Association between Gut Microbiome Composition and Rotavirus Vaccine Response among Nicaraguan Infants

Jonathan Fix University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;

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Kshipra Chandrashekhar University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;

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Johann Perez Center of Infectious Diseases, Department of Microbiology and Parasitology, Faculty of Medical Sciences, National Autonomous University of Nicaragua, León (UNAN-León), León, Nicaragua;

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Filemon Bucardo Center of Infectious Diseases, Department of Microbiology and Parasitology, Faculty of Medical Sciences, National Autonomous University of Nicaragua, León (UNAN-León), León, Nicaragua;

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Michael G. Hudgens University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;

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Lijuan Yuan Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia

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Erica Twitchell Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia

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Maria Andrea Azcarate-Peril University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;

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Samuel Vilchez Center of Infectious Diseases, Department of Microbiology and Parasitology, Faculty of Medical Sciences, National Autonomous University of Nicaragua, León (UNAN-León), León, Nicaragua;

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Sylvia Becker-Dreps University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;

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Rotavirus is the leading cause of childhood deaths due to diarrhea. Although existing oral rotavirus vaccines are highly efficacious in high-income countries, these vaccines have been demonstrated to have decreased efficacy in low- and middle-income countries. A possible explanation for decreased efficacy is the impact of gut microbiota on the enteric immune system’s response to vaccination. We analyzed the gut microbiome of 50 children enrolled in a prospective study evaluating response to oral pentavalent rotavirus vaccination (RV5) to assess associations between relative abundance of bacterial taxa and seroconversion following vaccination. Stool samples were taken before the first RV5 dose, and microbiome composition characterized using 16S rRNA amplicon sequencing and Quantitative Insights Into Microbial Ecology software. Relative abundance of bacterial taxa between seroconverters following the first RV5 dose, those with ≥ 4-fold increase in rotavirus-specific IgA titers, and nonseroconverters were compared using the Wilcoxon–Mann–Whitney test. We identified no significant differences in microbiome composition between infants who did and did not respond to vaccination. Infants who responded to vaccination tended to have higher abundance of Proteobacteria and Eggerthella, whereas those who did not respond had higher abundance of Fusobacteria and Enterobacteriaceae; however, these differences were not statistically significant following a multiple comparison correction. This study suggests a limited impact of gut microbial taxa on response to oral rotavirus vaccination among infants; however, additional research is needed to improve our understanding of the impact of gut microbiome on vaccine response, toward a goal of improving vaccine efficacy and rotavirus prevention.

Author Notes

Address correspondence to Jonathan Fix, University of North Carolina at Chapel Hill, McGavran Greenberg Hall, Chapel Hill, NC 27599. E-mail: jonathan_fix@med.unc.edu

Financial support: This research was supported by a Grand Challenges Grant # OPP1108188 from the Bill and Melinda Gates Foundation. The UNC Microbiome Core is supported by NIH P30 DK34987. M. G. H. reports grants from NIH during the conduct of the study. S. B. D. reports grants from the Bill & Melinda Gates Foundation and from the National Institute of Allergy and Infectious Diseases during the conduct of the study.

Authors’ addresses: Jonathan Fix, Kshipra Chandrashekhar, Michael G. Hudgens, Maria Andrea Azcarate-Peril, and Sylvia Becker-Dreps, University of North Carolina at Chapel Hill, Chapel Hill, NC, E-mails: jonathan_fix@med.unc.edu, kshipra@email.unc.edu, mhudgens@email.unc.edu, andrea_azcarate-peril@med.unc.edu, and sbd@email.unc.edu. Johann Perez, Filemon Bucardo, and Samuel Vilchez, Center of Infectious Diseases, Department of Microbiology and Parasitology, Faculty of Medical Sciences, National Autonomous University of Nicaragua, León (UNAN-León), León, Nicaragua, E-mails: johann2636@gmail.com, fili_bucardo@hotmail.com, samuelvilchez@gmail.com. Lijuan Yuan and Erica Twitchell, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, E-mails: lyuan@vt.edu and ericaltwitchell@gmail.com.

These authors contributed equally to this work.

  • 1.

    Liu L et al. Child Health Epidemiology Reference Group of WHO, Unicef, 2012. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 379: 21512161.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Tate JE, Burton AH, Boschi-Pinto C, Parashar UD; World Health Organization-Coordinated Global Rotavirus Surveillance Network, 2016. Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000–2013. Clin Infect Dis 62 (Suppl 2): S96S105.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Kotloff KL et al. 2013. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the global enteric multicenter study, GEMS): a prospective, case-control study. Lancet 382: 209222.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Vesikari T et al. 2006. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 354: 2333.

