Indian rotavirus vaccine concern over intussusception is unfounded, say researchersBMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h2867 (Published 27 May 2015) Cite this as: BMJ 2015;350:h2867
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Rotavirus vaccines in France : because of three infant death and too many serious side effects vaccines are no longer recommended for routine children immunization
Since the vaccination againts rotavirus is recommended by WHO in all the world and since it was already introduced in the vaccination schedule of many countries, I think safety information must be shared.
In France two vaccines Rotarix ® from GSK and Rotateq® commercialized by Merck-Sanofi joint venture are recommended for routine use in children since 2013 but were not reimbursed by public insurance.
The French Technical Committee for Pharmacovigilance met and issued a first report on December 9, 2014 on rotavirus vaccines safety monitoring and transmitted it to the National Agency of Drug Safety (ANSM). Despite alerting observations of the committee about the vaccine safety the agency didn’t throw alert until march, the 30, just a few hours before the information was published in a satirical newspaper. The committee expressed concern about the worrying rate of serious side effects notifications with the two vaccines and questioned about the appropriateness of recommendations. It pointed specially to two deaths following vaccination due to very severe forms of intussusceptions. It also took into account a third death following rotavirus vaccination due to necrotizing enterocolitis in an infant treated by Varitect® (a human varicella-zoster immunoglobulin) . A final report by the pharmacovigilance comettee was issued in February . It was estimated that 491000 infants had been vaccinated since 2006. In total, there were 508 side effects notifications (103,8/ 100 000) of which 201 serious side effects ( 39,57%, 40,9/100 000). 75% of the total side efffects were digestive . There were 47 intussusceptions too and among them 14 (29,80%) required chirurgical treatment. Most of them occurred after the first dose and the median age for post-vaccinal intussusceptions was 3 months. 21 of the 35 cases of intussusceptions with the vaccine Rotarix occurred during the first 7 days following vaccination and 6 of 12 for Rotateq. Two of the infants with intussusceptions died, one was vaccinated by Rotarix and the other by Rotateq. The infant death caused by Rotarix occurred in 2012 but GSK, in charge of the enhanced pharmacovigilance plan for Rotarix as it was allowed by the 2010/84/UE directive , declared it to public pharmacovigilance only in December 2014.
The conclusion of the pharmacovigilance committee was that the rate of side effects were worrying when compared to other pediatric vaccines. It noted also that the intussusceptions were more severe, probably, in part, because they occurred in younger infants.
The number of spontaneous intussusceptions by year for infants younger than one year was estimated to be about 200-250 in France , or 0,25 to 0,3 per 1000. During the five previous years only one death of intussusception was registered in French hospitals.
The vaccines were commercialized in France since 2006 and 2007 and the coverage was estimated from 5 to 9% depending on the years considered, since the parents had to pay the vaccine themselves. In 2013 and 2014 public health authorities and the two pharmaceutical companies negotiated the price of the vaccines in view of their introduction in the vaccination infant schedule and their reimbursement by public health insurance.
Following these events, health authorities refused to recommend and reimburse rotavirus vaccines.
It is noteworthy that clinical trials have never demonstrated a reduction in all cause mortality with these vaccines, neither in high nor in low income countries .
Merck and GSK rotavirus vaccines were prequalified by WHO and are going to be introduces by GAVI in low income countries .
 Réunion du Comité technique de Pharmacovigilance – CT012015023
Séance du mardi 10 février 2015 de 09h30 à 17h00 en salles 1 & 2
Competing interests: No competing interests
One fails to comprehend the hesitation of the investigators to reveal the raw data. Professor Kang's comment that the study was not powered to detect rare events also defies logic. In fact, if the risk of intussusception is remote the small numbers would fail to reveal an increased risk, which would go in favor of those advocating vaccine against rotavirus. The reluctance to reveal the raw data raises serious concerns about the possibility that attempts are being made to conceal complications due to the vaccine. Transparency in science never harmed anyone. Let them reveal the raw data. Later one can debate the finer statistical aspects. Professor Kang's statement about statistical "power" seems and attempts to confound the issue by using technical jargon.
Competing interests: No competing interests
The report contains a number of misleading assertions and a fundamental misunderstanding of statistics. These need to be corrected.
