Publications by authors named "Alessio Fasano"

283 Publications

SARS-CoV-2 mRNA vaccination elicits robust antibody responses in children.

Sci Transl Med 2022 Jul 26:eabn9237. Epub 2022 Jul 26.

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

Although children have been largely spared from coronavirus disease 2019 (COVID-19), the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) with increased transmissibility, combined with fluctuating mask mandates and school re-openings, have led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remains unclear. Here we aimed to deeply profile the vaccine-induced humoral immune response in 6 to 11 year old children receiving either a pediatric (50 μg) or adult (100 μg) dose of the mRNA-1273 vaccine and to compare these responses to vaccinated adults, infected children, and children that experienced multisystem inflammatory syndrome in children (MIS-C). Children elicited an IgG-dominant vaccine-induced immune response, surpassing adults at a matched 100 μg dose, but more variable immunity at a 50 μg dose. Irrespective of titer, children generated antibodies with enhanced Fc-receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron-specific receptor binding domain-binding, but robustly preserved omicron spike protein-binding. Fc-receptor binding capabilities were also preserved in a dose dependent manner. These data indicate that both the 50 μg and 100 μg doses of mRNA vaccination in children elicits robust cross-VOC antibody responses and that 100 μg doses in children results in highly preserved omicron-specific functional humoral immunity.
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http://dx.doi.org/10.1126/scitranslmed.abn9237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9348753PMC
July 2022

COVID-19 booster dose induces robust antibody response in pregnant, lactating, and nonpregnant women.

Am J Obstet Gynecol 2022 Jul 19. Epub 2022 Jul 19.

Department of Obstetrics & Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA, USA. Electronic address:

Background: While emerging data during the SARS-CoV-2 pandemic have demonstrated robust mRNA vaccine-induced immunogenicity across populations, including pregnant and lactating individuals, the rapid waning of vaccine-induced immunity and the emergence of variants of concern motivated the use of mRNA vaccine booster doses. Whether all populations, including pregnant and lactating individuals, will mount a comparable response to a booster dose is not known.

Objective: We sought to profile the humoral immune response to a COVID-19 mRNA booster dose in a cohort of pregnant, lactating, and age-matched nonpregnant women.

Study Design: We characterized the antibody response against ancestral Spike and Omicron in a cohort of 31 pregnant, 12 lactating and 20 nonpregnant age-matched controls who received a BNT162b2 or mRNA-1273 booster dose after primary COVID-19 vaccination. We also examined the vaccine-induced antibody profiles of 15 maternal:cord dyads at delivery.

Results: Receipt of a booster dose during pregnancy resulted in increased IgG1 against Omicron Spike (post-primary vaccination vs post-booster, p = 0.03). Pregnant and lactating individuals exhibited equivalent Spike-specific total IgG1, IgM and IgA levels and neutralizing titers against Omicron compared to nonpregnant women. Subtle differences in Fc-receptor binding and antibody subclass profiles were observed in the immune response to a booster dose in pregnant compared to nonpregnant individuals. Analysis of maternal and cord antibody profiles at delivery demonstrated equivalent total Spike-specific IgG1 in maternal and cord blood, yet higher Spike-specific FcγR3a-binding antibodies in the cord relative to maternal blood (p = 0.002), consistent with preferential transfer of highly functional IgG. Spike-specific IgG1 levels in the cord were positively correlated with time elapsed since receipt of the booster dose (Spearman R 0.574, p = 0.035).

Conclusions: These data suggest that receipt of a booster dose during pregnancy induces a robust Spike-specific humoral immune response, including against Omicron. If boosting occurs in the third trimester, higher Spike-specific cord IgG1 levels are achieved with greater time elapsed between receipt of the booster and delivery. Receipt of a booster dose has the potential to augment maternal and neonatal immunity.
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http://dx.doi.org/10.1016/j.ajog.2022.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295313PMC
July 2022

Maternal immune response and placental antibody transfer after COVID-19 vaccination across trimester and platforms.

Nat Commun 2022 06 28;13(1):3571. Epub 2022 Jun 28.

