ZyCoV-D is a platform for the future, says Zydus Cadila MD Sharvil Patel

You wanted to release ZyCoV-D on Gandhi Jayanti. Was it delayed because of pricing issues?

Our original plan was to release it in October. Now we are waiting for the pricing approval. It is more complicated because there are three doses plus the injector plus the adapters. We hope to clear all that by this week and launch it as soon as it is done. It will be competitively priced. Our pricing is based on the technology, scale, capacity and procurement. There are a lot of advantages to this vaccine, and not only for today. It is a platform for the future.

Tell us about plasmid DNA, the technology behind world's first such vaccine.

This vaccine is focused on the virus’s spike protein. When administered in a human body, the ZyCoV-D will produce the spike protein of the SARS-CoV-2 virus. There has been great interest in this technology because of its ability to elicit both humoral immune responses (relating to immune responses involving antibodies in body fluids) and cellular immune responses (antibodies in cells) and in showing relevant advantages regarding producibility, stability and storage.

The good part about this is that the vaccine constructs, which are generated quickly to deal with mutations in the virus, are non-replicating and there is no vector-based immunity built because we don’t use anything other than the spike protein. So there are no adjuvants (an ingredient used to create a stronger immune response) and no infectious vectors. All of it makes the administration of the vaccine easier. [The side effects, too, have been the lowest].

This is also a thermostable vaccine, which is stable at 2 to 8° Celsius (refrigeration temperature) and even at 25° Celsius for three months. Open vial studies have shown that they are stable for at least a week, so you don’t have to give the dose to everyone the same day [after opening a vial].

Then, of course, the vaccine is intra-dermal, which means a needle-free device is used for the application, minimising local side effects. When we inoculated 28,000 volunteers including 1,400 children, we did not have a single dropout. It was very well tolerated by all volunteers. Also, the great advantage of the DNA strategy is the short time required from design to clinical trials. Therefore, it may soon be possible to test together, in the same vaccine, different variants of antigens that cover circulating mutations.

Several companies across the world use the DNA plasmid technology, but you have outdone them.

This technology has been around since the time of the Ebola outbreak in the early 2000s. That was also the time when the World Health Organization said DNA technology could be a good platform to deal with viruses of such nature. The WHO has revised its guidelines twice on DNA platforms and has cleared all DNA vaccines for their safety. Even the US FDA has published its update on the DNA plasmid vaccine and considers this platform to be very safe.

At present, 14 trials are being undertaken across the world by different companies of which some are in phase 3. So it is not that this is unexplored, but we were able to do it in a shorter period of time. We were the first company in India to do the H1N1 vaccine and that was also done in a record period of nine months. Our R&D and execution efforts have been good and that is why we have done things earlier and faster.

Has this been a long time in the making? Also, how did you decide in favour of the DNA tech?

We started the development of this vaccine in February 2020, but the technology for DNA development has been around for the last 12 years. Of course, it was a big risk to pick up a platform for which currently there are no approved vaccines, but there were a lot of benefits in picking it up. When we looked at the virus which came from a family of coronaviruses, [we saw] all of them being significantly prone to mutations. So we felt we needed a platform that could be easily interchangeable to the developing viruses as they mutate. So all you needed was to change the sequence of the strains and your whole model, construct and process remain the same. So it was a plug-and-play technology wherein all you have to do is to change the gene of interest by the mutation that happens. You are basically not changing anything that is part of the vaccine platform. So, that was one important consideration.

The other consideration was that if it became a critical vaccine, then its supply chain would become critical and we knew that this is one of the vaccines that is thermostable. Finally, as a company we have always believed in innovation and bringing to the fore newer technologies and newer drug discoveries. We wanted to demonstrate and build a capability for newer technologies and that is why we picked up the DNA one versus the RNA one. The RNA-based one was also very interesting, but we knew about the challenges regarding cost and thermostability. We were also contemplating the measles platform. So we picked up two platforms to work with, but our earliest animal studies showed that the plasmid DNA model was far superior.

Is it true that with the DNA-based platform, the ease and speed of making the vaccine constructs is many times more and that is what makes it a potential game changer?

That has been our view and now the view of all scientists. If you want to use it for new constructs, this is one of the easiest platforms to do that. We have already completed our development for almost eight strains of Covid-19. We have started our animal studies to see if any of those strains can be neutralised. That is the beauty of this platform—it needs just six to eight weeks. Also, if mixing of multiple strains is the way to get the best immunity, so that none of the viruses escape, this will offer that capability, too.

We want to make sure that the next tech/platform upgrade is continued so that we have vaccines with significantly good efficacy. [The vaccines we had developed for tackling the original Wuhan strain of the novel coronavirus lacked the efficacy to tackle the Delta variant].

What is the science behind going needle-free?

If it is DNA, it has to go all the way into the cell membrane and nucleus. The best way to do it is intra-dermal. Intra-muscular was becoming harder because of the use of lipids, which could create challenges in administering the vaccine and also other reactions related to it. Globally, there are a lot of capabilities for delivering intra-dermally, but those are very expensive. We were able to find a platform which was approved by the FDA. It is a high-pressured injection, an almost non-intrusive dose given in the upper skin, which is pain free and will have minimal side effects.

Why are three doses needed?

Currently, there is a three-dose trial—day zero, day 28 and day 56. The recipient is fully vaccinated after day 56. We saw a longer immune response by the body after three doses, when we did animal studies. It is a challenge because the vaccine needs to be given on the upper skin and also because of the amount of vaccine that needs to be absorbed. So if we were to give a higher dose in a single shot, it will be difficult for the body to absorb it. But in order to get an ideal immune response, I have to give 6mg and that would be possible only over a period of three doses. We are also working on a two-dose system, but the dosage will be the same—that is 6mg, but it will be over 28 days, instead of 56 days.

You say the safety, immunogenicity and efficacy of the vaccine are well established. How does it compare with vaccines already available in India?

I don’t think there is a head-to-head comparison, but if you look at globally published papers... we are comparable with many of the prominent platforms. [As far as the overall efficacy of existing vaccines,] we are currently at 67 per cent in terms of getting Covid-19. [With our vaccine], as of now, we do not have any moderate and severe cases reported. Moreover, nobody has controlled data on the Delta variant as of now. All the earlier data was of the Wuhan strain. Our trial was during the Delta period, so we can say for sure that our vaccine will take care of the Delta cases. Even serosurveys suggested that 99 per cent of all cases in India were Delta cases and when we did the subset of our positive cases, all of them were Delta cases. So our data is more current to the Delta variant.

Is the plasmid DNA vaccine better for children?

Our vaccine does not have any adjuvants or infectious vectors, so the side effect profile will be far better tolerated. That is why this platform was approved to be tested on adolescents and now in younger children.

What about extending the coverage to children below 12?

We have only started. Now the new trial has just received approval and soon we will begin trials for children aged 5 to 12.