Publications by authors named "Arnaud Marchant"

95 Publications

Fc Glycosylation Characterization of Human Immunoglobulins G Using Immunocapture and LC-MS.

Methods Mol Biol 2021 ;2271:57-71

Pharmacognosy, Bioanalysis and Drug Discovery and Analytical Platform, RD3 Department, Faculty of Pharmacy, Université libre de Bruxelles, Brussels, Belgium.

Immunoglobulins G (IgG) are proteins produced by the immune system of higher life forms that play a central role in the defense against microbial pathogens. IgG bind pathogens with the hypervariable Fab component and mediate a diversity of effector functions by binding to immune effector cells via their crystallizable (Fc) component. All IgG Fc carry a polymorphic N-glycan that regulates its binding properties and thereby its effector functions. The glycosylation profile of IgG Fc is modulated by physiological and pathological conditions, including infectious diseases and inflammatory disorders. Characterization of IgG Fc glycosylation profiles is a promising approach to understand the pathogenesis of diseases involving the immune system and to develop novel biomarkers of disease activity. Measuring the proportion of the different IgG Fc glycoforms remains an analytical challenge, that requires a sensitive and reproducible analytical approach.This chapter describes an optimized approach for the preparation and the analysis of Fc N-glycans from total serum or plasma IgG using magnetic beads, RapiFluor MS label©, and LC-MS.
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http://dx.doi.org/10.1007/978-1-0716-1241-5_4DOI Listing
January 2021

One vaccine for life: Lessons from immune ontogeny.

J Paediatr Child Health 2021 Apr 16. Epub 2021 Apr 16.

Systems Vaccinology, Telethon Kids Institute, Perth, Western Australia, Australia.

There remains a general misconception that the immune status of the fetus and neonate is immature or insufficient. However, emerging research in immune ontogeny prompts reconsideration of this orthodoxy, reframing this period instead as one of unique opportunity. Vaccine responses (qualitative and quantitative) vary between individuals, and across demographic cohorts. Elements of baseline immune status and function predict vaccine response - some of these factors are well described, others remain a subject of ongoing research, especially with the rapidly expanding field of 'omics' research, enabled by development of highly granular immune profiling techniques and increasing computational capacity. Age is one of the strongest predictive factors associated with variability in the response to vaccination; and predictable variation in response to vaccination is a key to identify the crucial underlying mechanisms. Specifically, circulating maternal antibody in the young infant can modulate immune response to vaccination, acting as an 'undercover adjuvant' that, counter to current dogma, may offer a pathway to longer lasting, higher quality immune response to vaccination. Exciting avenues for novel research in this area have the potential to dramatically alter how we protect the world's most vulnerable population - the very young.
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http://dx.doi.org/10.1111/jpc.15511DOI Listing
April 2021

The Fifth International Neonatal and Maternal Immunization Symposium (INMIS 2019): Securing Protection for the Next Generation.

mSphere 2021 01 27;6(1). Epub 2021 Jan 27.

Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

Despite significant progress in reaching some milestones of the United Nations Sustainable Development Goals, neonatal and early infant morbidity and mortality remain high, and maternal health remains suboptimal in many countries. Novel and improved preventative strategies with the potential to benefit pregnant women and their infants are needed, with maternal and neonatal immunization representing effective approaches. Experts from immunology, vaccinology, infectious diseases, clinicians, industry, public health, and vaccine-related social sciences convened at the 5th International Neonatal and Maternal Immunization Symposium (INMIS) in Vancouver, Canada, from 15 to 17 September 2019. We critically evaluated the lessons learned from recent clinical studies, presented cutting-edge scientific progress in maternal and neonatal immunology and vaccine development, and discussed maternal and neonatal immunization in the broader context of infectious disease epidemiology and public health. Focusing on practical aspects of research and implementation, we also discussed the safety, awareness, and perception of maternal immunization as an existing strategy to address the need to improve maternal and neonatal health worldwide. The symposium provided a comprehensive scientific and practical primer as well as an update for all those with an interest in maternal and neonatal infection, immunity, and vaccination. The summary presented here provides an update of the current status of progress in maternal and neonatal immunization.
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http://dx.doi.org/10.1128/mSphere.00862-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885317PMC
January 2021

Biogeography of the Relationship between the Child Gut Microbiome and Innate Immune System.

mBio 2021 01 12;12(1). Epub 2021 Jan 12.

Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, Canada

The gut microbiome is a well-recognized modulator of host immunity, and its compositions differ between geographically separated human populations. Systemic innate immune responses to microbial derivatives also differ between geographically distinct human populations. However, the potential role of the microbiome in mediating geographically varied immune responses is unexplored. We here applied 16S amplicon sequencing to profile the stool microbiome and, in parallel, measured whole-blood innate immune cytokine responses to several pattern recognition receptor (PRR) agonists among 2-year-old children across biogeographically diverse settings. Microbiomes differed mainly between high- and low-resource environments and were not strongly associated with other demographic factors. We found strong correlations between responses to Toll-like receptor 2 (TLR2) and relative abundances of and populations, shared among Canadian and Ecuadorean children. Additional correlations between responses to TLR2 and bacterial populations were specific to individual geographic cohorts. As a proof of concept, we gavaged germfree mice with human donor stools and found murine splenocyte responses to TLR stimulation were consistent with responses of the corresponding human donor populations. This study identified differences in immune responses correlating to gut microbiomes across biogeographically diverse settings and evaluated biological plausibility using a mouse model. This insight paves the way to guide optimization of population-specific interventions aimed to improve child health outcomes. Both the gut microbiome and innate immunity are known to differ across biogeographically diverse human populations. The gut microbiome has been shown to directly influence systemic immunity in animal models. With this, modulation of the gut microbiome represents an attractive avenue to improve child health outcomes associated with altered immunity using population-specific approaches. However, there are very scarce data available to determine which members of the gut microbiome are associated with specific immune responses and how these differ around the world, creating a substantial barrier to rationally designing such interventions. This study addressed this knowledge gap by identifying relationships between distinct bacterial taxa and cytokine responses to specific microbial agonists across highly diverse settings. Furthermore, we provide evidence that immunomodulatory effects of region-specific stool microbiomes can be partially recapitulated in germfree mice. This is an important contribution toward improving global child health by targeting the gut microbiome.
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http://dx.doi.org/10.1128/mBio.03079-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845628PMC
January 2021

Virology, epidemiology, immunology and vaccine development of SARS-CoV-2, update after nine months of pandemic.

Biologicals 2021 Jan 19;69:76-82. Epub 2020 Nov 19.

International Alliance for Biological Standardization - IABS, Geneva, Switzerland. Electronic address:

This International Alliance for Biological Standardization COVID-19 webinar was organized to provide an update on the virology, epidemiology and immunology of, and the vaccine development for SARS-CoV-2, none months after COVID-19 was declared a public health emergency of international concern. It brought together a broad range of international stakeholders, including academia, regulators, funders and industry, with a considerable delegation from low- and middle-income countries.
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http://dx.doi.org/10.1016/j.biologicals.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676373PMC
January 2021

Innate Immune Responses and Gut Microbiomes Distinguish HIV-Exposed from HIV-Unexposed Children in a Population-Specific Manner.

J Immunol 2020 11 16;205(10):2618-2628. Epub 2020 Oct 16.

Department of Experimental Medicine, The University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.

In both high- and low-income countries, HIV-negative children born to HIV-positive mothers (HIV exposed, uninfected [HEU]) are more susceptible to severe infection than HIV-unexposed, uninfected (HUU) children, with altered innate immunity hypothesized to be a cause. Both the gut microbiome and systemic innate immunity differ across biogeographically distinct settings, and the two are known to influence each other. And although the gut microbiome is influenced by HIV infection and may contribute to altered immunity, the biogeography of immune-microbiome correlations among HEU children have not been investigated. To address this, we compared the innate response and the stool microbiome of 2-y-old HEU and HUU children from Belgium, Canada, and South Africa to test the hypothesis that region-specific immune alterations directly correlate to differences in their stool microbiomes. We did not detect a universal immune or microbiome signature underlying differences between HEU versus HUU that was applicable to all children. But as hypothesized, population-specific differences in stool microbiomes were readily detected and included reduced abundances of short-chain fatty acid-producing bacteria in Canadian HEU children. Furthermore, we did not identify innate immune-microbiome associations that distinguished HEU from HUU children in any population. These findings suggest that maternal HIV infection is independently associated with differences in both innate immunity and the stool microbiome in a biogeographical population-specific way.
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http://dx.doi.org/10.4049/jimmunol.2000040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653510PMC
November 2020

Varicella Vaccination, Counting Harms and Benefits, and Obligations to Others.

Am J Bioeth 2020 09;20(9):76-78

Université Libre de Bruxelles.

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http://dx.doi.org/10.1080/15265161.2020.1795536DOI Listing
September 2020

Objective Olfactory Findings in Hospitalized Severe COVID-19 Patients.

Pathogens 2020 Jul 31;9(8). Epub 2020 Jul 31.

COVID-19 Task Force of the Young-Otolaryngologists of the International Federations of Oto-Rhino-Laryngological Societies (YO-IFOS), F92150 Paris, France.