Department of Obstetrics & Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

The availability of three COVID-19 vaccines in the United States provides an unprecedented opportunity to examine how vaccine platforms and timing of vaccination in pregnancy impact maternal and neonatal immunity. Here, we characterize the antibody profile after Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination in 158 pregnant individuals and evaluate transplacental antibody transfer by profiling maternal and umbilical cord blood in 175 maternal-neonatal dyads. These analyses reveal lower vaccine-induced functions and Fc receptor-binding after Ad26.COV2.S compared to mRNA vaccination and subtle advantages in titer and function with mRNA-1273 versus BN162b2. mRNA vaccines have higher titers and functions against SARS-CoV-2 variants of concern. First and third trimester vaccination results in enhanced maternal antibody-dependent NK-cell activation, cellular and neutrophil phagocytosis, and complement deposition relative to second trimester. Higher transplacental transfer ratios following first and second trimester vaccination may reflect placental compensation for waning maternal titers. These results provide novel insight into the impact of platform and trimester of vaccination on maternal humoral immune response and transplacental antibody transfer.
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http://dx.doi.org/10.1038/s41467-022-31169-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9239994PMC
June 2022

Estimating typhoid incidence from community-based serosurveys: a multicohort study.

Lancet Microbe 2022 Aug 21;3(8):e578-e587. Epub 2022 Jun 21.

Center for Celiac Research and Treatment, MassGeneral Hospital for Children, Boston, MA, USA; Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Boston, MA, USA; Harvard Medical School, Harvard University, Boston, MA, USA.

Background: The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae (Salmonella enterica serovars Typhi and Paratyphi), is largely unknown in regions without blood culture surveillance. The aim of this study was to evaluate whether new diagnostic serological markers for typhoidal Salmonella can reliably estimate population-level incidence.

Methods: We collected longitudinal blood samples from patients with blood culture-confirmed enteric fever enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana between 2016 and 2021 and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to hemolysin E and S Typhi lipopolysaccharide. We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titres and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.

Findings: The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children younger than 5 years ranged between 58·5 per 100 person-years (95% CI 42·1-81·4) in Dhaka, Bangladesh, to 6·6 per 100 person-years (4·3-9·9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates.

Interpretation: The approach described here has the potential to expand the geographical scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographical regions and time.

Funding: Bill & Melinda Gates Foundation.

Translations: For the Nepali, Bengali and Urdu translations of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2666-5247(22)00114-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329131PMC
August 2022

Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.

Nutrients 2022 Jun 15;14(12). Epub 2022 Jun 15.

Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN 55907, USA.

Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. The median VH in NCGS was significantly shorter (600, IQR: 400-705) than controls (900, IQR: 667-1112) ( < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390-620) vs. 427 µm (IQR: 348-569, = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls ( < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. : NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.
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http://dx.doi.org/10.3390/nu14122487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9230100PMC
June 2022

Monocyte anisocytosis increases during multisystem inflammatory syndrome in children with cardiovascular complications.

BMC Infect Dis 2022 Jun 20;22(1):563. Epub 2022 Jun 20.

Harvard Medical School, Boston, MA, USA.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening complication that can develop weeks to months after an initial SARS-CoV-2 infection. A complex, time-consuming laboratory evaluation is currently required to distinguish MIS-C from other illnesses. New assays are urgently needed early in the evaluation process to expedite MIS-C workup and initiate treatment when appropriate. This study aimed to measure the performance of a monocyte anisocytosis index, obtained on routine complete blood count (CBC), to rapidly identify subjects with MIS-C at risk for cardiac complications.

Methods: We measured monocyte anisocytosis, quantified by monocyte distribution width (MDW), in blood samples collected from children who sought medical care in a single medical center from April 2020 to October 2020 (discovery cohort). After identifying an effective MDW threshold associated with MIS-C, we tested the utility of MDW as a tier 1 assay for MIS-C at multiple institutions from October 2020 to October 2021 (validation cohort). The main outcome was the early screening of MIS-C, with a focus on children with MIS-C who displayed cardiac complications. The screening accuracy of MDW was compared to tier 1 routine laboratory tests recommended for evaluating a child for MIS-C.

Results: We enrolled 765 children and collected 846 blood samples for analysis. In the discovery cohort, monocyte anisocytosis, quantified as an MDW threshold of 24.0, had 100% sensitivity (95% CI 78-100%) and 80% specificity (95% CI 69-88%) for identifying MIS-C. In the validation cohort, an initial MDW greater than 24.0 maintained a 100% sensitivity (95% CI 80-100%) and monocyte anisocytosis displayed a diagnostic accuracy greater that other clinically available hematologic parameters. Monocyte anisocytosis decreased with disease resolution to values equivalent to those of healthy controls.

Conclusions: Monocyte anisocytosis detected by CBC early in the clinical workup improves the identification of children with MIS-C with cardiac complications, thereby creating opportunities for improving current practice guidelines.
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http://dx.doi.org/10.1186/s12879-022-07526-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9208352PMC
June 2022

The Zonulin Pathway as a Potential Mediator of Gastrointestinal Dysfunction in Critical Illness.

