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• W2799334909 abstract "•Antibiotic exposure in infant mice impairs antibody responses to five vaccines•Restoring the commensal microbiota rescues impaired antibody responses•Antibiotic-treated adult mice exhibit normal antibody responses to vaccination•CD4+ T cells from antibiotic-exposed infant mice have enhanced cytokine recall responses Antibody-mediated responses play a critical role in vaccine-mediated immunity. However, for reasons that are poorly understood, these responses are highly variable between individuals. Using a mouse model, we report that antibiotic-driven intestinal dysbiosis, specifically in early life, leads to significantly impaired antibody responses to five different adjuvanted and live vaccines. Restoration of the commensal microbiota following antibiotic exposure rescues these impaired responses. In contrast, antibiotic-treated adult mice do not exhibit impaired antibody responses to vaccination. Interestingly, in contrast to impaired antibody responses, immunized mice exposed to early-life antibiotics display significantly enhanced T cell cytokine recall responses upon ex vivo restimulation with the vaccine antigen. Our results demonstrate that, in mice, antibiotic-driven dysregulation of the gut microbiota in early life can modulate immune responses to vaccines that are routinely administered to infants worldwide. Antibody-mediated responses play a critical role in vaccine-mediated immunity. However, for reasons that are poorly understood, these responses are highly variable between individuals. Using a mouse model, we report that antibiotic-driven intestinal dysbiosis, specifically in early life, leads to significantly impaired antibody responses to five different adjuvanted and live vaccines. Restoration of the commensal microbiota following antibiotic exposure rescues these impaired responses. In contrast, antibiotic-treated adult mice do not exhibit impaired antibody responses to vaccination. Interestingly, in contrast to impaired antibody responses, immunized mice exposed to early-life antibiotics display significantly enhanced T cell cytokine recall responses upon ex vivo restimulation with the vaccine antigen. Our results demonstrate that, in mice, antibiotic-driven dysregulation of the gut microbiota in early life can modulate immune responses to vaccines that are routinely administered to infants worldwide. The composition and function of the infant microbiota can be influenced by a range of factors, including gestational age, route of birth, and infant diet (Bäckhed et al., 2015Bäckhed F. Roswall J. Peng Y. Feng Q. Jia H. Kovatcheva-Datchary P. Li Y. Xia Y. Xie H. Zhong H. et al.Dynamics and stabilization of the human gut microbiome during the first year of life.Cell Host Microbe. 2015; 17: 852Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar, Fouhy et al., 2012Fouhy F. Ross R.P. Fitzgerald G.F. Stanton C. Cotter P.D. Composition of the early intestinal microbiota: knowledge, knowledge gaps and the use of high-throughput sequencing to address these gaps.Gut Microbes. 2012; 3: 203-220Crossref PubMed Scopus (164) Google Scholar, Madan et al., 2016Madan J.C. Hoen A.G. Lundgren S.N. Farzan S.F. Cottingham K.L. Morrison H.G. Sogin M.L. Li H. Moore J.H. Karagas M.R. Association of Cesarean delivery and formula supplementation with the intestinal microbiome of 6-week-old infants.JAMA Pediatr. 2016; 170: 212-219Crossref PubMed Scopus (182) Google Scholar); however, one of the most potent factors leading to dysregulation of the gut microbiota (termed dysbiosis) is antibiotic exposure (Vangay et al., 2015Vangay P. Ward T. Gerber J.S. Knights D. Antibiotics, pediatric dysbiosis, and disease.Cell Host Microbe. 2015; 17: 553-564Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar). A common reason for prolonged direct antibiotic exposure in neonates is for the treatment of neonatal sepsis (or suspected sepsis), which occurs in 1 to 4 per 1000 livebirths in the United States and is even more common in lower-resource countries (Shane et al., 2017Shane A.L. Sánchez P.J. Stoll B.J. Neonatal sepsis.Lancet. 