Can Changes to Scheduling Enhance the Performance of Rotavirus Vaccines in Low-Income Countries?

Two live, oral, attenuated vaccines are licensed for use in infancy for the global prevention of rotavirus disease, and other vaccines are being developed. The current vaccines include a monovalent human rotavirus vaccine (Rotarix, GlaxoSmithKline Biologicals, Rixensart, Belgium; hereafter “RV1”) and a pentavalent human-bovine reassortant rotavirus vaccine (Rotateq, Merck, West Point, PA; hereafter “RV5”). Prior to rotavirus vaccine introduction into childhood immunization programs, rotavirus gastroenteritis was responsible for an estimated 453 000 childhood deaths globally each year [1]. Both vaccines were highly (>85%) efficacious in reducing the number of severe rotavirus gastroenteritis episodes in high-income and middleincome countries [2]. The high efficacy of these vaccines in clinical trials has translated into impressive effectiveness following their subsequent adoption into infant schedules, with a marked decline in the number of rotavirus hospitalizations reported from the Americas and from Europe. A sustained reduction in the number of diarrheal deaths in Mexico, Brazil, and Panama has been attributed to rotavirus vaccine use [2]. However, the bulk (>90%) of infant deaths due to rotavirus gastroenteritis occur in low-income countries in Africa and Asia. Clinical trials of rotavirus vaccines displayed substantially lower efficacy (approximately 50%) in low-income countries with a high disease burden, including Malawi and Bangladesh. Despite this modest efficacy, the World Health Organization (WHO) extended its recommendation for routine use of rotavirus vaccines to emphasize introduction in low-income countries because of the very high burden of rotavirus disease experienced by children in such settings [3]. Uptake of rotavirus vaccine has been rapid in high-income and middle-income countries and even in countries eligible for the Global Alliance for Vaccines and Immunization (GAVI) in Africa and Latin America, with 80 countries having introduced it by end of 2015: 57 are using RV1, 19 are using RV5, and 4 are using both vaccines [4]. Adoption of rotavirus vaccine in middle-income and low-income countries in Asia has been much slower. There are, so far, limited data on the effectiveness of rotavirus vaccines from GAVI-eligible countries. In Bolivia, where RV1 was introduced in 2008 for administration at 2 and 4 months of age, a case-control study demonstrated vaccine effectiveness against severe rotavirus gastroenteritis of 69% (95% confidence interval [CI], 54%–79%) [5]. Using the accelerated EPI schedule of administration at 6 and 10 weeks of age for the RV1 vaccine and a similar design, vaccine effectiveness in Malawi was 64% (95% CI, 24%–83%) [6]. While these data from early adopter low-income countries offer hope that the rotavirus disease burden could be substantially reduced, the performance of the current live, oral rotavirus vaccines in the world’s poorest countries is clearly suboptimal. Reduced vaccine efficacy/effectiveness in the first year of life (where up to three quarters of the severe rotavirus disease burden lies) is a consistent finding in low-income countries and was documented with a further live, oral, monovalent human-bovine reassortant rotavirus vaccine (116E) in India [7], which showed 56% efficacy (95% CI, 37%– 70%) in a phase 3 clinical trial but has not yet been evaluated in programmatic use. Even when the vaccine does protect in infancy, the longevity of such protection through the second year of life is uncertain. Thus, while rotavirus is known to continue as a significant pathogen into the second year of life in low-income countries [8], current rotavirus vaccines have not consistently demonstrated protection beyond 1 year of age in such settings [9]. However, protection was maintained in the second year of life in a postintroduction study of RV1 in South Africa [10] and in the clinical trial of 116E in India [7]. Many factors have been proposed to explain the lower efficacy/effectiveness of rotavirus and other live, oral enteric vaccines in low-income countries, including interference of concurrent oral poliovirus vaccine (OPV) administration, Received and accepted 12 January 2016; published online 27 January 2016. Correspondence: N. A. Cunliffe, University of Liverpool, Liverpool, Merseyside, UK (n.a.cunliffe@liv.ac.uk; n.a.cunliffe@ liverpool.ac.uk). The Journal of Infectious Diseases 2016;213:1673–5 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup. com. DOI: 10.1093/infdis/jiw026