How Covaxin became a victim of vaccine triumphalism

On the 30th of March 2021, the Brazilian drug regulator published a worrying report on its website, pointing to flaws in how Hyderabad-based Bharat Biotech was making Covaxin, its Covid-19 vaccine.

According to the report, Bharat Biotech had skipped key steps in ensuring that the SARS-COV-2 virus in the vaccine was fully killed, or was incapable of multiplying in the human body. This created the very real risk that some batches of Covaxin could give people the disease they were to protect against. Based on the report, Brazil suspended its order of 20 million Covaxin doses from Bharat Biotech.

The news was met with raised eyebrows back home, where by then 9 million doses of the vaccine had been administered. How had the Indian drug regulator, the Drug Controller General of India (DCGI), given a green signal to the vaccine, if its manufacturing process had flaws? And what was Bharat Biotech’s explanation?

Instead of addressing the specific safety issues raised by Brazilian drug regulator Anvisa, the firm’s founder and chairman, Krishna Ella, in an interview with a television channel, blamed its observations on politics. Ella claimed that the regulator’s report was driven by Brazil’s “nationalism”, and a desire to keep an Indian vaccine out of the country.

This wasn’t the first time that Bharat Biotech had brushed away concerns around Covaxin. Poor transparency and mismanagement have plagued the development of the vaccine– touted by the government as India’s first fully indigenous Covid vaccine—since it commenced last May. The biggest example of this was Bharat Biotech’s application for regulatory approval for Covaxin in December 2020, even though it had no efficacy data—evidence that the vaccine prevented disease. A month later, when participants at the biggest site of a Covaxin clinical trial, a hospital in Bhopal, complained of mistreatment, the firm dismissed the complaints as baseless. And now, even though Anvisa’s observations have cast a shadow on the vaccine’s quality, Bharat Biotech has done little to clear the air. At the same time, four months after the vaccine was approved by the DCGI for use in India, the firm is yet to publish its efficacy data.

Troublingly, state institutions have played along. Instead of ensuring that the Covaxin clinical trials met the highest ethical and scientific standards, Bharat Biotech’s government partner in developing Covaxin, the Indian Council for Medical Research (ICMR), attempted to hurry the trials, and failed to address genuine questions around breaches of trial protocol in Bhopal. Government scientists also repeatedly made unsupported claims. The DCGI, for instance, claimed that Covaxin was “110%” safe, even before trials to establish safety had concluded. While making a similar exaggerated claim that all vaccines approved in India were “absolutely safe”, Vinod K. Paul, a member of NITI Aayog, repeatedly invoked pride in the Make-in-India (atmanirbharta) campaign for developing a Covid vaccine in record time.

Ironically, many believe that the hastened approval of Covaxin hurt the reputation of the Make-in-India campaign, instead of bolstering it. “This is a very short-sighted way of doing things, and undermines the purpose of the Atmanirbharta campaign. True self-reliance means you have a globally competitive product, not just cost-wise, but quality-wise,” says D Raghunandan, the director of Delhi Science Forum, a non-profit.

Gagandeep Kang, a microbiologist at CMC Vellore, who helped develop India’s first rotavirus vaccine, agrees that the Indian drug regulator should have strived to meet global standards, which meant that Covaxin shouldn’t have been approved without efficacy data. “Being calm and being scientific about the road ahead is very important. When you stop doing that, you lose the recognition of the rest of the world.”

The biggest tragedy, however, is that the hurried development could have triggered vaccine hesitancy among Indians during a once-in-a-century pandemic. And despite the problems with its development and manufacture, Covaxin has the intrinsic potential to be effective, says Satyajit Rath, an immunologist who retired as faculty of New Delhi’s National Institute of Immunology. “Covaxin is likely to provide reasonable protection against Covid, at least in the short run. But there is no doubt that this project was handled poorly.”

Bharat Biotech, ICMR director general Balram Bhargava, the DCGI and NITI Aayog’s Paul did not respond to questions.

Killed vaccines: not a slam dunk
Covaxin’s story began on May 9, 2020, when the National Institute of Virology, an agency under ICMR, announced that it had transferred a strain of SARS-CoV-2 to Bharat Biotech. This was the strain that Bharat Biotech was planning to use in its vaccine. By then, dozens of vaccine developers across the world were already in the race, with AstraZeneca and Pfizer already having begun phase 2 trials. So, Bharat Biotech was off to a relatively slow start.

