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BENGALURU : On 10 October 2022, Karnataka’s department of health and family welfare sent an odd circular to all of its district health officers. The circular, written in Kannada, spoke about the stock-out of a vaccine against the Kyasanur Forest Disease (KFD), a deadly disease that stalks mainly forest and agricultural workers. In light of this stock-out, no vaccine would be available for the upcoming November-May disease season of KFD, the circular said. And so, the health department asked the officers to control this tick-borne disease through other measures, such as educating people on how to avoid tick bites.

The circular was odd for several reasons. The KFD vaccine is widely seen as the top-line defence against the disease. After all, there is no specific treatment for KFD, and it is hard for forest workers, who are most at risk, to avoid tick bites. Also, the vaccine had been used in the state for some 33 years. So, why did the health department suddenly decide to stop using the vaccine?

What the circular didn’t reveal was that this decision, in fact, hadn’t been sudden. On the contrary, the vaccine had been riddled with both regulatory and quality problems for over two decades. Among these problems, India’s apex drug regulator, the Central Drugs Standard Control Organisation (CDSCO), had not given permission to the vaccine’s manufacturer, the Bengaluru-based Institute of Animal Health and Veterinary Biologicals (IAHVB), to make the KFD vaccine since at least 2002. In other words, the sale of this vaccine in India had arguably been illegal for 21 years. These are the findings of a Mint investigation that began much before the October 2022 circular.

With the CDSCO missing from the picture, the vaccine’s quality had deteriorated measurably in the previous two decades. Specifically, the vaccine had been failing ‘potency’ tests repeatedly. The potency of a vaccine, which is measured in animals, is an indicator of how well the vaccine can prevent KFD in humans. In other words, potency is closely linked to the ‘effectiveness’ of the vaccine. So, if a vaccine fails a potency test, it means the vaccine may not be able to protect people well against KFD anymore.

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Damningly, Mint uncovered atleast two instances in which the KFD vaccine’s manufacturer, IAHVB, and quality-testing laboratory, the Shivamogga-based Government Virus Diagnostic Laboratory (VDL), had released the vaccine to the public despite the vaccine failing potency tests. And the Karnataka health department had okayed these troubling decisions.

Nor had the IAHVB, VDL and the health department acted in isolation, Mint’s investigation found. Their decisions were enabled by one of the country’s top public health agencies, the National Institute of Virology (NIV). Mint learnt that NIV repeatedly suggested cosmetic-fixes to the problem of falling potency, instead of asking IAHVB to stop manufacturing altogether. In doing so, the NIV, which falls under India’s apex government medical-research organisation, the Indian Council of Medical Research, had helped the manufacturer release an ineffective vaccine to people.

Ultimately, people paid the price of this multi-level institutional failure. Historically, atleast five Indian states, namely Karnataka, Goa, Maharashtra, Tamil Nadu and Kerala, have purchased the KFD vaccine from IAHVB. But these states were spending money on a shot that worked poorly, and whose quality and safety were questionable.

Studies conducted by the Chennai-based National Institute of Epidemiology show that the vaccine’s effectiveness had dropped dramatically by the mid-2000s. Using 2005-2010 KFD data, the National Institute of Epidemiology, a sister agency of NIV under the Indian Council of Medical Research, found that the effectiveness of one vaccine dose was zero during this period, compared to 79.3% in a 1994 study. Meanwhile, the effectiveness of two doses was a mere 62%, compared to 93.5% in 1994.

This meant that most recipients of a single dose were unprotected against the potentially deadly KFD. The disease, which sickens some 500 people annually in the Western Ghats regions of the affected states, is mild in most cases, characterised by fever and chills. But in 5-10% of patients, the virus can take a severe course, resulting in death. In severe disease, the virus impacts multiple organs, or causes haemorrhagic symptoms—like bleeding from the eyes, nose and intestines. Between 5 and 10% is not an insignificant case fatality rate; dengue, in comparison, kills around 2.6% of confirmed cases, as per one estimate.

