Accounting for indirect protection in the benefit–risk ratio estimation of rotavirus vaccination in children under the age of 5 years, France, 2018

Background Rotavirus is a major cause of severe gastroenteritis in children worldwide. The disease burden has been substantially reduced in countries where rotavirus vaccines are used. Given the risk of vaccine-induced intussusception, the benefit–risk balance of rotavirus vaccination has been assessed in several countries, however mostly without considering indirect protection effects. Aim We performed a benefit–risk analysis of rotavirus vaccination accounting for indirect protection in France among the 2018 population of children under the age of 5 years. Methods To incorporate indirect protection effects in the benefit formula, we adopted a pseudo-vaccine approach involving mathematical approximation and used a simulation design to provide uncertainty intervals. We derived background incidence distributions from quasi-exhaustive health claim data. We examined different coverage levels and assumptions regarding the waning effects and intussusception case fatality rate. Results With the current vaccination coverage of < 10%, the indirect effectiveness was estimated at 6.4% (+/− 0.4). For each hospitalisation for intussusception, 277.0 (95% uncertainty interval: (165.0–462.1)) hospitalisations for rotavirus gastroenteritis were prevented. Should 90% of infants be vaccinated, indirect effectiveness would reach 57.9% (+/− 3.7) and the benefit–risk ratio would be 192.4 (95% uncertainty interval: 116.4–321.3). At a coverage level of 50%, indirect protection accounted for 27% of the prevented rotavirus gastroenteritis cases. The balance remained in favour of the vaccine even in a scenario with a high assumption for intussusception case fatality. Conclusions These findings contribute to a better assessment of the rotavirus vaccine benefit–risk balance.


SM1 Multiplicative correction factor for rotavirus gastroenteritis background incidence and benefit calculations
This factor is:  (2) in the manuscript, and ̅̅̅̅ is an average value for direct efficacy, computed as explained below: where -̅̅̅̅̅ (resp. ̅̅̅̅̅ ) stands for the average direct efficacy of the d th dose of Rotarix (resp RotaTeq) -,1 , ,2&3 and ,4&5 stands for the direct efficacy of the d th dose of Rotarix during the 1 st year of life, during the 2 nd and 3 rd years of life and during the 4 th and 5 th year of life. Similar notations with "rq" instead of "rx" superscript were used for RotaTeq.
-Eq (2.2a) and (2.2b) state that the vaccination schedule is not necessarily complete (we assumed that only 96% of children who received a given dose will receive the following one, following Sabbe's observations (3)).
-Eq (2.3a) and (2.3b) state that efficacy of the d th dose of Rotarix (resp. RotaTeq) depends on the age of the children. Three periods have been considered: the first period corresponds to the first year of life, whatever the actual age of the child at the first dose.
-is an averaged parameter; in particular, it does not depend on age.
For each simulation, is derived from f, which is fixed, and from all direct efficacies, that is, , and , , d = 1 to 3 and  = 1, 2&3, 4&5 which are sampled.
This correction factor is then introduced in the benefit calculation. Let ( ) be the observed number of infants hospitalized for RVGE at age w. ( ) is the product of the sampled annual incidence of RVGE (see Supplement Table S1) and the fixed proportion of cases at age w (see Supplement Figure S2). Then 0 ( ) = × ( ) is the background number of children hospitalized for RVGE at age w. where is computed with formula (2) of the manuscript, from the chosen vaccine coverage VC and from the sampled 0 and direct efficacies , and , , d = 1 to 3 and  = 1, 2&3, 4&5 using the same averaging principle as the one described in equations (2.1) to (2.3b).
Overall, for each simulation, the algorithm for calculating all efficacies and effectiveness is:

SM2 Multiplicative correction factor for intussusception background incidence and risk calculations
This factor is the attributable fraction due to vaccine exposure: where: -f =0.095 is the proportion of vaccinated children at the time of the survey (1), -̅̅̅̅ is the relative risk, here, the average risk to which children are exposed until the age of 5 years old, computed as explained below: where -̅̅̅̅̅̅̅ (resp. ̅̅̅̅̅̅̅ ) stands for the average relative risk for children having received the d first doses of Rotarix (resp RotaTeq) -( ) (resp. ( )) stands for the relative risk for children having received the d th dose of Rotarix (resp RotaTeq) in the t th week.
-Eq (1.2a) and (1.2b) state that the vaccination schedule is not necessarily complete (we assumed that only 96% of children who received a given dose will receive the following one).
-Eq (1.3a) and (1.3c) state that the vaccine-induced risk occurs only during the 3 weeks following the first dose, so the risk equals 1 during the 261 − 3 remaining weeks for those having received one dose.
-Eq (1.3b) and (1.3d) state that the vaccine-induced risk occurs during the 3 weeks following the first dose and during the 3 weeks following the second dose, so the risk equals 1 during the 261 − 6 remaining weeks for those having received two doses.
-Eq (1.3e) states that the risk is similar for children having received 2 or 3 doses of RotaTeq, because the third dose has no vaccine-induced risk, ie, 3 ( ) = 1.

For each simulation,
is derived from f, which is fixed, and from all vaccine-induced relative risks, that is, ( ) and ( ), d = 1, 2 and t = 1 to 3, which are sampled.
This correction factor is then introduced in the risk calculation. Let ( ) be the observed number of infants experiencing the adverse event at age w. ( ) is the product of the sampled annual incidence of IS (see Supplement Table S2) and the fixed proportion of cases at age w (see Supplement Figure S3). Then 0 ( ) = × ( ) is the background number of children experiencing the adverse event at age w.
(w) (resp (w)) is the proportion of the population vaccinated by dose d of Rotarix (resp RotaTeq) at age w (see Supplement Table S3 for details).   (7). As a 10% decrease in efficacy has been observed between the first and second year in children with the full schedule, we derived the bounds of confidence intervals hypothesizing the same 10% decrease in children with the partial schedule.  The vaccination schedules were assumed to be those recommended by the manufacturers, and the weekly number of vaccinated infants was considered to be constant within the recommended age intervals.