For a few months recently, Krishna Ella had been in the eye of a storm.
It all started in early January, when India gave restricted emergency approval for his company’s indigenously developed Covid-19 vaccine, Covaxin, as part of the countrywide vaccine rollout plan. At that time, Covaxin was still in the midst of its phase 3 trials involving over 26,000 people, and no data regarding its efficacy had been published.
Covaxin, manufactured by Ella’s 25-year-old company, Bharat Biotech
, was developed using a whole-virion inactivated vero cell, according to the company. That means, the vaccine was made of killed coronaviruses, which when administered, allowed immune cells to recognise the dead virus, prompting the immune response against the virus.
While the phase 1 and phase 2 clinical trials conducted in 755 participants demonstrated a high safety profile of the vaccine with seroconversion rates of 98.3 percent and 81.1 percent on day 56 and 104, respectively, questions still loomed over the efficacy of the vaccine in controlling the spread of the virus.
The concerns were further accentuated when Adar Poonawalla, whose company,
Serum Institute of India (SII)
, the world’s largest manufacturer of vaccines and the maker of the Covishield vaccine—the Indian version of the popular Oxford-AstraZeneca vaccine—claimed that only three vaccines in the world had passed all the scientific evaluations with others only “safe like water”. Poonawalla’s statement came immediately after the government approved Covishield and Covaxin for emergency use.
That remark had irked Ella, who called a press conference to refute the allegations and said the company always conducted “200 percent honest clinical trials” and was yet receiving backlash. “Some companies have branded me (our vaccine) like ‘water’. I want to deny that. We are scientists,” Ella, chairman and managing director, had said then.
While Ella and Poonawalla ironed out their differences later and issued a joint statement, Covaxin’s future was in doubt after the company sought beneficiaries of the vaccine to sign a consent form, and said the company would pay a compensation if they suffer a serious adverse reaction to the vaccine.
As a result, in the early days of the vaccination programme starting January 16, Covaxin found it difficult to find takers as India rolled out the world’s largest vaccination drive. In the state of Karnataka, for instance, only about 2.3 percent of the doses supplied were reportedly used, with the remaining vials lying in storage.
"Remembering people criticising us, saying our data is not transparent, not in the public domain, I am today proud to say that our data are in the public domain in six publications,” Ella said in a video message posted on March 3. “If people have got patience, they should read those articles."
Ella’s message came on the backdrop of the company announcing its interim analysis of the phase 3 trials, which showed the vaccine had an 81 percent efficacy against the virus. “Today is an important milestone in vaccine discovery, for science and our fight against the coronavirus,” Ella said. “With today’s results from our phase 3 clinical trials, we have now reported data on our Covid-19 vaccine from phase 1, 2, and 3 trials involving around 27,000 participants. Covaxin demonstrates high clinical efficacy trend against Covid-19 but also significant immunogenicity against the rapidly emerging variants.”
On March 1, the vaccine received a much-needed boost after Prime Minister Narendra Modi took Covaxin as India embarked on its second phase of vaccination.
“It remains a puzzle why India's regulatory authority permitted the widespread use of this vaccine without these preliminary data about protection,” says Satyajit Rath, scientist at the National Institute of Immunology and the adjunct professor at the Indian Institute of Science Education and Research. “That decision meant that it was or is being used in 'clinical trial' mode, which means that people being given it have to sign a consent from, making them volunteers. Yet, if they did not want to sign, they were being denied alternative vaccination, making the process uncomfortably coercive. The decision did not seem to add big numbers to the vaccination campaign either; only about 10 percent of the total vaccinations so far have been reported to be with Covaxin. So, all this apparently premature aggressive 'vaccine nationalism' seemed to do was to add to the already existing vaccine anxieties.”
In his previous interaction with Forbes India, Ella had spoken about his track record as a vaccine maker as an attestation to his credibility, "Bharat Biotech was the first company to identify, purify and sequence Chikungunya during the 2006 epidemic in Kerala and Tamil Nadu. We were also the foremost company in the world to predict, work and file the patent on the Zika vaccine before the US and WHO [World Health Organization] recognised the problem," he had said, adding that ninety percent of Bharat Biotech's vaccines are sold in "lower-middle-income countries" with affordable pricing. "We fervently work towards successful development of efficacious vaccines for neglected diseases."
... With Covaxin showing 81 percent efficacy, it seems like Ella can finally heave a sigh of relief. While clinical trial experts and immunologists call the latest results encouraging and positive, all eyes are on Ella yet again, as he and Bharat Biotech now conduct an additional interim analysis for 87 cases and a final analysis for 130 cases in order to put out the final data to be peer-reviewed and published.
