On 2014 Apr 18, Jacob Puliyel commented:

None

On 2014 Apr 16, Arun Gupta commented:

What is the hurry ?

I would think it to be fundamentally flawed to introduce a vaccine based on a research that is not completed and its results have not been fully studied. Whatever the results are available show that the vaccine is not even cost effective. If you ask me that every child of India should get this I fail to understand the logic except that market must prevail because we live in the world which gives way to globalsation.

On 2014 Apr 15, Jacob Puliyel commented:

50% More Intussusception Among Vaccinated: Full Trial Data Is Awaited

According to the Clinical Trials Registry this study, started in March 2011 was estimated to be complete in April 2014.

The data published in Lancet on March 12, 2014 refers only to the first half of the study (efficacy and safety of ORV 116E assessed in the first year of life). Data on efficacy and safety up to 2 years (from 14 days following the 3rd dose till the age of 2 years (24 months) + up to 14 days.) is still awaited.

Even in this small sample studied for 1 year, the incidence of intussusception among the vaccinated was 50% more than controls. The rush to recommend licensing this drug before presenting the full trial data is surprising.

Furthermore, contrary to expectations, it is now known that transplacental rotavirus IgG interferes with immune response to the live oral rotavirus vaccine (ORV-116E) in Indian infants Appaiahgari MB, 2014. The very low incidence of severe rotavirus gastroenteritis (SRVGE)seen in the study of Bhandari N, 2014 may be due to the protective effect of the transplacental antibodies. The vaccine is probably not needed in these circumstances.

However Appaiahgari MB, 2014 found that higher doses of the vaccine was able to overcome the inhibitory effect of this RV IgG. The safety of the high-dose-vaccine has not been studied and so cannot be recommended as yet.

On 2014 Apr 09, B M Hegde commented:

While I am in total agreement with the views of Dr. Puliyal on this vaccine, I have some more questions!

While to cost effectiveness is ridiculously low, our incidence of this kind of diarrhea is also very low, why do we need to push this vaccine down our poor children’s throats. In a village if we have good primary care centers to look after children with diarrhea, with enough IV fluids and oral re-hydration solutions, the rotavirus is not a problem at all. Diarrhea eliminates the virus and the child recovers not because of the virus being killed but because of the good re-hydration.

I remember my student days we used to have cholera epidemics very, very frequently. What mattered even then was just re-hydration and not the cholera vibrio. I am sure cholera was much more dangerous than simple viral diarrhea. In the former, vomiting was so troublesome it would not easily allow oral re-hydration. Despite that, studies showed that a good oral re-hydration was better than IV fluids even in that situation.

Our administrators should do something for the ubiquitous calorie protein malnutrition in children that depletes the immune system attracting many infectious diseases. This kills thousands of children in India.I call that 'Nutritional Immune Deficiency Syndrome' (NIDS).

We are wasting our time and money on vaccines and antibiotics instead. That saving must be used in feeding all our children and pregnant mothers in the first trimester of pregnancy. What we are doing now is dangerous and not science. Exporting American “science” to the third world worries some of the thinkers among the best brains in the world. www.edge.org presents some thoughts from the best scientific brains in this area.

B. M. Hegde MD, FRCP(Lond.), FRCP(Edin.), FRCP(Glas.), FRCP(Dub.), FACC(U.S.A.). Formerly Vice Chancellor, Manipal Academy of Higher Education, Manipal, India

On 2014 Apr 07, Amitav Banerjee commented:

DEVELOPING COUNTRIES ARE BEING PUSHED INTO A "CATCH-22" SITUATION. Developing countries provide a happy hunting ground for clinical trials. Medical researchers in developing countries are lured into conducting drug and vaccine trials. This is an absurdity. We have more pressing problems in developing countries such as malnutrition, infant diarrhea, malaria,and other infections besides emerging noninfectious diseases and all the resources are diverted to teach clinicians how to do clinical trials. Clinical trials are useful since it is about time clinicians became a little more scientific about what they do. However, it would help if these clinicians who are trained in doing drug trials realize that epidemiology is more important than drug tests and become genuine epidemiologists and public health workers. Who decides which technologies are important to those countries that do not produce them directly? Technology manufacturers and health ministries govern these decisions. For launching any vaccine or even for starting any trial of vaccine, the first consideration should be to find out the prevalent disease burden of the concerned disease. In case these data are not gathered before launching a vaccine, the window of opportunity is lost giving rise to a Catch-22 situation. We will never know whether the vaccine is preventing the disease or the disease was having low incidence in the targeted population before launch of the vaccine. Therefore resources should first be used to gather these basic data before starting any vaccine trial. That this is not done for most vaccines which are being hastily introduced in developing countries gives rise to doubts of serious "conflicts of interest" of the decision makers.

On 2014 Apr 04, Jacob Puliyel commented:

MINISCULE RISK REDUCTION MAKES $1 ROTAVIRUS VACCINE (116E) UNECONOMICAL IN INDIA

The authors must be congratulated for this study and the candid reporting of the absolute risk reduction (ARR) and numbers needed to treat (NNT).