The apparent loss of vaccine efficacy didn’t go unnoticed by healthcare workers in KFD-affected regions, many of whom lost confidence in the vaccine. “I don’t think it works," Krishna (who goes by one name), a community health officer in the Kannangi village of Karnataka’s Shivamogga district, told Mint in a July 2022 interview.

The entire saga also raises questions about CDSCO’s performance as India’s national regulator, already in question after the deaths of 69 children in The Gambia, following the consumption of adulterated Indian cough syrup.

Mint learnt that even though the CDSCO was repeatedly made aware—since atleast 2020— about the KFD vaccine being used in Karnataka without its permission, the national regulator didn’t do anything to tackle the issue.

The beginnings

Despite NIV’s troubling role in the KFD vaccine story, the institute’s historical contributions to studying the disease and developing the vaccine are recognised as pioneering. In 1957, NIV scientists were the first to isolate the virus from the Kyasanur Forest—a hilly tropical forest, interspersed with rice farms.

They were investigating a mysterious outbreak of haemorrhagic fever among locals, which coincided with the deaths of monkeys in the region. This had raised questions about whether the outbreak was Yellow Fever. This fever, that had hitherto been restricted to South America and Africa, was also a haemorrhagic fever that affected both humans and monkeys.

But when NIV’s scientists isolated the virus from a Hanuman langur, they found it to be a pathogen distinct from the Yellow Fever virus. They named the virus after the Kyasanur Forest, where it was first found.

It was also NIV’s scientists who came up with an early working hypothesis of where in the forest the virus was coming from — their research suggested that the virus survived in rodents. However, they found that monkeys also played an important role in disease transmission. When ticks transmitted the virus to monkeys, monkeys amplified the virus, thus turning their bodies into disease hotspots. Unsuspecting forest dwellers venturing near these sick monkeys were highly likely to become infected, again through tick bites. This is how KFD got its common moniker: the Monkey Fever or manganakayile in Kannada.

In the 1960s, the NIV made another breakthrough: a team of their virologists, led by CN Dandawate, developed the formalin-inactivated vaccine. Early studies among NIV staff and Shivamogga’s residents showed that the vaccine induced protective antibodies against KFD and also prevented disease.

The timing of Dandawate’s work couldn’t have been better: the geographic footprint of KFD, initially restricted to Shivamogga, was expanding steadily. After appearing in new Karnataka districts for roughly four decades, the virus eventually spread to Maharashtra, Goa, Kerala and Tamil Nadu.

In all these regions, the disease typically affects forest or agricultural workers. A severe case can either kill, or put a person out of action for months, leading to substantial loss of income.

Raghavendra C S, a 42-year-old school headmaster in the Davangere district of Karnataka, is one such patient. In January 2022, Raghavendra developed a fever, which just wouldn’t subside. Because he lives in Davangere, where a KFD outbreak has never occurred, no doctor suspected he had this tick-borne fever. But when the fever didn’t subside for almost ten days, his family took him to a hospital in the Shivamogga district, about an hour away. Soon after reaching the hospital, he slipped into a coma, as the infection had reached his brain.

It was at this point that a doctor in the Shivamogga hospital suspected KFD and sent samples for testing. The result was positive. Raghavendra today believes he may have acquired the infection during a brief, day-long trip from Davangere to another village in Shivamogga, where KFD outbreaks do occur.

Altogether, Raghavendra says he spent 12 days in the hospital, with several of them on a mechanical ventilator. His family spent over 3 lakh on the bills. When he emerged from the coma, Raghavendra says, he had lost substantial weight and had neurological symptoms. “It was hell. It is difficult to say how it felt. Everything was difficult, including walking". Today, close to three years later, he says he has recovered almost fully, but still has symptoms such as forgetfulness.

The great danger this disease poses to the residents of Karnataka’s forested Western Ghats region is why the control of KFD is an important political plank. And because forest dwellers can only do so much to prevent tick bites, an effective vaccine is in high demand. In 2019, two Shivamogga-based advocates filed a public-interest litigation in the High Court of Karnataka—they argued that the state hadn’t done enough to control KFD. Out of the six prayers the advocates made, the first was wider availability of the KFD vaccine.