‘Ella Always Aims High’
is a big victory for Ella and is likely to propel Bharat Biotech as one of the foremost vaccine makers of the world, it is just one of the many milestones that the research scientist has seen in his entrepreneurial journey.
Since he started Bharat Biotech in 1996, the company has delivered vaccine doses to over 70 countries in the world, held over 140 global patents and has an R&D pipeline with 11 vaccine candidates for various diseases, including three for the coronavirus. In the past 25 years, Ella has consistently come out with a vaccine every three to four years.
Those who know and have worked with Ella call him a soft-spoken scientist who has always believed in working hard and dreaming big. “You cannot come this far without quality, enthusiasm and unshakable confidence in your science, and Dr Ella has those qualities in plenty,” says Rakesh Kumar Mishra, director of the Centre for Cellular and Molecular Biology (CCMB) in Hyderabad.
Mishra has worked closely with Ella [who was also a member of CCMB’s research advisory council in the past] over the last 10 years, with the duo collaborating more recently to conduct a Covid-19 sero-survey in Hyderabad. “Dr Ella is an optimistic and positive person who wants to break all barriers and believes in taking risks. He has worked so hard to deliver an indigenous vaccine from scratch in less than a year, which is commendable,” says Mishra, who believes Ella is a good scientist who knows how to take responsibility for his risks and his business decisions, and as a person, has always been encouraging those around him to nurture bigger aspirations.
Much of that has probably come from his own journey—from a village in Tamil Nadu to building one of the country’s foremost vaccine facilities, whose vaccine is being used by numerous ministers of the Modi cabinet. Born to a middle-income family of farmers in a village near Thiruthani in Tamil Nadu, Ella found himself walking on a career path that took him away from his plans. “There were no businessmen, entrepreneurs or professionals in the family, only farmers. After my schooling, I decided to study agriculture [at Bengaluru’s University of Agricultural Sciences], which my father did not approve of. He felt nobody became a farmer just by studying agriculture! But I got interested in the subject and wanted to be a farmer,” Ella told Rediff
After his studies, in order to provide financial support to his family, Ella started working in the agriculture division of Bayer, a pharmaceutical and crop science company. During his time there, he received a fellowship from Rotary International to pursue higher education in the US. “I would not have gone to study if there was no scholarship,” Ella told Rediff
. This time, he chose molecular biology, and there was no looking back.
After working as a researcher at the Medical University of South Carolina in the US, Ella returned to India, keen on doing something on his own, and ready to take risks. What started with a small lab in Hyderabad to develop a Hepatitis vaccine with a yeast molecular gene in 1995 turned into Bharat Biotech a year later. In fact, it was the first company to be set up in Hyderabad’s biotechnology park, Genome Valley. Ella co-founded Bharat Biotech with wife Suchitra, who brought to the company her expertise in marketing, business development and operations. An economics graduate from the University of Madras, Suchitra studied business development in the US before earning a postgraduate diploma in patent law from NALSAR, Hyderabad. She is currently the joint managing director of Bharat Biotech.
Bharat Biotech was started with a seed funding of Rs12.5 crore, which included equity of Rs3 crore from the promoters and Rs2 crore from IDBI; the rest was a loan from IDBI Bank and the Technology Development Board of the Department of Science and Technology. Today, almost 75 percent of the company’s equity rests with the Ellas. Bharat Biotech has about 12 institutional funders and among them are grant-making entities Department of Biotechnology, the Gates Foundation and the Coalition for Epidemic Preparedness Innovations.
After starting out with launching a cesium chloride-free Hepatitis-B vaccine, which the company claims is the first in the world, Bharat Biotech received a grant from the Bill & Melinda Gates Foundation to develop vaccines against malaria and rotavirus in 2002. Ella then went on to develop the typhoid conjugate and rotavirus vaccines, both of which were pre-qualified by the World Health Organization (WHO) in 2018.
In fact, the rotavirus vaccine [Rotavac] developed by Bharat Biotech is a five-drop vaccine, which is in line with Ella’s aim to develop vaccines with simple delivery mechanisms; vaccines “that can be given like polio drops”. Ella told Forbes India
in an earlier interaction that his philosophy has always been to develop vaccines to prevent neglected diseases that might, in the long term, have the potential to become a pandemic. “The path for developing a vaccine against Covid-19, and many others that have been developed, was not easy. For instance, our Rotavac vaccine took around 20 years which involved global scale public-private partnerships, and a large-scale clinical trial,” he had said.