Nonetheless, the company was taking one of the most tried and tested approaches to vaccine development: the inactivated whole-virus vaccine, also known as the killed vaccine. “It is the simplest possible vaccine design, which goes back to the 19th century and Louis Pasteur,” says Rath. Bharat Biotech had made several killed vaccines in the past, for rabies, influenza and other diseases. In contrast, US firms Pfizer and Moderna were experimenting with the cutting-edge mRNA vaccine technology, which had never been deployed in a commercial vaccine before, increasing the risk of failure. And British firm AstraZeneca was experimenting with the adenovirus vector technology, that had been tested in more humans than the mRNA vaccines had, but had never been licensed for human use previously, either.

The core idea of making Covaxin was simple: Bharat Biotech would inactivate the virus with a chemical called beta propiolactone. This chemical jumbles up the RNA, which is the genetic code of the virus. While this jumbling takes away the virus’ ability to infect people, it still leaves the pathogen’s outer shell intact.

When these shells are injected into the human body, the body mounts an immune response to the proteins on the shell, known as antigens. This immune response consists of the so-called humoral immunity, which includes proteins called antibodies, and cellular immunity, which includes special cells like T cells, which can together fight the virus. Because this immune response persists in the body for a while, it is able to combat future SARS-CoV-2 invasions.

But despite being an age-old technology, killed vaccines are not easy to do. For one, manufacturing them comes with weighty challenges, one reason why few countries across the world are investing in them today. To make them, the manufacturer has to grow large numbers of the virus and inactivate them fully. And because the SARS-CoV-2 virus is dangerous to humans, the live virus must be grown in a Biosafety Level 3 (BSL3) manufacturing facility, which deploy dozens of safety measures to prevent viral escape.

“Growing so much virus in a BSL-3 facility, and ensuring there is enough (inactivated) virus in each 0.5 ml dose is a humongous task,” says Vineeta Bal, an immunologist at the Indian Institute of Science Education and Research (IISER), Pune. The challenge is made harder by the fact that India has only a handful of BSL-3 level manufacturing facilities (one industry expert estimated there were only around five in India). This means that scaling up to manufacturing millions of doses is hard. In contrast, mRNA vaccines and adenovirus vector vaccines can be made in the more widely distributed BSL-1 and BSL-2 facilities, respectively, says Atin Tomar, the CEO of Yapan Bio, a Hyderabad based biotech firm.

Apart from the difficulty of growing large quantities of live virus, Bharat Biotech was also struggling with another obstacle that all Indian vaccine manufacturers have faced in the last one year: a shortage of raw materials. In a press conference held on March 31, 2021, Ella listed beta-propiolactone, bioreactor bags and microcarrier beads, as raw materials in short supply. Both bioreactor bags and microcarrier beads are needed to grow the live virus, before inactivating it.

Demand for all these products, made by American or European manufacturers, had shot up in 2020, creating global shortages. In the midst of this, in January 2021, the US banned exports of raw materials required by American vaccine manufacturers. This effectively crippled Indian vaccine makers, who had few alternative suppliers.

To its credit, Bharat Biotech took some early steps to protect itself from such raw material shortages. One of the ingredients in Covaxin is an adjuvant, a chemical used to boost the immune response to the killed virus. And Bharat Biotech had formulated Covaxin using an adjuvant called Algel-IMDG, which it had licensed from a US-based firm called Virovax. To avoid relying on imports, in mid-2020, the firm asked the Indian Institute of Chemical Technology (IICT), a Hyderabad based government lab, to develop a process for manufacturing Algel-IMDG in India. “We were able to replace expensive chemicals and reagents in the process with locally available materials,” said S. Chandrasekhar, the director of IICT.

But sourcing other raw materials continues to remain a challenge.

First signs of pressure
The first sign that both Bharat Biotech and ICMR were under pressure from the government to roll out the vaccine was a July 2, 2020 letter by ICMR’s director general Balram Bhargava. By then, Bharat Biotech had already tested its vaccine in animals, and was ready to advance it to a human safety study, called a phase 1 trial.

In the letter, addressed to the investigators of the phase 1 trial, Bhargava made several surprising claims. First, he informed them that the Covaxin project was being monitored at the “topmost level of the government”. Then, he wrote that the vaccine would be launched a mere month-and-a-half later, on August 15, 2020, India’s independence day. He ended with the demand that investigators begin recruiting trial participants within a week, and that any non-compliance on their part would be “viewed seriously”.