2017; 390: 1770-1780Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar). Furthermore, up to 40% of newborns are indirectly exposed to intrapartum antibiotics (Azad et al., 2016Azad M.B. Konya T. Persaud R.R. Guttman D.S. Chari R.S. Field C.J. Sears M.R. Mandhane P.J. Turvey S.E. Subbarao P. et al.CHILD Study InvestigatorsImpact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study.BJOG. 2016; 123 (Published online September 28, 2015): 983-993Crossref PubMed Scopus (361) Google Scholar). The effects of a single course of intrapartum antibiotics on the composition of the infant microbiota has been shown to persist to at least three months of age (Azad et al., 2016Azad M.B. Konya T. Persaud R.R. Guttman D.S. Chari R.S. Field C.J. Sears M.R. Mandhane P.J. Turvey S.E. Subbarao P. et al.CHILD Study InvestigatorsImpact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study.BJOG. 2016; 123 (Published online September 28, 2015): 983-993Crossref PubMed Scopus (361) Google Scholar). By one year, up to 50% of infants will have been directly exposed to antibiotics, with an average exposure rate of >5 days (Anderson et al., 2017Anderson H. Vuillermin P. Jachno K. Allen K.J. Tang M.L. Collier F. Kemp A. Ponsonby A.L. Burgner D. Barwon Infant Study Investigator GroupPrevalence and determinants of antibiotic exposure in infants: A population-derived Australian birth cohort study.J. Paediatr. Child Health. 2017; 53: 942-949Crossref PubMed Scopus (24) Google Scholar). Early-life intestinal dysbiosis has been associated with a wide variety of diseases including metabolic syndrome (Vijay-Kumar et al., 2010Vijay-Kumar M. Aitken J.D. Carvalho F.A. Cullender T.C. Mwangi S. Srinivasan S. Sitaraman S.V. Knight R. Ley R.E. Gewirtz A.T. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5.Science. 2010; 328: 228-231Crossref PubMed Scopus (1527) Google Scholar), obesity (Turnbaugh et al., 2006Turnbaugh P.J. Ley R.E. Mahowald M.A. Magrini V. Mardis E.R. Gordon J.I. An obesity-associated gut microbiome with increased capacity for energy harvest.Nature. 2006; 444: 1027-1031Crossref PubMed Scopus (8182) Google Scholar), and allergic asthma (Russell et al., 2012Russell S.L. Gold M.J. Hartmann M. Willing B.P. Thorson L. Wlodarska M. Gill N. Blanchet M.R. Mohn W.W. McNagny K.M. Finlay B.B. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma.EMBO Rep. 2012; 13: 440-447Crossref PubMed Scopus (587) Google Scholar). A recent study has also reported that antibiotic exposure in pregnancy is associated with an increased risk of hospitalization with infection in children born to these mothers (Miller et al., 2018Miller J.E. Wu C. Pedersen L.H. de Klerk N. Olsen J. Burgner D.P. Maternal antibiotic exposure during pregnancy and hospitalization with infection in offspring: a population-based cohort study.Int. J. Epidemiol. 2018; 4 (Published online February 4, 2018)Google Scholar). Direct antibiotic exposure in preterm infants has also been associated with increased susceptibility to late-onset sepsis (Kuppala et al., 2011Kuppala V.S. Meinzen-Derr J. Morrow A.L. Schibler K.R. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants.J. Pediatr. 2011; 159: 720-725Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar). Work, mainly in animal models, has now revealed that the microbiota plays a key role in programming the development of innate (Gomez de Agüero et al., 2016Gomez de Agüero M. Ganal-Vonarburg S.C. Fuhrer T. Rupp S. Uchimura Y. Li H. Steinert A. Heikenwalder M. Hapfelmeier S. Sauer U. et al.The maternal microbiota drives early postnatal innate immune development.Science. 2016; 351: 1296-1302Crossref PubMed Scopus (667) Google Scholar) and adaptive immune responses (Honda and Littman, 2016Honda K. Littman D.R. The microbiota in adaptive immune homeostasis and disease.Nature. 2016; 535: 75-84Crossref PubMed Scopus (980) Google Scholar), providing a likely mechanistic rationale for these observed associations. Globally, an estimated 4–19 million children born each year receive routine vaccines against childhood infections but remain unprotected because of limited vaccine effectiveness (Grassly et al., 2015Grassly N.C. Kang G. Kampmann B. Biological challenges to effective vaccines in the developing world.