When the first Corona cases surfaced during January and February in Kerala and Mumbai, it was an opportunity for scientists at the Indian Council of Medical Research (ICMR)'s National Institute of Virology (NIV) in Pune to study the virus. Professor Priya Abraham, a renowned pathologist and former head of department of Clinical Virology at Christian Medical College, Vellore, had taken over as the new NIV director a couple of months before. Abraham and her team isolated 11 strains of the virus, making India the fifth country after China, the US, Thailand and Japan to do so. Scientists realised the strains were 99.98 per cent similar to the virus then causing havoc in Wuhan. Vaccine development was a possibility. After completing characterisation, immunological biomarker studies and initial pre-clinical studies such as stability, they planned two animal studies. By March, the vaccine was injected in 20 monkeys and the results were 100 per cent sterilising immunity (the virus will not spread to others and within the body) without a single infection. The trial on Syrian Hamsters (a rodent used in trials because they can have similar viral infections in human) also proved 100 per cent immunity. Within two months, ICMR roped in Hyderabad-based Bharat Biotech as the technical partner and industry collaborator.
Around the same time, Adar Poonawala, CEO, Serum Institute of India, was among the first to get in touch with Oxford University's Jenner Institute and Oxford Vaccine Group, led by Professor Sarah Gilbert and Professor Adrian Hill, who started work on a vaccine from January 10. Jenner Institute had been working on one against another coronavirus, Middle East Respiratory Syndrome (MERS), with trials scheduled in Saudi Arabia, and on a malaria vaccine for two decades, using a technology that centered on altering the genetic code of a familiar virus.
Serum had been a partner to Jenner and had licensed the 'R21 malaria vaccine candidate' in 2017. After successful results in rhesus macaque monkeys, which are closest in genetic make-up with humans, the newly developed Corona candidate vaccine - ChAdOx1 nCoV-19 - was tried on 1,077 healthy adults in five UK hospitals in April and May. Data revealed it induced strong antibody and T-cell immune responses for up to 56 days. When Oxford roped in AstraZeneca by end-April as global partner for further development, the Anglo-Swedish drug maker and Oxford were happy to board Serum Institute.
Zydus Cadila is the third Indian company that got involved in Covid-19 vaccine development. Unlike the other two, Zydus is a pharmaceutical company with strong interest in vaccines. Pankaj Patel, Chairman, Zydus Cadila Group and his son Dr Sharvil Patel, had in 2010 developed India's first H1N1 vaccine and later, tetravalent seasonal influenza and varicella (chickenpox) vaccines. Zydus researchers had started studying the novel coronavirus in January. Two teams were formed, one at the Zydus Vaccine Research Centre in Ahmedabad and another at Etna Biotech in Italy, an acquired research facility. A few years ago, they had developed a vaccine candidate for MERS and SARS virus, from the same family of Covid-19. It entered the first-phase clinical trials, but by then the virus vanished and the company stalled research. But the results were promising. It was a DNA plasmid platform and the team in Ahmedabad resurrected the project to pursue Covid-19 vaccine.
"It is an opportunity to show India's scientific skills to the world," says Krishna Ella, Chairman and MD of Hyderabad-based Bharat Biotech. What makes this battle special is the vigour Indian manufacturers have shown for cutting-edge research. It has been 12 months of quick research decisions, enriching partnerships, capacity expansions and funding arrangements. Indian regulators, too, have been highly supportive. Never have approvals come so quickly. Three of Covid vaccine candidates are already undergoing final stages (Phase III) of clinical trials in India. Globally, there are about a dozen that are in final stages of trial.
And all these just within a year after the first case of Covid-19 was officially declared. While it took 34 years of global research to launch the world's first chickenpox vaccine, the one for cervical cancer was released after 15 years of research. Mumps, measles and polio vaccines took four, nine and seven years, respectively, to complete the whole lab-to-market cycle. On an average, it takes 10.7 years to get a vaccine out into the market. But then, those were pre-Covid days.
Here's the inside story of how Indian vaccine makers did it in the final lap of the sprint, even eclipsing many big global life science companies. The results will soon be visible as a quarter of Covid-19 vaccines for the world will be produced in India. It's all the more important since at a time when governments in the US and the UK were pumping billions of dollars to aid big pharma research to find Covid-19 vaccines, Indian firms by and large were doing it on their own - with meagre funds, scientific resources and infrastructure.
Soon after ICMR transferred the virus strains to Bharat Biotech, Ella hand-picked a 40-member scientific team comprising mostly young people and excluded those above 55 years. They were asked to drop their families to their native places and the company paid for those expenses. The 40-member team was to stay together in a guest house adjacent to the plant in Hyderabad's Genome Valley. In the 24X7 work during June, July and August, the team was broken into two shifts. One shift would start at 4 a.m. and end by 2 p.m. The second team would begin their shift soon after. They were not allowed to interact with other teams or workers in the plant, even visit the canteen or stroll outside. Others were banned from entering their work areas.
