Post-Marketing Benefit-Risk Assessment of Rotavirus Vaccination in Japan: A Simulation and Modelling Analysis

Abstract

Introduction: Rotarix™, GSK's live attenuated rotavirus vaccine, was introduced in Japan in 2011. A recent trend in reduction of rotavirus gastroenteritis (RVGE) due to this vaccine was described. However, an observed/expected analysis showed a temporal association with intussusception within 7 days post dose 1.

Objective: In this paper, we compare the benefit and risk of vaccination side-by-side in a benefit-risk analysis.

Methods: The number of vaccine-preventable RVGE-associated hospitalizations and deaths (benefit) and intussusception-associated hospitalizations and deaths (risk) following two doses of Rotarix™ in Japan was compared using simulations. Source data included peer-reviewed clinical and epidemiological publications, Japanese governmental statistics (Statistics Bureau, Ministry of Internal Affairs and Communications), and market survey data.

Results: For a birth cohort of 1 million vaccinated Japanese children followed for 5 years, the benefit-risk analysis suggested that the vaccine would prevent ~17,900 hospitalizations and ~6.3 deaths associated with RVGE. At the same time, vaccination would be associated with about ~50 intussusception hospitalizations and ~0.017 intussusception deaths. Therefore, for every intussusception hospitalization caused by vaccination and for one intussusception-associated death, 350 (95 % CI 69-2510) RVGE-associated hospitalizations and 366 (95 % CI 59-3271) RVGE-associated deaths are prevented, respectively, by vaccination.

Conclusions: The benefit-risk balance for Rotarix™ is favorable in Japan. From a public health perspective, the benefits in terms of prevented RVGE hospitalizations and deaths for the vaccinated population far exceed the estimated risks due to intussusception.

Fig. 1

Interpolation of age-specific rotavirus gastroenteritis hospitalization rates in children 0–60 months of age (a) and age-specific intussusception hospitalization rates in infants (0–12 months of age) (b). a The observed values represent the rotavirus gastroenteritis hospitalization rate, by age, in two cities (Tsu and Ise) from the Mie Prefecture, Japan, 2003–2007 [7]. Vertical bars define the 95 % confidence interval around mean age-specific rotavirus gastroenteritis rates. Horizontal bars define the age range over which the hospitalization rate was estimated. The coefficients of the fitted curve, exp(3.16 × exp(–0.027 × age) – 3.16 × exp(–0.043 × age² + 0.045 × age)), were determined by least-squares and contributed to the calculation of the preventable fraction of the rotavirus gastroenteritis rate. b The observed values represent the intussusception hospitalization rate among children ≤24 weeks of age in Akita Prefecture, Japan, between 2001 and 2010 [22]. Vertical bars define the 95 % confidence interval around mean age-specific intussusception rates. Horizontal bars define the age range over which the hospitalization rate was estimated. The coefficients of the fitted curve, 10 × exp[9.18 × exp(–0.062 × (age – 1.62)) – 9.18 × exp(–0.438 × (age – 1.62))], were determined by least-squares and were used to calculate the mean intussusception rate over a 7-day risk window after each of the two vaccinations. IS intussusception, RVGE rotavirus gastroenteritis

Fig. 2

Two-dimensional plot of the overall reduction in numbers of rotavirus gastroenteritis hospitalizations over a 5-year risk window (x-axis) and the increase in numbers of intussusception hospitalizations post-vaccination over two 7-day risk windows (y-axis) for a cohort of 1 million vaccinated Japanese children. Each point represents the joint calculations of benefits and risks under a specific scenario selected at random from each of the random distributions of the input parameters. The results presenting the highest frequencies across the 10⁶ simulations are red. The plot illustrates the dominance of the hospitalization benefits in comparison to the hospitalization risks under all scenarios. The distribution of the reduction in the number of rotavirus gastroenteritis hospitalizations over a 5-year risk window in 1 million vaccinees, averaged across all intussusception results, is presented on the upper x-axis. The distribution of the increase in numbers of intussusception hospitalizations post-vaccination over two 7-day risk windows in 1 million vaccinees, averaged across all rotavirus gastroenteritis results, is presented on the right y-axis. IS intussusception, RVGE rotavirus gastroenteritis

Fig. 3

Sensitivity analyses assessing the impact of the variability of model parameters on the benefit–risk ratio (a) and benefit–risk difference (b) for hospitalization. The x-axis of the tornado diagrams shows the variations of the benefit–risk ratio around its mean value as a result of variations of the main input parameters. The left and right limits of each horizontal bar indicate the change in benefit–risk ratio calculated for the 1 and 99 % percentile values of the input parameter mentioned. Other symbols indicate the benefit–risk variations expected for those percentiles of the input parameter. BR benefit–risk, D1 dose 1, D2 dose 2, hosp. hospitalization, IS intussusception, Max maximum, Min minimum, Q1 first quartile, Q3 third quartile, RR relative risk, RVGE rotavirus gastroenteritis, VE vaccine efficacy