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BENGALURU : The National Institute of Virology (NIV) has historically been deeply involved in the production of the Kyasanur Forest Disease (KFD) vaccine.

After it first developed the vaccine in the 1970s, NIV scientists transferred the technology to the Government Virus Diagnostic Laboratory (VDL), Shivamogga, in 1989. Subsequently, the NIV provided logistical support to VDL Shivamogga until 1998, according to ICMR documents.

Next, when VDL Shivamogga transferred the vaccine technology to the Institute of Animal Health and Veterinary Biologicals (IAHVB) in Hebbal, Bengaluru, in 2000, the VDL retained the responsibility of conducting one quality test for the vaccine – namely the safety test in monkeys. Later, in 2013, VDL also began doing the potency test, conducted in mice.

During the post-2000 period, NIV continued to advice VDL Shivamogga, while also helping with the safety testing, by ensuring the monkeys used were free of KFD-antibodies. This relationship between NIV and VDL wasn’t a formal one, but an ad hoc one, according to Pragya Yadav, a virologist with NIV.

“There is no (memorandum of understanding) with VDL to advise them as such. Being a government body, anyone can call us for a meeting, and we have to go," Yadav told Mint.

It was during this time that NIV gave questionable advice on the vaccine. Despite repeated hints that the vaccine was failing potency tests due to manufacturing flaws, NIV virologists suggested cosmetic fixes that would help the jab pass minimum quality tests, enabling its release to the public.

Advice in 2012

 

In 2012, VDL and IAHVB approached NIV when a KFD-vaccine batch failed a potency test. The minutes of meeting of a sub-committee constituted under the KFD technical advisory committee (a committee of scientists and bureaucrats constituted on a per-need basis to advice the Karnataka department of health and family welfare) from the same year show that members believed this loss of potency could be due to the “seed virus having undergone passages over a period of time."

The concern that the seed virus had undergone too many passages was voiced in several KFD technical committee meetings over the years. For instance, the minutes of a 19 August 2021 meeting note that the then-IAHVB-director, S M Byregowda, “mentioned about the numerous passages undergone by the present KFDV seed culture available at IAH&VB. He also requested the committee to initiate the process to get fresh KFDV seed virus from NIV, Pune".

A third mention of the same problem occurred in a July 2022 technical committee meeting, in which Pallavi DM, a VDL microbiologist, attributed the loss of potency to “several passages in mice".

Mint asked Byregowda how the virus had undergone numerous passages, when the World Health Organisation’s Good Manufacturing Practices for biological products, CDSCO guidelines on vaccine manufacture, and the Indian Pharmacopoeia explicitly require a vaccine-maker to limit the number of passages.

Byregowda responded that IAHVB had not been implementing Good Manufacturing Practices before 2016 because it didn’t have funds to do so. “Earlier, our labs were not following Good Manufacturing Practices. Though the Drug Controller gave direction to upgrade our facilities to comply with GMP, the government didn’t give us money for upgradation. We eventually started upgradation in 2013 and finished in 2016."

It is pertinent to note here that under the Drugs and Cosmetics Act 1940, implementing Good Manufacturing Practices has been mandatory for all manufacturers from much before 2016.

Given this background, excessive passaging and failure to comply with other Good Manufacturing Practices was very likely a possible explanation for the failing potency tests. If so, the answer would have been for IAHVB to get fresh master seed from NIV, and then prepare new working seed from it, while also implementing Good Manufacturing Practices before proceeding further. Indeed, the IAHVB did seek fresh master seed multiple times from NIV, the minutes of KFD technical committee meetings show. However, NIV did not send any master seed to IAHVB since 2013, despite these requests.

What the NIV did, instead, was advice IAHVB to change its method of potency testing in such a way that the vaccinated mice mounted a stronger antibody response, thus improving the results of test (See ‘How the KFD vaccine is made and tested’ (to be hyperlinked) to understand the original potency test method).

As the following chart shows, NIV virologist Devendra T Mourya told IAHVB and VDL to increase the time between the first and second vaccine dose given to mice, while also administering the challenge virus at a later time-point. The challenge virus is the live KFD virus given to mice, in order to measure how well the vaccine protects them against disease. The extra time between vaccination and the challenge virus would allow the vaccinated mice to produce long-term antibodies against the KFD virus, called IgG antibodies, which in turn could beef-up the results of the potency test.