The technology and platform that Ella and his team were working on were not different from four out of the five Chinese vaccines under development, with inactivated attenuated viruses. Immunoglobulin G (IgG) is a common antibody seen in blood and other body fluids to protect against any viral infections. The Chinese were using aluminum hydroxide gel to trigger the IgG immune response, a common practice in making viral vaccines. But it could induce respiratory diseases (VIRD) and had less efficacy.
"We wanted to beat the Chinese on that aspect, in safety and efficacy of the vaccine," says Ella. T-cells, which are developed in the thymus gland (located between the lungs), play a crucial role in triggering the body's immune system. Ella's team thought of various ways to boost the 'T-cell response', a cell-mediated response critical in boosting production of antibodies and killing the infection causing viruses. It can stay longer in the body and give better results. Ella spoke to his friends at the National Institute of Health (NIH) in the US and they facilitated a technology collaboration with Kansas-based ViroVax. Dr Sunil David of ViroVax had developed a superior technology chemical adjuvant, which acts as an immunity booster for cancer drugs. Bharat Biotech licensed the technology, Alhydroxiquim-II (Algel-IMDG), which can induce TH1 level (a scientific term to gauge the level of efficacy) of immune response as in polio or cancer vaccines. The results will be different from the TH2-level efficacy in normal viral vaccines such as the ones being developed in China.
Meanwhile, Serum licensed the Oxford vaccine candidate as 'Covishield', and approached the Indian drug regulator - Drugs Controller General of India (DCGI)- to approve later stage (Phase II and III) clinical trials in India since the animal and first-phase trials were already done in the UK and large trials were going on in the US, Europe and Brazil.
Zydus' leader and veteran R&D head Pankaj Patel was not wrong in his assumptions that their research might work. "Viruses have the habit of mutating and that may necessitate new vaccines. The DNA Plasmid platform can easily adapt in case of mutations," he says. In this, Plasmid DNA, a small circular piece of DNA found in the cells, would be introduced into the host cells, where it would be translated into the viral protein and elicit a strong immune response in the human immune system.
Though R&D was exempted during the lockdown, it was difficult for the team to reach the research centre. "With passion, they managed it every day and full credit goes to them," says Patel. Another difficulty was mobilising a few research tools and raw materials, which had to be imported from the US and Europe. Regulatory processes were accelerated by the DCGI and Zydus' ZyCov-D progressed to clinical trials as the second fully indigenous Covid-19 vaccine after Bharat Biotech's Covaxin.
Making In India
At Serum Institute's advanced manufacturing facility at Hadapsar in Pune, robotic arms handle viruses. They also handle the cell factory and cell cube for growing cells, manufacturing of many recombinant vaccines and production of monoclonal antibodies. The vaccines flow through sophisticated tunnels. High-speed machines wash vials, clean, dry, fill and seal containers with amazing speed and accuracy - about 500 containers per minute. Automatic screeners with advanced cameras can detect any minute particulate matter in the product, undetectable to the human eye. "India can easily manufacture half of the Covid-19 vaccines required for the world," says Adar Poonawala. Serum can produce 1.5 billion doses of vaccine a year, and Serum Institute Life Sciences (SILS) is building capacity for another one billion doses. It sells vaccines in 170 countries and 65 per cent of children across the world receive at least one vaccine manufactured by it.
Cumulatively, Indian vaccine manufacturers such as Serum, Bharat Biotech, Panacea Biotech, Sanofis Shanta Biotech, Biological E, Hester Biosciences and ZydusCadila have an installed capacity to make 8.2 billion doses of different vaccines in a year. If required, these capacities can be tweaked to manufacture the Covid-19 vaccine. In addition, Auroboindo and Serum are creating new capacities. Considering that World Health Organization's (WHO's) own assessment of vaccines it promotes will mean a demand of 3.5 billion doses annually, India's vaccine manufacturing capacity is not something that can be overcome overnight. It is one reason why WHO's Covax Alliance, an initiative to secure 2 billion Covid-19 vaccine doses to help over 90 low and middle-income countries access the vaccine equitably, expects India to play a major role in fighting the coronavirus threat. Alliance partner Unicef estimates that in 2020, 19 per cent of those doses for Covax Alliance will come from manufacturers in China and 22 per cent from India - from the likes of Serum, Indian Immunologicals, Bharat Biotech, Biological E and Panacea Biotech. The rest of the suppliers will be from the UK, France, Switzerland, Russia, Japan, Brazil and the US. It also estimates by 2023, 49 per cent of supplies will be from China and 22 per cent from India. Bharat Biotech's Ella says in the case of Covid-19 vaccines at least, the US market will be taken care of by the likes of Moderna, Pfizer and J&J, while the European market will be served by AstraZeneca, GSK and Sanofi. "The rest of the world will have to depend mainly on India, as the world is unlikely to buy from China," he says.
