Researched by: Sara Varghese and Panu Hejmadi

Tell me about the vaccine…

The company: Zydus Cadila is an Ahmedabad-based company—and the fourth largest player in the Indian pharmaceutical industry. It has a proven track record in developing vaccines. The vaccine was developed with the support of the National Biopharma Mission—which is an initiative of the Biotechnology Department. Also collaborating on the project: the National Institute of Virology, Pune, and its parent body, the Indian Council of Medical Research (ICMR). 

The vaccine: is called ZyCoV-D and here’s how it works:

• The vaccine injects ‘plasmids’ of genetically engineered DNA into human cells. Plasmids are small, circular pieces of DNA that replicate independently—without the need of chromosomal DNA found within cells. 
• Plasmids created in a lab are typically used to introduce foreign DNA into a cell. In this case, they were assembled to carry instructions on how to produce the spike protein of the coronavirus.
• Unlike messenger RNA vaccines, these plasmids penetrate the nucleus of the cell—triggering the production of spike proteins, which then spurs the body to produce antibodies.

How is it different? There are four kinds of Covid vaccines right now. 

• Whole virus vaccines use a weakened version of the coronavirus to trigger an immune response. The ‘inactivated’ variation uses viruses whose genetic material has been destroyed so they cannot replicate, but can still trigger an immune response. Examples: Covaxin, Sinovac and Sinopharm.
• Subunit vaccines use a fragment of the coronavirus’ protein to achieve the same result. Example: Novavax.
• Viral vector vaccines use a harmless virus—like adenovirus which causes the common cold—to deliver instructions on how to produce the spike protein. Examples: Covishield, Sputnik V, Johnson & Johnson. 
• Nucleic acid vaccines include ZyCoV-D and messenger RNA vaccines like Pfizer and Moderna. They use genetic material to provide cells with the instructions on how to make the spike protein.

Ok, is it better than the others?

As with any vaccine technology, there are pros and cons.

The upside: include the following:

• There are no needles! It is delivered via a needle-free injector that is spring powered—and uses a narrow stream of the fluid to break through the skin and deliver the jab to the targeted tissue. So it doesn’t hurt as much:) Watch how a similar mechanism works here.
• Production needs are less stringent since it only entails level 1 of Bio Safety Level requirements. Others need level 3 and 4 facilities—which take longer to set up and maintain. 
• Storage requirements are less demanding as it can be stored at higher temperatures—minus 2°C to 8°C—compared to the mRNA vaccines. And the company claims it remains stable at 25°C for at least three months. This is a big plus in India where vaccines have to be delivered to remote areas.
• And DNA vaccines have a ‘plug and play’ advantage. When new variants come along, all we have to do is tweak the engineered DNA to match changes in the spike protein. 

The downside: The dosage requires three shots, delivered in 28 day intervals. So it takes longer to be fully inoculated. Though the company is testing a two-dose protocol. The bigger problem is that DNA vaccines have not proven very effective in humans—compared to animals. The key reason, according to experts: “Plasmid DNA vaccines have been tried in the past. But we know it's very difficult to get plasmid DNA into the nucleus of human cells, especially in adults.” This also means the dosage is high. An average sized human requires 5-20 mg of a DNA vaccine compared to just 0.7mg for flu vaccines.

Point to note: There are no other DNA vaccines approved for widespread human use in the world. The US Department of Agriculture has approved veterinary uses, including protection against the West Nile virus in horses, and against melanoma in dogs. There are 160 clinical human trials in the US alone—of which 62% target cancer and 33% HIV. There were emergency vaccines developed in Africa for use against the Zika virus—but they never made it past the clinical trial stage due to lack of funding.

You haven’t told me about efficacy rates…

Yes, because that brings us to the tricky territory of trial data. 

Efficacy claims: According to Zydus Cadila, it has conducted phase 3 trials with 28,216 participants across 59 sites in India. These include 1,000 kids between the ages of 12 and 18. The three-dose regimen prevented symptomatic disease in 66% of those who were vaccinated. And after two doses, it is 100% effective in preventing severe death and disease. The jab was found to be “safe and very well tolerated” by the 12-18 year old cohort.

Point to note: The company underlined the fact that its phase 3 trials kicked off in January—and extended through late April. Hence, its results specifically show its efficacy against the Delta variant—which led to the massive second wave in that time period.

The troubling questions: As with Bharat Biotech’s Covaxin, the government has once again approved a vaccine without proper phase 3 trial data—which is the most critical in proving a vaccine’s efficacy. Here’s the only data we have on ZyCoV-D:

• In February, ICMR scientists uploaded a preprint paper publishing results in rhesus monkeys—proving its safety.
• A phase 1 trial with 48 participants established safety in humans.
• Phase 2 results were released not in an established medical journal but via a company press release. The study of 1,000 participants apparently showed both that the vaccine is safe and triggers an immune response—but there is no preprint or published paper with the data. But the company claims that an independent data safety monitoring board reviewed the results.
• The most important phase 3 results also have not been published—or even publicly shared. And the little information that has been shared does not really tell us about its effectiveness—or how the company arrived at its conclusions. 
• And whatever data has been collected and analysed only covers two months—since the trial started on January 20. Given the 28-day interval between the three jabs, observations on its effectiveness could only have begun in late April. And the interim analysis was announced on July 1. 

Point to note: Despite a very small subset of just 1,000 children, the government has already approved its use for everyone above the age of 12. 

The bottomline: Dr Jammi Nagaraj Rao in The Wire sums it up best: 

“In sum, ZyCov-D may well be a remarkable innovation story for Indian science—but remarkability does not mean it can remain immune to demands of transparency and approval after due process, with publicly available data. In fact, once again, we are on the cusp of a success story being turned into a blemish on the face of Indian science.”

Reading list

BBC News and Indian Express have the best overviews of the vaccine. The Wire’s detailed critique of the trial data results is a must read. Mint looks at the vaccine’s likely impact on school openings. Indian Express looks at concerns about availability—since Zydus Cadila is way behind the government’s allotted targets. Also watch: Dr Randeep Guleria’s take on the vaccine on NDTV.