Pediatr Crit Care Med 2022 May 10. Epub 2022 May 10.

Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA.

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http://dx.doi.org/10.1097/PCC.0000000000002985DOI Listing
May 2022

Durability and Cross-Reactivity of SARS-CoV-2 mRNA Vaccine in Adolescent Children.

Vaccines (Basel) 2022 Mar 23;10(4). Epub 2022 Mar 23.

Massachusetts General Hospital Department of Pediatrics, Mucosal Immunology and Biology Research Center, Boston, MA 02114, USA.

Emergent SARS-CoV-2 variants and waning humoral immunity in vaccinated individuals have resulted in increased infections and hospitalizations. Children are not spared from infection nor complications of COVID-19, and the recent recommendation for boosters in individuals ages 12 years or older calls for broader understanding of the adolescent immune profile after mRNA vaccination. We tested the durability and cross-reactivity of anti-SARS-CoV-2 serologic responses over a six-month time course in vaccinated adolescents against the SARS-CoV-2 D614G ("wild type") and Omicron antigens. Serum from 77 adolescents showed that anti-Spike antibodies wane significantly over six months. After completion of a two-vaccine series, cross-reactivity against Omicron-specific receptor-binding domain (RBD) was seen. Functional humoral activation against wild type and Omicron SARS-CoV-2 also declines over time in vaccinated adolescent children. Evidence of waning mRNA-induced vaccine immunity underscores vulnerabilities in long-term pediatric protection against SARS-CoV-2 infection, while cross-reactivity highlights the additional benefits of vaccination. Characterization of adolescent immune signatures post-vaccination will inform guidance on vaccine platforms and timelines, and ultimately optimize immunoprotection of children.
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http://dx.doi.org/10.3390/vaccines10040492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032590PMC
March 2022

The Gut and Blood Microbiome in IgA Nephropathy and Healthy Controls.

Kidney360 2021 08 9;2(8):1261-1274. Epub 2021 Jun 9.

Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Background: IgA nephropathy (IgAN) has been associated with gut dysbiosis, intestinal membrane disruption, and translocation of bacteria into blood. Our study aimed to understand the association of gut and blood microbiomes in patients with IgAN in relation to healthy controls.

Methods: We conducted a case-control study with 20 patients with progressive IgAN, matched with 20 healthy controls, and analyzed bacterial DNA quantitatively in blood using 16S PCR and qualitatively in blood and stool using 16S metagenomic sequencing. We conducted between-group comparisons as well as comparisons between the blood and gut microbiomes.

Results: Higher median 16S bacterial DNA in blood was found in the IgAN group compared with the healthy controls group (7410 versus 6030 16S rDNA copies/l blood, =0.04). - and -Diversity in both blood and stool was largely similar between the IgAN and healthy groups. In patients with IgAN, in comparison with healthy controls, we observed higher proportions of the class Coriobacteriia and species of the genera , , and in blood, and species of the genera , , and some in stool. Taxa distribution were markedly different between the blood and stool samples of each subject in both IgAN and healthy groups, without any significant correlation between corresponding gut and blood phyla.

Conclusions: Important bacterial taxonomic differences, quantitatively in blood and qualitatively in both blood and stool samples, that were detected between IgAN and healthy groups warrant further investigation into their roles in the pathogenesis of IgAN. Although gut bacterial translocation into blood may be one of the potential sources of the blood microbiome, marked taxonomic differences between gut and blood samples in each subject in both groups confirms that the blood microbiome does not directly reflect the gut microbiome. Further research is needed into other possible sites of origin and internal regulation of the blood microbiome.
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http://dx.doi.org/10.34067/KID.0000132021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8676391PMC
August 2021

Reaching and Grasping Movements in Parkinson's Disease: A Review.

J Parkinsons Dis 2022 ;12(4):1083-1113

The BioRobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy.

Parkinson's disease (PD) is known to affect the brain motor circuits involving the basal ganglia (BG) and to induce, among other signs, general slowness and paucity of movements. In upper limb movements, PD patients show a systematic prolongation of movement duration while maintaining a sufficient level of endpoint accuracy. PD appears to cause impairments not only in movement execution, but also in movement initiation and planning, as revealed by abnormal preparatory activity of motor-related brain areas. Grasping movement is affected as well, particularly in the coordination of the hand aperture with the transport phase. In the last fifty years, numerous behavioral studies attempted to clarify the mechanisms underlying these anomalies, speculating on the plausible role that the BG-thalamo-cortical circuitry may play in normal and pathological motor control. Still, many questions remain open, especially concerning the management of the speed-accuracy tradeoff and the online feedback control. In this review, we summarize the literature results on reaching and grasping in parkinsonian patients. We analyze the relevant hypotheses on the origins of dysfunction, by focusing on the motor control aspects involved in the different movement phases and the corresponding role played by the BG. We conclude with an insight into the innovative stimulation techniques and computational models recently proposed, which might be helpful in further clarifying the mechanisms through which PD affects reaching and grasping movements.
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http://dx.doi.org/10.3233/JPD-213082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198782PMC
January 2022

Zonulin Antagonist, Larazotide (AT1001), As an Adjuvant Treatment for Multisystem Inflammatory Syndrome in Children: A Case Series.

