Potential intussusception risk versus health benefits from rotavirus vaccination in Latin America.

BACKGROUND: With the recent postlicensure identification of an increased risk of intussusception with rotavirus vaccine, the 14 Latin American countries currently using rotavirus vaccine must now weigh the health benefits versus risks to assess whether to continue vaccination. To inform policy considerations, we estimated excess intussusception cases and mortality potentially caused by rotavirus vaccine for each of the 14 countries and compared these estimates to hospitalizations and deaths expected to be averted through vaccination. METHODS: We used regional rotavirus disease burden and rotavirus vaccine efficacy data, global natural intussusception and regional rotavirus vaccine-related risk estimates, and country-specific diphtheria, tetanus, and pertussus vaccination coverage rates to estimate rotavirus vaccine coverage rates. We performed a probabilistic sensitivity analysis to account for uncertainty in these parameters. RESULTS: For an aggregate hypothetical birth cohort of 9.5 million infants in these 14 countries, rotavirus vaccine would annually prevent 144 746 (90% confidence interval [CI], 128 821-156 707) hospitalizations and 4124 deaths (90% CI, 3740-4239) due to rotavirus in their first 5 years of life but could cause an additional 172 hospitalizations (90% CI, 126-293) and 10 deaths (90% CI, 6-17) due to intussusception, yielding benefit-risk ratios for hospitalization and death of 841:1 (90% CI, 479:1 to 1142:1) and 395:1 (90% CI, 207:1 to 526:1), respectively. In an uncertainty analysis using 10 000 simulations of our probabilistic parameters, in comparing rotavirus disease averted to intussusception events caused, the hospitalization ratio was never below 100:1, and our death ratio fell below 100:1 only once. CONCLUSIONS: The health benefits of vaccination far outweigh the short-term risks and support continued rotavirus vaccination in Latin America.

Removing the age restrictions for rotavirus vaccination: a benefit-risk modeling analysis.

BACKGROUND: To minimize potential risk of intussusception, the World Health Organization (WHO) recommended in 2009 that rotavirus immunization should be initiated by age 15 weeks and completed before 32 weeks. These restrictions could adversely impact vaccination coverage and thereby its health impact, particularly in developing countries where delays in vaccination often occur. METHODS AND FINDINGS: We conducted a modeling study to estimate the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination when administered on the restricted schedule versus an unrestricted schedule whereby rotavirus vaccine would be administered with DTP vaccine up to age 3 years. Countries were grouped on the basis of child mortality rates, using WHO data. Inputs were estimates of WHO rotavirus mortality by week of age from a recent study, intussusception mortality based on a literature review, predicted vaccination rates by week of age from USAID Demographic and Health Surveys, the United Nations Children's Fund (UNICEF) Multiple Indicator Cluster Surveys (MICS), and WHO-UNICEF 2010 country-specific coverage estimates, and published estimates of vaccine efficacy and vaccine-associated intussusception risk. On the basis of the error estimates and distributions for model inputs, we conducted 2,000 simulations to obtain median estimates of deaths averted and caused as well as the uncertainty ranges, defined as the 5th-95th percentile, to provide an indication of the uncertainty in the estimates. We estimated that in low and low-middle income countries a restricted schedule would prevent 155,800 rotavirus deaths (5th-95th centiles, 83,300-217,700) while causing potentially 253 intussusception deaths (76-689). In contrast, vaccination without age restrictions would prevent 203,000 rotavirus deaths (102,000-281,500) while potentially causing 547 intussusception deaths (237-1,160). Thus, removing the age restrictions would avert an additional 47,200 rotavirus deaths (18,700-63,700) and cause an additional 294 (161-471) intussusception deaths, for an incremental benefit-risk ratio of 154 deaths averted for every death caused by vaccine. These extra deaths prevented under an unrestricted schedule reflect vaccination of an additional 21%-25% children, beyond the 63%-73% of the children who would be vaccinated under the restricted schedule. Importantly, these estimates err on the side of safety in that they assume high vaccine-associated risk of intussusception and do not account for potential herd immunity or non-fatal outcomes. CONCLUSIONS: Our analysis suggests that in low- and middle-income countries the additional lives saved by removing age restrictions for rotavirus vaccination would far outnumber the potential excess vaccine-associated intussusception deaths. Please see later in the article for the Editors' Summary.

Cost-effectiveness of rotavirus vaccination in peru.