Objective: We investigate the prevalence of the self-reported and objective sudden loss of smell (SLS) in patients with severe coronavirus disease 2019 (COVID-19).

Methods: Severe COVID-19 patients with self-reported SLS were recruited at hospitalization discharge. Epidemiological and clinical data were collected. The Sino-nasal Outcome Test-22 (SNOT-22) was used to evaluate rhinological complaints. Subjective olfactory and gustatory functions were assessed with the National Health and Nutrition Examination Survey (NHNES). Objective SLS was evaluated using psychophysical tests. Potential associations between olfactory evaluation and the clinical outcomes (duration of hospitalization; admission biology; one month serology (IgG), and chest computed tomography findings) were studied.

Results: Forty-seven patients completed the study (25 females). Subjectively, eighteen (38.3%) individuals self-reported subjective partial or total SLS. Among them, only three and four were anosmic and hyposmic, respectively (38.9%). Considering the objective evaluation in the entire cohort, the prevalence of SLS was 21.3%. Elderly patients and those with diabetes had lower objective olfactory evaluation results than young and non-diabetic individuals.

Conclusions: The prevalence of SLS in severe COVID-19 patients appears to be lower than previously estimated in mild-to-moderate COVID-19 forms. Future comparative studies are needed to explore the predictive value of SLS for COVID-19 severity.
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http://dx.doi.org/10.3390/pathogens9080627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460289PMC
July 2020

SARS-CoV-2: Virology, epidemiology, immunology and vaccine development.

Biologicals 2020 Jul 23;66:35-40. Epub 2020 Jun 23.

International Alliance for Biological Standardization - IABS, Geneva, Switzerland. Electronic address:

This first International Alliance for Biological Standardization Covid-19 webinar brought together a broad range of international stakeholders, including academia, regulators, funders and industry, with a considerable delegation from low- and middle-income countries, to discuss the virology, epidemiology and immunology of, and the vaccine development for SARS-CoV-2.
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http://dx.doi.org/10.1016/j.biologicals.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309765PMC
July 2020

Vaccination strategies to enhance immunity in neonates.

Science 2020 05;368(6491):612-615

Center for Inflammation and Tolerance and Division of Infectious Disease, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.

Neonates are particularly susceptible to infection. This vulnerability occurs despite their responsiveness to most vaccines. However, current vaccines do not target the pathogens responsible for most of the severe neonatal infections, and the time it takes to induce protective pathogen-specific immunity after vaccination limits protection in the first days to weeks of life. Alternative strategies include using vaccines to broadly stimulate neonatal immunity in a pathogen-agnostic fashion or vaccinating women during pregnancy to induce protective antibodies that are vertically transferred to offspring within their window of vulnerability. Protection may be further improved by integrating these approaches, namely vaccinating the neonate under the cover of vertically transferred maternal immunity. The rationale for and knowledge gaps related to each of these alternatives are discussed.
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http://dx.doi.org/10.1126/science.aaz9447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734703PMC
May 2020

Improving Vaccine-Induced Immunity: Can Baseline Predict Outcome?

Trends Immunol 2020 06 8;41(6):457-465. Epub 2020 Apr 8.

Telethon Kids Institute, Perth Children's Hospital, University of Western Australia, Nedlands, WA, Australia. Electronic address:

Immune signatures measured at baseline and immediately prior to vaccination may predict the immune response to vaccination. Such pre-vaccine assessment might allow not only population-based, but also more personalized vaccination strategies ('precision vaccination'). If baseline immune signatures are predictive, the underlying mechanism they reflect may also determine vaccination outcome. Thus, baseline signatures might contribute to identifying interventional targets to be modulated prior to vaccination in order to improve vaccination responses. This concept has the potential to transform vaccination strategies and usher in a new approach to improve global health.
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http://dx.doi.org/10.1016/j.it.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142696PMC
June 2020

Maternal HIV Infection Alters Antimicrobial Immunity in Exposed and Uninfected Infants.

Pediatr Infect Dis J 2020 05;39(5):e47-e48

Department of Pediatrics, Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium.

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http://dx.doi.org/10.1097/INF.0000000000002614DOI Listing
May 2020

Maternal determinants of infant immunity: Implications for effective immunization and maternal-child health.

Vaccine 2020 06 25;38(28):4491-4494. Epub 2020 Feb 25.

Institute for Medical Immunology, Université libre de Bruxelles, Charleroi, Belgium. Electronic address:

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http://dx.doi.org/10.1016/j.vaccine.2020.01.056DOI Listing
June 2020

Immunological mechanisms of inducing HIV immunity in infants.