Crit Care Explor 2022 Feb 18;10(2):e0641. Epub 2022 Feb 18.

Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA.

Objectives: A recent study suggests that Multisystem Inflammatory Syndrome in Children (MIS-C) is triggered by gastrointestinal breach of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral particles from the gut lumen into systemic circulation. The virus remains in the gut weeks to months after respiratory infection, causing zonulin release from the intestinal epithelial cells. Zonulin loosens tight junctions, permitting trafficking of highly inflammatory viral particles into circulation. Current MIS-C treatments target the subsequent immune hyperactivation, not the causative loss of mucosal barrier integrity. Larazotide, a zonulin inhibitor, prevents breakdown of tight junctions, limiting antigen trafficking.

Design: Children with MIS-C were treated with larazotide as an adjuvant to steroid/intravenous immunoglobulin therapy. Clinical outcomes, SARS-CoV-2 antigenemia, and cytokine profiles are reported. Outcomes were compared with children with MIS-C receiving steroids and/or IVIG therapy alone.

Patients: Four children with MIS-C, ages 3-17 years, were enrolled.

Interventions: Patients were treated with open label larazotide 10 mcg/kg (maximum 500 mcg/dose) orally four times daily for 21 days.

Measurements And Main Results: All four patients tolerated larazotide without adverse effects and displayed reduction in Spike antigenemia to undetectable levels. When compared with 22 children with MIS-C receiving steroids and/or intravenous immunoglobulin therapy alone, larazotide-treated patients reported significantly improved time to resolution of gastrointestinal symptoms ( = 0.03), and time to clearance of Spike antigenemia ( = 0.04), plus a trend towards shorter length of stay.

Conclusions: Larazotide appears safe and well-tolerated and may offer potential benefit as an adjuvant to immune-targeted therapies. Expansion of clinical trials is urgently needed to ascertain the clinical impact of larazotide on MIS-C.
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http://dx.doi.org/10.1097/CCE.0000000000000641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8860335PMC
February 2022

Durability and cross-reactivity of SARS-CoV-2 mRNA vaccine in adolescent children.

medRxiv 2022 Feb 16. Epub 2022 Feb 16.

Massachusetts General Hospital Department of Pediatrics, Mucosal Immunology and Biology Research Center, Boston, MA, USA.

Emergent SARS-CoV-2 variants and waning humoral immunity in vaccinated individuals have resulted in increased infections and hospitalizations. Children are not spared from infection nor complications of COVID-19, and the recent recommendation for boosters in individuals ages 12 years or older calls for broader understanding of the adolescent immune profile after mRNA vaccination. We tested the durability and cross-reactivity of anti-SARS-CoV-2 serologic responses over a six-month time course in vaccinated adolescents against the SARS-CoV-2 wild type and Omicron antigens. Serum from 77 adolescents showed that anti-Spike antibodies wane significantly over 6 months. After completion of a two-vaccine series, cross-reactivity against Omicron-specific receptor-binding domain (RBD) was seen. Evidence of waning mRNA-induced vaccine immunity underscores vulnerabilities in long-term pediatric protection against SARS-CoV-2 infection, while cross-reactivity highlights the additional benefits of vaccination. Characterization of adolescent immune signatures post-vaccination will inform guidance on vaccine platforms and timelines, and ultimately optimize immunoprotection of children.
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http://dx.doi.org/10.1101/2022.01.05.22268617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8863160PMC
February 2022

Effect of Gliadin Stimulation on HLA-DQ2.5 Gene Expression in Macrophages from Adult Celiac Disease Patients.

Biomedicines 2021 Dec 29;10(1). Epub 2021 Dec 29.

Institute of Genetics and Biophysics "A. Buzzati-Traverso", Italian National Council of Research (CNR), 80131 Naples, Italy.

