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Principal Investigator: Barbara Rehermann
Organization: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Fiscal Year: 2024
Award: $1,814,404
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Chronic HBV infection progresses through distinct phases often with flares in disease severity. Flares cannot be predicted, and their pathogenesis is unknown. Pregnancy represents an excellent model to study the role of immune responses in disease flares because flares occur predominantly in the third trimester of pregnancy and after delivery. Supported by an NIH Bench-to-Bedside Award, we are studying innate and adaptive immune responses and the gut microbiome prospectively in HBV-infected patients and uninfected controls during pregnancy and postpartum. The patients were clinically followed Dr. Daryl Lau, Harvard Medical School, and bio-samples are sent to NIH.
First, the fecal microbiota of HBV patients and uninfected controls were analyzed by 16s rRNA gene sequencing. HBV patients displayed reduced alpha diversity of microbiota compared to uninfected controls. PCoA analysis revealed separate clustering of microbial taxa of patients with and without postpartum hepatitis flares and uninfected controls, and this pattern was maintained throughout pregnancy and postpartum.
Second, single-cell RNA-seq analysis of peripheral blood mononuclear cells (pseudo-bulk differential expression analysis) revealed a significant difference in the first, second, and third trimester immune profile of HBV patients who never developed hepatitis flares compared to HBV patients with flares in the second trimester, HBV patients with flares postpartum, and HBV-uninfected controls. Gene enrichment analysis showed for second and third trimester peripheral blood mononuclear cells of patients who never developed hepatitis flares (i) a negative enrichment of TNF-alpha signaling and inflammatory response pathways; and (ii) a positive enrichment for B cell-related modules. This observation held true for comparison of patients who never developed flared with all other groups. Unsupervised clustering of B cells revealed in HBV patients without hepatitis flares an expanded B cell subset with enriched regulatory B cell gene signature. Collectively, these data suggest that HBV patients who control liver inflammation during and after pregnancy are characterized by a distinct gut microbiota composition and a B cell profile enriched for regulatory pathways.
In a separate study, we followed up on our previous report that the efficacy of pegylated interferon alpha (peg-IFN-alpha) for treatment of hepatitis B is diminished by preexisting antibodies against polyethylene glycol (PEG) (Nishio et al., Science Translational Medicine 2021). Polyethylene glycol (PEG) is found in several commercial products, including cosmetics and soaps, in drugs including pegylated interferon alpha, sofosbuvir, anti-cancer drugs, and in nanoparticle vaccines. To assess whether antibody levels against PEG increased in patients treated with pegylated drugs and pegylated nanoparticle mRNA vaccines, we conducted a retrospective/prospective study to assess changes in anti-PEG levels among 48 patients with viral hepatitis, followed up to 24 years prior to and 4 years after the COVID-19 pandemic.
We found that all patients had IgG and IgM antibodies against PEG at the last visit (2018/2019) prior to the pandemic. In the 24 years prior to the SARS-CoV-2 pandemic, anti-PEG levels increased transiently after peg-IFN-alpha treatment of patients with chronic viral hepatitis, but there was lasting increase in the patient population during the pre-pandemic follow up. In contrast, there was a lasting increase in anti-PEG levels in the first 4 years of the pandemic. The Moderna mRNA vaccine induced a greater fold-increase in both anti-PEG IgM and IgG levels than the Pfizer mRNA vaccine. Baseline anti-PEG IgM antibody levels negatively correlated with the induction of antibodies against the SARS-CoV-2 spike protein.
In conclusion, the multivalent PEG on mRNA nanoparticles is much more immunogenic than the single-chain PEG on pegylated PEG-IFN-alpha. The recent, significant increase in PEG-specific antibody levels may affect the pharmacokinetics of pegylated drugs, which in the presence of these antibodies, will be sequestered and cleared faster.