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2015; 370: 20140138Crossref PubMed Scopus (19) Google Scholar). Given the increasingly established links between the microbiota and the immune system, we and others have postulated that the microbiota may also influence vaccine-mediated immune responses, which vary substantially among individuals (Lynn and Pulendran, 2018Lynn D.J. Pulendran B. The potential of the microbiota to influence vaccine responses.J. Leukoc. Biol. 2018; 103 (Published online December 28, 2017): 225-231PubMed Google Scholar). Evidence to support this hypothesis is growing. Two recent studies have shown that the composition of the stool microbiota in infants is correlated with vaccine-specific immune responses (Harris et al., 2017Harris V.C. Armah G. Fuentes S. Korpela K.E. Parashar U. Victor J.C. Tate J. de Weerth C. Giaquinto C. Wiersinga W.J. et al.Significant correlation between the infant gut microbiome and rotavirus vaccine response in rural Ghana.J. Infect. Dis. 2017; 215: 34-41Crossref PubMed Scopus (186) Google Scholar, Huda et al., 2014Huda M.N. Lewis Z. Kalanetra K.M. Rashid M. Ahmad S.M. Raqib R. Qadri F. Underwood M.A. Mills D.A. Stephensen C.B. Stool microbiota and vaccine responses of infants.Pediatrics. 2014; 134: e362-e372Crossref PubMed Scopus (258) Google Scholar). Interestingly, germ-free mice have also been found to have impaired antibody responses to immunization with the model antigen ovalbumin (Lamousé-Smith et al., 2011Lamousé-Smith E.S. Tzeng A. Starnbach M.N. The intestinal flora is required to support antibody responses to systemic immunization in infant and germ free mice.PLoS ONE. 2011; 6: e27662Crossref PubMed Scopus (64) Google Scholar). Recently, antibody responses to the non-adjuvanted influenza vaccine have been found to be impaired in germ-free, antibiotic-treated, and Toll-like receptor 5 (Tlr5)-deficient mice (Oh et al., 2014Oh J.Z. Ravindran R. Chassaing B. Carvalho F.A. Maddur M.S. Bower M. Hakimpour P. Gill K.P. Nakaya H.I. Yarovinsky F. et al.TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination.Immunity. 2014; 41: 478-492Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar), suggesting that TLR5-mediated sensing of flagellin produced by the microbiota could act as a natural adjuvant for non-adjuvanted vaccines. However, antibody responses to several adjuvanted and live vaccines were not found to be impaired in the adult mice investigated in this study. We hypothesized that antibiotic-driven dysbiosis in early life would have a more profound impact on the immune system than adult antibiotic exposure and that it would lead to impaired responses to both adjuvanted and live vaccines. This is important, given that adjuvanted and live vaccines represent all vaccines that are commonly administered to infants. To investigate this hypothesis, we used a maternal antibiotic treatment (MAT) mouse model of early-life antibiotic exposure (Uchiyama et al., 2014Uchiyama R. Chassaing B. Zhang B. Gewirtz A.T. Antibiotic treatment suppresses rotavirus infection and enhances specific humoral immunity.J. Infect. Dis. 2014; 210: 171-182Crossref PubMed Scopus (137) Google Scholar). Briefly, dams and their pups were exposed to ampicillin and neomycin via their drinking water in late pregnancy and throughout the pre-weaning mouse infant period. Ampicillin and neomycin represent two classes of antibiotic that are administered to human infants with suspected sepsis (Fuchs et al., 2016Fuchs A. Bielicki J. Mathur S. Sharland M. Van Den Anker J.N. Antibiotic Use for Sepsis in Neonates and Children: 2016 Evidence Update.WHO Reviews. 2016; http://www.who.int/selection_medicines/committees/expert/21/applications/s6_paed_antibiotics_appendix4_sepsis.pdfGoogle Scholar), although they would not usually be administered orally and our model uses a supra-physiological dose of neomycin (see STAR Methods). Antibiotic exposure resulted in significant dysbiosis, characterized by up to a 4-log-fold reduction in bacterial load in fecal samples collected from the dams (data not shown) and their offspring at the end of the antibiotic exposure period (day 21) (Figure 1A ). At 1 week post-antibiotic exposure (D28), the bacterial load in mice exposed to antibiotics (we refer to these pups as “ABX” mice) had returned to levels more