Josephine van Dongen

Chapter 5 122 et al. and Zeller et al., respectively. 10,11 The obtained sequences were used for rotavirus type determination in the web-based typing tool RotaC. 12 2) Comparison of baseline characteristics between the groups was done using Chi- square, student-T or non-parametric tests depending on the distribution. For the primary tolerability outcome of at least one AE we used a mixed model with binomial distribution and a random intercept per infant. We estimated odds ratios for type of vaccine administration (NIP, HRV or NIP+HRV), adjusting for age at vaccination. Odds ratio was transformed into risk ratio (RR) using the method described by Knol et al. 13 Predefined covariates in multivariate analysis included: GA, small for gestational age, presence of congenital disorders, older siblings, parental age, parental background and, socio-economic status. To assess whether the effect of co-administration of HRV on solicited AE was dependent on GA, we added an interaction term to the model. The final model was selected based on the Akaike Information Criterion. For the number of solicited AE experienced after vaccine administration, we estimated adjusted incidence rate ratio (IRR) using negative binomial regression. We performed complete case analysis, potentially induced bias was explored by comparing complete cases to those with missing information.As statistical software SPSS version 25.0.0.2 and RStudio version 3.6.1 were used, with packages lme4, MASS . Results 1) Safety A total of 5730 high-risk premature infants ≥ 27 weeks of GA fulfilled the eligibility criteria, figure 2. The median GA was 33 weeks and 1 days, 1962 (34.2%) were small for gestational age and, 549 (9.6%) had one or more congenital pathologies. Among 2077 HRV vaccinated infants ten vaccine related SAE were documented, 0.25 per 100 vaccine doses.These included two cases of intussusception (one ultrasound confirmed), two cases of necrotizing enterocolitis and, one clinical sepsis (no pathogen detected). One infant developed acute gastroenteritis that required hospital admission (shor tly after vaccination, no stool sample available) and one infant lactose intolerance (occurrence of diarrhea and severe abdominal cramps after both vaccine doses, which resolved after lactose free formula milk was introduced). Three infants developed sudden cardiorespiratory events. For detailed information see Appendix A table S1. All infants recovered and there were no deaths. Two infants with hospitalized rotavirus acute gastroenteritis were classified as vaccine failures, par tially heterotypic genotypes were detected in sampled feces. In par ticular regarding the VP4 genotype, which in both cases did not match the genotype of the vaccine strain. Five out of 13 hospitals had a policy to vaccinate infants with GA < 27 weeks, 82 out of 92 (85.9%) eligible infants were vaccinated with at least one dose of HRV. No vaccine related SAE were documented. For safety data concerning term infants with congenital disorders, see appendix B , among 118 vaccinated infants two vaccine related SAE were documented.