  • 5.

    Armah GE et al. 2010. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial. Lancet 376: 606614.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Zaman K et al. 2010. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial. Lancet 376: 615623.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Ruiz-Palacios GM et al. 2006. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 354: 1122.

  • 8.

    Vesikari T, Karvonen A, Prymula R, Schuster V, Tejedor JC, Cohen R, Meurice F, Han HH, Damaso S, Bouckenooghe A, 2007. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study. Lancet 370: 17571763.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Madhi SA et al. 2010. Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med 362: 289298.

  • 10.

    Linhares AC et al. 2008. Efficacy and safety of an oral live attenuated human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in Latin American infants: a randomised, double-blind, placebo-controlled phase III study. Lancet 371: 11811189.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Bhandari N et al. 2014. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. Lancet 383: 21362143.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Isanaka S et al. 2017. Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger. N Engl J Med 376: 11211130.

  • 13.

    Murgas Torrazza R, Neu J, 2011. The developing intestinal microbiome and its relationship to health and disease in the neonate. J Perinatol 31 (Suppl 1): S29S34.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Brestoff JR, Artis D, 2013. Commensal bacteria at the interface of host metabolism and the immune system. Nat Immunol 14: 676684.

  • 15.

    Atarashi K et al. 2011. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331: 337341.

  • 16.

    Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL, 2005. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122: 107118.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Neu J, Rushing J, 2011. Cesarean versus vaginal delivery: long-term infant outcomes and the hygiene hypothesis. Clin Perinatol 38: 321331.

  • 18.

    Pandey PK, Verma P, Kumar H, Bavdekar A, Patole MS, Shouche YS, 2012. Comparative analysis of fecal microflora of healthy full-term Indian infants born with different methods of delivery (vaginal vs cesarean): Acinetobacter sp. prevalence in vaginally born infants. J Biosci 37: 989998.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    O’Sullivan A, Farver M, Smilowitz JT, 2015. The influence of early infant-feeding practices on the intestinal microbiome and body composition in infants. Nutr Metab Insights 8: 19.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Fujimura KE, Slusher NA, Cabana MD, Lynch SV, 2010. Role of the gut microbiota in defining human health. Expert Rev Anti Infect Ther 8: 435454.

  • 21.

    Korpe PS, Petri WA Jr., 2012. Environmental enteropathy: critical implications of a poorly understood condition. Trends Mol Med 18: 328336.

  • 22.

    Parker EP, Ramani S, Lopman BA, Church JA, Iturriza-Gomara M, Prendergast AJ, Grassly NC, 2018. Causes of impaired oral vaccine efficacy in developing countries. Future Microbiol 13: 97118.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Huda MN, Lewis Z, Kalanetra KM, Rashid M, Ahmad SM, Raqib R, Qadri F, Underwood MA, Mills DA, Stephensen CB, 2014. Stool microbiota and vaccine responses of infants. Pediatrics 134: e362e372.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Praharaj I et al. 2019. Influence of nonpolio enteroviruses and the bacterial gut microbiota on oral poliovirus vaccine response: a study from south India. J Infect Dis 219: 11781186.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Huda MN, Ahmad SM, Alam MJ, Khanam A, Kalanetra KM, Taft DH, Raqib R, Underwood MA, Mills DA, Stephensen CB, 2019. Bifidobacterium abundance in early infancy and vaccine response at 2 years of age. Pediatrics 143: e20181489.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Harris VC et al. 2017. Significant correlation between the infant gut microbiome and rotavirus vaccine response in rural Ghana. J Infect Dis 215: 3441.

  • 27.

    Harris V et al. 2017. Rotavirus vaccine response correlates with the infant gut microbiota composition in Pakistan. Gut Microbes 9:93101.

  • 28.

    Twitchell EL et al. 2016. Modeling human enteric dysbiosis and rotavirus immunity in gnotobiotic pigs. Gut Pathog 8: 51.

  • 29.