Ironically, it is public pressure such as this that may have played a role in the Karnataka health department continuing to deploy the vaccine long after its quality came into question.

Vaccine production begins

Recognising the need for a vaccine, in 1989, the Karnataka government set up a manufacturing unit under VDL Shivamogga. The NIV transferred CN Dandawate’s technology to this facility, and supported manufacture for almost a decade. During this period Dandawate’s team conducted a second field study to estimate the vaccine’s effectiveness. This is when they found the vaccine to be 79.3% effective after one dose, and 93.5% after the second, hearteningly high numbers.

VDL didn’t make the vaccine for long, however. In 2000, the Karnataka government decided to move manufacture to IAHVB, because VDL didn’t have adequate infrastructure. Yet, IAHVB was never the ideal place to make the vaccine. Until then, the institute had only made the less-regulated veterinary vaccines. So, why did the government choose this site?

The answer lies partly in the fact that more experienced, private-sector vaccine manufacturers approached by the department weren’t interested in making the KFD shot. Given the disease’s restricted geographic range, only 1-5 lakh vaccine doses are made each year to cover at-risk population. This small number is not attractive for private-sector manufacturers, several department officials told Mint. “If anyone came forward to make it, we would have given it to them. But nobody is coming forward", said KJ Harshavardhan, deputy chief medical officer at VDL, in a June interview.

Given these constraints, IAHVB began production in 2000, with a joint licence from the CDSCO and the Karnataka drugs control department. This licence, according to documents viewed by Mint, was due to expire in December 2001.

Whenever the CDSCO permits a manufacturer to make a vaccine, it approves both the vaccine manufacturing method, as well as all the quality-control tests the manufacturer must conduct on every batch. Once this is done, if the manufacturer releases a vaccine that fails a quality-control test, it is a violation under India’s drug laws.

The KFD vaccine manufacturing method is as follows: first, IAHVB takes a sample of a 1957 strain of the KFD virus from the NIV, known as the master seed. This master seed is then multiplied in mice once. The result is a large amount of virus, known as the working seed.

The working seed is then multiplied one more time in chicken embryo cells. Next, IAHVB uses the chemical formalin to inactivate the virus. This yields the vaccine, which IAHVB purifies and bottles.

Read: How the KFD vaccine is made and tested

The next step is to conduct the final quality-control tests. Out of the several quality tests the CDSCO required the vaccine to undergo, one was the potency test. CDSCO approved both the method of conducting the potency test, and the minimum bar of potency each batch had to meet.

The potency-test method approved by the CDSCO was, broadly, as follows: first, a technician would vaccinate one group of mice with two doses of the KFD vaccine, three days apart. Seven days after this, the vaccinated mice, and another unvaccinated group, called controls, would be inoculated with the live KFD virus.

By comparing the numbers of mice which died in both groups, the technician would arrive at a potency value, say X. In order for the vaccine to be released to the public, X had to be greater than a minimum value, say Y.

The CDSCO disappears

 

Things began to go wrong for the KFD vaccine as early as December 2001, when IAHVB’s first licence to make the vaccine expired. At this point, the institute applied to the Karnataka drugs control department, asking for the licence to be renewed for a five-year period, between 2002 and 2006.

It is pertinent to note here that under India’s joint licencing system for vaccines, it is the drugs control department of the state in which the manufacturer is located who issues the licence. However, it cannot do so until the CDSCO has first given the go-ahead.

But the Karnataka drugs control department didn’t respond to IAHVB’s application, B M Chandra Naik, a scientist overseeing KFD vaccine manufacturing at IAHVB, told Mint in an August interview. Yet, IAHVB continued making the vaccine, relying on a loophole in the Drugs and Cosmetics Act. This loophole says a manufacturer’s licence remains in force as long as they have applied for a renewal before the expiry of the previous licence period, and as long as their application isn’t explicitly rejected.

