How Covaxin became a victim of vaccine triumphalism

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65 highlights

• 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.

• 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.

• 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.

• Ironically, many believe that the hastened approval of Covaxin hurt the reputation of the Make-in-India campaign, instead of bolstering it.

• 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.

• 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.

• 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.

• 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

• 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.

• 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.

• 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).

• In contrast, mRNA vaccines and adenovirus vector vaccines can be made in the more widely distributed BSL-1 and BSL-2 facilities

• 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.

• To its credit, Bharat Biotech took some early steps to protect itself from such raw material shortages.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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

• 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).

• 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.

• 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.

• 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.

• 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.

• 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?

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• Many of these participants had not gone back to receive their second vaccine dose.

• 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.

• 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.

• 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.

• 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.

• 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.

• The biggest threat to Covaxin’s acceptance then, was not a lack of faith, but the government’s own opacity and triumphalism.