Noninterference of Rotavirus Vaccine With Measles-Rubella Vaccine at 9 Months of Age and Improvements in Antirotavirus Immunity: A Randomized Trial

The Journal of Infectious Diseases MAJOR ARTICLE Noninterference of Rotavirus Vaccine With MeaslesRubella Vaccine at 9 Months of Age and Improvements in Antirotavirus Immunity: A Randomized Trial K. Zaman,1 Jessica A. Fleming,2 John C. Victor,2 Mohammad Yunus,1 Tajul Islam A. Bari,3 Tasnim Azim,1 Mustafizur Rahman,1 Syed Mohammad Niaz Mowla,1 William J. Bellini,4 Monica McNeal,5 Joseph P. Icenogle,4 Ben Lopman,4 Umesh Parashar,4 Margaret M. Cortese,4 A. Duncan Steele,2,a and Kathleen M. Neuzil2,a 1 International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh; 2PATH, Seattle, Washington; 3Office of the Directorate General of Health Services, Dhaka, Bangladesh; 4Centers for Disease Control and Prevention, Atlanta, Georgia; and 5Cincinnati Children’s Hospital Medical Center, Ohio Background. The burden of rotavirus morbidity and mortality is high in children aged <5 years in developing countries, and evaluations indicate waning protection from rotavirus immunization in the second year. An additional dose of rotavirus vaccine may enhance the immune response and lengthen the period of protection against disease, but coadministration of this dose should not interfere with immune responses to concurrently given vaccines. Methods. A total of 480 9-month-old participants from Matlab, Bangladesh, were enrolled in a study with a primary objective to establish noninferiority of concomitant administration of measles-rubella vaccine (MR) and a third dose of human rotavirus vaccine (HRV; MR + HRV), compared with MR given alone. Secondary objectives included noninferiority of rubella antibody seroconversion and evaluating rotavirus IgA/IgG seroresponses in MR + HRV recipients. Results. Two months after vaccination, 75.3% and 74.3% of MR + HRV and MR recipients, respectively, had seroprotective levels of measles virus antibodies; 100.0% and 99.6%, respectively, showed anti–rubella virus immunoglobulin G (IgG) seroprotection. In the MR + HRV group, antirotavirus immunoglobulin A and IgG seropositivity frequencies before vaccination (52.7% and 66.3%, respectively) increased to 69.6% and 88.3% after vaccination. Conclusions. Vaccine-induced measles and rubella antibody responses are not negatively affected by concomitant administration of HRV. The HRV dose increases antirotavirus serum antibody titers and the proportion of infants with detectable antirotavirus antibody. Clinical Trials Registration. NCT01700621. Keywords. rotavirus vaccine; measles vaccine; rubella vaccine; vaccine co-administration; non-interference. Rotavirus-associated morbidity and mortality are high in infants in developing countries and continue to be important through the second year of life [1, 2]. In rural Bangladesh, for example, 45% of the cases of severe rotavirus disease in children <5 years of age occur after the first year of life [3]. Developing world clinical trials and postlicensure evaluations of currently Received 23 October 2015; accepted 1 December 2015; published online 27 January 2016. Presented in part: 11th International Rotavirus Symposium, New Delhi, India, 3–5 September 2014. a Present affiliations: Enteric and Diarrheal Diseases, Bill and Melinda Gates Foundation, Seattle, Washington (A. D. S.); and Center for Vaccine Development and Institute for Global Health, University of Maryland, College Park, Maryland (K. M. N.). Correspondence: J. A. Fleming, PATH, 2201 Westlake Ave, Ste 200, Seattle, WA 98121 (). The Journal of Infectious Diseases® 2016;213:1686–93 © 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/jiw024 1686 • JID 2016:213 (1 June) • Zaman et al available human rotavirus vaccines (HRVs) indicate that protection is sub-optimal and may wane in the second year of life [4–6]. An additional dose of HRV given at 9 months of age along with other Expanded Program on Immunization (EPI) vaccines such as measles-rubella vaccine (MR) might enhance immunity to rotavirus and extend the duration of protection. To consider an additional dose of HRV for inclusion in the current schedule requires the demonstration that co-administration does not interfere with the immune response to the existing MR [7, 8]. We therefore tested the primary hypothesis that the immunogenicity of measles vaccine coadministered with monovalent HRV (Rotarix, GSK Biologicals, Dresden, Germany) at 9 months of age was not inferior to that of measles vaccine (given as MR) when administered alone. Secondary aims included (1) describing the safety profile of concomitant administration of MR and HRV, (2) assessing the noninferiority of the immune response to rubella immunization (as MR) when given concomitantly with HRV, and (3) evaluating the immune response to an additional dose of HRV given at 9 months of age. (See the editorial commentary by Cunliffe and Kang on pages 1673–5, and major article by Armah et al on pages 1678–85.) METHODS Study Design and Participants Procedures Participants were recruited and sequentially assigned in a 1:1 ratio, via block randomization with a block size of 6, to receive either subcutaneous injection of MR (Measles and Rubella Virus Vaccine Live USP, Serum Institute of India, Pune, India) plus lyophilized oral HRV (hereafter, “MR + HRV”) or MR only. Group assignment was masked for all laboratory personnel responsible for immunogenicity and stool testing. All infants were observed for 30 minutes after vaccination, and parents were instructed to seek care at the study clinic for any illnesses in participants during the study period. Local and systemic adverse events were assessed on days 4 (±1), 7 (±1), 11 (±2), 14 (±2), and 28 (±3) after vaccination, through home visits by trained field workers. Solicited adverse events included diarrhea, fever, vomiting, loss of appetite, irritability, and signs of intussusception (defined as colicky abdominal pain or paroxysms of crying and/or screaming, abdominal distention or Outcomes Sera were analyzed for the presence of measles virus serum neutralizing antibodies (SNAs), using a standardized plaquereduction neutralization (PRN) assay, in which PRN titers, defined as the serum dilutions that reduced the number of plaques by 50%, were calculated using the Kärber method [12]. A 1:100 dilution of World Health Organization (WHO) Second International Standard Anti-Measles Serum (IS, coded 66/202, supplied by the National Institute for Biological Standards and Control, South Mimms, United Kingdom) was tested in parallel with each serum specimen to calculate the recipro (...truncated)