How the KFD vaccine is made and tested
The manufacturing process for the vaccine has not changed since the 1980s, when the vaccine was originally developed by the National Institute of Virology (NIV)’s CN Dandawate and his team.
The starting point of this process is a strain of the KFD virus, which the NIV isolated from Shivamogga in 1957. This virus is called the master seed for the vaccine. The NIV was supposed to share this master seed with the Government Virus Diagnostic Laboratory (VDL), Shivamogga every few years. VDL is not only an important nodal lab for KFD research, but also performed a critical role in the quality control of the KFD vaccine. VDL then transferred this master seed to IAHVB. According to senior NIV virologist Pragya Yadav, the volume of master seed typically transferred was 1 ml.
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After receiving the master seed, the IAHVB would multiply it by injecting it into mice brains, and then extracting the virus. This step accomplished two goals: It increased the quantity of the virus, and also helped the virus adapt to growing in animal cells. This was important for the next step in vaccine production, in which the virus was multiplied again in chick embryo cells.
The virus recovered from mice brains was called working seed, and was stored until a new batch of vaccine was to be manufactured.
Each time such a new batch was to be made, the working seed would be inoculated into chick embryo cells (a type of cell extracted from chicken eggs). This would help the virus multiply again. This high-titre virus would then be inactivated with the chemical formalin, and the mixture purified and filtered. The result was the final vaccine product, which was then bottled.
It is important to note here that Dandawate’s original method of vaccine manufacture allowed only two passages between the master seed and the final product: one passage in mice brains and one in chick embryo cells, respectively. That is how Dandawate and team prepared the vaccine which they showed to be effective in human studies. And, it was Dandawate’s method of manufacture that the CDSCO approved when it gave permission to IAHVB to make the vaccine in 2000.
This means that IAHVB was not allowed to change this method of manufacture, or exceed the number of passages described in the original method.
The general principle, that the approved vaccine cannot exceed the number of passages in the vaccine tested in human studies, is spelt out in several regulatory documents. For instance, a chapter in the Indian Pharmacopoeia, called “General Requirements” for vaccines, says, “Unless otherwise justified and authorised, in the production of a final lot of vaccine, the number of passages of a virus…from the master seed lot shall not exceed that used for production of the vaccine shown in clinical studies to be satisfactory with respect to safety and efficacy.” The Indian Pharmacopoeia contains the official standards which all drugs and vaccines sold in the country are supposed to follow.
Quality tests
After the final vaccine is ready, it must pass several quality tests before it can be released to people. The IAHVB conducts some of these tests, while the VDL conducts the rest.
Between 2013 and 2022, the tests that IAHVB conducted in-house included pyrogenicity and sterility. A pyrogenicity test checks for impurities that can trigger fever and other adverse effects in vaccine recipients. A sterility test checks for microbial contamination in the vaccine.
At the same time, the VDL was conducting both potency and safety tests. The potency test checks whether the vaccine is effective against disease in mice. The passing value for this test is set in such a way that it correlates with the efficacy of the vaccine – the vaccine’s ability to protect against disease in humans. The safety test, on the other hand, checks for whether any live KFD virus has remained in the vaccine after inactivation.
In 2012, NIV virologist DT Mourya suggested a change in the potency-test method, according to the minutes of an October 4, 2012 KFD technical committee meeting accessed by Mint.
The original potency test, developed by Dandawate, was as follows: Two groups of mice were to be assigned to the vaccine arm and the control arm. The mice in the vaccine arm were given a diluted dose of the vaccine on the first and the fourth day of the experiment.
Seven days after the second dose, the mice in both the vaccine and the control arm were injected with the live KFD virus. A technician would then count how many mice died in both arms. Then, the technician would use a statistical formula to calculate a value called a log protective index, which is the potency of the vaccine.
As per the minutes of a KFD technical committee meeting held in July 2022, the minimum log protective index at the time was 5.4. A batch manufactured by IAHVB in 2021 had failed to reach this value in the potency test. Other internal documents accessed by Mint show that the actual log protective index the batch reached was 3.6. However, this batch was later retested, and shown to pass the potency test.
The second test conducted by VDL was the safety test, which ensures there is no live KFD virus in the vaccine. To do this, VDL staff injected the vaccine into a monkey, and then extracted the monkey’s blood several times in the following days to check for the presence of live virus. Prior to this vaccination, however, VDL had to ensure that the monkey was not infected with KFD, since this might give the wrong result in the safety test.
Documents accessed by Mint show that VDL ensured the monkey was KFD-free by extracting serum (a component of blood) from the monkeys and sending it to NIV. NIV then tested the monkey serum for a type of KFD antibody, called an IgG antibody.
If the monkey was negative for this antibody, it would mean the monkey hadn’t been infected in the past. Thus, NIV played an integral role in the release of the KFD vaccine to the public, by helping VDL conduct the final quality tests on the vaccine.