Macrophages play an important role in the pathogenesis of celiac disease (CD) because they are involved in both inflammatory reaction and antigen presentation. We analyzed the expression of CD-associated HLA-DQ2.5 risk alleles on macrophages isolated by two cohorts of adult patients, from the U.S. and Italy, at different stages of disease and with different genotypes. After isolating and differentiating macrophages from PBMC, we assessed the HLA genotype and quantified the HLA-DQ2.5 mRNAs by qPCR, before and after gliadin stimulation. The results confirmed the differences in expression between DQA1*05:01 and DQB1*02:01 predisposing alleles and the non-CD associated alleles, as previously shown on other types of APCs. The gliadin challenge confirmed the differentiation of macrophages toward a proinflammatory phenotype, but above all, it triggered an increase of DQA1*05:01 mRNA, as well as a decrease of the DQB1*02:01 transcript. Furthermore, we observed a decrease in the DRB1 genes expression and a downregulation of the CIITA transactivator. In conclusion, our findings provide new evidences on the non-coordinated regulation of celiac disease DQ2.5 risk genes and support the hypothesis that gliadin could interfere in the three-dimensional arrangement of chromatin at the HLA locus.
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http://dx.doi.org/10.3390/biomedicines10010063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773327PMC
December 2021

Comprehensive antibody profiling of mRNA vaccination in children.

bioRxiv 2022 Jan 4. Epub 2022 Jan 4.

While children have been largely spared from COVID-19 disease, the emergence of viral variants of concern (VOC) with increased transmissibility, combined with fluctuating mask mandates and school re-openings have led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remains unclear. Given the recent announcement of incomplete immunity induced by the pediatric dose of the BNT162b2 vaccine in young children, here we aimed to deeply profile and compare the vaccine-induced humoral immune response in 6-11 year old children receiving the pediatric (50μg) or adult (100μg) dose of the mRNA-1273 vaccine compared to adults and naturally infected children or children that experienced multi inflammatory syndrome in children (MIS-C) for the first time. Children elicited an IgG dominant vaccine induced immune response, surpassing adults at a matched 100μg dose, but more variable immunity at a 50μg dose. Irrespective of titer, children generated antibodies with enhanced Fc-receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron receptor binding domain-binding, but robustly preserved omicron Spike-receptor binding, with robustly preserved Fc-receptor binding capabilities, in a dose dependent manner. These data indicate that while both 50μg and 100μg of mRNA vaccination in children elicits robust cross-VOC antibody responses, 100ug of mRNA in children results in highly preserved omicron-specific functional humoral immunity.

One-sentence Summary: mRNA vaccination elicits robust humoral immune responses to SARS-CoV-2 in children 6-11 years of age.
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http://dx.doi.org/10.1101/2021.10.07.463592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750651PMC
January 2022

Autonomic Nervous System Neuroanatomical Alterations Could Provoke and Maintain Gastrointestinal Dysbiosis in Autism Spectrum Disorder (ASD): A Novel Microbiome-Host Interaction Mechanistic Hypothesis.

Nutrients 2021 Dec 24;14(1). Epub 2021 Dec 24.

Bio-Modeling Systems, Tour CIT, 3 Rue de l'Arrivée, 75015 Paris, France.

Dysbiosis secondary to environmental factors, including dietary patterns, antibiotics use, pollution exposure, and other lifestyle factors, has been associated to many non-infective chronic inflammatory diseases. Autism spectrum disorder (ASD) is related to maternal inflammation, although there is no conclusive evidence that affected individuals suffer from systemic low-grade inflammation as in many psychological and psychiatric diseases. However, neuro-inflammation and neuro-immune abnormalities are observed within ASD-affected individuals. Rebalancing human gut microbiota to treat disease has been widely investigated with inconclusive and contradictory findings. These observations strongly suggest that the forms of dysbiosis encountered in ASD-affected individuals could also originate from autonomic nervous system (ANS) functioning abnormalities, a common neuro-anatomical alteration underlying ASD. According to this hypothesis, overactivation of the sympathetic branch of the ANS, due to the fact of an ASD-specific parasympathetic activity deficit, induces deregulation of the gut-brain axis, attenuating intestinal immune and osmotic homeostasis. This sets-up a dysbiotic state, that gives rise to immune and osmotic dysregulation, maintaining dysbiosis in a vicious cycle. Here, we explore the mechanisms whereby ANS imbalances could lead to alterations in intestinal microbiome-host interactions that may contribute to the severity of ASD by maintaining the brain-gut axis pathways in a dysregulated state.
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http://dx.doi.org/10.3390/nu14010065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8746684PMC
December 2021

Neutrophil Profiles of Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children.

