Increased cases of Rotavac-induced intussusceptions after the third dose explained by background rates

This article is in response to “Increased cases of Rotavac-induced intussusceptions”, July 5, 2024 by Brian Hooker and Jacob Puliyel

In the paper published in the journal International Journal of Risk & Safety in Medicine (IJRSM), Brian Hooker and Jacob Puliyel say the risk of intussusception increased to nearly 2.5 times within 21 days after the third dose when self-controlled case series (SCCS) analysis was done after removing the unvaccinated from the analysis. Figure 1 of the New England Journal of Medicine (NEJM) paper shows that the third dose administration peaked at 16-17 weeks and then dropped sharply till 20-21 weeks and tapered till the end of 26-27 weeks. Unlike in the case of clinical trials, the uptake of rotavirus vaccine (any dose) during the universal immunisation programme was not precisely at the scheduled time periods of 6, 10 and 14 weeks, which is clearly shown in figure 1.  

Explaining the reason for more number of cases in the high-risk period of 21 days after the third dose, the NEJM paper referring to figure 1 says: “The third dose of vaccine is scheduled to be administered at 14 weeks of age, but children presented at a median age of 18 weeks, which overlapped with the peak age of intussusception.” This explains why more cases were seen among the vaccinated infants after the third dose. 

Increased number of cases after the third dose (first 21 days after vaccination and the window after the high-risk period) is clearly illustrated in the bar chart in figure 2 of the NEJM paper. Figure 2 shows the number and the distribution of intussusception cases among the vaccinated infants during the first 21 days (the high-risk period) after any dose and the number of cases till 59 days after vaccine administration. Figure 2 also shows that the large number of cases during and after the risk-period following the third dose correlates with the delayed administration of the third dose.

According to the IJRSM paper, “susceptibility to adverse events need not be highest immediately after vaccination”. But all SCCS studies on rotavirus vaccines carried out across the world have used the 1-21 days after a vaccine dose as the high-risk period. Similarly, as per the IJRSM paper, two time windows, 0-30 days and 31-60 days after the last rotavirus vaccination were chosen to “detect a temporal association with vaccination”. However, across the world, temporal association with rotavirus vaccination is defined by the high-risk period of 1-21 days and compared with the non-risk period 22 days and beyond after a dose of vaccine.

Cases of intussusception following vaccination do not suddenly stop after 60 days, as the figure 2 in the NEJM paper and other SCCS studies using other rotavirus vaccines have shown. As per the figure 2 and table 1 of the NEJM paper, the number of cases during the high-risk window (1-21 days) after the first dose were four after the first dose, 19 after the second dose and 37 after the second dose. During the period 22-59 days, there were 27 cases after the first dose, 59 cases after the second dose and 69 cases after the third dose. As per the figure 2 caption, there were 345 cases more than 59 days after the first dose, 265 cases more than 59 days after the second dose, and 181 cases more than 59 days after the third dose.

So restricting the comparison of intussusception frequencies to the time windows 0-30 days and 31-60 days makes it appear that more cases (92) are temporally associated with the last dose of vaccination in the 0-30 days compared with 63 cases in the 31-60 days window. Thus the choice of the two windows to find a temporal association with the last dose of vaccination appears misleading.

With regard to shortening the analysis time to 180 days, the IJRSM paper says: “We selected to limit our analysis to 6 months because intussusceptions peak around 7 months in the unvaccinated.” But the rejoinder says intussusceptions cases are “rare” during the 180-day period. According to the WHO, in Asia, the “median age [for intussusception] was around 4 to 8 months”. A retrospective surveillance of 19 sentinel hospitals in India carried out between July 2010 and March 2016 before Rotavax was included in the universal immunisation programme, found the median age for intussusception to be eight months with 34.6% aged two-six months. Another paper based on a study at CMC Vellore found the peak to be between four and six months of age.

The figure 1 in the NEJM paper shows the distribution of cases following Rotavax vaccination staying high till the end of the first year, with 10 cases appearing even in the weeks 50-51, which is the lowest after the third dose administration peaked at 16-17 weeks. So calculating the risk of intussusception after any dose of the vaccine by restricting the timeframe to six months is misleading.