A Randomized, Controlled Trial of the Impact of Alternative Dosing Schedules on the Immune Response to Human Rotavirus Vaccine in Rural Ghanaian Infants

The Journal of Infectious Diseases MAJOR ARTICLE A Randomized, Controlled Trial of the Impact of Alternative Dosing Schedules on the Immune Response to Human Rotavirus Vaccine in Rural Ghanaian Infants George Armah,1 Kristen D. C. Lewis,4,a Margaret M. Cortese,5 Umesh D. Parashar,5 Akosua Ansah,2 Lauren Gazley,4,a John C. Victor,4 Monica M. McNeal,6 Fred Binka,3 and A. Duncan Steele4,a 1 Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, 2Navrongo Health Research Centre, and 3University of Health and Allied Health Services, Ho, Ghana; 4PATH, Seattle, Washington; 5Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; and 6Department of Pediatrics, Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Ohio (See the editorial commentary by Cunliffe and Kang on pages 1673–5, and major article by Zaman et al on pages 1686–93.) Rotavirus is a leading cause of diarrhea-associated mortality among children <5 years of age in low-income countries (LICs) [1, 2], with countries in sub-Saharan Africa exhibiting the highest rates of rotavirus-associated mortality [2]. In Ghana, rotavirus is a common cause of diarrhea, circulating from approximately September/October to February/March [3–6]. Prior to widespread introduction of rotavirus vaccine, Received 14 August 2015; accepted 30 November 2015; published online 27 January 2016. Presented in part: Vaccines for Enteric Diseases Conference, Bangkok, Thailand, 6–8 November 2013; African Rotavirus Symposium, Livingstone, Zambia, 12–13 June 2014. a Present affiliations: Pneumonia Global Health Program (K. D. C. L.) and Enteric and Diarrheal Diseases Global Health Program (A. D. S.), Bill & Melinda Gates Foundation, Seattle, Washington; and Trillium Community Health Plan, Eugene, Oregon (L. G.). Correspondence: K. D. C. Lewis, PO Box 23350, Seattle, WA 98102-0650 (kristen.lewis@ gatesfoundation.org). The Journal of Infectious Diseases® 2016;213:1678–85 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/ 4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, contact . DOI: 10.1093/infdis/jiw023 1678 • JID 2016:213 (1 June) • Armah et al rotavirus was responsible for approximately 50% of diarrheal hospitalizations among children aged <5 years [7]. Two orally administered human rotavirus vaccines (HRVs), Rotarix (GSK Biologicals, Rixensart, Belgium) and RotaTeq (Merck, West Point, Pennsylvania), are recommended by the World Health Organization (WHO) for inclusion in the infant immunization series. While antirotavirus immunoglobulin A (IgA) seroconversion frequencies with these vaccines range between approximately 87% and 95% in high-income countries (HICs) [8, 9], rates in Africa and Asia have been consistently lower, between 36% and 78% [3, 10–12]. Similarly, IgA geometric mean concentrations (GMCs) in LICs are approximately 5–10 times lower than those in HICs [3], and, while vaccine efficacy against severe rotavirus diarrhea in HICs is high [8, 13], there is moderate efficacy among children in LICs [10, 14–16]. The reasons postulated for the observed reduced response to rotavirus vaccines in LICs include the presence of high maternal antirotavirus antibody titers, interference by the first dose of coadministered oral polio vaccine (OPV), altered gut microbiota, enteropathy, and malnutrition [17–20]. In LICs, HRV is administered in a 2-dose schedule at 6 and 10 weeks of age (WHO Background. The recommended schedule for receipt of 2-dose human rotavirus vaccine (HRV) coincides with receipt of the first and second doses of diphtheria, pertussis, and tetanus vaccine (ie, 6 and 10 weeks of age, respectively). Alternative schedules and additional doses of HRV have been proposed and may improve vaccine performance in low-income countries. Methods. In this randomized trial in rural Ghana, HRV was administered at ages 6 and 10 weeks (group 1), 10 and 14 weeks (group 2), or 6, 10, and 14 weeks (group 3). We compared serum antirotavirus immunoglobulin A (IgA) seroconversion (≥20 U/mL) and geometric mean concentrations (GMCs) between group 1 and groups 2 and 3. Results. Ninety-three percent of participants (424 of 456) completed the study per protocol. In groups 1, 2, and 3, the IgA seroconversion frequencies among participants with IgA levels of <20 U/mL at baseline were 28.9%, 37.4%, and 43.4%, respectively (group 1 vs group 3, P = .014; group 1 vs group 2, P = .163). Postvaccination IgA GMCs were 22.1 U/mL, 26.5 U/mL, and 32.6 U/mL in groups 1, 2, and 3, respectively (group 1 vs group 3, P = .038; group 1 vs group 2, P = .304). Conclusions. A third dose of HRV resulted in increased seroconversion frequencies and GMCs, compared with 2 doses administered at 6 and 10 weeks of age. Since there is no correlate of protection, a postmarketing effectiveness study is required to determine whether the improvement in immune response translates into a public health benefit in low-income countries. Clinical Trials Registration. NCT015751. Keywords. rotavirus; rotavirus vaccines; randomized controlled trial; immunogenicity; infant; vaccines; developing countries; immunization schedules. Helsinki (2008), in compliance with good clinical practice guidelines, and approved by the following ethics review committees: the Ghana Health Service Ethics Review Board, the Navrongo Health Research Center Institutional Review Board (IRB), the Noguchi Memorial Institute for Medical Research (NMIMR) IRB, the Centers for Disease Control and Prevention IRB, and the Western IRB (Olympia, Washington). Randomization and Procedures METHODS All infants eligible for vaccination were randomly assigned to receive liquid HRV at 6 and 10 weeks of age (group 1), 10 and 14 weeks of age (group 2), or 6, 10, and 14 weeks of age (group 3). Randomization was conducted using a computer-generated algorithm, with infants assigned to study groups in blocks of 3 in a 1:1:1 ratio. A baseline blood specimen was collected prior to receipt of the first dose of HRV. A stool specimen was also collected before each HRV dose. All study groups received their rotavirus vaccinations concomitantly with routine EPI vaccines (OPV, pneumococcal conjugate vaccine, and pentavalent diphtheria, pertussis, tetanus, Haemophilus influenzae type b, and hepatitis B vaccine). Breastfeeding was not restricted. Trained field workers visited participants at their homes to collect stool specimens 4 and 7 days (±1 day) after each HRV dose. All participants were asked to report to the study clin (...truncated)