Vaccine 2020 01 21;38(3):411-415. Epub 2019 Nov 21.

Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.

The potential advantages and unique challenges of the early life immune system for the development of HIV-specific broadly neutralizing antibodies were discussed during a workshop entitled "Immunological Mechanisms of Inducing HIV Immunity in Infants" sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) in conjunction with the 2018 HIVR4P Conference held in Madrid, Spain. A safe and effective HIV vaccine remains a critical need in the fight against the HIV pandemic, especially to prevent emerging infections in infants, adolescents, and young adults. To successfully target these populations, a vaccine should ideally induce protective immune responses during childhood. Interestingly, several recent studies highlighting differences in immune responses between adults and children have suggested that the early life immune system could present advantages for the elicitation of broadly neutralizing antibodies (bnAbs), a response highly desired for an HIV vaccine. Notably, HIV-infected children develop bnAbs responses earlier and more frequently than infected adults; with emerging evidence that the pathways of elicitation of bnAb lineages may differ between adults and children. Moreover, there is precedent for the prevention of lifelong infections with pediatric immunization, and early life provides a unique window of opportunity for the administration of a multi-dose HIV vaccine that will likely be needed to achieve protective immunity. Further understanding of how the distinct early life immune system can be harnessed to trigger bnAb lineages for induction of durable and polyfunctional HIV-specific immunity is warranted. This strategy will include testing promising HIV vaccine candidates in pediatric populations in preclinical and clinical studies. Novel approaches to identify molecular markers of protection are also key to guide and accelerate pediatric HIV vaccine development.
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http://dx.doi.org/10.1016/j.vaccine.2019.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955149PMC
January 2020

Fc Glycan-Mediated Regulation of Placental Antibody Transfer.

Cell 2019 06 13;178(1):202-215.e14. Epub 2019 Jun 13.

Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. Electronic address:

Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta. To understand this, we used systems serology to define Fc features associated with antibody transfer. The Fc-profile of neonatal and maternal antibodies differed, skewed toward natural killer (NK) cell-activating antibodies. This selective transfer was linked to digalactosylated Fc-glycans that selectively bind FcRn and FCGR3A, resulting in transfer of antibodies able to efficiently leverage innate immune cells present at birth. Given emerging data that vaccination may direct antibody glycosylation, our study provides insights for the development of next-generation maternal vaccines designed to elicit antibodies that will most effectively aid neonates.
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http://dx.doi.org/10.1016/j.cell.2019.05.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741440PMC
June 2019

Maternal immunization confers protection against neonatal herpes simplex mortality and behavioral morbidity.

Sci Transl Med 2019 04;11(487)

Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.

Neonatal herpes simplex virus (nHSV) infections cause devastating morbidity and mortality in infants. Most nHSV cases are associated with primary maternal infection, consistent with the hypothesis that maternal immunity is protective. In humans, we found HSV-specific neutralizing antibodies in newborns of immune mothers, indicating that placentally transferred HSV-specific antibody is protective. Using a murine model, we showed that passive administration of HSV-specific antibody to dams prevented disseminated infection and mortality in pups. Maternal immunization with an HSV-2 replication-defective vaccine candidate, 5-29, led to transfer of HSV-specific antibodies into neonatal circulation that protected against nHSV neurological disease and death. Furthermore, we observed considerable anxiety-like behavior in adult mice that had been infected with low doses of HSV as neonates, despite a notable lack of signs of infection. This phenotype suggests that nHSV infection can have an unsuspected and permanent impact on behavior. These behavioral sequelae of nHSV were prevented by maternal immunization with 5-29, demonstrating an unexpected benefit of immunization. These findings also support the general concept that maternal immunization can prevent neurotropic neonatal infections and associated morbidity and mortality.
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http://dx.doi.org/10.1126/scitranslmed.aau6039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681804PMC
April 2019

Inflammatory parameters associated with systemic reactogenicity following vaccination with adjuvanted hepatitis B vaccines in humans.

Vaccine 2019 03 5;37(14):2004-2015. Epub 2019 Mar 5.

GSK, Rixensart/Wavre, Belgium.

Background: Adjuvants like AS01 increase the immunogenicity of vaccines and generally cause increased transient reactogenicity compared with Alum. A phase II randomized trial was conducted to characterize the response to AS01 and Alum adjuvanted vaccines. A post-hoc analysis was performed to examine the associations between reactogenicity and innate immune parameters.

