Rotavirus vaccine: False safety warnings from faulty data analysis

Rotavirus vaccine: False safety warnings from faulty data analysis


Criticising a recent paper published by Dr Jacob Puliyel of the International Institute of Health Management Research, New Delhi, on rotavirus vaccine safety, microbiologist Dr Gagandeep Kang says: “If you do 20 different analyses, one of them will appear to be significant. It is actually picking the data selectively, changing the data, adjusting the data, not using the entire data to find something. [that shows the vaccine is not safe]Dr. Kang was the principal investigator of the rotavirus vaccine trials and corresponding author of the 2020 paper. The New England Journal of MedicineWhose data was used by Dr. Puliyel for his re-analysis.

Dr Kang's study was a post-licensure, hospital-based, active surveillance study conducted in 27 hospitals across 10 states in India. For the study, 589 infants aged 28 to 365 days were recruited as study participants who were admitted to hospitals due to intussusception (where one part of the intestine moves into the part next to the intestine) and who met certain criteria. The main objective was to monitor any increased risk of intussusception after any dose of Bharat Biotech's rotavirus vaccine (Rotavac). Three doses of the vaccine are given at 6, 10 and 14 weeks of age. The vaccine was introduced in the universal immunization program in some states in 2016 and across India in 2019.

Since the phase-3 trial with only 6,799 participants did not have the power to pick up cases of intussusception, active surveillance of hospitalised cases of intussusception was conducted. The NEJM study used the self-controlled case series method to assess the risk of intussusception after vaccine administration. The relative risk was calculated by comparing events in three risk windows – one-seven days, 8-21 days and 1-21 days after each dose of vaccine – with events in all other observed non-risk periods for each case patient. A case-controlled study was also conducted to see if there was any difference in the risk rate between vaccinated and non-vaccinated people. There was no increased risk of intussusception due to vaccination during the risk period and in the case-controlled study. vaccine A study conducted in July 2020 and January 2021 also did not find that the vaccine was associated with an increased risk of intussusception after any dose.

While the NEJM study limited the analysis to 365 days to look at the risk more carefully, Dr. Puliyel shortened the observation period to six months and found 59 cases in the high-risk period and 90 cases in the low-risk period. Based on this, Dr. Puliyel concluded that “the risk of intussusception with rotavirus vaccine was significantly higher in the high-risk period”. The basis for limiting the observation period to six months is that intussusception peaks around seven months in those who are not vaccinated. “No, it peaks anywhere between 6-15 months. Intussusception in children is usually seen around 10-12 months, depending on which country you are in. You see the most cases at the end of the first year of life,” says Dr. Kang. “The distribution of all cases of intussusception in vaccinated infants in our study shows that cases are increasing and remain high for a long time. It certainly does not stop at seven months.” According to the NEJM study, cases of intussusception peaked at 31 weeks, with about 55 cases, and remained high with 35-42 cases per week between 22 and 37 weeks, and 10-15 cases per week between 46 and 51 weeks.

“What we are seeing is that the pattern of intussusception due to vaccination is not different from the natural pattern of intussusception. There is no peak,” says Dr Kang. The data shows cases of intussusception after each dose, and there are many more cases after the third dose, but there is no peak. Explaining why more cases are seen after the third dose, Dr Kang says it is because children are reaching the age when natural intussusception is increasing. “We have more cases anyway after a month of the third dose, whether vaccinated or not,” she says.

In the first three weeks after vaccination, four cases were reported after the first dose, 19 after the second dose and 37 after the third dose. Overall, 31 cases were observed within 59 days of the first dose and 345 after 59 days, 78 cases were observed within 59 days of the second dose and 265 after 59 days, and 108 cases were observed within 59 days of the third dose and 181 after 59 days.

On the basis that susceptibility to adverse events should not be highest immediately after vaccination, Dr. Puliyel considered 21 days after any dose of vaccine to be a high-risk period. But data published worldwide suggests that if there is any risk from rotavirus vaccine, it will occur within three weeks of the child receiving the vaccine dose. According to the CDC, “Intussusception from rotavirus vaccination usually occurs within one week of receiving the vaccine dose”.

In another analysis, Dr. Puliyel excluded non-vaccinated people and found that the risk of intussusception increased after the third dose of the vaccine. “In the US, Australia, the UK and other countries, where they actually found an increased risk of intussusception after vaccination, unlike our study of Indian children, the risk is usually in the first week after the first dose. You don’t get it after the second or third dose. One study in Brazil found a slight increase after the second dose.” A meta-analysis of 10 self-controlled case series studies found that the relative risk of intussusception was highest after the first dose and much lower after the second and third doses.

Importantly, 0.5 billion doses of Rotovac have been used globally to date. Developed countries with good AEFI reporting would certainly have recognised any increased cases of intussusception, especially since it was known that rotavirus vaccines could cause more intussusception.

Dr Giridhar Babu, epidemiologist at the Public Health Foundation of India, Bengaluru, says the self-controlled risk interval (SCRI) analysis done by Dr Puliyel is less common and requires a larger sample size and representative sampling to adjust for age-related confounding. “A small sample size of only vaccinated infants can reduce statistical power compared with analyses involving larger groups,” he says. “The relatively small sample size of the study and the resulting wide confidence interval further reduce the statistical power and precision of the findings. The effect of a vaccine on a rare outcome can have a serious bias when the data lack sufficient case numbers for some combination of vaccine and intussusception levels.”

Commenting on the different analyses conducted by Dr. Puliyel, Dr. Babu says: “Using different analytical methods, though robust, complicates the interpretation of the results and may lead to inconsistent findings.”


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