BACKGROUND: There are plans to introduce the oral rotavirus vaccine Rotarix (GlaxoSmithKline), 1 of 2 recently developed vaccines against rotavirus, in Peru. METHODS: We modeled the cost-effectiveness of adding a rotavirus vaccine to the Peruvian immunization program under 3 scenarios for the timing of vaccination: (1) strictly according to schedule, at 2 and 4 months of age (on time); (2) distributed around the target ages in the same way as the actual timings in the program (flexible); and (3) flexible but assuming vaccination is not initiated for infants >12 weeks of age (restricted). We assumed an introductory price of US $7.50 per dose, and varied the annual rate of price decrease in sensitivity analyses. RESULTS: The discounted cost per disability-adjusted life-year averted for restricted, flexible, and on-time schedules was $621, $615, and $581, respectively. For each of the 3 scenarios, the percentage reduction in deaths due to rotavirus infection was 53%, 66%, and 69%, respectively. The cost per disability-adjusted life-year averted for alternative "what-if" scenarios ranged from $229 (assuming a 1-dose schedule, administered on time) to $1491 (assuming a 2-dose schedule, with half the baseline vaccine efficacy rates and a restricted timing policy). CONCLUSIONS: On the basis of current World Health Organization guidelines, rotavirus vaccination represents a highly cost-effective intervention in Peru. Withholding the vaccine from children who present for their first dose after 12 weeks of age would reduce the number of deaths averted by approximately 20%. A single dose may be more cost-effective than 2 doses, but more evidence on the protection conferred by a single dose is required.

Update on the global epidemiology of intussusception: a systematic review of incidence rates, age distributions and case-fatality ratios among children aged <5 years, before the introduction of rotavirus vaccination.

BACKGROUND: In some countries that have introduced oral rotavirus vaccines, a small but elevated risk of intussusception-a rare bowel disorder-has been reported. Updated estimates on the global epidemiology of intussusception are needed to help predict the potential number of intussusception cases that could be caused by the vaccine in different settings. METHODS: We estimated incidence rates, age distributions and case-fatality ratios (CFRs) for intussusception hospital admissions among children aged <5 years, before the introduction of rotavirus vaccines. We included all articles identified in a systematic review between January 2002 and January 2018, and contacted authors for more granular unpublished data on age distributions. RESULTS: We identified 128 articles containing 227 country datasets (61 age distributions, 71 incidence rates and 95 CFRs). The median age of intussusception ranged from 29 weeks in Africa (83% of cases in the first year of life) to 70 weeks in the Western Pacific region (35% of cases in the first year of life). The median (range) annual incidence of intussusception hospital admissions per 100 000 aged <1 year ranged from 34 (13-56) in Africa to 90 (9-380) in the Western Pacific region. We found extreme differences between the CFRs in Africa (1 death in every 10 hospital admissions) and the rest of the world (fewer than 1 death in every 100-2000 hospital admissions). CONCLUSION: Intussusception epidemiology varies by country and region. Understanding and recognizing these differences will be important when assessing the potential number of intussusception cases associated with rotavirus vaccines.

Broadening the age restriction for initiating rotavirus vaccination in regions with high rotavirus mortality: benefits of mortality reduction versus risk of fatal intussusception.

INTRODUCTION: Recently developed rotavirus vaccines have the potential to reduce diarrhea mortality in children in developing countries. Available data to date do not indicate risk of intussusception with these new vaccines. To avoid a potential unanticipated risk post-licensure, it is recommended that rotavirus immunization be initiated before 12 weeks of age when background intussusception rates are low. This policy could exclude a substantial number of children from vaccination, especially in developing countries where delays in vaccination are common. METHODS: We conducted a scenario analysis to assess the potential benefits of mortality reduction from rotavirus versus the risk of fatal intussusception when the first dose of the vaccine is strictly administered by 12 weeks of age compared with a free strategy with vaccine administered before 1 year of age using data on rotavirus disease, vaccine safety and efficacy, and current diphtheria-tetanus-pertussis vaccination rates, and by incorporating hypothetical risks of intussusception. RESULTS: In developing countries, assuming vaccine efficacy of 50% and 75% for doses 1 and 2, respectively, and a hypothetical sixfold and threefold increased relative risk of intussusception within 7 days of doses 1 and 2, respectively, initiating rotavirus immunization before 12 weeks of age would prevent 194,564 of the 517,959 annual rotavirus-associated deaths among children <5 years, while potentially resulting in 1106 fatal intussusception events. Administration of the first dose to infants up to 1 year of age would prevent an additional 54,087 rotavirus-associated deaths (total=248,651) while potentially resulting in an additional 1226 intussusception deaths (total=2332). CONCLUSION: In developing countries, the additional lives saved by broadening the age restrictions for initiation of rotavirus vaccination would far outnumber the hypothetical excess intussusception deaths that would accompany such an approach.