The contents and the tone of the letter shocked many in the Indian scientist community. Not only did it imply that Bharat Biotech was planning to skip phase 2 and 3 trials, it also risked signalling to investigators that it was okay to cut corners in the interest of speed. “We were up in arms when we saw this letter, because the direct consequence of it was that people would think there was unwritten permission to take short cuts. When you place pressure, people make choices, without understanding the potential consequences,” recalls Jacob John, a professor of community medicine at the Christian medical College, Vellore, who had publicly criticized the letter in July.

It was also worrying that the goal of accelerating the Covaxin clinical trials, and the August 15 deadline, seemed calculated to help Prime Minister Narendra Modi talk up the Make-in-India (Atmanirbhar) campaign during his yearly Independence Day speech. The All India People’s Science Network (AIPSN), a network of Indian scientists, called ICMR out on this implication. “A desire to grandstand and please the political masters seems to have overtaken science and ethics within ICMR. AIPSN deplores the emerging trend in India of short-circuiting established protocols for trials of Covid19 vaccines and treatment drugs,” the network wrote.

Whether aimed at scoring political brownie points or not, the suggestion that Bharat Biotech would skip phase 2 or 3 trials was worrying for many reasons. For one thing, regulatory agencies across the world were already expediting vaccine approvals as much as they could.

When there’s no ongoing pandemic, drug regulators require extensive data on safety and efficacy before approving a vaccine. After a phase 1 trial, which studies the safety of the vaccine in humans at varying doses, a vaccine maker will need to do a phase 2 trial, which examines whether the jab provokes an immune response.

Once this is completed, the next step is to prove that this immune response actually protects people against disease. To do so, investigators conduct a phase 3 trial, in which they follow participants until some fall sick. Then, they compare numbers of those who fell sick among vaccine recipients with the unvaccinated, to arrive at an efficacy estimate. In addition, they also follow vaccine recipients for at least six months after their second dose, to catch any adverse events. Only then do drug regulators approve vaccines for human use.

But with the onset of the Covid pandemic, most regulators were planning to use legal provisions that allowed expedited approvals during health emergencies. One of the most stringent drug regulators in the world, the United States Food and Drug Administration (FDA), for instance, was planning to invoke a provision called the ‘Emergency Use Authorisation” (EUA). The FDA would award an EUA if the vaccine maker merely shared an efficacy estimate, and only two months of adverse-effect data after the final dose in half of the trial participants. After an EUA, a vaccine maker was free to launch the product, but had to continue collecting data required for a full approval.

While the drug regulators of most countries had their own versions of the EUA, there was broad consensus among scientists that rolling out vaccines without phase 3 trials was risky. The reasons were many. For one, while immune responses, as measured in Phase 2 trials, were expected to protect against disease, these immune responses consist of several antibodies and cells. And scientists didn’t know then what levels and which types of antibodies or cells were central to protecting against Covid.

For instance, scientists expected that a type of antibody, called a neutralising antibody, had a role in preventing Covid infections. But how much of it would have to be present in a person’s blood to keep them safe from disease? This level, known as an “immune correlate of protection” is something scientists ordinarily spend years to measure, says Kang. And no one knew the immune-correlate for Covid, one year into the pandemic. In the absence of this knowledge, many believed that Phase 3 trials were non-negotiable.

It was against this background that Bhargava’s letter appeared, suggesting that the Indian public would be getting Covaxin after a phase 1 trial alone. Later, the ICMR head attempted to clear the air, claiming that his words were intended to cut through red-tape, and not at skipping due diligence. Still, his letter set off speculation that the “topmost level of the government”, which he had referred to in the letter, was pressurising Bharat Biotech to skip key stages in vaccine testing. And a hurriedly launched vaccine could be a disaster—it would not just leave question marks about efficacy and safety, it would also destroy vaccine confidence.

The safest vaccine in the world?
When it came to safety, Bharat Biotech repeatedly emphasized that, being an inactivated vaccine, a technology that had been deployed in several vaccines before, Covaxin’s safety was guaranteed. In fact, the communication from both the firm and key government officials was often characterised by hyperbole. This was then used to support the waiver of a pre-launch phase 3 trial for Covaxin. For instance, in a January 2021 interview, Ella called Covaxin “the safest vaccine in the world”. Around the same time, V.G. Somani, the DCGI, told a group of reporters that the vaccine was “110% safe”.

