Association of Rotavirus Vaccines With Reduction in Rotavirus Gastroenteritis in Children Younger Than 5 Years: A Systematic Review and Meta-analysis of Randomized Clinical Trials and Observational Studies

Abstract

Importance: Rotavirus vaccines have been introduced worldwide, and the clinical association of different rotavirus vaccines with reduction in rotavirus gastroenteritis (RVGE) after introduction are noteworthy.

Objective: To evaluate the comparative benefit, risk, and immunogenicity of different rotavirus vaccines by synthesizing randomized clinical trials (RCTs) and observational studies.

Data sources: Relevant studies published in 4 databases: Embase, PubMed, the Cochrane Library, and Web of Science were searched until July 1, 2020, using search terms including "rotavirus" and "vaccin*."

Study selection: Randomized clinical trials and cohort and case-control studies involving more than 100 children younger than 5 years that reported the effectiveness, safety, or immunogenicity of rotavirus vaccines were included.

Data extraction and synthesis: A random-effects model was used to calculate relative risks (RRs), odds ratios (ORs), risk differences, and 95% CIs. Adjusted indirect treatment comparison was performed to assess the differences in the protection of Rotarix and RotaTeq.

Main outcomes and measures: The primary outcomes were RVGE, severe RVGE, and RVGE hospitalization. Safety-associated outcomes involved serious adverse events, intussusception, and mortality.

Results: A meta-analysis of 20 RCTs and 38 case-control studies revealed that Rotarix (RV1) significantly reduced RVGE (RR, 0.316 [95% CI, 0.224-0.345]) and RVGE hospitalization risk (OR, 0.347 [95% CI, 0.279-0.432]) among children fully vaccinated; RotaTeq (RV5) had similar outcomes (RVGE: RR, 0.350 [95% CI, 0.275-0.445]; RVGE hospitalization risk: OR, 0.272 [95% CI, 0.197-0.376]). Rotavirus vaccines also demonstrated higher protection against severe RVGE. Additionally, no significant differences in the protection of RV1 and RV5 against rotavirus disease were noted in adjusted indirect comparisons. Moderate associations were found between reduced RVGE risk and Rotavac (RR, 0.664 [95% CI, 0.548-0.804]), Rotasiil (RR, 0.705 [95% CI, 0.605-0.821]), and Lanzhou lamb rotavirus vaccine (RR, 0.407 [95% CI, 0.332-0.499]). All rotavirus vaccines demonstrated no risk of serious adverse events. A positive correlation was also found between immunogenicity and vaccine protection (eg, association of RVGE with RV1: coefficient, -1.599; adjusted R2, 99.7%).

Conclusions and relevance: The high protection and low risk of serious adverse events for rotavirus vaccines in children who were fully vaccinated emphasized the importance of worldwide introduction of rotavirus vaccination. Similar protection provided by Rotarix and RotaTeq relieves the pressure of vaccines selection for health care authorities.

Figure 1.. Random-Effects Model of Rotavirus Vaccine Protection Against Rotavirus Gastroenteritis (RVGE) and RVGE Hospitalization, by Country Income Level, in Randomized Clinical Trials

HIC indicates high-income countries; LIC, low-income countries; LLR, Lanzhou lamb rotavirus; MIC, middle-income countries; RR, relative risk; RV1, monovalent rotavirus vaccine.

Figure 2.. Random-Effects Model of Rotavirus Vaccine Protection against Rotavirus Gastroenteritis (RVGE) and RVGE Hospitalization, by Country Income Level, in Case-Control Studies

HIC indicates high-income countries; LIC, low-income countries; LLR, Lanzhou lamb rotavirus; MIC, middle-income countries; OR, odds ratio; RV1, monovalent rotavirus vaccine; RV5, pentavalent rotavirus vaccine.

Figure 3.. Subgroup Analysis for Rotavirus Vaccine Protection, Stratified by Follow-up Duration and Vaccination Schedule

In randomized clinical trials (RCTs), the first column shows the number of cases in the vaccine group and the total population in the vaccine group. In case-control studies, these numbers denote the number of vaccinated children in the case group and the sum of children with no vaccination plus those receiving full doses in the case group. In RCTs, the second column shows the number of cases in the placebo group and the total population in placebo group. In case-control studies, this column shows the number of vaccinated children in the control group and the sum of children with no vaccination plus those receiving full doses in the control group. Odds ratios (ORs) were used for case-control studies; relative risks (RRs), for RCTs. RV1 indicates monovalent rotavirus vaccine; RV5, pentavalent rotavirus vaccine.

Figure 4.. Metaregression Between Immunogenicity and Vaccine Protection

The coefficient is the regression correlation coefficient, and the adjusted R² is the proportion of between-study variance explained. Metaregression between immunogenicity and logRR against rotavirus gastroenteritis (RVGE) for RV1 and RV5 (A), RVGE for RV1 (B), severe RVGE for RV1 and RV5 (C), severe RVGE for RV1 (D), and severe RVGE for RV5 (E). RV1 indicates monovalent rotavirus vaccine; RV5, pentavalent rotavirus vaccine.