bioRxiv 2021 Dec 20. Epub 2021 Dec 20.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a delayed-onset, COVID-19-related hyperinflammatory systemic illness characterized by SARS-CoV-2 antigenemia, cytokine storm and immune dysregulation; however, the role of the neutrophil has yet to be defined. In adults with severe COVID-19, neutrophil activation has been shown to be central to overactive inflammatory responses and complications. Thus, we sought to define neutrophil activation in children with MIS-C and acute COVID-19. We collected samples from 141 children: 31 cases of MIS-C, 43 cases of acute pediatric COVID-19, and 67 pediatric controls. We found that MIS-C neutrophils display a granulocytic myeloid-derived suppressor cell (G-MDSC) signature with highly altered metabolism, which is markedly different than the neutrophil interferon-stimulated gene (ISG) response observed in pediatric patients during acute SARS-CoV-2 infection. Moreover, we identified signatures of neutrophil activation and degranulation with high levels of spontaneous neutrophil extracellular trap (NET) formation in neutrophils isolated from fresh whole blood of MIS-C patients. Mechanistically, we determined that SARS-CoV-2 immune complexes are sufficient to trigger NETosis. Overall, our findings suggest that the hyperinflammatory presentation of MIS-C could be mechanistically linked to persistent SARS-CoV-2 antigenemia through uncontrolled neutrophil activation and NET release in the vasculature.

One Sentence Summary: Circulating SARS-CoV-2 antigen:antibody immune complexes in Multisystem Inflammatory Syndrome in Children (MIS-C) drive hyperinflammatory and coagulopathic neutrophil extracellular trap (NET) formation and neutrophil activation pathways, providing insight into disease pathology and establishing a divergence from neutrophil signaling seen in acute pediatric COVID-19.
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http://dx.doi.org/10.1101/2021.12.18.473308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722589PMC
December 2021

Characterization of the blood microbiota in children with Celiac disease.

Curr Res Microb Sci 2021 Dec 30;2:100069. Epub 2021 Aug 30.

Center for Celiac Research and Treatment, MassGeneral Hospital for Children, Yawkey Center for Outpatient Care, Suite 6B, 32 Fruit Street, Boston, MA 02114, USA.

Celiac Disease (CD) is an autoimmune disorder triggered by gluten ingestion that can develop in genetically predisposed individuals. Alterations in the gut microbiota have been suggested to contribute to development of autoimmune conditions including CD. Recent work suggests the existence of a blood microbiota. Evidence that alterations in the blood microbiota potentially influence the development of chronic immune based diseases is increasing. However, there is no published literature regarding the blood microbiota in children, including those with CD. This study aimed to characterize the diversity and taxonomic composition of the blood microbiota of children with CD compared to controls. Whole blood samples were collected from children with active CD, CD in remission, and control subjects and 16S rRNA sequencing was utilized to analyze the blood microbiota. We found 16s rRNA present throughout all pediatric blood samples, providing evidence for the presence of a pediatric blood microbiota. We found significant differences in beta diversity and in abundance of certain taxa (Campylobacterales order, Odoribacteraceae and Helicobacteraceae families, genus and species, and species) between subjects with active CD and controls. These taxa have been previously reported to be associated with immune response and gut-inflammatory diseases. We did not find significant differences between subjects with active and remission CD or between remission CD and controls. Conclusions: We provide evidence for a pediatric blood microbiota and identified higher beta diversity and alterations in the composition of blood microbiota in subjects with active CD compared to controls.
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http://dx.doi.org/10.1016/j.crmicr.2021.100069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610358PMC
December 2021

Novel role of zonulin in the pathophysiology of gastro-duodenal transit: a clinical and translational study.

Sci Rep 2021 11 17;11(1):22462. Epub 2021 Nov 17.

Department of Pediatrics, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.

We examined the relationship between zonulin and gastric motility in critical care patients and a translational mouse model of systemic inflammation. Gastric motility and haptoglobin (HP) 2 isoform quantification, proxy for zonulin, were examined in patients. Inflammation was triggered by lipopolysaccharide (LPS) injection in C57Bl/6 zonulin transgenic mouse (Ztm) and wildtype (WT) mice as controls, and gastro-duodenal transit was examined by fluorescein-isothiocyanate, 6 and 12 h after LPS-injection. Serum cytokines and zonulin protein levels, and zonulin gastric-duodenal mRNA expression were examined. Eight of 20 patients [14 years, IQR (12.25, 18)] developed gastric dysmotility and were HP2 isoform-producing. HP2 correlated with gastric dysmotility (r = - 0.51, CI - 0.81 to 0.003, p = 0.048). LPS injection induced a time-dependent increase in IL-6 and KC-Gro levels in all mice (p < 0.0001). Gastric dysmotility was reduced similarly in Ztm and WT mice in a time-dependent manner. Ztm had 16% faster duodenal motility than WT mice 6H post-LPS, p = 0.01. Zonulin mRNA expression by delta cycle threshold (dCT) was higher in the stomach (9.7, SD 1.4) than the duodenum (13.9, SD 1.4) 6H post-LPS, p = 0.04. Serum zonulin protein levels were higher in LPS-injected mice compared to vehicle-injected animals in a time-dependent manner. Zonulin correlated with gastric dysmotility in patients. A mouse model had time-dependent gastro-duodenal dysmotility after LPS-injection that paralleled zonulin mRNA expression and protein levels.
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http://dx.doi.org/10.1038/s41598-021-01879-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599512PMC
November 2021