By end-June, the DCGI had shortened the protocols and granted permission to initiate Phase I and II human clinical trials under an accelerated approval process to Bharat Biotech. The trials were done on 1,125 volunteers at 12 centres in India. After assessing the safety and efficacy data, the DCGI gave permission for final trials. "We are going to test among 27,000 volunteers, which will be the largest Covid-19 trial in India," says Ella. If the government wants, it can even start supplies from December, he adds. The company has started stockpiling the vaccine in small quantities, hoping final-phase trials will succeed in making Covaxin India's first fully indigenously developed Covid-19 vaccine. Already, Ella has put in Rs 300-400 crore on Covaxin, at risk.
The second-phase trials of Zydus Cadila's vaccine candidate are also progressing in India among 1,048 volunteers. The third phase may start in December, among 30,000 volunteers. If all goes well, the vaccine should be ready for launch by March. The company has created an in-house manufacturing capacity for 100 million doses per year, and an additional 150 million doses from a contract manufacturer. "We have started manufacturing and stockpiling the vaccines in small quantities and will scale up production closer to the launch," says Sharvil Patel.
Near The Finishing Line
Pfizer and Moderna have recently claimed the initial results from clinical trials of their Covid-19 vaccine candidates are extremely promising. Researchers working on Oxford University's vaccine candidate and Russian Covid-19 vaccine - Sputnik V - had also made such claims earlier.
These promises will not mean much to India unless these vaccines can be transported, stored and administered in the country under its climatic conditions and infrastructure capabilities. Pfizer's Covid-19 vaccine needs to be stored at -70 degrees Celsius. Moderna's vaccine requires -20 degree Celsius. In comparison, the vaccine candidates being developed by Indian companies can be stored at 2-8 degree Celsius range. Since the supply chain infrastructure India has built for its universal immunisation programmes falls within this temperature range, the choice of Indian vaccine makers have been perfect. Price is another factor. While foreign vaccines can cost anything close to $20 per dose, India can offer it at a quarter or less of that price. Considering the funds philanthropies and government foundations are putting in, and the efforts of global agencies such as WHO to build a vaccine pool for developing and poor countries, price may not be a problem for the consumer, but will certainly give an edge to low-cost vaccine makers from India.
Also, Indian companies have more Covid-19 vaccines in the pipeline, apart from those in the final trials.
In March, Serum had licensed a 'Matrix-M' vaccine adjuvant booster from Novovax, a US-based, Nasdaq-listed vaccine research company for its malaria vaccine licensed from Jenner Institute. Novovax was also developing NVX-CoV2373 (renamed as Covovax), a vaccine candidate using their recombinant nanoparticle technology to generate the antigen derived from the coronavirus spike protein. Serum will make Covovax in India, besides helping Novavax to make it in the facility sold to the latter in May. It is in the second phase of development, after Phase I clinical trials in Australia. The Phase III clinical trial with up to 30,000 subjects will soon begin. Serum has teamed up with ICMR to conduct clinical trials of this vaccine in India.
Serum has also teamed up with Codagenix, a US-based biotech firm, which developed a vaccine candidate by re-coding the genome of the Covid-19 virus using its codon de-optimisation software platform. Serum has started manufacturing the intranasal live-attenuated vaccine candidate, COVI-VAC. Codagenix expects to initiate a Phase I first-in-human clinical trial in the UK by the end of 2020. "With Serum Institute's financial and technical support, we expect to rapidly propel the vaccine into the clinical trial stage before the end of 2020," says Robert Coleman, CEO, Codagenix. In addition, UK-based Spy Biotech and Serum Institute are currently undertaking a Phase I/II trial of a novel virus-like particle vaccine (VLP) targeting Covid-19. Spy Biotech has an exclusive global licensing agreement with Serum for the development of the candidate vaccine.
Pankaj Patel's team in Italy is also pursuing a live attenuated recombinant measles virus vectored vaccine against Covid-19. A recombinant measles virus vaccine was actually a part of the earlier research pipeline of Zydus. The recombinant measles virus (rMV) produced by reverse genetics would express proteins of the novel coronavirus and will induce long-term specific neutralising antibodies, providing protection from the infection. "So far results from pre-clinical studies are promising and we expect to get the pre-clinical data by January," says Pankaj Patel.
For Ella, the biggest bet is a single-dose nasal Covid vaccine in the works, a partnership with Washington University. Bharat Biotech is getting the vaccine candidate ready for Phase I clinical trials by December. Ella says if the government can develop a total protocol for all phases of clinical trials now, the company can get the nasal vaccine into the market by June 2021. "The facility is in place already. If successful, I can make more than one billion doses," says Ella.
Global firms may have an upper hand in first-generation vaccines, but it's worth the wait to see how the next-generation vaccine plans of Indian players pan out.