big enough impact on the immune system.
2) Unproven: Before India’s approval of Cadila Healthcare’s ZyCoV-D vaccine, no DNA vaccine has been licensed for use in humans (though dozens of DNA vaccines are now in clinical trials).
Compared to the millions or billions of bases that make up the entire genome, plasmids typically contain thousands at most. Some of the advantages of plasmids:
• They’re relatively small
• Stable
• Easy to manipulate
Where do plasmids come from?
In nature, they’re found in microbes, like bacteria. In 1952, Nobel laureate Joshua Lederberg and his collaborators at the University of Wisconsin first used to the term “plasmid” as a generic term for any extrachromosomal genetic particle. He used it to describe "any extrachromosomal hereditary element” in a paper he published describing some experiments he and his graduate student Norton Zinder conducted on Salmonella bacteria and its virus P22.
Since the 1940s, scientists have found that there are “heritable” cytoplasmic factors that could be transferred between cells. Occasionally, plasmids that are linear, or made of RNA, exist. They may be found as single or multiple copies and may carry from half a dozen to several hundred genes.
Plasmids can only multiply inside a host cell. Most plasmids inhabit bacteria: around 50% of bacteria found in the wild contain one or more plasmids. Plasmids are also found in higher organisms such as yeast and fungi. The 2-micron circle of yeast is a well-known example that has been modified for use as a cloning vector.
How many DNA vaccines for COVID-19 are undergoing trials?
There are currently 12 in various clinical trial phases in Japan, South Korea, Thailand, Australia, Italy, US and Canada, in addition to India.
What happens next?
The approval of ZyCoV-D as the world’s first DNA vaccine is a key moment in medical science. There are yet unanswered questions:
- How fast can Zydus manufacture and distribute the vaccines?
- What are the long-term effects of plasmid DNA vaccines?
- How much would it cost?
- Will they apply for EUA in other countries?
- How soon will the other DNA vaccines complete clinical trials and get approved?
- What other diseases will be addressed by DNA vaccines?
It would be interesting to watch what happens next. What's clear is that, after more than 60 years, extensive research on plasmid DNA vaccines has finally paid off. And if they do prove their worth in the real world, experts say DNA vaccines, alongside gene guns, could altogether transform vaccinology.
