Significant Correlation Between the Infant Gut Microbiome and Rotavirus Vaccine Response in Rural Ghana

The Journal of Infectious Diseases MAJOR ARTICLE Significant Correlation Between the Infant Gut Microbiome and Rotavirus Vaccine Response in Rural Ghana Vanessa C. Harris,1,2 George Armah,5 Susana Fuentes,3 Katri E. Korpela,6 Umesh Parashar,7 John C. Victor,8 Jacqueline Tate,7 Carolina de Weerth,4 Carlo Giaquinto,9 Willem Joost Wiersinga,2 Kristen D. C. Lewis,2,a and Willem M. de Vos3,6 1 Amsterdam Institute for Global Health and Development, 2Center for Experimental and Molecular Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Laboratory of Microbiology, Wageningen University, and 4Behavioral Science Institute, Radboud University, Nijmegen, The Netherlands; 5Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon; 6Department of Bacteriology and Immunology, and Immunobiology, University of Helsinki, Finland; 7Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Center for Disease Control and Prevention, Atlanta, Georgia; 8PATH, Vaccine Access and Delivery, Seattle, Washington; and 9Department of Paediatrics, University of Padova, Italy 3 (See the editorial commentary by Iturriza-Gómara and Cunliffe on pages 8–10.) Rotavirus (RV) is the leading cause of diarrhea-related death in children worldwide, with 95% of RV deaths occurring in lowincome countries in Africa and Asia [1]. Oral RV vaccines (RVVs) have the potential to dramatically reduce the morbidity and mortality caused by RV infection, but RVVs demonstrate significantly lower efficacy in low-income countries [2]. Large clinical efficacy studies showed a combined vaccine efficacy Received 9 August 2016; accepted 16 September 2016; published online 31 October 2016. Presented in part: European Congress of Clinical Microbiology and Infectious Diseases, Amsterdam, The Netherlands, 9–12 April 2016. a Present affiliation: Bill & Melinda Gates Foundation, Seattle, Washington. Correspondence: V. C. Harris, Amsterdam Institute for Global Health and Development and Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, The Netherlands (). The Journal of Infectious Diseases® 2017;215:34–41 © 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/jiw518 34 • JID 2017:215 (1 January) • Harris et al against severe RV gastroenteritis ranging from 48% to 64% for both Rotarix and RotaTeq vaccines in Africa and Asia [3–5]. Emerging effectiveness data in Africa provides similar estimates of RVV protection [6]. This compares to an observed efficacy of 85%–98% against severe RV in trials in wealthier countries in Latin America and Europe [7–10]. Understanding the pathophysiologic mechanism driving this diminished efficacy in developing countries is critical, because even small improvements in vaccine efficacy could increase the number of children’s lives saved by the vaccine by hundreds of thousands over the next 15 years [11]. There are several hypotheses as to why oral RVVs are underperforming in Africa and Asia [12]. These include interference with the first dose of coadministered oral poliovirus vaccine, RVV immune response suppression through high prevaccination levels of serum immunoblogulin (Ig) G, including transplacentally derived IgG, high levels of breast milk–derived RV-specific IgA, and HLA blood group antigen type [13–16]. However, none of these explanations have adequately and sufficiently explained Background. Rotavirus (RV) is the leading cause of diarrhea-related death in children worldwide and 95% of RV-associated deaths occur in Africa and Asia where RV vaccines (RVVs) have lower efficacy. We hypothesize that differences in intestinal microbiome composition correlate with the decreased RVV efficacy observed in poor settings. Methods. We conducted a nested, case-control study comparing prevaccination, fecal microbiome compositions between 6week old, matched RVV responders and nonresponders in rural Ghana. These infants’ microbiomes were then compared with 154 age-matched, healthy Dutch infants’ microbiomes, assumed to be RVV responders. Fecal microbiome analysis was performed in all groups using the Human Intestinal Tract Chip. Results. We analyzed findings in 78 Ghanaian infants, including 39 RVV responder and nonresponder pairs. The overall microbiome composition was significantly different between RVV responders and nonresponders (FDR, 0.12), and Ghanaian responders were more similar to Dutch infants than nonresponders (P = .002). RVV response correlated with an increased abundance of Streptococcus bovis and a decreased abundance of the Bacteroidetes phylum in comparisons between both Ghanaian RVV responders and nonresponders (FDR, 0.008 vs 0.003) and Dutch infants and Ghanaian nonresponders (FDR, 0.002 vs 0.009). Conclusions. The intestinal microbiome composition correlates significantly with RVV immunogenicity and may contribute to the diminished RVV immunogenicity observed in developing countries. Keywords. rotavirus vaccine; intestinal microbiome; mucosal immunity. METHODS Study Design and Participants Ghanaian Infants The original trial within which this trial was nested was conducted in Navrongo, a rural setting in Northern Ghana where >70% of the population belong to the lowest wealth quintile in Ghana, in 2012. The neonatal and mortality rates are 24 and 46 deaths per 1000 live births, respectively [19]. All participating infants were healthy infants with a birth weight > 2000 g and/or a gestational age >38 weeks. The infants were enrolled at 6 weeks of age in a previously reported phase IV randomized clinical trial conducted in 2012 in Navrongo to evaluate the immunogenicity of the Rotarix vaccine after different dosing schedules (at age 6 and 10 weeks, 10 and 14 weeks, or 6, 10, and 14 weeks) (NCT01575197, clinicaltrials.gov) [20]. In this trial, all infants received concomitant standard Expanded Program on Immunization vaccinations, including the trivalent oral poliovirus vaccine and pentavalent vaccine (diphtheria, tetanus, wholecell pertussis, hepatitis B, and Haemophilus influenza type). Only infants from the 6- and 10-week and the 6-, 10-, and 14week dose arms of the clinical trial were included in this microbiome study. A serum samples was collected before the receipt of the first dose of vaccine (at 6 weeks of age) and serum was collected again approximately 4 weeks after the last dose of vaccine (at age 14 or 18 weeks, depending on the study arm) for anti-RV IgA antib (...truncated)