scholarly journals Machine learning-based single cell and integrative analysis reveals that baseline mDC predisposition predicts protective Hepatitis B vaccine response

2021 ◽  
Author(s):  
Brian Aevermann ◽  
Casey P. Shannon ◽  
Mark Novotny ◽  
Rym Ben-Othman ◽  
Bing Cai ◽  
...  
Keyword(s):  
Machine Learning ◽  
Single Dose ◽  
Dendritic Cell ◽  
Hepatitis B ◽  
Single Cell ◽  
Immune Cell ◽  
Serum Antibody ◽  
Vaccine Response ◽  
Hbv Vaccine ◽  
Antibody Levels

AbstractVaccination to prevent infectious disease is one of the most successful public health interventions ever developed. And yet, variability in individual vaccine effectiveness suggests a better mechanistic understanding of vaccine-induced immune responses could improve vaccine design and efficacy. We have previously shown that protective antibody levels could be elicited in a subset of recipients with only a single dose of the hepatitis B virus (HBV) vaccine. Why some, but not all, recipients responded in this way was not clear. Using single cell RNA sequencing of sorted innate immune cell subsets, we identified two distinct myeloid dendritic cell subsets (NDRG1-expressing mDC2 and CDKN1C-expressing mDC4), the ratio of which at baseline (pre-vaccination) predicted immune response to a single dose of HBV vaccine. Our results suggest that the participants in our vaccine study were in one of two different dendritic cell dispositional states at baseline – an NDRG2-mDC2 state in which the vaccine elicited an antibody response after a single immunization or a CDKN1C-mDC4 state in which the vaccine required two or three doses for induction of antibody responses. Genes expressed in these mDC subsets were used as an approach for feature selection prior to the construction of a predictive model using supervised canonical correlation machine learning. The resulting model showed an improved ability to predict serum antibody titers in response to vaccination. Taken together, these results suggest that the propensity of circulating dendritic cells toward either activation or suppression, their “dispositional endotype”, could dictate response to vaccination. The fact that these mDCs could be modulated via TLR stimulation could guide progress towards design of effective single dose vaccination strategies.

scholarly journals Machine Learning-Based Single Cell and Integrative Analysis Reveals That Baseline mDC Predisposition Correlates With Hepatitis B Vaccine Antibody Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Brian D. Aevermann ◽  
Casey P. Shannon ◽  
Mark Novotny ◽  
Rym Ben-Othman ◽  
Bing Cai ◽  
...  
Keyword(s):  
Machine Learning ◽  
Single Dose ◽  
Dendritic Cell ◽  
Hepatitis B ◽  
Antibody Response ◽  
Single Cell ◽  
Serum Antibody ◽  
Hbv Vaccine ◽  
Wide Range ◽  
Antibody Levels

Vaccination to prevent infectious disease is one of the most successful public health interventions ever developed. And yet, variability in individual vaccine effectiveness suggests that a better mechanistic understanding of vaccine-induced immune responses could improve vaccine design and efficacy. We have previously shown that protective antibody levels could be elicited in a subset of recipients with only a single dose of the hepatitis B virus (HBV) vaccine and that a wide range of antibody levels were elicited after three doses. The immune mechanisms responsible for this vaccine response variability is unclear. Using single cell RNA sequencing of sorted innate immune cell subsets, we identified two distinct myeloid dendritic cell subsets (NDRG1-expressing mDC2 and CDKN1C-expressing mDC4), the ratio of which at baseline (pre-vaccination) correlated with the immune response to a single dose of HBV vaccine. Our results suggest that the participants in our vaccine study were in one of two different dendritic cell dispositional states at baseline – an NDRG2-mDC2 state in which the vaccine elicited an antibody response after a single immunization or a CDKN1C-mDC4 state in which the vaccine required two or three doses for induction of antibody responses. To explore this correlation further, genes expressed in these mDC subsets were used for feature selection prior to the construction of predictive models using supervised canonical correlation machine learning. The resulting models showed an improved correlation with serum antibody titers in response to full vaccination. Taken together, these results suggest that the propensity of circulating dendritic cells toward either activation or suppression, their “dispositional endotype” at pre-vaccination baseline, could dictate response to vaccination.