LOW DISEASE BURDEN

Although rotavirus vaccine efficacy is lower in developing countries, it is advocated for poor countries because of the higher disease burden. Severe rotavirus gastroenteritis (SRVGE) was more common in Malawi than South Africa (13.1 vs. 5.4) and even though efficacy was lower in Malawi (49.4% vs. 76.9%) more cases of SRVGE were prevented by vaccination (6.7 vs. 4.2) Madhi SA, 2010. This is often given as the justification for using the vaccine with such low efficacy in poor countries.

The incidence SRVGE was low very low in the unvaccinated in India (3.4%) compared to 13.1 in Malawi and 5.4 in South Africa. This raises questions about the need for the vaccine in India using the ‘disease burden’ argument.

The absolute risk reduction (ARR) by vaccination was small (1.7). This is much lower than the benefit in Malawi (6.7) and even South Africa (4.2) Madhi SA, 2010.

The NNT was 55. At $3/child, vaccination will cost $ 165 per SRVGE avoided. This is four times the societal cost of hospitalized diarrhea in India ($40.60) Mendelsohn AS, 2008

RISK OF INTUSSUSCEPTIONS

Intussusceptions are more dangerous in developing countries where facilities for its diagnosis and treatment are not easily available in remote areas. The earlier rotavirus vaccine RotaShield had been approved after clinical trials involving 10,054 children. It was then withdrawn from the market for causing intussusceptions (1 in 12,000 children).

After the RotaSheild fiasco, FDA approval of RotaTeq based on results of three phase III trials of the drug which treated a combined 72,324 infants in 11 countries.

The 116E has been studied in only 4532 with 2187 controls (total 6719). This is grossly inadequate for studying safety of this drug. The authors seem to suggest that this small study is sufficient for licensing the drug and safety can be examined during post marketing surveillance! It will indeed be a very brave licensing authority who, based on this study of 6719 children, will license the drug in countries like India where active post marketing surveillance is non-existent and where there is no proper ‘VAERS-like’ system available. In this context Paul King has proposed an effective system for AEFI surveillance with meaningful penalties for any healthcare provider's failure to report any possible AEFI to those maintaining this AEFI database.

Perhaps those keen on the roll out of the vaccine may put such a system in place and some good may come from this vaccine.

Saurabh Kumar, Jacob Puliyel

On 2014 Apr 04, Jacob Puliyel commented:

MINISCULE RISK REDUCTION MAKES $1 ROTAVIRUS VACCINE (116E) UNECONOMICAL IN INDIA

The authors must be congratulated for this study and the candid reporting of the absolute risk reduction (ARR) and numbers needed to treat (NNT).

LOW DISEASE BURDEN

Although rotavirus vaccine efficacy is lower in developing countries, it is advocated for poor countries because of the higher disease burden. Severe rotavirus gastroenteritis (SRVGE) was more common in Malawi than South Africa (13.1 vs. 5.4) and even though efficacy was lower in Malawi (49.4% vs. 76.9%) more cases of SRVGE were prevented by vaccination (6.7 vs. 4.2) Madhi SA, 2010. This is often given as the justification for using the vaccine with such low efficacy in poor countries.

The incidence SRVGE was low very low in the unvaccinated in India (3.4%) compared to 13.1 in Malawi and 5.4 in South Africa. This raises questions about the need for the vaccine in India using the ‘disease burden’ argument.

The absolute risk reduction (ARR) by vaccination was small (1.7). This is much lower than the benefit in Malawi (6.7) and even South Africa (4.2) Madhi SA, 2010.

The NNT was 55. At $3/child, vaccination will cost $ 165 per SRVGE avoided. This is four times the societal cost of hospitalized diarrhea in India ($40.60) Mendelsohn AS, 2008

RISK OF INTUSSUSCEPTIONS

Intussusceptions are more dangerous in developing countries where facilities for its diagnosis and treatment are not easily available in remote areas. The earlier rotavirus vaccine RotaShield had been approved after clinical trials involving 10,054 children. It was then withdrawn from the market for causing intussusceptions (1 in 12,000 children).

After the RotaSheild fiasco, FDA approval of RotaTeq based on results of three phase III trials of the drug which treated a combined 72,324 infants in 11 countries.

The 116E has been studied in only 4532 with 2187 controls (total 6719). This is grossly inadequate for studying safety of this drug. The authors seem to suggest that this small study is sufficient for licensing the drug and safety can be examined during post marketing surveillance! It will indeed be a very brave licensing authority who, based on this study of 6719 children, will license the drug in countries like India where active post marketing surveillance is non-existent and where there is no proper ‘VAERS-like’ system available. In this context Paul King has proposed an effective system for AEFI surveillance with meaningful penalties for any healthcare provider's failure to report any possible AEFI to those maintaining this AEFI database.

