Representative image of a tick. Photo: Marino Linic/Unsplash
- The vaccine to inoculate people against the Kyasanur forest disease (KFD), a potentially fatal tick-borne illness, had poor potency and effectiveness for nearly two decades, an investigation has found.
- Despite the ineffectiveness being clear to government bodies for several years, the vaccine was used until October this year.
- The investigation says India’s drug regulator did not perform any of the duties it was supposed to, while the National Institute of Virology provided dubious advice to the manufacturer.
Hyderabad: In yet another blow to the credibility of India’s drug regulation regime, an investigation by Mint found that systemic failures meant that a vaccine that was not only ineffective but also unlicensed was administered to people in Karnataka for two decades.
The vaccine was meant to inoculate people against the Kyasanur forest disease (KFD), a potentially fatal tick-borne illness that affects around 500 people annually in the Western Ghats region that spreads across five states – Kerala, Tamil Nadu, Karnataka, Goa and Maharashtra. According to Mint, though the disease only causes fever and chills in most cases, it can take a severe course in 5-10% of patients and result in death. If it progresses to a severe condition, KFD can impact multiple organs or cause haemorrhage.
The newspaper’s investigation found that the vaccine was “riddled with both regulatory and quality problems for over two decades”. Alarmingly, the report says that India’s apex drug regulator, the Central Drugs Standard Control Organisation (CDSCO), “did not give 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”.
The vaccine’s quality “deteriorated measurably” since then, failing potency tests on multiple occasions. “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,” the report says.
The CDSCO was not the only government agency that failed in its duties, according to Mint. The Karnataka health department okayed the release of vaccine doses to the public on at least two instances by the manufacturer and the quality-testing Virus Diagnostic Laboratory (VDL), despite them failing potency tests. One of the country’s top public health agencies, the National Institute of Virology (NIV), “repeatedly suggested cosmetic fixes to the problem of falling potency, instead of asking IAHVB to stop manufacturing altogether,” the Mint report says, adding that in the process it helped the manufacturer release an ineffective vaccine to the people.
The report is the latest to expose the dismal performance of India’s drug regulators – especially the CDSCO – in quality control and testing. There has been heightened scrutiny of drugs produced in India after a cough syrup produced by a Haryana-based company resulted in the deaths of 66 children in the Gambia. Ranbaxy whistleblower Dinesh Thakur and lawyer Prashant Reddy T., discussing their recently released book The Truth Pill: The Myth of Drug Regulation in India, told The Wire that poor regulation has led to the proliferation of substandard drugs across the country.
A history of the disease and vaccine
According to Mint, though NIV provided dubious suggestions to the vaccine manufacturer when potency was falling, it played a pioneering role in the discovery of the disease and the development of the vaccine.
Scientists from the institute were the first to isolate the virus in 1957 from the Kyasanur forest, which is a “hilly tropical forest, interspersed with rice farms”. NIV scientists also came up with an early working hypothesis that the virus survived in rodents and later identified the role played by monkeys 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,” the Mint report says.
In the 1960s, a team of NIV virologists led by C.N. Dandawate developed a formalin-inactivated vaccine, which was administered in Shivamogga and was found to induce protective antibodies and also prevent disease. The timing also proved crucial, as KFD was spreading from Shivamogga to other Karnataka districts to Maharashtra, Goa, Kerala and Tamil Nadu. Most of the affected persons were either forest officers or agricultural workers.
But the Karnataka government only set up a manufacturing unit in 1989, under VDL Shivamogga. According to Mint, the NIV transferred Dandawate’s technology to this facility and supported manufacturing for almost a decade. A second field study conducted by Dandawate’s team in 1994 found the vaccine to be 79.3% effective after one dose and 93.5% after the second.
In 2000, the government moved the manufacturing to IAHVB which “was never the ideal place to make the vaccine” because it had until then made only veterinary vaccines, where regulation standards were weaker. But the decision may have been spurred by the fact that experienced private sector firms were disinterested in manufacturing a vaccine which will need only 1-5 lakh doses each year to cover at-risk populations, according to Mint.
After getting the green light from the CDSCO, the IAHVB was licensed by the Karnataka drugs control department to manufacture the vaccine until December 2001. When the company wrote to the drugs control department seeking a five-year renewal, it did not get any response.
“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,” the Mint report says. The same situation occurred when it sought a license renewal for the 2007-2011 and the 2012-2016 periods.
IAHVB finally heard back from the drugs control department in 2020, when it issued two retrospective licences (for the 2007-2011 and 2012-2016 periods) and one prospective license (for the 2017-2021 period). But, in all three licences, the CDSCO had “retrospectively cancelled the firm’s licence to make the vaccine”, Mint said.
Officials from the Karnataka drugs controls department told the newspaper that though the CDSCO had “struck out the name” of the KFB vaccine in the list of products that the IAHVB was allowed to manufacture, “they didn’t know what the striking out meant”. The report adds that Bhagoji Khanapure, the drugs controller of Karnataka, asked the head of the CDSCO, the Drugs Controller General of India V.G. Somani, several times since 2020 what the striking out meant but did not get a response.
“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,” Mint said.
The newspaper found other problems, including that the CDSCO’s lab Central Drugs Laboratory in Kasauli, Himachal Pradesh – which evaluates the quality of each human vaccine batch before it is released for public use – had never tested the KFD vaccine. The CDSCO’s website also says that the regulator had stopped treating IAHVB as a manufacturer of human vaccines since 2009.
Why was potency low?
According to the report, problems with the potency of the KFD vaccine were identified by the time the Karnataka health department held a meeting in 2012. It was attended by representatives from IAHVB, the Karnataka drugs control department, then-additional drugs controller and VDL. The reason for failing potency tests was that the vaccine virus had undergone numerous “passages” over a period of time. The master seed – a sample from the strain isolated by the NIV in 1957 – “ought to be multiplied only twice before the vaccine was made—once in mice and once in chicken-embryo cells”. But it had been multiplied many more times, which is a violation of good manufacturing practices because it could alter the virus’ genetic sequence and make the vaccine less potent.
The manufacturer could have solved the problem by getting a new master seed from the NIV, but the latter only provided “cosmetic” fixes like changing the potency-test method.
With low potency, the vaccine also proved to be ineffective. According to Mint, frequent outbreaks of the disease led to health workers and locals reaching the conclusion that the vaccine did not work.
Manoj Murhekar, the head of the National Institute of Epidemiology in Chennai, told the newspaper, “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.” His team conducted a study on the vaccine’s effectiveness, which was published in 2013 and found that “one dose of the vaccine offered almost no protection to Shivamogga’s locals during the 2011-12 outbreak”.
When they conducted a second study that inspected old data between 2005 and 2019, they once again found that one dose offered almost no protection. Two doses conferred only 62.4% protection, much lower than the 93.5% effectiveness that was recorded in 1994.
The vaccine was only stopped being used last month, October 2022, when Karnataka’s department of health and family welfare sent a circular that vaccines would not be available for the upcoming November-May disease season of KFD.
Even if a new manufacturer for the KFD vaccine solves these problems, “several questions will remain”, the Mint report says. These are:
“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?”