Methods: The trial involved 60 hepatitis B-naïve adults aged 18-45 years randomized 1:1 to receive either two doses of HBsAg-AS01 on Day (D)0 and D30, or three doses of HBsAg-Alum on D0, D30, D180. Prior to vaccination, all subjects received placebo injection in order to differentiate the impact of injection process and the vaccination. Main outcomes included reactogenicity symptoms, vital signs, blood cytokines, biochemical and hematological parameters after vaccination. Associations were explored using linear regression.

Findings: The vaccine with AS01 induced higher HBsAg-specific antibody levels than Alum. Local and systemic symptoms were more frequent in individuals who received HBsAg AS01/Alum vaccine or placebo, but were mild and short-lived. Blood levels of C-reactive protein (CRP), bilirubin, leukocyte, monocyte and neutrophil counts increased rapidly and transiently after AS01 but not after Alum or placebo. Lymphocyte counts decreased in the AS01 group and lactate dehydrogenase levels decreased after Alum. Modelling revealed associations between systemic symptoms and increased levels of CRP and IL-6 after the first HBsAg-AS01 or HBsAg-Alum immunization. Following the second vaccine dose, CRP, IL-6, IP-10, IFN-γ, MIP-1β and MCP-2 were identified as key parameters associated with systemic symptoms. These observations were confirmed using an independent data set extracted from a previous study of the immune response to HBsAg-adjuvanted vaccines (NCT00805389).

Conclusions: IL-6 and IFN-γ signals were associated with systemic reactogenicity following administration of AS01-adjuvanted vaccine. These signals were similar to those previously associated with antibody and T-cell responses induced by HBsAg-adjuvanted vaccines, suggesting that similar innate immune signals may underlie adjuvant reactogenicity and immunogenicity.

Trial Registration: www.clinicaltrials.gov NCT01777295.
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http://dx.doi.org/10.1016/j.vaccine.2019.02.015DOI Listing
March 2019

Prevalence, Risk Factors, and Serotype Distribution of Group B Streptococcus Colonization in HIV-Infected Pregnant Women Living in Belgium: A Prospective Cohort Study.

Open Forum Infect Dis 2018 Dec 30;5(12):ofy320. Epub 2018 Nov 30.

Department of Pediatrics, Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium.

Background: Group B streptococcus (GBS) infection is a leading cause of severe neonatal infection. Maternal GBS carriage during pregnancy is the main risk factor for both early-onset and late-onset GBS disease. High incidence of GBS infection has been reported in HIV-exposed but -uninfected infants (HEU). We aimed to determine the prevalence, characteristics, and risk factors for GBS colonization in HIV-infected and HIV-uninfected pregnant women living in Belgium.

Methods: Between January 1, 2011, and December 31, 2013, HIV-infected (n = 125) and -uninfected (n = 120) pregnant women had recto-vaginal swabs at 35-37 weeks of gestation and at delivery for GBS detection. Demographic, obstetrical, and HIV infection-related data were prospectively collected. GBS capsular serotyping was performed on a limited number of samples (33 from HIV-infected and 16 from HIV-uninfected pregnant women).

Results: There was no significant difference in the GBS colonization rate between HIV-infected and -uninfected pregnant women (29.6% vs 24.2%, respectively). HIV-infected women were more frequently colonized by serotype III (36.4% vs 12.5%), and the majority of serotype III strains belonged to the hypervirulent clone ST-17. Exclusively trivalent vaccine serotypes (Ia, Ib, and III) were found in 57.6% and 75% of HIV-infected and -uninfected women, respectively, whereas the hexavalent vaccine serotypes (Ia, Ib, II, III, IV, and V) were found in 97% and 100%, respectively.

Conclusions: HIV-infected and -uninfected pregnant women living in Belgium have a similar GBS colonization rate. A trend to a higher colonization rate with serotype III was found in HIV-infected women, and those serotype III strains belong predominantly to the hypervirulent clone ST17.
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http://dx.doi.org/10.1093/ofid/ofy320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306564PMC
December 2018

The Fourth International Neonatal and Maternal Immunization Symposium (INMIS 2017): Toward Integrating Maternal and Infant Immunization Programs.

mSphere 2018 11 7;3(6). Epub 2018 Nov 7.

Institute for Medical Immunology, Universite Libre de Bruxelles, Brussels, Belgium.