The Zonulin-transgenic mouse displays behavioral alterations ameliorated via depletion of the gut microbiota.

Tissue Barriers 2022 Jul 14;10(3):2000299. Epub 2021 Nov 14.

Department of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.

The gut-brain axis hypothesis suggests that interactions in the intestinal milieu are critically involved in regulating brain function. Several studies point to a gut-microbiota-brain connection linking an impaired intestinal barrier and altered gut microbiota composition to neurological disorders involving neuroinflammation. Increased gut permeability allows luminal antigens to cross the gut epithelium, and via the blood stream and an impaired blood-brain barrier (BBB) enters the brain impacting its function. Pre-haptoglobin 2 (pHP2), the precursor protein to mature HP2, is the first characterized member of the zonulin family of structurally related proteins. pHP 2 has been identified in humans as the thus far only endogenous regulator of epithelial and endothelial tight junctions (TJs). We have leveraged the Zonulin-transgenic mouse (Ztm) that expresses a murine pHP2 (zonulin) to determine the role of increased gut permeability and its synergy with a dysbiotic intestinal microbiota on brain function and behavior. Here we show that Ztm mice display sex-dependent behavioral abnormalities accompanied by altered gene expression of BBB TJs and increased expression of brain inflammatory genes. Antibiotic depletion of the gut microbiota in Ztm mice downregulated brain inflammatory markers ameliorating some anxiety-like behavior. Overall, we show that zonulin-dependent alterations in gut permeability and dysbiosis of the gut microbiota are associated with an altered BBB integrity, neuroinflammation, and behavioral changes that are partially ameliorated by microbiota depletion. Our results suggest the Ztm model as a tool for the study of the cross-talk between the microbiome/gut and the brain in the context of neurobehavioral/neuroinflammatory disorders.
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http://dx.doi.org/10.1080/21688370.2021.2000299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9359372PMC
July 2022

Maternal SARS-CoV-2 infection elicits sexually dimorphic placental immune responses.

Sci Transl Med 2021 Oct 27;13(617):eabi7428. Epub 2021 Oct 27.

Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

There is a persistent bias toward higher prevalence and increased severity of coronavirus disease 2019 (COVID-19) in males. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of COVID-19 disease in adults and play a key role in the placental antiviral response. Moreover, the interferon response has been shown to alter Fc receptor expression and therefore may affect placental antibody transfer. Here, we examined the intersection of maternal-fetal antibody transfer, viral-induced placental interferon responses, and fetal sex in pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Placental Fc receptor abundance, interferon-stimulated gene (ISG) expression, and SARS-CoV-2 antibody transfer were interrogated in 68 human pregnancies. Sexually dimorphic expression of placental Fc receptors, ISGs and proteins, and interleukin-10 was observed after maternal SARS-CoV-2 infection, with up-regulation of these features in placental tissue of pregnant individuals with male fetuses. Reduced maternal SARS-CoV-2–specific antibody titers and impaired placental antibody transfer were also observed in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.
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http://dx.doi.org/10.1126/scitranslmed.abi7428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8784281PMC
October 2021

COVID-19 mRNA vaccines drive differential antibody Fc-functional profiles in pregnant, lactating, and nonpregnant women.

Sci Transl Med 2021 Oct 27;13(617):eabi8631. Epub 2021 Oct 27.