Today, the company is simultaneously working on another possible Covid-19 candidate that is likely to start phase 1 clinical trials next week. The vaccine, an intranasal candidate called CoroFlu, is being made with vaccine maker FluGen and virologists at the University of Wisconsin-Madison in the US. “CoroFlu has already shown to be safe and well-tolerated in humans. Bharat Biotech will manufacture the vaccine, conduct clinical trials, and prepare to produce almost 300-plus million doses of vaccine for global distribution,” Ella told Forbes India
in June 2020, adding that apart from being safe and efficacious, vaccines “have to be made available quickly and in large quantities to have a greater impact”.
Meanwhile, Ella also believes that it was the company’s February 2019 acquisition of Chiron Behring Vaccines, a small unit of pharma company GlaxoSmithKline (GSK), that specialised in rabies vaccine, for an undisclosed amount that played a crucial role in making Bharat Biotech a global company. “GSK could have shut down the plant, but it said that India and the developing world should not suffer due to the lack of this vaccine, and that this vaccine company should be with good people with a passion to drive good-quality vaccines. That’s why they said we are the right people, although eight companies bid for the proposal,” Ella had said at the time, adding that according to him, it was just the beginning of Bharat Biotech’s journey.
“There is a lot more to happen, [lot more] innovation to become global,” he had said. “As we speak, we are doing clinical trials in Vietnam, Zambia, Cuba… we’ve been doing effectiveness studies in Palestine. We’re reaching different parts of the world as clinical trial researchers. And our vision is to make Bharat Biotech a truly multinational company. I don’t know if we will reach that vision in my generation, but certainly, the vision is there.”
With the interim data now in public, Covaxin has also leapt past Covishield in terms of its vaccine efficacy. Covishield, currently has an efficacy of 63.09 percent against symptomatic Sars-CoV-2 infection, according to the WHO. India is still awaiting data from Hyderabad-based Dr Reddy’s
on the phase 3 trials using the Russian-made Sputnik V vaccine
, before a decision is taken on allowing the vaccine for countrywide use. Sputnik V has an efficacy of 91.6 percent.
Covaxin’s third phase trials, which began in November last year, had enrolled 25,800 participants aged between 18 and 98, including 2,433 over the age of 60 and 4,500 with comorbidities. “The primary endpoint of phase 3 clinical trial is based on the first occurrence of PCR-confirmed symptomatic (mild, moderate or severe) Covid-19 with onset at least 14 days after the second study vaccination in serologically negative (to Sars-CoV-2) adult participants at baseline,” the company said in a statement.
The interim analysis included a preliminary review of the safety database, which showed that severe, serious and medically attended adverse events occurred at low levels and were balanced between the vaccine and placebo groups. The trial's conduct and monitoring were as per global guidelines and were outsourced to New-York based clinical research firm IQVIA.
“The significance of Covaxin’s efficacy data is that the vaccine now has some evidence about protection; this was lacking so far,” says Rath. “It was expected, of course, that the vaccine would work, since it had been shown to generate good antibody responses, and since a similar vaccine of Chinese origin had already been shown to work in preliminary evidence. But it is reassuring to hear that there is now some actual protection-related evidence for Covaxin itself.”
That would likely put concerns about the vaccine at bay for now. “The numbers reported seem quite small as yet, but some other vaccines have been authorised with similarly small numbers,” adds Rath. “We should keep in mind that all such data, for every Covid-19 vaccine authorised so far the world over, are quite preliminary evidence from ongoing clinical trials. So the actual exact number is not particularly significant at this point of time; all we can take away from such preliminary evidence is that the vaccine likely provides a reasonable degree of protection. There is no reliable way of predicting what the final number at the end of the clinical trial would be either.”
Anant Bhan, a global health, bioethics and health policy researcher, agrees with Rath. According to him, it is important for the company and the regulator to keep up with the trials to determine long-term efficacy. “On the face of it, these results are fairly good compared to most other vaccines. The interim efficacy data is not yet independently verified, and is coming from announcements made by the sponsors and co-sponsor of the vaccine. But this has been the case through the pandemic by other companies as well,” he explains. “Hopefully, it [Bharat Bitoech] will put out the [final] data soon to be peer-reviewed and published.”
Rath explains that while Bharat Biotech will have to wait for a formal peer review before it can be widely accepted across the world, “reviewing and publishing these preliminary data from ongoing phase 3 clinical trials may have its own difficulties”. “However, again, this has not necessarily been done for the other Covid-19 vaccines developed, especially since reviewing and publishing these preliminary data from ongoing phase 3 clinical trials may have their own difficulties,” Rath says.
For now, it’s been a long journey from Thiruthani to Hyderabad. And Ella’s journey is only starting all over again.