    Uchiyama R, Chassaing B, Zhang B, Gewirtz AT, 2014. Antibiotic treatment suppresses rotavirus infection and enhances specific humoral immunity. J Infect Dis 210: 171182.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Becker-Dreps S, Vilchez S, Bucardo F, Twitchell E, Choi WS, Hudgens MG, Perez J, Yuan L, 2017. The association between fecal biomarkers of environmental enteropathy and rotavirus vaccine response in Nicaraguan infants. Pediatr Infect Dis J 36: 412416.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Lozupone CA, Turnbaugh PJ, Fierer N, Knight R, 2011. Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample. Proc Natl Acad Sci USA 108 (Suppl 1): 45164522.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Allali I et al. 2017. A comparison of sequencing platforms and bioinformatics pipelines for compositional analysis of the gut microbiome. BMC Microbiol 17: 194.

  • 33.

    Illumina Inc., 2016. Bcl2Fastq 2.18.0.12. San Diego, CA.

  • 34.

    Caporaso JG et al. 2010. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 7: 335336.

  • 35.

    Aronesty E, 2013. Comparison of sequencing utility programs. Open Bioinform J 7: 18.

  • 36.

    Babraham Institute, 2014. FastQC 0.11.2. Cambridge, United Kingdom.

  • 37.

    Edgar RC, 2010. Search and clustering orders of magnitude faster than BLAST. Bioinformatics 26: 24602461.

  • 38.

    Rognes T, Flouri T, Nichols B, Quince C, Mahe F, 2016. VSEARCH: a versatile open source tool for metagenomics. PeerJ 4: e2584.

  • 39.

    Haas BJ et al. 2011. Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons. Genome Res 21: 494504.

  • 40.

    DeSantis TZ, Hugenholtz P, Larsen N, Rojas M, Brodie EL, Keller K, Huber T, Dalevi D, Hu P, Andersen GL, 2006. Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB. Appl Environ Microbiol 72: 50695072.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Caporaso JG, Bittinger K, Bushman FD, DeSantis TZ, Andersen GL, Knight R, 2010. PyNAST: a flexible tool for aligning sequences to a template alignment. Bioinformatics 26: 266267.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Price MN, Dehal PS, Arkin AP, 2010. FastTree 2—approximately maximum-likelihood trees for large alignments. PLoS One 5: e9490.

  • 43.

    Lozupone C, Hamady M, Knight R, 2006. UniFrac—an online tool for comparing microbial community diversity in a phylogenetic context. BMC Bioinf. 7: 371.

  • 44.

    Lozupone C, Knight R, 2005. UniFrac: a new phylogenetic method for comparing microbial communities. Appl Environ Microbiol 71: 82288235.

  • 45.

    Dabdoub SM, Fellows ML, Paropkari AD, Mason MR, Huja SS, Tsigarida AA, Kumar PS, 2016. PhyloToAST: bioinformatics tools for species-level analysis and visualization of complex microbial datasets. Sci Rep 6: 29123.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Kearse M et al. 2012. Geneious basic: an integrated and extendable desktop software platform for the organization and analysis of sequence data. Bioinformatics 28: 16471649.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Letunic I, Bork P, 2007. Interactive tree of life (iTOL): an online tool for phylogenetic tree display and annotation. Bioinformatics 23: 127128.

  • 48.

    Letunic I, Bork P, 2011. Interactive tree of life v2: online annotation and display of phylogenetic trees made easy. Nucleic Acids Res 39: W475W478.

  • 49.

    Letunic I, Bork P, 2016. Interactive tree of life (iTOL) v3: an online tool for the display and annotation of phylogenetic and other trees. Nucleic Acids Res 44: W242W245.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Gardiner BJ, Tai AY, Kotsanas D, Francis MJ, Roberts SA, Ballard SA, Junckerstorff RK, Korman TM, 2015. Clinical and microbiological characteristics of Eggerthella lenta bacteremia. J Clin Microbiol 53: 626635.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Parker EPK et al. 2018. Influence of the intestinal microbiota on the immunogenicity of oral rotavirus vaccine given to infants in south India. Vaccine 36: 264272.

  • 52.

    Zimmermann P, Curtis N, 2018. The influence of the intestinal microbiome on vaccine responses. Vaccine 36: 44334439.

  • 53.

    Naito Y, Uchiyama K, Takagi T, 2018. A next-generation beneficial microbe: Akkermansia muciniphila. J Clin Biochem Nutr 63: 3335.

  • 54.

    Chelakkot C et al. 2018. Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions. Exp Mol Med 50: e450.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55.

    Aldridge KE, Ashcraft D, O’Brien M, Sanders CV, 2003. Bacteremia due to Bacteroides fragilis group: distribution of species, beta-lactamase production, and antimicrobial susceptibility patterns. Antimicrob Agents Chemother 47: 148153.

    • PubMed
    • Search Google Scholar
    • Export Citation
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