Prevention of serious infections in pregnant mothers, newborns, and young infants through immunization during pregnancy and in early life has the potential to further reduce maternal and neonatal morbidity and mortality worldwide. In the past decade, research in this field has advanced substantially, from the understanding of the biology and immunology of pregnancy and early life, to the active development of several candidate vaccines, for which challenges and opportunities for global implementation are under consideration. Experts from academia, industry, regulatory and funding agencies, public health, and international organizations met in Brussels (Belgium) from 10 to 12 September 2017, at the 4th International Neonatal and Maternal Immunization Symposium (INMIS), to review the most relevant advances in maternal and neonatal immunization. The overarching focus of the conference was to identify the path forward to achieve integration of maternal and early life immunization strategies for the successful implementation of vaccines in antenatal care and pediatric programs for reduction of maternal and infant mortality worldwide. This report provides an overview of the proceedings of the 4th International Maternal and Neonatal Immunization Symposium, where presentations focused on the state-of-the-art research on the development and implementation of vaccines given during pregnancy for the protection of mothers and infants.
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http://dx.doi.org/10.1128/mSphere.00221-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222055PMC
November 2018

Initiation of Antiretroviral Therapy Before Pregnancy Reduces the Risk of Infection-related Hospitalization in Human Immunodeficiency Virus-exposed Uninfected Infants Born in a High-income Country.

Clin Infect Dis 2019 03;68(7):1193-1203

Institute for Medical Immunology, Université libre de Bruxelles, Charleroi, Belgium.

Background: Epidemiological studies conducted in low- and high-income countries showed that infants exposed to maternal human immunodeficiency virus (HIV) have a high risk of severe infections. Immune alterations during fetal life have been proposed as a possible mechanism.

Methods: This prospective study assessed the relative risk of hospitalization for infection in HIV-exposed uninfected (HEU) infants as compared to HIV-unexposed (HU) infants born in a high-income country (HIC). Markers of monocyte activation and levels of pathogen-specific antibodies were measured at birth to identify correlates of infant susceptibility.

Results: There were 27 of 132 HEU infants and 14 of 123 HU infants hospitalized for infection during the first year of life (adjusted hazard ratio [aHR] 2.33, 95% confidence interval [CI] 1.10-4.97). Most of this increased risk was associated with the time of initiation of maternal antiretroviral therapy (ART). As compared to HU infants, the risk of hospitalization for infection of HEU infants was 4-fold higher when mothers initiated ART during pregnancy (aHR 3.84, 95% CI 1.69-8.71) and was not significantly increased when ART was initiated before pregnancy (aHR 1.42, 95% CI 0.58-3.48). The activation of newborn monocytes and the reduced transfer of maternal antibodies were most intense following ART initiation during pregnancy, and predicted the risk of infant hospitalization.

Conclusions: These observations indicate that initiation of maternal ART before pregnancy reduces the susceptibility of HEU infants born in a HIC to severe infections, and that this effect could be related to the prevention of immune alterations during fetal life.
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http://dx.doi.org/10.1093/cid/ciy673DOI Listing
March 2019

Nonprimary Maternal Cytomegalovirus Infection After Viral Shedding in Infants.

Pediatr Infect Dis J 2018 07;37(7):627-631

Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Most infants with congenital Cytomegalovirus (CMV) infection are born to seropositive women as a result of maternal CMV nonprimary infection (reinfection or reactivation). Although infected children are known to transmit CMV to their seronegative mothers, the frequency and magnitude of nonprimary maternal CMV infection after exposure to viral shedding by children in their household have not been characterized.

Methods: A cohort of Ugandan newborns and their mothers were tested weekly for CMV by quantitative polymerase chain reaction of oral swabs. Infant primary infection and maternal nonprimary infection were defined by the onset of persistent high-level oral CMV shedding. Strain-specific antibody testing was used to assess maternal reinfection. Cox regression models with time-dependent covariates were used to evaluate risk factors for nonprimary maternal infection.

Results: Nonprimary CMV infection occurred in 15 of 30 mothers, all after primary infection of their infants by a median of 6 weeks (range: 1-10) in contrast to none of the mothers of uninfected infants. The median duration of maternal oral shedding lasted 18 weeks (range: 4-42) reaching a median maximum viral load of 4.69 log copies/mL (range: 3.22-5.64). Previous-week infant CMV oral quantities strongly predicted maternal nonprimary infection (hazard ratio: 2.32 per log10 DNA copies/swab increase; 95% confidence interval: 1.63-3.31). Maternal nonprimary infections were not associated with changes in strain-specific antibody responses.

Conclusions: Nonprimary CMV infection was common in mothers after primary infection in their infants, consistent with infant-to-mother transmission. Because infants frequently acquire CMV from their mothers, for example, through breast milk, this suggests the possibility of "ping-pong" infections. Additional research is needed to characterize the antigenic and genotypic strains transmitted among children and their mothers.
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http://dx.doi.org/10.1097/INF.0000000000001877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016842PMC
July 2018

The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes.

Elife 2018 02 28;7. Epub 2018 Feb 28.

Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium.