This situation recurred when IAHVB’s second, third and fourth licence periods, namely the 2002-2006, 2007-2011 and the 2012-2016 periods, respectively, expired. In other words, every time the IAHVB applied for renewal, the Karnataka drugs control department failed to respond. Yet, IAHVB continued making the vaccine.

According to Chandra Naik, the company finally heard back from the drugs control department only in 2020. This is when, in one shot, the department sent the company three licenses in one go—two retrospective licences (for the 2007-2011 and 2012-2016 periods) and one prospective license (for 2017-2021 period).

But these much-delayed licences only complicated things further. Oddly, in all the three licences, the CDSCO had conspicuously struck out the name of the KFD vaccine in the list of products that the IAHVB was allowed to manufacture. That is, the CDSCO had retrospectively cancelled the firm’s licence to make the vaccine.

Mint asked officials of the Karnataka drugs control department why IAHVB was permitted to manufacture the vaccine despite the cancelled licences. In a September 2022 interview, the officials said it was CDSCO that had struck out the name, but that they didn’t know what the striking out meant. Bhagoji Khanapure, the drugs controller of Karnataka, said he had asked the head of the CDSCO, V G Somani, several times since 2020 what it meant. But Somani never answered, he said. “He himself doesn’t know what it means".

In the absence of any response from Somani, and given that the CDSCO had never explained why the licences had been cancelled, the drugs control department assumed the licences were valid.

Khanapure’s interpretation is dubious, however. Mint found that for the period during which the CDSCO had struck out the name of the KFD vaccine, starting 2006, the CDSCO had not discharged any of the responsibilities of a licencing body.

For instance, for every licenced human vaccine sold in India, a CDSCO lab called the Central Drugs Laboratory in Kasauli, Himachal Pradesh, evaluates the quality of each batch, before the public receives it. However, when Mint sent a query under the Right to Information Act to the Kasauli lab, the lab responded that it has never tested the KFD vaccine.

Further, another document, published on the CDSCO’s website, suggests that the CDSCO had stopped treating IAHVB as a manufacturer of human vaccines since atleast 2009. The document, a list of all CDSCO-approved manufacturers for human vaccines since 2009, has no mention of IAHVB.

CDSCO head VG Somani did not respond to repeated questions from Mint.

Read: The mystery of missing CDSCO scrutiny

A low potency batch

 

With the CDSCO carrying out none of its responsibilities, the quality of the KFD vaccine plummeted. To tackle the quality problems, the Karnataka health department repeatedly turned to the NIV for advice, even though the NIV had no expertise in large-scale vaccine manufacture. And the advice NIV gave was questionable.

An early hint of these problems appear in the minutes of a Karnataka health department meeting in 2012. Held on 4 October, the meeting was attended by senior representatives from IAHVB, as well as an official from the Karnataka drugs control department, the then-additional drugs controller Raghuram Bhandary. Officials from the Shivamogga Government Virus Diagnostic Laboratory (VDL), who were helping IAHVB conduct some of the final quality tests for the vaccine at the time, were also present.

The meeting was kicked off by a joint director from the health department. After welcoming the attendees, he told them that the potency of a recent batch of the KFD vaccine was “slightly low". However, he said, “in view of the urgency"—a reference to the fact the KFD outbreak season was a mere month away—the attendees should permit the release of the batch.

The attendees agreed, the minutes show. Mint reached out to five of the attendees, including Bhandary, to ask how they had okayed the release of a low potency batch, even though it would have been against the law. All refused to comment.

Next, the joint-director made another request to the attendees. He said that a senior NIV virologist, Devendra T Mourya, had suggested a “minor change" to the method used by IAHVB to measure vaccine potency in mice. Mourya was then in the top cadre of scientists at NIV, and had done extensive research on viral pathogens. The very next year, he would go on to become the director of NIV. The joint director wanted another sub-committee of experts to be formed to okay the change suggested by Mourya.