Terms: <(TNF)-α><16S gene sequencing><16S rRNA amplicon sequencing><16S rRNA gene amplicon sequencing><16S rRNA gene sequencing><16S rRNA genomic profiling><16S rRNA sequencing><16S ribosomal RNA gene sequencing><16S ribosomal RNA sequencing><16S sequencing><19S Gamma Globulin><1st trimester><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2nd trimester><3rd trimester><7S Gamma Globulin><Active Follow-up><Acute><Affect><Anti-Cancer Agents><Anti-viral Therapy><Antibodies><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Area><Award><B blood cells><B cell><B cells><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 S protein><COVID-19 antibody><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 years><Cachectin><Cancer Drug><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Chronic Hepatitis B><Chronic viral hepatitis><Cirrhosis><Clinical><Cosmetics><Cytokines and Inflammatory Response><DNA Viruses><Data><Delta Agent><Delta Virus><Disease><Disorder><Drug Kinetics><Drugs><Early Placental Phase><First Pregnancy Trimester><First Trimester><Flare><GI microbiome><GI microbiota><Gastrointestinal microbiota><Gene Transcription><Genes><Genetic Transcription><Genome><Gestation><HBV><HBV therapy><HBV treatment><HCV><Hepatic Cancer><Hepatic Cells><Hepatic Parenchymal Cell><Hepatitis><Hepatitis B Therapeutic><Hepatitis B Therapy><Hepatitis B Treatment><Hepatitis B Virus><Hepatitis C virus><Hepatitis D Virus><Hepatitis Delta Virus><Hepatitis Viruses><Hepatitis δ Virus><Hepatocyte><Homologous Serum Hepatitis Virus><IgG><IgM><Immune><Immune response><Immunes><Immunoglobulin G><Immunoglobulin M><Immunological response><Immunology><Infection><Inflammatory Response Pathway><Innate Immune Response><Intracellular Communication and Signaling><Last Trimester><Liver Cells><Macrogols><Macrophage-Derived TNF><Malignant neoplasm of liver><Medication><Messenger RNA><Midtrimester><Modeling><Monocyte-Derived TNF><NIH><National Institutes of Health><Neoplastic Disease Chemotherapeutic Agents><Nucleus><PBMC><PEG-IFN-a><PEG-interferon alfa><Pathogenesis><Patients><Pattern><Pegylated Interferon Alfa><Peripheral Blood Mononuclear Cell><Persons><Pharmaceutical Preparations><Pharmacokinetics><Phase><Play><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polyoxyethylenes><Postpartum Period><Pregnancy><Preventative vaccine><Preventive vaccine><Process><Prophylactic vaccine><Prospective Studies><RNA Expression><RNA Viruses><RNA vaccine><RNA-based vaccine><Regulatory Pathway><Reporting><Research><Role><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 antibody><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Second Pregnancy Trimester><Second Trimester><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Soaps><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Third Pregnancy Trimester><Third Trimester><Transcription><Translational Research><Translational Science><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor-Specific Treatment Agents><United States National Institutes of Health><Vaccines><Vertical Disease Transmission><Vertical Transmission><Viral><Viral hepatitis><Visit><active followup><adaptive immune response><after pregnancy><anti-cancer drug><antibody against COVID-19><antibody against SARS-CoV-2><antibody against coronavirus disease 2019><antibody against severe acute respiratory syndrome coronavirus 2><antibody to COVID-19><antibody to SARS-CoV-2><antibody to coronavirus disease 2019><antibody to severe acute respiratory syndrome coronavirus 2><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><biological signal transduction><chronic HBV infection><chronic hepatitis B virus infection><chronic infection><circular RNA><cirrhotic><closed circular RNA><co-infection><coinfection><coronavirus disease 2019 S protein><coronavirus disease 2019 antibody><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cosmetic product><cost><differential expression><differentially expressed><digestive tract microbiome><disease severity><drug/agent><effective therapy><effective treatment><end stage liver disease><end stage liver failure><enteric microbial community><enteric microbiome><enteric microbiota><fecal microbial community><fecal microbiota><follow up><follow-up><followed up><followup><gastrointestinal microbial flora><gastrointestinal microbiome><gene signatures><genetic signature><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut-associated microbiome><hepatic inflammation><hepatitis virus infection><host response><immune system response><immunogenic><immunoresponse><inflamed liver><intestinal biome><intestinal flora><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal tract microflora><liver cancer><liver inflammation><liver malignancy><mRNA><mRNA vaccine><mRNA-based vaccine><malignant liver tumor><medical college><medical schools><microbial><microbial consortia><microbial flora><microbiota><microbiota composition><microflora><mother to child transmission><multispecies consortia><nano particle><nano-sized particle><nanoparticle><nanosized particle><pandemic><pandemic disease><patient population><persistent infection><post pregnancy><post-partum><pre-pandemic><programs><prospective><scRNA-seq><school of medicine><severe acute respiratory syndrome coronavirus 2 antibody><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><spike proteins on SARS-CoV-2><transcriptional differences><translation research><translational investigation><translational medicine><unsupervised clustering><viral infectious disease treatment>