These statements had little scientific basis, however. First, even though inactivated vaccines are in widespread use today, Covaxin included an adjuvant, called Algel-IMDG, that had never been used in a commercial human vaccine before. This means that its impact on human health was yet to be properly tested. The guidelines by the Central Drugs Standard Control Organisation for Covid vaccines reflected this uncertainty, requiring the safety follow-up for vaccines with novel adjuvants to go on for longer than six months.

A second concern with inactivated whole virus vaccines is enhanced-respiratory disease (ERD),a phenomenon in which the vaccine triggers more severe Covid instead of preventing it.

ERD has been documented with several respiratory virus vaccines in the past, including an inactivated whole virus one for the Respiratory Syncytial Virus, which causes pneumonia in babies. And vaccine candidates for SARS-COV-2’s close relatives, the Severe Acute Respiratory Syndrome (SARS) virus and the Middle Eastern Respiratory Syndrome (MERS), have shown the potential to trigger ERD in animal studies.

While ERD is a possibility with all Covid vaccine platforms, the biology of killed vaccines increases the chance of the phenomenon occurring, says Rath. The reason is that most vaccine platforms today, including the mRNA and adenovirus vector vaccines, only introduce the spike antigen into the body. The spike antigen elicits a type of antibody—called a neutralising antibody—that can prevent the virus from getting tightly attached to human cells.

In contrast, a whole virus vaccine introduces a large array of antigens that dot the surface of the virus. And these antigens elicit antibodies that cannot prevent the virus from attaching to cells (non-neutralising antibodies). Not only that, paradoxically, these non-neutralising antibodies may also help the virus infect human cells better, causing ERD. “This is why, if you have the entire virus particle as a vaccine, biologists begin to worry. If you are only using the spike protein, you would worry much less,” says Rath.

Bharat Biotech did try to pre-empt the possibility of ERD by using the Algel-IMDG adjuvant. This adjuvant induces a type of immune response which lowers the risk of ERD in people, but doesn’t eliminate it. So, phase 3 trials remained crucial for both assessing the probability of ERD and to establish efficacy. And it’s not as if company officials were oblivious to the importance of these.

On 31 October 2020, during a webinar organised by online medical consulting services provider Practo, an audience member asked a panellist whether Bharat Biotech would apply for early approval. The panellist was Raches Ella, the son of Bharat Biotech chairman Krishna Ella, and the company’s lead for its SARS-CoV-2 vaccines project. Raches said immune response could not predict efficacy. For this reason, he explained, seeking approval based on phase 2 results alone was not the right approach. “I don’t believe in it, per se, and Bharat Biotech doesn’t believe in it either,” he said.

Accelerated approval
Whatever might have been the personal beliefs of Raches Ella, in December, the worst fears of several Indian clinical researchers came true. On 8 December 2020, the Press Trust of India reported, quoting unnamed sources, that Bharat Biotech had sought accelerated approval from the DCGI. Accelerated approval is the Indian equivalent of the FDA’s Emergency Use Authorisation.

At this time, Bharat Biotech’s phase 3 trial was far from finished; in fact, it had barely begun. The first participant was enrolled only on November 11. In contrast, two other companies who had also sought accelerated approval for their vaccines from DCGI at roughly the same time—Pfizer Inc and the Serum Institute of India—were far ahead in their testing pipeline.

Pfizer had data from a phase 3 trial in the USA for its mRNA vaccine, based on which it arrived at an efficacy estimate of 95%. The firm also had adverse event data from 38,000 participants, half of whom had been followed up for two months after their second dose. AstraZeneca also had an efficacy estimate of 62% from a phase 3 trial, although its investigators blundered by mixing up doses in the trial, raising questions about how reliable the estimate was. Nevertheless, apart from the efficacy estimate, the firm also had adverse event data from 23,848 participants, half of whom had been followed up for two months after the second dose. And Serum Institute India was applying for licensure of a version of AstraZeneca’s vaccine, called Covishield, in India.

Bharat Biotech neither had any efficacy estimate, nor any adverse event data, given that not even a single participant in its phase 3 trial would have received a second Covaxin dose until then. So, what gave the firm, and its partner ICMR, the confidence to apply when they did?