Cytotoxic CD4 (CD4) T cells are emerging as an important component of antiviral and antitumor immunity, but the molecular basis of their development remains poorly understood. In the context of human cytomegalovirus infection, a significant proportion of CD4 T cells displays cytotoxic functions. We observed that the transcriptional program of these cells was enriched in CD8 T cell lineage genes despite the absence of ThPOK downregulation. We further show that establishment of CD4-specific transcriptional and epigenetic programs occurred in a stepwise fashion along the Th1-differentiation pathway. In vitro, prolonged activation of naive CD4 T cells in presence of Th1 polarizing cytokines led to the acquisition of perforin-dependent cytotoxic activity. This process was dependent on the Th1 transcription factor Runx3 and was limited by the sustained expression of ThPOK. This work elucidates the molecular program of human CD4 T cells and identifies potential targets for immunotherapy against viral infections and cancer.
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http://dx.doi.org/10.7554/eLife.30496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844691PMC
February 2018

Breastmilk cell trafficking induces microchimerism-mediated immune system maturation in the infant.

Pediatr Allergy Immunol 2018 03 8;29(2):133-143. Epub 2018 Jan 8.

Pathogenesis and Control of Chronic Infections, INSERM, EFS, Université de Montpellier, Montpellier, France.

Initiating breastfeeding within the first hour of life confers an important benefit in terms of child mortality and severe morbidity. Intestinal permeability to ingested macromolecules and immunoglobulins is limited to the first days of human life. These exchanges cease in the very early post-partum period but may increase beyond the neonatal period in response to local inflammation or introduction of a weaning food. From animal- and limited human-based observations, compelling evidence points out to breastmilk cells also trafficking from mother to infant mucosal tissues and participating to the maternal microchimerism. The precise nature of breastmilk cells that are involved is presently not known but likely includes progenitor/stem cells-representing up to 6% of breastmilk cells-with possible contribution of mature immune cells. Stem cell microchimerism may induce tolerance to non-inherited maternal antigens (NIMAs), breastfeeding generating regulatory T cells (T ) that suppress antimaternal immunity. Therefore, in complement to pregnancy-induced microchimerism, breastfeeding-induced microchimerism may be pivotal in infant immune development, intestinal tissue repair/growth and protection against infectious diseases. As a continuum of the gestational period, the neonatal gut may be considered as a temporary, but important developmental extension of the role played by the placenta during intrauterine life; breastmilk playing the role of maternal blood by delivering maternal soluble factors (macromolecules, Ig, cytokines) and immunologically active milk cells. A better understanding of breastfeeding-induced maternal microchimerism would provide further evidence in support of public health messages that reinforce the importance of early initiation of breastfeeding.
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http://dx.doi.org/10.1111/pai.12841DOI Listing
March 2018

Immunity and immunopathology in early human life.

Semin Immunopathol 2017 11 23;39(6):575-576. Epub 2017 Nov 23.

Institute for Medical Immunology, Université libre de Bruxelles, Charleroi, Belgium.

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http://dx.doi.org/10.1007/s00281-017-0657-6DOI Listing
November 2017

Genomic Programming of Human Neonatal Dendritic Cells in Congenital Systemic and Cytomegalovirus Infection Reveal Plastic and Robust Immune Pathway Biology Responses.

Front Immunol 2017 25;8:1146. Epub 2017 Sep 25.

Division of Infection and Pathway Medicine, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Neonates and especially premature infants are highly susceptible to infection but still can have a remarkable resilience that is poorly understood. The view that neonates have an incomplete or deficient immune system is changing. Human neonatal studies are challenging, and elucidating host protective responses and underlying cognate pathway biology, in the context of viral infection in early life, remains to be fully explored. In both resource rich and poor settings, human cytomegalovirus (HCMV) is the most common cause of congenital infection. By using unbiased systems analyses of transcriptomic resources for HCMV neonatal infection, we find the systemic response of a preterm congenital HCMV infection, involves a focused IFN regulatory response associated with dendritic cells. Further analysis of transcriptional-programming of neonatal dendritic cells in response to HCMV infection in culture revealed an early dominant IFN-chemokine regulatory subnetworks, and at later times the plasticity of pathways implicated in cell-cycle control and lipid metabolism. Further, we identify previously unknown suppressed networks associated with infection, including a select group of GPCRs. Functional siRNA viral growth screen targeting 516-GPCRs and subsequent validation identified novel GPCR-dependent antiviral (ADORA1) and proviral (GPR146, RGS16, PTAFR, SCTR, GPR84, GPR85, NMUR2, FZ10, RDS, CCL17, and SORT1) roles. By contrast a gene family cluster of protocadherins is significantly differentially induced in neonatal cells, suggestive of possible immunomodulatory roles. Unexpectedly, programming responses of adult and neonatal dendritic cells, upon HCMV infection, demonstrated comparable quantitative and qualitative responses showing that functionally, neonatal dendritic cell are not overly compromised. However, a delay in responses of neonatal cells for IFN subnetworks in comparison with adult-derived cells are notable, suggestive of subtle plasticity differences. These findings support a set-point control mechanism rather than immaturity for explaining not only neonatal susceptibility but also resilience to infection. In summary, our findings show that neonatal HCMV infection leads to a highly plastic and functional robust programming of dendritic cells and . In comparison with adults, a minimal number of subtle quantitative and temporal differences may contribute to variability in host susceptibility and resilience, in a context dependent manner.
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http://dx.doi.org/10.3389/fimmu.2017.01146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622154PMC
September 2017