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The manufacturing process for the vaccine has not changed since the 1980s, when the vaccine was originally developed by the National Institute of Virology (NIV)’s CN Dandawate and his team.
The starting point of this process is a strain of the KFD virus, which the NIV isolated from Shivamogga in 1957. This virus is called the master seed for the vaccine. The NIV was supposed to share this master seed with the Government Virus Diagnostic Laboratory (VDL), Shivamogga every few years. VDL is not only an important nodal lab for KFD research, but also performed a critical role in the quality control of the KFD vaccine. VDL then transferred this master seed to IAHVB. According to senior NIV virologist Pragya Yadav, the volume of master seed typically transferred was 1 ml.
View Full Image
After receiving the master seed, the IAHVB would multiply it by injecting it into mice brains, and then extracting the virus. This step accomplished two goals: It increased the quantity of the virus, and also helped the virus adapt to growing in animal cells. This was important for the next step in vaccine production, in which the virus was multiplied again in chick embryo cells.
The virus recovered from mice brains was called working seed, and was stored until a new batch of vaccine was to be manufactured.
Each time such a new batch was to be made, the working seed would be inoculated into chick embryo cells (a type of cell extracted from chicken eggs). This would help the virus multiply again. This high-titre virus would then be inactivated with the chemical formalin, and the mixture purified and filtered. The result was the final vaccine product, which was then bottled.
It is important to note here that Dandawate’s original method of vaccine manufacture allowed only two passages between the master seed and the final product: one passage in mice brains and one in chick embryo cells, respectively. That is how Dandawate and team prepared the vaccine which they showed to be effective in human studies. And, it was Dandawate’s method of manufacture that the CDSCO approved when it gave permission to IAHVB to make the vaccine in 2000.
This means that IAHVB was not allowed to change this method of manufacture, or exceed the number of passages described in the original method.
The general principle, that the approved vaccine cannot exceed the number of passages in the vaccine tested in human studies, is spelt out in several regulatory documents. For instance, a chapter in the Indian Pharmacopoeia, called “General Requirements” for vaccines, says, “Unless otherwise justified and authorised, in the production of a final lot of vaccine, the number of passages of a virus…from the master seed lot shall not exceed that used for production of the vaccine shown in clinical studies to be satisfactory with respect to safety and efficacy.” The Indian Pharmacopoeia contains the official standards which all drugs and vaccines sold in the country are supposed to follow.
Quality tests
After the final vaccine is ready, it must pass several quality tests before it can be released to people. The IAHVB conducts some of these tests, while the VDL conducts the rest.
Between 2013 and 2022, the tests that IAHVB conducted in-house included pyrogenicity and sterility. A pyrogenicity test checks for impurities that can trigger fever and other adverse effects in vaccine recipients. A sterility test checks for microbial contamination in the vaccine.
At the same time, the VDL was conducting both potency and safety tests. The potency test checks whether the vaccine is effective against disease in mice. The passing value for this test is set in such a way that it correlates with the efficacy of the vaccine – the vaccine’s ability to protect against disease in humans. The safety test, on the other hand, checks for whether any live KFD virus has remained in the vaccine after inactivation.
In 2012, NIV virologist DT Mourya suggested a change in the potency-test method, according to the minutes of an October 4, 2012 KFD technical committee meeting accessed by Mint.
The original potency test, developed by Dandawate, was as follows: Two groups of mice were to be assigned to the vaccine arm and the control arm. The mice in the vaccine arm were given a diluted dose of the vaccine on the first and the fourth day of the experiment.
Seven days after the second dose, the mice in both the vaccine and the control arm were injected with the live KFD virus. A technician would then count how many mice died in both arms. Then, the technician would use a statistical formula to calculate a value called a log protective index, which is the potency of the vaccine.
As per the minutes of a KFD technical committee meeting held in July 2022, the minimum log protective index at the time was 5.4. A batch manufactured by IAHVB in 2021 had failed to reach this value in the potency test. Other internal documents accessed by Mint show that the actual log protective index the batch reached was 3.6. However, this batch was later retested, and shown to pass the potency test.
The second test conducted by VDL was the safety test, which ensures there is no live KFD virus in the vaccine. To do this, VDL staff injected the vaccine into a monkey, and then extracted the monkey’s blood several times in the following days to check for the presence of live virus. Prior to this vaccination, however, VDL had to ensure that the monkey was not infected with KFD, since this might give the wrong result in the safety test.
Documents accessed by Mint show that VDL ensured the monkey was KFD-free by extracting serum (a component of blood) from the monkeys and sending it to NIV. NIV then tested the monkey serum for a type of KFD antibody, called an IgG antibody.
If the monkey was negative for this antibody, it would mean the monkey hadn’t been infected in the past. Thus, NIV played an integral role in the release of the KFD vaccine to the public, by helping VDL conduct the final quality tests on the vaccine.
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Download The Mint News App to get Daily Market Updates.
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