Several scientists have speculated that Bharat Biotech knew Covaxin would receive special consideration from the DCGI, because it was India’s first fully indigenous vaccine. In contrast, Covishield was based on a candidate developed by the UK’s Oxford University. The Pfizer vaccine was developed in the US. So, Covaxin’s simultaneous approval with Covishield or Pfizer’s vaccine would be seen as a Make in India success story. Bhargava’s letter on July 2 added fuel to this speculation.

Prime Minister Modi had also shown a strong interest in India’s vaccine development programmes, visiting Serum Institute of India, Bharat Biotech and the Gujarat-based Zydus Cadila’s manufacturing facilities in late November (Zydus Cadila was also developing a Covid vaccine, which hadn’t begun phase 3 trials yet). Previously, in May, Modi had advised a national task force of experts on vaccine development, whose members included the DCGI, V.K. Paul and Bhargava, to speed-up India’s “creaky and cumbersome” drug and vaccine regulatory processes.

Politically motivated or not, premature approvals have been routine in this pandemic. Apart from Covaxin, the years 2020 and 2021 saw a slew of ill-considered approvals of locally tested or developed drugs. Among them was a drug called itolizumab, developed by the Bengaluru-based Biocon and licensed by the DCGI in July 2020, based on a trial of 32 patients. Approving a drug based on such a small trial is unheard of, and was widely criticized by clinical research experts. This was followed by the approval of favipiravir, an antiviral from Mumbai-firm Glenmark, based on a trial whose results didn’t fulfil its primary criterion of success. Subsequently, two more drugs, Zydus Cadila’s pegylated interferon 2g and the Defence Research & Development Organisation’s (DRDO) 2-deoxy-d-glucose have come under fire for approval based on small, poorly designed and as-yet-unpublished trials.

This slew of ill-thought approvals has hurt the reputation of the Indian regulator, of agencies like the ICMR, and of Indian pharma companies, several experts say. Health emergencies like the Covid pandemic tend to create public and political pressure for the quick approval of new drugs. Several such instances have occurred historically, such as during the Ebola epidemic in West Africa, which led to citizens of some countries demanding untested drugs and vaccines. But it is the job of drug regulators to resist this pressure, and to refrain from approving interventions unless their benefits clearly outweigh risks. And it is in the interest of pharmaceutical companies to do the same, because yielding to such pressure could lead to a loss of trust in their products.

Delhi Science Forum’s Raghunandan points to a recent example of when vaccine manufacturers did show such foresight. When the US president Donald Trump repeatedly made the untenable claim in 2020 that a Covid vaccine would be ready before the presidential election in November that year–a claim that threatened to erode public trust in vaccines–nine global manufacturers pushed back. In September 2020, these firms, which included Pfizer and AstraZeneca, published a statement promising to uphold the integrity of the scientific process, and to apply for EUAs only after they had results for their phase 3 trials.

Indian companies and research agencies should have taken a leaf out of the same book, even if there was political pressure to launch quickly, Raghunandan says. “That is the ethical stand to take. It speaks badly of the organizations who have developed these products, because as good self-respecting scientists or technologists, they should have said, no, we will not apply, until we have satisfactory data.”

Vigorous advocacy
On January 3, 2021, the DCGI gave Covaxin an accelerated approval, despite the stark absence of phase 3 data. The move dismayed several scientists. Speaking to Science Magazine, IISER Pune’s Vineeta Bal called the approval “unconscionable”.

Top government officials dismissed all such criticism, in the days leading up to and after its announcement. They claimed that accelerated approvals based on phase 2 data weren’t unheard of, holding up Russia and China as examples of countries that had done the same. NITI Aayog’s Paul repeated an assertion that the DCGI had relied on to approve Covaxin: that a killed whole virus vaccine was more likely to protect against new, more transmissible variants of the SARS-COV-2 virus, such as the B.1.1.7, which had just made an appearance in India.

Paul and ICMR’s Bhargava both argued that Covaxin’s approval didn’t mean that people would get the vaccine with no safety monitoring. They pointed out that the DCGI had approved the vaccine under a special provision, called a “Clinical Trial Mode”, which meant that the safety and efficacy of the vaccine would be closely tracked even after rollout.

In addition to all this, Paul often invoked pride in a made-in-India vaccine, chastising people for not having enough faith in the Indian drug regulator and Indian scientists. “Doubts should not be created when our regulator and scientific institutions, who are reputed across the world… have said something… Please have faith in our institutions,” he said in a December press conference soon after Bharat Biotech had applied.