Breastfeeding-related maternal microchimerism.

Nat Rev Immunol 2017 11 3;17(11):729-1. Epub 2017 Oct 3.

Pathogenesis and Control of Chronic Infections, INSERM, EFS, Université de Montpellier, 34394 Montpellier, France; and at CHU Montpellier, Department of Bacteriology-Virology and Department of Medical Information, 34295 Montpellier, France.

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http://dx.doi.org/10.1038/nri.2017.115DOI Listing
November 2017

Transfer of maternal immunity and programming of the newborn immune system.

Semin Immunopathol 2017 11 2;39(6):605-613. Epub 2017 Oct 2.

Institute for Medical Immunology, Université Libre de Bruxelles, Rue Adrienne Bolland 8, 6041 Gosselies, Charleroi, Belgium.

As placental mammals, the pregnant women and the fetus have intense and prolonged interactions during gestation. There is increasing evidence that multiple molecular as well as cellular components originating in pregnant women are transferred to the fetus. The transfer of maternal antibodies has long been recognized as a central component of newborn immunity against pathogens. More recent studies indicate that inflammatory mediators, micronutrients, microbial products and maternal cells are transferred in utero and influence the fetal immune system. Together, these multiple signals are likely to form a complex network of interactions that program the neonatal immune system and tune its homeostatic regulation. Maternal disorders, in particular infectious diseases, modify these signals and may thereby alter immunity in early life. Understanding maternal programming of the newborn immune system could provide a basis for interventions promoting child health.
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http://dx.doi.org/10.1007/s00281-017-0653-xDOI Listing
November 2017

Different Adjuvants Induce Common Innate Pathways That Are Associated with Enhanced Adaptive Responses against a Model Antigen in Humans.

Front Immunol 2017 14;8:943. Epub 2017 Aug 14.

GSK, Rixensart, Belgium.

To elucidate the role of innate responses in vaccine immunogenicity, we compared early responses to hepatitis B virus (HBV) surface antigen (HBsAg) combined with different Adjuvant Systems (AS) in healthy HBV-naïve adults, and included these parameters in multi-parametric models of adaptive responses. A total of 291 participants aged 18-45 years were randomized 1:1:1:1:1 to receive HBsAg with AS01, AS01, AS03, AS04, or Alum/Al(OH) at days 0 and 30 (ClinicalTrials.gov: NCT00805389). Blood protein, cellular, and mRNA innate responses were assessed at early time-points and up to 7 days after vaccination, and used with reactogenicity symptoms in linear regression analyses evaluating their correlation with HBs-specific CD4 T-cell and antibody responses at day 44. All AS induced transient innate responses, including interleukin (IL)-6 and C-reactive protein (CRP), mostly peaking at 24 h post-vaccination and subsiding to baseline within 1-3 days. After the second but not the first injection, median interferon (IFN)-γ levels were increased in the AS01 group, and IFN-γ-inducible protein-10 levels and IFN-inducible genes upregulated in the AS01 and AS03 groups. No distinct marker or signature was specific to one particular AS. Innate profiles were comparable between AS01, AS01, and AS03 groups, and between AS04 and Alum groups. AS group rankings within adaptive and innate response levels and reactogenicity prevalence were similar (AS01 ≥ AS01 > AS03 > AS04 > Alum), suggesting an association between magnitudes of inflammatory and vaccine responses. Modeling revealed associations between adaptive responses and specific traits of the innate response post-dose 2 (activation of the IFN-signaling pathway, CRP and IL-6 responses). In conclusion, the ability of AS01 and AS03 to enhance adaptive responses to co-administered HBsAg is likely linked to their capacity to activate innate immunity, particularly the IFN-signaling pathway.
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http://dx.doi.org/10.3389/fimmu.2017.00943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557780PMC
August 2017