comparable (within 1-log-fold) to untreated mice of the same age (“NO ABX” mice). Despite the recovery in bacterial load at D28, 16S rRNA sequencing revealed significant changes in the composition of the microbiota in the ABX mice and a significant loss in bacterial diversity (Figures 1B and 1C and Table S1). These differences in the composition of the microbiota remained significant for up to 13 weeks post-antibiotic exposure (Figure 1D). Dysbiosis following antibiotic exposure was characterized by the loss of Bacteroidetes and the colonization of a severely restricted microbiota initially dominated by the Lachnospiraceae and/or Enterobacteriaceae families of bacteria, and followed by a subsequent overgrowth of Akkermansia. A similar pattern was observed in each independent experiment, although the specific composition following antibiotic exposure was variable (Figures S1A–S1J). This mirrors the situation in human infants, in which antibiotic exposure alters the diversity, maturation, and composition of the microbiota but the dominant bacterial species after antibiotic exposure varies significantly between individuals (Bokulich et al., 2016Bokulich N.A. Chung J. Battaglia T. Henderson N. Jay M. Li H. D Lieber A. Wu F. Perez-Perez G.I. Chen Y. et al.Antibiotics, birth mode, and diet shape microbiome maturation during early life.Sci. Transl. Med. 2016; 8: 343ra82Crossref PubMed Scopus (734) Google Scholar). To assess the impact of antibiotic-driven dysbiosis on subsequent vaccine responses in these mice, we began by immunizing 28-day-old (day V) ABX and NO ABX pups with a live attenuated vaccine, the Bacillus Calmette-Guerin (BCG) vaccine. BCG is one of the most widely administered vaccines worldwide, with over 120 million doses given each year to infants to provide protection against tuberculosis (TB) (Ritz et al., 2008Ritz N. Hanekom W.A. Robins-Browne R. Britton W.J. Curtis N. Influence of BCG vaccine strain on the immune response and protection against tuberculosis.FEMS Microbiol. Rev. 2008; 32: 821-841Crossref PubMed Scopus (145) Google Scholar). While protection is thought to be predominantly T cell mediated, antibody-mediated immunity has been suggested to play a significant role in providing protection against TB (Achkar and Casadevall, 2013Achkar J.M. Casadevall A. Antibody-mediated immunity against tuberculosis: implications for vaccine development.Cell Host Microbe. 2013; 13: 250-262Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). We found that antigen-specific IgG responses were significantly impaired in ABX mice vaccinated with the BCG vaccine for up to 12 weeks post-immunization (Figure 1E). IgG1, IgG2c, and IgM responses were also all significantly lower in the ABX mice (Figures S2A–S2C). Boosting the initial antibody response by administering another dose of BCG vaccine at V+2 weeks did not rescue impaired responses. Interestingly, adult mice treated with the same dose of antibiotics for 3 weeks did not have impaired IgG responses to BCG vaccination (Figure S2D). It should be noted that BCG was administered to pups at D28 in our model, whereas it is recommended for administration at birth in infants. However, in low-resource countries, where dysbiosis is common, administration of BCG to infants is frequently delayed until infants are several months old (Clark and Sanderson, 2009Clark A. Sanderson C. Timing of children’s vaccinations in 45 low-income and middle-income countries: an analysis of survey data.Lancet. 2009; 373: 1543-1549Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, Olusanya, 2010Olusanya B.O. Pattern and determinants of BCG immunisation delays in a sub-Saharan African community.Health Res. Policy Syst. 2010; 8: 1Crossref PubMed Scopus (29) Google Scholar). We next investigated antibody responses in ABX mice immunized with one of four adjuvanted vaccines that are frequently administered to human infants (Feldstein et al., 2017Feldstein L.R. Mariat S. Gacic-Dobo M. Diallo M.S. Conklin L.M. Wallace A.S. Global routine vaccination coverage, 2016.Wkly. Epidemiol. Rec. 2017; 92: 701-707PubMed Google Scholar, Medini et al., 2015Medini D. Stella M. Wassil J. MATS: Global coverage estimates for 4CMenB, a novel multicomponent meningococcal B vaccine.Vaccine. 