Vaccine 32 (2014) 651–656 Contents lists available at ScienceDirect Vaccine jou rn al hom ep age: www.elsevier.com/locat e/vaccine Transplacental rotavirus IgG interferes with immune response to live oral rotavirus vaccine ORV-116E in Indian infants  Mohan Babu Appaiahgari a , Roger Glass b , Shakti Singh c , Sunita Taneja c , Temsunaro Rongsen-Chandola c , Nita Bhandari c , Sukhdev Mishra d , Sudhanshu Vrati a,e,∗ a Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Gurgaon 122016, India b Fogarty International Centre, NIH, Bethesda, MD 20892, USA c Society for Applied Studies, New Delhi 110016, India d Clinical Development Services Agency, Translational Health Science and Technology Institute, Gurgaon 122016, India e National Institute of Immunology, New Delhi 110067, India a r t i c l e i n f o Article history: Received 1 July 2013 Received in revised form 15 October 2013 Accepted 10 December 2013 Available online 25 December 2013 Keywords: Maternal antibody Dose Seroconversion IgA Rotavirus Vaccine a b s t r a c t The lower immune response and efficacy of live oral rotavirus (RV) vaccines tested in developing countries may be due in part to high levels of pre-existing RV antibodies transferred to the infant from mother via the placenta. The candidate RV vaccine strain 116E was isolated from a newborn indicating that it might grow well even in the presence of this transplacental rotavirus antibody. Since the immune response to this vaccine among infants in the Indian subcontinent has been greater than that of the commercially licensed vaccines, we questioned whether this might be due to the ability of RV 116E to grow well in infants despite the presence of maternal RV antibody. To this end, we tested pre-immunization sera from Indian infants enrolled in a phase Ia/IIb trial of candidate RV vaccine ORV-116E for transplacental RV IgG to see whether it affected the immune responses and seroconversion to the vaccine. We found that the high titers of transplacental RV IgG diminished the immune responses of infants to ORV-116E vaccine. However, the vaccine was able to overcome the inhibitory effect of this RV IgG in a dose-dependent manner. This report clearly demonstrates the interference of maternal antibody on RV vaccine immunogenicity in infants in a field study as well as the ability of ORV-116E to overcome this interference when used at a higher dose. © 2013 Published by Elsevier Ltd. 1. Introduction Rotavirus (RV) is the leading cause of severe gastroenteritis (GE) in children <5 years of age and is estimated to cause ∼125 million clinical cases of GE worldwide and ∼275,000–450,000 deaths every year, ∼85% of which occur in low income countries [1,2]. Two vac- cines, Rotarix ® and Rotateq ® , are currently licensed internationally [3]. The efficacy of these vaccines against severe rotavirus gastroen- teritis (SRGE) was 85–98% in developed countries, but only ∼51% efficacy in low income settings of Africa and Asia [3–8]. Several factors have been hypothesized to explain this failure, including  Clinical trials registration: NCT00439660 and ISRCTN57452882. ∗ Corresponding author at: Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, 496, Udyog Vihar Phase III, Gurgaon 122016, India. Tel.: +91 124 2876301; fax: +91 124 2876402. E-mail address: vrati@thsti.res.in (S. Vrati). the RV antibodies in breast milk and the high levels of circulating pre-existing maternal RV antibody in the infant that could inhibit replication of these live oral vaccines [3,9–13]. In the late 1980’s, a RV isolate, now known as strain 116E, was identified in neonates at a hospital in New Delhi. Further charac- terization of this strain established it to be a natural human-bovine reassortant [14,15]. Strain 116E was found to have 10 gene seg- ments from a human RV, but a single gene encoding the surface VP4 protein from a bovine strain. VP4 is a hemagglutinin critical for virus attachment and entry and a target for neutralizing antibodies [10]. The bovine origin of this gene was speculated to allow this virus to replicate well in newborns despite the presence of high titers of transplacental RV antibodies [16,17]. In fact, newborns naturally infected with this strain were asymptomatic and shed virus in their stool, mounted high levels of RV-specific IgA following the infec- tion, and were subsequently found to be protected against SRGE [18,19]. A candidate vaccine, ORV-116E, was developed from this strain and phase I and II trials in infants in India demonstrated high 0264-410X/$ – see front matter © 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.vaccine.2013.12.017