Mortality reduction benefits and intussusception risks of rotavirus vaccination in 135 low-income and middle-income countries: a modelling analysis of current and alternative schedules

Abstract

Background Infant rotavirus vaccines have led to substantial reductions in hospital admissions and deaths due to gastroenteritis, but some studies have reported an elevated risk of intussusception, a rare bowel disorder. This analysis aimed to provide evidence on the potential mortality reduction benefits and intussusception risks of current rotavirus vaccination schedules, and to explore whether alternative schedules could have advantages.Methods All 135 low-income and middle-income countries, defined by gross national income per capita of less than US$12 236 in the 2018 fiscal year, were included in the model. Mortality reduction benefits and intussusception risks of rotavirus vaccination were modelled by use of an Excel-based static cohort model with a finely disaggregated age structure. Numbers of rotavirus gastroenteritis deaths and intussusception deaths in each week of age were calculated for all infants born in the year 2015 between birth and age 5•0 years, with and without restrictions on age at administration. Benefit-risk ratios (rotavirus gastroenteritis deaths prevented per excess intussusception death) and other indicators were calculated for two vaccination schedules currently recommended by WHO and 16 alternative schedules. Of these schedules, it was assumed that between one and three doses would be given; the first dose of the rotavirus vaccine would be co-administered with either BCG or diphtheria-tetanus-pertussis (DTP)1; and the second or third dose would be co-administered with either DTP1, DTP2, DTP3, or measles (Meas)1.Findings A three-dose schedule co-administered with DTP (without age restrictions) could prevent about 74 000 (95% uncertainty interval 59 000-100 000) rotavirus gastroenteritis deaths (38% reduction) and could lead to 201 (77-550) excess intussusception deaths (1•4% increase) compared with no vaccination, resulting in a benefit-risk ratio of 369:1 (160:1-895:1). The benefit-risk ratio was most favourable when the relative risk of intussusception was assumed to decline with the national under-5 mortality rate (2386:1) and least favourable with pessimistic assumptions about access to hospital for intussusception treatment (168:1). Schedules that involve giving the first dose with BCG and the second with DTP1 had the fewest excess intussusception deaths and most favourable benefit-risk ratios.Interpretation Rotavirus vaccines have a favourable benefit-risk profile in LMICs. Neonatal schedules have the potential to prevent more rotavirus gastroenteritis deaths and cause fewer excess intussusception deaths than the schedules currently recommended by WHO, but more efficacious rotavirus vaccines would be needed to achieve more substantial mortality reduction benefits.Funding Bill & Melinda Gates Foundation.

Introduction of rotavirus vaccination in Palestine: An evaluation of the costs, impact, and cost-effectiveness of ROTARIX and ROTAVAC

“…UNIVAC is a static model which likely underestimates the benefits of vaccination by not accounting for potential herd effects. Others have studied the effect of rotavirus vaccination using dynamic models but findings from different countries tend to show uncertainty around the scale and duration of predicted herd effects [13]. In this analysis, we assumed ROTARIX and ROTAVAC to have similar efficacy, leading to an equivalent health impact.…”

“…UNIVAC generates transparent and conservative estimates of projected impact and cost-effectiveness of new vaccines based on parameters such as population, disease incidence, vaccine schedule, efficacy, and coverage, healthcare costs and vaccine program costs. More details on UNIVAC are available elsewhere [13]. UNIVAC was developed to assist decision makers by generating evidence around the use of new vaccines, including rotavirus vaccines, and has been used in several cost-effectiveness studies to date [14,15].…”

Benefit-Risk Assessment of Vaccines. Part II: Proposal Towards Consolidated Standards of Reporting Quantitative Benefit-Risk Models Applied to Vaccines (BRIVAC)

“…Central estimates were also calculated for six what-if scenarios: relative risks (RRs) of intussusception varying with under-5 mortality ( figure, appendix p 12); double the RR of intussusception for the first dose when given after 15 weeks of age; vaccine efficacy and waning equivalent to low mortality settings; less rapid waning efficacy (based on a power function described in detail elsewhere); less rapid waning efficacy for all primary doses administered as part of a neonatal schedule (appendix p 14); and pessimistic access to hospital for intussusception cases (based on the proportion of children who could reach a public hospital within 2 h). (Example based on Clark et al [67]).…”

Letter to the editor concerning the article ‘Association between rotavirus vaccination and risk of intussusception among neonates and infants: a systematic review and meta-analysis’ (JAMA Netw Open. 2019;2(10):e1912458)

“…[2][3][4] The increased risk of IS has been demonstrated in several large population-based studies. 5,6 The authors missed to mention important limitations of their work, discussed below.…”

“…6 This safety concern has been carefully evaluated by the WHO Global Safety evaluation committee and the Centers for Disease Control and Prevention, with the conclusion that the benefit of the widely used RV vaccines largely outweigh this slight increased risk of IS. 5 In the context of RV vaccination, it remains important to educate health-care practitioners of the rare occurrence of IS, and in addition, to make them aware that the consequences of IS can be better managed with parental counseling, early diagnosis and timely treatment. 2,3 In fact, early vaccination may even help to reduce the risk of IS by avoiding an overlap with the peak period of natural IS onset.…”