This sub-committee, which included IAHVB’s director, met two months later, in December 2012. The minutes of this meeting contain multiple revelations. The committee notes that the reason the vaccine was failing potency tests could be because the vaccine-virus had undergone numerous ‘passages’ over a period of time.

Simply put, this means that even though master seed from NIV ought to be multiplied only twice before the vaccine was made—once in mice and once in chicken-embryo cells—it had been multiplied many more times, a violation of good manufacturing practices. Such excessive passaging can alter the virus’ genetic sequence in ways that make the vaccine less potent.

If this is what the sub-committee suspected, the only way for IAHVB to solve the problem would have been to get new master seed from NIV, and make the vaccine afresh. Instead, the minutes reveal, Mourya was suggesting a change to the potency-test method to tackle this problem.

Apart from this being a cosmetic fix to the potency problem, IAHVB wasn’t supposed to make such changes to a licenced vaccine without informing the CDSCO. But as Mint’s investigation shows, CDSCO had stopped renewing the licence to the company long before then.

Mint asked Mourya, both by email and through Whatsapp, why he suggested the change to a CDSCO-approved test method when it was unlikely to solve the real problem, namely the excessive passaging of the virus. Mourya, who retired from NIV in 2019, didn’t respond.

This wasn’t the last time NIV offered questionable solutions to IAHVB. It happened later again, in 2022.

Read: NIV’s troubling role in the KFD vaccine saga

Vaccine effectiveness drops

As IAHVB was grappling with the falling potency, the vaccine’s effectiveness was also dropping. Early hints of this appear in the published scientific literature in the 2000s. In 2006, a review by a virologist from the Defence Research and Development Establishment, Gwalior, cited data from five Karnataka districts to show that, despite routine vaccination, the number of KFD cases had grown between 1999 and 2004.

More concrete evidence that the vaccine was failing came seven years later. In 2011-12, the Shivamogga district saw a large KFD outbreak, with many who fell sick having received two vaccine doses. This was odd, because Dandawate’s 1994 study had pegged effectiveness of two doses to be 93.5%.

The recurrent outbreaks had also triggered speculation among locals that the vaccine wasn’t working, recalls Manoj Murhekar, who heads the National Institute of Epidemiology in Chennai, a sister institution of NIV under the Indian Council of Medical Research. “If you talked to any medical officer of the district (at that time), they would all say that the vaccine, really, is of no value; it offers very little protection," Murhekar told Mint.

To dig deeper, Murhekar’s team conducted an effectiveness study in Shivamogga, along with officials from the health department. This study, published in 2013, found that one dose of the vaccine offered almost no protection to Shivamogga’s locals during the 2011-12 outbreak.

Intrigued by the findings, the team conducted a second study, this time turning to old data from 2005 to 2010. Again, they found that those who received one dose were not protected at all. Further, two doses conferred only 62.4% protection, compared to the 93.5% suggested by Dandawate’s study.

When a second outbreak occurred in Shivamogga in 2013-14, Murhekar et al crunched the numbers again. The finding didn’t change: the first dose was useless against the disease, while the second dose was not as good as previously believed.

This loss of effectiveness was a double whammy for state governments. Logistically speaking, the KFD vaccine is already a tough one for state governments to administer, because it requires recipients to be given booster shots every single year after the first two doses.

On top of it, says Pradeep Awate, Maharashtra’s state surveillance officer under the India’s Integrated Disease Surveillance Programme, many people find the KFD shot to be painful, making them hesitant about repeat shots. “People taking the first dose sometimes don’t want to take the second," he told Mint. Against this background, the Maharashtra government’s own unpublished data showed low effectiveness of the vaccine. All this, put together, led to the Maharashtra government discontinuing vaccine use in 2019.

Few linked the loss of effectiveness with the potency test failures, however, because the latter wasn’t public information. To Murhekar, the dropping effectiveness was a puzzle, because it flew in the face of Dandawate’s findings. All he knew at the time, Murhekar says, was that between Dandawate’s 1994 paper and his studies, “something drastic had happened."