Mourya’s advice was questionable because the original potency-test method was designed in a way that a “pass" result in it correlated with vaccine-effectiveness in humans. Tweaking this method, without testing if the correlation remained, would mean that the new method could result in false positives. In other words, it could allow IAHVB to get a “pass" result, even if the vaccine was less effective, thus defeating the purpose of a potency test.

Graphic: Sarvesh Kumar Sharma
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Graphic: Sarvesh Kumar Sharma

Mint asked Mourya on email and via WhatsApp why he advised IAHVB and VDL to change the potency test method, rather than to remake the batch afresh from new master seed. Mourya didn’t respond.

Advice in 2022

Despite the change suggested by Mourya, IAHVB’s batches continued failing the potency test over the years, documents viewed by Mint showed. In 2021, this problem became severe enough for VDL to approach the KFD technical advisory committee again. The minutes of a July 2022 meeting show that a recently-manufactured batch hadn’t met the minimum potency bar of 5.4. The actual potency reached by the batch was 3.6.

This time around, VDL approached NIV virologist Pragya Yadav; Mourya had already retired in 2019. Yadav’s advice to VDL was to retest the batch.

In a letter from the deputy director of VDL to the Karnataka department of health and family welfare, dated 17 February 2022, VDL requested permission to retest the failed batch, citing advice from Yadav. The retest was due to be conducted at IAHVB, instead of VDL.

In another letter dated 14 February 2022, the deputy director offered six possible reasons that may have impacted the results of the first failed potency test. These included “mice health," “maintenance of mice", “inoculation technique", “volume of inoculum", “10-fold serial dilution" and “maintenance of cold chain during the process of serial dilution".

The implication of the letter was that these six conditions had to be properly controlled for the potency test to give accurate results. And that the vaccine may have failed the potency test because the technician may have erred on any of these counts. For instance, the technician may have failed to ensure the mice were in proper health, or may have failed to inoculate the mice in the potency test properly, thus leading to incorrect results.

The February 2022 letter, however, does not identify any specific error in the conduct of the potency test; it merely speculates on possibilities.

The Karnataka health department eventually gave VDL permission to retest the batch. This is when the batch was retested at IAHVB, to get a “pass" result of over 5.4. At this point, VDL disregarded the “fail" results in the previous potency test, and released the batch to the public.

Mint asked Yadav why she advised such repeat-testing, given that it was an instance of “Testing into Compliance", and therefore a violation of Good Manufacturing Practices.

Yadav said VDL had told her that there was a possibility that the test had failed due to the error of the technician. “I suggested that if you have a doubt on the procedure, you can repeat the test. But without proving the potency, you cannot release the batch," Yadav responded. She further added that, to her knowledge, the batch had not been released after retesting. However, VDL microbiologist Pallavi DM confirmed to Mint that the batch was indeed released after it passed the potency test.

NIV stops using vaccine

Since 2006, the NIV has been conducting research into the KFD virus in a high biocontainment facility, called a Biosafety Level 3 lab. The reason NIV uses this lab is that, historically, the central government’s department of biotechnology has been classifying the KFD virus as a risk-group 4 virus.

This means that the KFD virus is thought to have high outbreak potential, and anyone conducting infectious research into it must do so only in a BSL-3 or BSL-4 facility. In 2022, the department of biotechnology downgraded KFD to a risk-group 3 virus. This again doesn’t change the fact that research with potential to infect the researchers, such as the work NIV does, must be restricted to BSL-3 labs.

One of the safety measures BSL labs follow is to vaccinate lab-workers. So, NIV was using IAHVB’s vaccine to protect its employees against infections.

All this changed after the NIV developed assays to test for two types of antibodies that are formed after KFD infection, called IgM and IgG antibodies. According to Yadav, these assays were used to test vaccinated NIV employees for antibodies, and the results were unsatisfactory. The lack of an antibody response convinced NIV to stop using the vaccine in 2018.

NIV never published these results. Yadav, however, continued to help VDL with releasing the vaccine. The help included carrying out antibody tests to allow VDL to complete the safety testing, and to advice on potency issues.

Asked why she chose to help VDL, even if the NIV did not consider the vaccine suitable for its own staff, Yadav claimed it was because the Karnataka government had no alternative to manage KFD. “I was the first person to tell them to stop using it," she said.

But when the government tried to approach more experienced manufacturers than IAHVB, they didn’t have much luck, she added. “For making KFD vaccine, no pharma is coming forward. And no one has interest in the small money, because only very few doses are made." This left the health department with no option but to keep using the vaccine, she said.

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