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

Substantial immunological changes occur throughout pregnancy to render the mother immunologically tolerant to the fetus and allow fetal growth. However, additional local and systemic immunological adaptations also occur, allowing the maternal immune system to continue to protect the dyad against pathogens both during pregnancy and after birth through lactation. This fine balance of tolerance and immunity, along with physiological and hormonal changes, contributes to increased susceptibility to particular infections in pregnancy, including more severe coronavirus disease 2019 (COVID-19). Whether these changes also make pregnant women less responsive to vaccination or induce altered immune responses to vaccination remains incompletely understood. To define potential changes in vaccine response during pregnancy and lactation, we undertook deep sequencing of the humoral vaccine response in a group of pregnant and lactating women and nonpregnant age-matched controls. Vaccine-specific titers were comparable between pregnant women, lactating women, and nonpregnant controls. However, Fc receptor (FcR) binding and antibody effector functions were induced with delayed kinetics in both pregnant and lactating women compared with nonpregnant women after the first vaccine dose, which normalized after the second dose. Vaccine boosting resulted in high FcR-binding titers in breastmilk. These data suggest that pregnancy promotes resistance to generating proinflammatory antibodies and indicates that there is a critical need to follow prime-boost timelines in this vulnerable population to ensure full immunity is attained.
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http://dx.doi.org/10.1126/scitranslmed.abi8631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9067624PMC
October 2021

Virologic Features of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children.

J Infect Dis 2021 12;224(11):1821-1829

Harvard Medical School, Boston, Massachusetts, USA.

Background: Data on pediatric coronavirus disease 2019 (COVID-19) has lagged behind adults throughout the pandemic. An understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral dynamics in children would enable data-driven public health guidance.

Methods: Respiratory swabs were collected from children with COVID-19. Viral load was quantified by reverse-transcription polymerase chain reaction (RT-PCR); viral culture was assessed by direct observation of cytopathic effects and semiquantitative viral titers. Correlations with age, symptom duration, and disease severity were analyzed. SARS-CoV-2 whole genome sequences were compared with contemporaneous sequences.

Results: One hundred ten children with COVID-19 (median age, 10 years [range, 2 weeks-21 years]) were included in this study. Age did not impact SARS-CoV-2 viral load. Children were most infectious within the first 5 days of illness, and severe disease did not correlate with increased viral loads. Pediatric SARS-CoV-2 sequences were representative of those in the community and novel variants were identified.

Conclusions: Symptomatic and asymptomatic children can carry high quantities of live, replicating SARS-CoV-2, creating a potential reservoir for transmission and evolution of genetic variants. As guidance around social distancing and masking evolves following vaccine uptake in older populations, a clear understanding of SARS-CoV-2 infection dynamics in children is critical for rational development of public health policies and vaccination strategies to mitigate the impact of COVID-19.
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http://dx.doi.org/10.1093/infdis/jiab509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643403PMC
December 2021

Reply to Chen and Vitetta: Unraveling the complex interactions among organisms in the microbiome is necessary to identify unique signatures predicting CD onset.

Proc Natl Acad Sci U S A 2021 10;118(41)

Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02114.

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http://dx.doi.org/10.1073/pnas.2114053118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521656PMC
October 2021

Peptide Derivatives of the Zonulin Inhibitor Larazotide (AT1001) as Potential Anti SARS-CoV-2: Molecular Modelling, Synthesis and Bioactivity Evaluation.

Int J Mol Sci 2021 Aug 30;22(17). Epub 2021 Aug 30.

European Biomedical Research Institute of Salerno (EBRIS), Via Salvatore de Renzi 50, 84125 Salerno, Italy.

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been identified as the pathogen responsible for the outbreak of a severe, rapidly developing pneumonia (Coronavirus disease 2019, COVID-19). The virus enzyme, called 3CLpro or main protease (M), is essential for viral replication, making it a most promising target for antiviral drug development. Recently, we adopted the drug repurposing as appropriate strategy to give fast response to global COVID-19 epidemic, by demonstrating that the zonulin octapeptide inhibitor AT1001 (Larazotide acetate) binds M catalytic domain. Thus, in the present study we tried to investigate the antiviral activity of AT1001, along with five derivatives, by cell-based assays. Our results provide with the identification of AT1001 peptide molecular framework for lead optimization step to develop new generations of antiviral agents of SARS-CoV-2 with an improved biological activity, expanding the chance for success in clinical trials.
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http://dx.doi.org/10.3390/ijms22179427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431481PMC
August 2021

The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children.

J Clin Invest 2021 10;131(20)

Departments of Pediatrics, Division of Infectious Diseases and Immunology, and Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences and.

Multisystem inflammatory syndrome in children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here, we utilized proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, and complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-Spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.
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http://dx.doi.org/10.1172/JCI151520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516454PMC
October 2021

Editorial: Intestinal Dysbiosis in Inflammatory Diseases.

Front Immunol 2021 30;12:727485. Epub 2021 Jul 30.

Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States.

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http://dx.doi.org/10.3389/fimmu.2021.727485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362080PMC
November 2021
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