NIV stops usage

As doubts about the vaccine mounted, the NIV independently concluded that the vaccine was not worth using. For years, NIV had researched the KFD virus in its own high-biocontainment facility. To protect its staff against accidental infections, it had been vaccinating them with IAHVB’s product.

Sometime prior to 2018, the NIV developed tests to detect two types of antibodies that are formed after infection or vaccination. Subsequently, the organisation tested its vaccinated staff for these antibodies. “We didn’t see a very good antibody response. The vaccine wasn’t working," Pragya Yadav, a senior virologist at NIV, told Mint. After Mourya retired in 2019, the Karnataka health department had been turning mainly to Yadav for advice.

Yadav is also a storied virologist, whose work includes isolating the SARS-COV-2 virus which went into India’s flagship covid vaccine, Covaxin. She told Mint that the poor antibody response led to NIV stopping vaccine-use altogether in 2018.

Yet, Yadav’s team never published the findings. She also continued to support VDL and IAHVB with production. For instance, Mint found evidence that Yadav had been helping VDL with conducting one of the quality-control tests required to be done prior to release–a so-called “safety test".

Against this background, in December 2021, another batch of the KFD vaccine failed a potency test. Documents accessed by Mint show that even at this time, IAHVB was continuing to use a virus that was passaged too many times, explaining the loss of potency. In other words, they had still not received fresh master seed from NIV.

Instead of asking them to tackle the problem of passaging, however, Yadav told VDL to retest the batch. By this year, VDL was also conducting the potency test, which IAHVB had been doing in 2012. Yadav’s suggestion was as problematic as Mourya’s was, because VDL had not identified any technical error in the way potency was tested earlier.

A potency failure can occur due to two reasons: either the manufacturing process could be flawed, leading to an actual loss of potency, or a technician could have committed an error while doing the test. An example of the first is excessive passaging of the seed virus, while an example of the second is if the mice in the potency test are not injected correctly, throwing off the results.

Good manufacturing practices require that, in the event of a failure, potency tests be repeated only if a clear error is identified. If there is a flaw in the manufacturing process, the batch must be made afresh. Repeat testing when there is no error in the test method, with the sole aim of getting the product to pass quality tests, is called “testing into compliance", and is discouraged by regulators across the world.

Yet, according to documents viewed by Mint, VDL followed Yadav’s advice, retested the vaccine, and got a passing result the second time. In January 2022, this batch was administered to many in Karnataka, after ignoring the first “fail" result.

Asked why she advised VDL to retest when no errors in the testing method were identified, Yadav didn’t respond. Mint also asked Yadav why she had never explicitly told the health department to stop making the vaccine. Yadav claimed she had given this advice multiple times, but the health department hadn’t listened, because the state had no alternative solutions to control KFD.

“The vaccine has genuine problems. I am telling you frankly…Everybody, in every meeting, said this vaccine is not worth pursuing, but there was no option, that is why they kept continuing."

When Mint asked the Karnataka health department commissioner, Randeep Dev, in September, about the repeated releases of a failing vaccine, Dev said he couldn’t answer specific questions, because he wasn’t aware of historical details. However, he said the department had begun looking for alternative manufacturers, and would not release a vaccine again until its potency was proven.

In October 2022, the circular from his department finally stopped vaccine use, some two decades after the CDSCO stopped renewing permission to the manufacturer.

Even if Karnataka state finds a new manufacturer for the KFD vaccine, and solves the problems plaguing the shot, several questions will remain. How did the state allow an ineffective vaccine to be administered to people for so long, despite being aware of its shortcomings? How did the CDSCO and the Karnataka drugs control department look away in the face of blatant illegalities? Why was the NIV okay with common people getting a vaccine its own staff wouldn’t use? And will public faith in the vaccine, lost due to poor government decisions, ever come back?

Priyanka Pulla is a Bengaluru-based reporter covering health. Her reporting on this story is supported by a grant from the Thakur Family Foundation. The Foundation exerts no editorial influence on her work.

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