The Rotavirus 116E trial was registered with the Clinical Trials Registry ClinicalTrials.gov (NCT01305109) and was done at 3 centers. One of the outcomes measured was ‘safety of ORV 116E for intussusception events in comparison to a placebo from day of 1st dose till the age of 2 years’. According to the study report (1) intussusception was ‘suspected’ from symptoms, if a child had three or more vomiting in an hour, or blood in stools or increase in abdominal girth by 2 cm or more in a 4 hour period or a abdominal mass palpable per abdomen. Such children were examined by a pediatrician and if they felt intussusception was ‘possible’, the baby had an ultrasound examination within 8 hours.
Aggregated data from the three centers has been published (1,2). This shows that the incidence rate of ultrasound-diagnosed-intussusceptions was 37.5/10,000 among the vaccinated and 26.3/10,000 among placebo recipients. There were 11/10,000 more intussusceptions among those who received the 116E vaccine. This is nearly 70 times higher than the risk of intussusceptions with the current, internationally licensed vaccine, Merck’s RotaTeq.
The 116E trial also reported that was regional differences in the susceptibility to intussusceptions with the incidence in Vellore 20 times higher than in Delhi. Given this high susceptibility in Vellore, a request for disaggregated data on numbers with symptoms of intussusceptions and number of ultrasound diagnosed intussusceptions in each the three centers over the 2 year period, was made (3). It is understood that some intussusceptions are transient and may have resolve even before the ultrasound examination was performed.
Dr Kang told the BMJ that “it is misleading and statistically incorrect to use rates of intussusception from a 6800 child study to claim that the vaccine is risky” - as the study was not powered to look for rare events. This is a grave misunderstanding of the statistics involved. If statistical difference is seen in the 1000 vaccinated children in Vellore compared to 500 controls, it is evidence that the vaccine is unsafe in that population. As the incidence of intussusceptions is several folds higher with the 116E vaccine (than with RotaTeq) a smaller sample will show statistical differences. If a statistical difference is demonstrated, it means the study was powered adequately and it is not wrong to declare that it is risky to use the vaccine in that community.
Dr Kang does not provide the data that will allow easy calculation of the risk in Vellore but she quotes the WHO reporting that “existing data on Rotavac do not point to an increased risk from intussusceptions”. The data, when provided, will speak for itself and we do not have to rely on the say-so of the WHO.
The authors have published aggregated data from the 3 centers where there was no statistically significant difference in intussusceptions in vaccine recipients and controls. Dr VijayaRaghavan of the Department of Biotechnology (DBT) under whom the multi-center trial was done, says that the disaggregated data has been provided to the National Technical Advisory Group on Immunization (NTAGI). As a member of this apex advisory body of the Government of India, I can say that I have requested this data and it has not been provided to the NTAGI as yet. Dr VijayaRaghavan goes on to say that in response to various queries that they have received he will ensure “data is available for analysis by a competent body, meeting the requirements of analytical rigor and transparency.” As the analytic skills needed here are very basic and the aggregated data is already in the public domain, it is not clear only a DBT-selected ‘competent body’ can be privy to the Vellore figures.
Dr Kang told the BMJ, “We are trying to be as responsible as possible" but she is not disclosing the data requested. The primary responsibility of the researchers is to protect children not the interest of vaccine manufacturers. Providing the data would be the responsible thing to do.
1. John J, Kawade A, Rongsen-Chandola T, Bavdekar A, Bhandari N, Taneja S, Antony K, Bhatnagar V, Gupta A, Kabra M, Kang G. Active surveillance for intussusception in a phase III efficacy trial of an oral monovalent rotavirus vaccine in India. Vaccine 2011;32 (suppl 1):A104-9.
2. Bhandari N, Rongsen-Chandola T, Bavdekar A, John J, Antony K, Taneja S, Goyal N, Kawade A, Kang G, Rathore SS, Juvekar S, Muliyil J, Arya A, Shaikh H, Abraham V, Vrati S, Proschan M, Kohberger R, Thiry G, Glass R, Greenberg HB, Curlin G, Mohan K, Harshavardhan GV, Prasad S, Rao TS, Boslego J, Bhan MK; India Rotavirus Vaccine Group. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. Lancet. 2014;383(9935):2136-43.
3. Bajaj J, Puliyel JM. Intussusception risk with 116E rotavirus vaccine in Vellore, south India. Vaccine 2015;pii:S0264-410X(15)00293-5.
Competing interests: No competing interests