Perhaps those keen on the roll out of the vaccine may put such a system in place and some good may come from this vaccine.

Saurabh Kumar, Jacob Puliyel

On 2014 Apr 07, Amitav Banerjee commented:

DEVELOPING COUNTRIES ARE BEING PUSHED INTO A "CATCH-22" SITUATION. Developing countries provide a happy hunting ground for clinical trials. Medical researchers in developing countries are lured into conducting drug and vaccine trials. This is an absurdity. We have more pressing problems in developing countries such as malnutrition, infant diarrhea, malaria,and other infections besides emerging noninfectious diseases and all the resources are diverted to teach clinicians how to do clinical trials. Clinical trials are useful since it is about time clinicians became a little more scientific about what they do. However, it would help if these clinicians who are trained in doing drug trials realize that epidemiology is more important than drug tests and become genuine epidemiologists and public health workers. Who decides which technologies are important to those countries that do not produce them directly? Technology manufacturers and health ministries govern these decisions. For launching any vaccine or even for starting any trial of vaccine, the first consideration should be to find out the prevalent disease burden of the concerned disease. In case these data are not gathered before launching a vaccine, the window of opportunity is lost giving rise to a Catch-22 situation. We will never know whether the vaccine is preventing the disease or the disease was having low incidence in the targeted population before launch of the vaccine. Therefore resources should first be used to gather these basic data before starting any vaccine trial. That this is not done for most vaccines which are being hastily introduced in developing countries gives rise to doubts of serious "conflicts of interest" of the decision makers.

On 2014 Apr 09, B M Hegde commented:

While I am in total agreement with the views of Dr. Puliyal on this vaccine, I have some more questions!

While to cost effectiveness is ridiculously low, our incidence of this kind of diarrhea is also very low, why do we need to push this vaccine down our poor children’s throats. In a village if we have good primary care centers to look after children with diarrhea, with enough IV fluids and oral re-hydration solutions, the rotavirus is not a problem at all. Diarrhea eliminates the virus and the child recovers not because of the virus being killed but because of the good re-hydration.

I remember my student days we used to have cholera epidemics very, very frequently. What mattered even then was just re-hydration and not the cholera vibrio. I am sure cholera was much more dangerous than simple viral diarrhea. In the former, vomiting was so troublesome it would not easily allow oral re-hydration. Despite that, studies showed that a good oral re-hydration was better than IV fluids even in that situation.

Our administrators should do something for the ubiquitous calorie protein malnutrition in children that depletes the immune system attracting many infectious diseases. This kills thousands of children in India.I call that 'Nutritional Immune Deficiency Syndrome' (NIDS).

We are wasting our time and money on vaccines and antibiotics instead. That saving must be used in feeding all our children and pregnant mothers in the first trimester of pregnancy. What we are doing now is dangerous and not science. Exporting American “science” to the third world worries some of the thinkers among the best brains in the world. www.edge.org presents some thoughts from the best scientific brains in this area.

B. M. Hegde MD, FRCP(Lond.), FRCP(Edin.), FRCP(Glas.), FRCP(Dub.), FACC(U.S.A.). Formerly Vice Chancellor, Manipal Academy of Higher Education, Manipal, India

On 2014 Apr 15, Jacob Puliyel commented:

50% More Intussusception Among Vaccinated: Full Trial Data Is Awaited

According to the Clinical Trials Registry this study, started in March 2011 was estimated to be complete in April 2014.

The data published in Lancet on March 12, 2014 refers only to the first half of the study (efficacy and safety of ORV 116E assessed in the first year of life). Data on efficacy and safety up to 2 years (from 14 days following the 3rd dose till the age of 2 years (24 months) + up to 14 days.) is still awaited.

Even in this small sample studied for 1 year, the incidence of intussusception among the vaccinated was 50% more than controls. The rush to recommend licensing this drug before presenting the full trial data is surprising.

Furthermore, contrary to expectations, it is now known that transplacental rotavirus IgG interferes with immune response to the live oral rotavirus vaccine (ORV-116E) in Indian infants Appaiahgari MB, 2014. The very low incidence of severe rotavirus gastroenteritis (SRVGE)seen in the study of Bhandari N, 2014 may be due to the protective effect of the transplacental antibodies. The vaccine is probably not needed in these circumstances.

However Appaiahgari MB, 2014 found that higher doses of the vaccine was able to overcome the inhibitory effect of this RV IgG. The safety of the high-dose-vaccine has not been studied and so cannot be recommended as yet.

On 2014 Apr 16, Arun Gupta commented:

What is the hurry ?

I would think it to be fundamentally flawed to introduce a vaccine based on a research that is not completed and its results have not been fully studied. Whatever the results are available show that the vaccine is not even cost effective. If you ask me that every child of India should get this I fail to understand the logic except that market must prevail because we live in the world which gives way to globalsation.

On 2014 Apr 18, Jacob Puliyel commented:

None