2015; 33: 2629-2636Crossref PubMed Scopus (88) Google Scholar): these included the Bexsero meningococcal serogroup B vaccine (MenB); the NeisVac-C meningococcal serogroup C vaccine (MenC); the Prevenar 13-valent pneumococcal conjugate vaccine (PCV13); and the INFANRIX Hexa combination vaccine (Hexa), which contains antigens from hepatitis B, diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, and inactivated poliomyelitis virus (IPV). Each vaccine was investigated as an independent experiment. As with the BCG experiment, we found that up to 12 weeks after the initial immunization (V+12 weeks), ABX mice had significantly impaired antigen-specific IgG responses to all four vaccines compared to unexposed mice (Figures 1F–1I). Infants usually receive multiple doses of each vaccine in their first year of life to achieve optimal antibody responses. PCV13 and Hexa vaccine responses were boosted at V+2 and V+4 weeks, which was intended to broadly model the three doses of these vaccines that human infants receive at 2, 4, and 6 months of age in Australia and the United States. The MenB vaccine was boosted at V+2 weeks. Boosting vaccine responses appeared to partially rescue the impaired antibody responses in some cases; however, this was transient, and by V+12 weeks, IgG responses to all of the vaccines were significantly impaired in ABX mice. On average, antigen-specific IgG titers at V+12 weeks were 50% higher in mice not exposed to early-life antibiotics. There was no significant difference in total IgG between antibiotic-exposed and unexposed mice, indicating that the impairment was not due to a gross defect in humoral immunity in these mice (Figures S2E–S2H). Interestingly, we observed a much more modest impairment of antibody responses (at V+2 weeks only) to the non-adjuvanted seasonal influenza vaccine (Influvac) in ABX mice (Figure 1J) than has been previously reported (Oh et al., 2014Oh J.Z. Ravindran R. Chassaing B. Carvalho F.A. Maddur M.S. Bower M. Hakimpour P. Gill K.P. Nakaya H.I. Yarovinsky F. et al.TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination.Immunity. 2014; 41: 478-492Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar). Furthermore, we did not find antibody responses to this vaccine to be significantly impaired in Tlr5−/− mice in comparison to littermate wild-type mice (Figure S3A). The reasons for these discrepancies with the previous study are currently unclear, but may relate to differences in the microbiota, differences in the ages of the mice, or differences in the strain of influenza used in the vaccine, which changes from year to year. Interestingly, we did observe significant differences in PCV13 antibody responses between non-littermate wild-type and Tlr5−/− mice, which appeared to be driven by differences in the microbiota of these mice (Figures S3B–S3D). Antibody responses were not impaired in Tlr5−/− mice following backcrossing to standardize the microbiota in the Tlr5−/− and wild-type mice (Figures S3E–S3G). This suggests that differences in the composition of the microbiota could influence vaccine antibody responses irrespective of antibiotic exposure. Our model includes a much longer antibiotic exposure period than would be common in most clinical situations. We therefore next considered whether shorter periods of antibiotic exposure would also lead to impaired antibody responses. To investigate this, dams were exposed to the same dose of antibiotics from approximately embryonic day 14 (E14) to the birth of their pups (D1) (i.e., 5 to 6 days of exposure), from E14 to D7 post-birth, or from E14 to D14 post-birth. Each different duration of antibiotic exposure resulted in significant dysbiosis around the time of the initial immunization at D28 (Figures S1G–S1I). The pups born to these dams were vaccinated with the PCV13 vaccine at D28 (i.e., up to 4 weeks after antibiotic exposure ceased). Colonization with Akkermansia was more common in these mice at D28 compared to mice exposed to antibiotics until D21, which may reflect the longer time period since the cessation of antibiotic exposure. We found that, despite receiving a prime and two boost immunizations (at V+2 and V+4 weeks), PCV13-specific or pneumococcal