Again, all these arguments were misleading. While it was true that Russia had rolled out its Sputnik V vaccine without a phase 3 trial, and China had similarly launched vaccines developed by its state-owned firms Sinovac and Sinopharm, these approvals were far from uncontroversial. Sputnik V’s approval in August had attracted strong condemnation from scientists the world over for jeopardizing the lives of Russians. American virologist Florian Krammer, who has worked on characterizing the human immune response to covid-19, had tweeted: “Not sure what Russia is up to, but I certainly would not take a vaccine that hasn’t been tested in Phase III. Nobody knows if it’s safe or if it works. They are putting HCWs (healthcare workers) and their population at risk.”

Nor was it true that a whole virus vaccine would automatically protect against new variants such as B.1.1.7, a version of the SARS-CoV-2 virus first identified in the UK. The logic behind Paul’s and the DCGI’s claim seemed to be that most vaccines today, such as the mRNA and adenovirus vector vaccines, only introduced the spike antigen into the human body. So, if mutations in variants such as B.1.1.7 changed the shape of the spike antigen significantly, antibodies induced by a vaccine based on the spike antigen wouldn’t recognize the virus. However, a whole virus vaccine, which introduced many more antigens into the body, would still work.

But this logic was theoretical at the best, at a time when Bharat Biotech was yet to prove that Covaxin protected against disease caused by currently circulating variants, Kang had pointed out. Subsequent developments from China have since raised questions about the efficacy of killed whole-virus vaccines developed there. In April 2021, the head of China’s Centre for Disease Prevention and Control, George Gao, said publicly that the country’s two killed vaccines weren’t working as well as expected.

Against this background, many Indian scientists hoped that Covaxin’s phase 3 results would be published soon after the accelerated approval. Krishna Ella also promised in January that this would happen by March 2021. Additionally, external experts also believed that the mass roll-out of Covaxin in a clinical trial mode provided a golden opportunity for Bharat Biotech and ICMR to collect data on Covaxin’s effectiveness.

The effectiveness of a vaccine is distinct from its efficacy; while the former is a measure of how well the vaccine prevents disease in real life, the latter applies to the controlled conditions of a phase 3 clinical trial. And because clinical trials cannot simulate the chaos of real-world immunization programmes, effectiveness can differ substantially from efficacy.

For instance, clinical trials often do not include certain people, although these people do receive the vaccine once it is launched. As an example, Bharat Biotech did not enrol participants with HIV or Hepatitis infections, or participants with a history of Covid in its phase 3 study. What’s more, in real life, vaccine recipients may not receive doses at the right time, or receive doses that have not been refrigerated properly. How do all these differences impact the vaccine’s performance once it is rolled out widely?

To answer such questions about the mRNA and adenovirus vector vaccines, which the US and the UK had approved under versions of the Emergency Use Authorisation by January, both countries had begun effectiveness studies. And data from these studies arrived soon after. One study, published in the British Medical Journal, calculates that a single dose of either the AstraZeneca and Pfizer vaccines is at least 80% effective at preventing hospital admissions due to Covid.

Such studies also have the potential to measure the vaccine’s effectiveness against new variants of the virus. For instance, another UK study published last week found that two doses of the AstraZeneca vaccine were more than 60% effective against symptomatic disease caused by the B.1.617.2 variant, which first emerged in India. However, a single dose was only 33% effective.

Post-approval blues
India has had no such luck with such data. At the time of publishing this story—end-May, four months have passed since the launch of Covaxin in India. Over 21 million doses of the vaccine have been administered, and yet, Bharat Biotech is yet to publish its phase 3 efficacy data. Nor has the firm shared any effectiveness data.

To be sure, on April 21, 2021, the company did publish an efficacy estimate of 78% from the phase 3 trial, via a press release. But this press release left big questions unanswered. For instance, the release, and a previous one, suggested that out of the 25,800 people enrolled in the trial, all were allocated to the vaccine and placebo arm in a 1:1 ratio, and that the final efficacy estimate was based on this ratio.

This is surprising, says Jammi Nagaraj Rao, a public health physician in the United Kingdom. In any given phase 3 trial, some participants drop out early or cannot be reached for follow-up. When this happens, they are excluded from the calculation of the efficacy estimate, which Bharat Biotech doesn’t seem to have done.