polysaccharide serotype 3 (PPS3)-specific antibody responses were significantly impaired up to 8 weeks post-vaccination (Figures 2A–2C and Figures S2I–S2K). These data show that indirect maternal antibiotic exposure is sufficient to lead to impaired vaccine antibody responses. We noted that by V+12 weeks, responses were not significantly different. This was in contrast to PCV13-immunized mice exposed to antibiotics to D21 (Figure 1H). Additionally, in some of the PCV13 experiments we observed that responses were impaired at V+4 weeks but not in others. This suggests that the nature of dysbiosis at the time of the initial immunization, which varied substantially (Figure S1), and/or at the time of boosting may play important roles. Further work is needed to more fully investigate this. Interestingly, as we observed with BCG-immunized adult mice, adult mice exposed to the same dose of antibiotics for 3 weeks did not have impaired IgG responses to the PCV13 vaccine (Figure 2D), even though adult mice developed similar antibiotic-driven dysbiosis (Figure S1J). These data indicate that antibiotic-driven dysbiosis, specifically in early-life, leads to impaired antibody responses to vaccination. We hypothesized that colonization with a dysbiotic microbiota following the cessation of antibiotics was a critical factor leading to impaired antibody responses to vaccination, rather than antibiotic exposure per se. To investigate this, we exposed dams to the same dose of antibiotics from E14 to D21, and then continued this antibiotic exposure in their offspring after weaning and for the duration of the experiment (ABX throughout). Continuous antibiotic treatment resulted, as expected, in a significant and continuous reduction in bacterial load throughout the experiment and prevented the overgrowth of a dysbiotic microbiota in these mice (data not shown). Consistent with our hypothesis, PCV13-specific IgG antibody responses in mice continuously exposed to antibiotics were not significantly different from those in untreated mice (Figure 2E). To further investigate this, we attempted to rescue impaired vaccine antibody responses in ABX mice by partially reconstituting the commensal microbiota after the cessation of antibiotic exposure. To do this, ABX mice were gavaged with the cecal contents of age-matched, untreated control mice. ABX mice that received a fecal microbiota transfer (FMT) from untreated mice did not have impaired responses to PCV13 vaccination (Figure 2F). In contrast, ABX mice that received a FMT of cecal contents collected from other antibiotic exposed mice had significantly impaired IgG responses to PCV13. The cecal contents of the antibiotic treated mice used in the “dysbiotic” FMT consisted predominantly of Enterobacter (relative abundance > 90% as determined by 16S rRNA sequencing; data not shown). MALDI biotype analysis and genome sequencing identified isolates cultured from the cecal contents as Enterobacter cloacae. Blooms of Enterobacter are commonly observed in humans and mice following antibiotic exposure (Zeng et al., 2017Zeng M.Y. Inohara N. Nuñez G. Mechanisms of inflammation-driven bacterial dysbiosis in the gut.Mucosal Immunol. 2017; 10: 18-26Crossref PubMed Scopus (366) Google Scholar). Further work in germ-free mice is needed to determine if Enterobacter is causatively linked to impaired antibody responses. Vaccine-mediated immunity is highly dependent on the induction of antibody responses against vaccine antigens. However, the generation of long-term T cell memory responses has also been shown to regulate the protective effects of some vaccines, including those against influenza, measles, pertussis, and tuberculosis (Siegrist, 2008Siegrist C.A. Vaccine immunology. Vaccines S.A. Plotkin.in: Orenstein W.A. Offit P.A. Elsevier Inc, Philadelphia, PA2008: 17-36Google Scholar). Surprisingly, in contrast to impaired antigen-specific antibody responses, splenocytes or purified CD4+ T cells that were isolated from ABX mice up to 12 weeks following initial immunization with PCV13 and re-stimulated in culture with vaccine antigen had significantly higher production of interferon γ (IFNγ) (Figures 2G and 2H) and other cytokines (Figures S4A–S4F) than cells isolated from