This issue becomes even more pertinent if one considers that in January, the participants at one of the sites of the Covaxin phase 3 trial had complained about breaches of protocol. Dozens of participants, who were enrolled at a Bhopal-based hospital—one of the 26 trial sites for Covaxin—had alleged that the trial investigators did not tell them they were participating in an experiment, and not a vaccination drive. They also said they did not receive copies of the documents which recorded their consent to participate in the trial, a fact that the hospital officials admitted to. This is a violation under India’s Drugs and Cosmetics Act, which requires each participant to receive a copy of the signed “informed consent” form. Many of these participants had not gone back to receive their second vaccine dose.

Subsequently, ICMR and Bharat Biotech had dismissed these allegations, claiming the trial was carried out in accordance with Indian laws and ethical requirements. But if the complainants had never gone back for a second dose, and had dropped out of the trial, this would mean the investigators would have no data of safety or efficacy from them. In this situation, the efficacy analysis ought to have excluded them.

These and other questions give Rao pause, who wants to see the findings of the phase 3 trial published in a scientific paper. “I do believe that publicizing the trial results, especially when they claim efficacy, by press release alone, leaves a lot to be desired. Bharat Biotech has the resources to write up the full results,” he says.

Swapneil Parikh, a Mumbai-based infectious diseases specialist, points out that full results of the phase 3 trial could help India fine-tune its immunization strategy. For instance, if the data shows that the first dose had high efficacy, India could widen the interval between two doses of Covaxin, thus getting the vaccine to more people as supply is ramped up.

Bharat Biotech and ICMR did not respond to multiple questions about why it was taking so long to publish the results.

Missed opportunities
While scientists await Covaxin data, in March, another bugbear raised its head. An agreement which the Bharat Biotech entered into with the Brazilian government to supply 20 million doses of Covaxin, fell through. The reason? The Brazilian regulator Anvisa had inspected the firm’s manufacturing facilities, and found that the firm hadn’t taken adequate precautions to ensure that the SARS-CoV-2 virus in its vaccine was fully inactivated.

Given that Indian laws also require these precautions to be taken, it was unclear why the DCGI had allowed the vaccine to be launched without them. Neither Bharat Biotech, nor the DCGI, responded to questions about whether these requirements had been waived for Bharat Biotech, as part of the accelerated approval.

Still, as the pandemic’s second wave hits with a breathtaking ferocity, many Indians are less concerned about the vaccine’s quality, as they are about being immunized. Oddly, despite rushing to claim the success of the indigenous vaccine, the government did little to ensure that the vaccine was also being produced in adequate quantities.

Since the middle of last year, Bharat Biotech has been clear about how many doses of Covaxin it can produce. The firm’s estimate of its capacity in July 2020, for instance, was 200 million doses annually–a paltry number given that India was planning to vaccinate 300 million people by July 2021, and over 1 billion people eventually.

To go beyond the 200 million limit, Bharat Biotech would have had to enter into partnerships with other firms that also had BSL-3 facilities, of which there are a handful in India. So, if the central government was betting on Covaxin, it ought to have placed orders last year, giving the firm incentive to expand production, says Neeta Sanghi, a pharmaceutical industry supply chain specialist. Yet, the government never placed any orders until January this year. As things stand, Bharat Biotech began entering partnerships to produce Covaxin only this year. And while it has promised to expand capacity to 700 million doses by July, many experts like Sanghi are sceptical, given how late the firm embarked on the capacity expansion.

The story of Covaxin holds many lessons for future pandemics and for public-private partnerships. Despite being India’s flagship indigenous vaccine, one year later, Covaxin is a story of missed opportunities. The premature approval in January led to substantial vaccine hesitancy, with at least one Indian state government, Chattisgarh, refusing to use the jab. And manufacturing troubles mean that today, even those who want the vaccine are struggling to access it, with under 10% of vaccine doses administered by India until now being Covaxin.

When questions were raised about the hurried launch, Paul and other government spokespersons demanded greater public faith in the regulator, instead of sharing data. This didn’t do much to address skepticism, because the skepticism wasn’t driven by a lack of faith in the first place. Scientists always believed that, as an inactivated vaccine, Covaxin had a good chance of being efficacious. They just wanted evidence of efficacy to be collected, and due process to be followed. The biggest threat to Covaxin’s acceptance then, was not a lack of faith, but the government’s own opacity and triumphalism. Live Mint