unexposed mice. Co-culture of purified CD4+ T cells with antigen-presenting cells (APC) from either ABX or unexposed mice resulted in comparable levels of IFNγ production (Figure 2H), suggesting that the effect is T cell intrinsic, although this does not rule out a differential role for APCs in immune priming in ABX mice at the time of immunization. Interestingly, splenocytes isolated from mice continuously exposed to antibiotics did not produce more IFNγ in response to ex vivo stimulation (Figure 2I), suggesting that this effect is also driven by dysbiosis after antibiotic exposure. Stimulation of splenocytes isolated from an independent group of INFANRIX Hexa-immunized ABX mice with the vaccine antigens pertactin (Figure 2J), inactivated pertussis toxin, diphtheria toxoid, or tetanus toxoid (Figures S4G–S4I) also induced significantly enhanced IFNγ production. These data suggest that early-life antibiotic-driven dysbiosis may enhance T cell recall responses to vaccines, though further work in vivo and in the context of infection is now needed to confirm this. Vaccines are one of the most effective frontline strategies available to prevent infectious diseases; however, inter-individual responses to vaccination are highly variable (Finan et al., 2008Finan C. Ota M.O. Marchant A. Newport M.J. Natural variation in immune responses to neonatal Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccination in a cohort of Gambian infants.PLoS ONE. 2008; 3: e3485Crossref PubMed Scopus (29) Google Scholar, Payton et al., 2013Payton T. Girgenti D. Frenck R.W. Patterson S. Love J. Razmpour A. Sidhu M.S. Emini E.A. Gruber W.C. Scott D.A. Immunogenicity, safety and tolerability of 3 lots of 13-valent pneumococcal conjugate vaccine given with routine pediatric vaccinations in the United States.Pediatr. Infect. Dis. J. 2013; 32: 871-880Crossref PubMed Scopus (17) Google Scholar). In this study, we demonstrated that early-life antibiotic-driven dysbiosis in mice led to significantly impaired antibody responses to five different adjuvanted and live vaccines that are routinely administered to infants worldwide. Twelve weeks after the initial immunizations, antibody responses were impaired in antibiotic exposed mice by up to 50%, suggesting that the duration of antibody responses in antibiotic-exposed mice may be particularly impacted. These data suggest that the microbiota is an important factor influencing vaccine responsiveness and may also be a contributing factor to the lower rates of vaccine immunogenicity that are observed in developing-world populations in which infant dysbiosis is common (Valdez et al., 2014Valdez Y. Brown E.M. Finlay B.B. Influence of the microbiota on vaccine effectiveness.Trends Immunol. 2014; 35: 526-537Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). Our data suggest that early-life antibiotic exposure is particularly important in shaping subsequent responses to vaccines, as adult mice exposed to the same dose and duration of antibiotics did not have impaired vaccine antibody responses. Other recent studies also suggest that the immune system may be particularly susceptible to influence by the microbiota early in life (Gensollen et al., 2016Gensollen T. Iyer S.S. Kasper D.L. Blumberg R.S. How colonization by microbiota in early life shapes the immune system.Science. 2016; 352: 539-544Crossref PubMed Scopus (956) Google Scholar). Given that up to 50% of human infants are exposed to antibiotics (Anderson et al., 2017Anderson H. Vuillermin P. Jachno K. Allen K.J. Tang M.L. Collier F. Kemp A. Ponsonby A.L. Burgner D. Barwon Infant Study Investigator GroupPrevalence and determinants of antibiotic exposure in infants: A population-derived Australian birth cohort study.J. Paediatr. Child Health. 2017; 53: 942-949Crossref PubMed Scopus (24) Google Scholar), our findings, if confirmed in infants, could have significant implications for vaccination programs worldwide. Interestingly, we also found that differences in the compo" @default.
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• W2799334909 title "Early-Life Antibiotic-Driven Dysbiosis Leads to Dysregulated Vaccine Immune Responses in Mice" @default.
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