scholarly journals IMMU-35. TRANSCRIPTIONALLY DEFINED IMMUNE CONTEXTURE IN HUMAN GLIOMAS AT SINGLE-CELL RESOLUTION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii112-ii112
Author(s):  
Pravesh Gupta ◽  
Minghao Dang ◽  
Krishna Bojja ◽  
Tuan Tran M ◽  
Huma Shehwana ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Immune Cell ◽  
Wild Type ◽  
Sequencing Data ◽  
Human Gliomas ◽  
Cell Clusters ◽  
Recurrent Gliomas ◽  
Antigen Presenting

Abstract The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression and a comprehensive understanding of the glioma-centric immune cell repertoire beyond a priori cell types and/or states is uncharted. Consequently, we performed single-cell RNA-sequencing on ~123,000 tumor-derived immune cells from 17-pathologically stratified, IDH (isocitrate dehydrogenase)-differential primary, recurrent human gliomas, and non-glioma brains. Our analysis delineated predominant 34-myeloid cell clusters (~75%) over 28-lymphoid cell clusters (~25%) reflecting enormous heterogeneity within and across gliomas. The glioma immune diversity spanned functionally imprinted phagocytic, antigen-presenting, hypoxia, angiogenesis and, tumoricidal myeloid to classical cytotoxic lymphoid subpopulations. Specifically, IDH-mutant gliomas were enriched for brain-resident microglial subpopulations in contrast to enhanced bone barrow-derived infiltrates in IDH-wild type, especially in a recurrent setting. Microglia attrition in IDH-wild type -primary and -recurrent gliomas were concomitant with invading monocyte-derived cells with semblance to dendritic cell and macrophage/microglia like transcriptomic features. Additionally, microglial functional diversification was noted with disease severity and mostly converged to inflammatory states in IDH-wild type recurrent gliomas. Beyond dendritic cells, multiple antigen-presenting cellular states expanded with glioma severity especially in IDH-wild type primary and recurrent- gliomas. Furthermore, we noted differential microglia and dendritic cell inherent antigen presentation axis viz, osteopontin, and classical HLAs in IDH subtypes and, glioma-wide non-PD1 checkpoints associations in T cells like Galectin9 and Tim-3. As a general utility, our immune cell deconvolution approach with single-cell-matched bulk RNA sequencing data faithfully resolved 58-cell states which provides glioma specific immune reference for digital cytometry application to genomics datasets. Resultantly, we identified prognosticator immune cell-signatures from TCGA cohorts as one of many potential immune responsiveness applications of the curated signatures for basic and translational immune-genomics efforts. Thus, we not only provide an unprecedented insight of glioma TIME but also present an immune data resource that can be exploited to guide pragmatic glioma immunotherapy designs.

540 Transcriptionally defined immune landscape in human gliomas

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A576-A576
Author(s):  
Pravesh Gupta ◽  
Minghao Dang ◽  
Krishna Bojja ◽  
Huma Shehwana ◽  
Tuan Tran ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Wild Type ◽  
Cell Clusters ◽  
Md Anderson ◽  
Antigen Presenting

BackgroundBrain immunity is largely myeloid cell dominated rather than lymphoid cells in healthy and diseased state including malignancies of glial origins called as gliomas. Despite this skewed myeloid centric immune contexture, immune checkpoint and T cell based therapeutic modalities are generalizably pursued in gliomas ignoring the following facts i) T cells are sparse in tumor brain ii) glioma patients are lymphopenic iii) gliomas harbor abundant and highly complex myeloid cell repertoire. We recognized these paradoxes pertaining to fundamental understanding of constituent immune cells and their functional states in the tumor immune microenvironment (TIME) of gliomas, which remains elusive beyond a priori cell types and/or states.MethodsTo dissect the TIME in gliomas, we performed single-cell RNA-sequencing on ~123,000 tumor-derived sorted CD45+ leukocytes from fifteen genomically classified patients comprising IDH-mutant primary (IMP; n=4), IDH-mutant recurrent (IMR; n=4), IDH-wild type primary (IWP; n=3), or IDH-wild type recurrent (IWR; n=4) gliomas (hereafter referred as glioma subtypes) and two non-glioma brains (NGBs) as controls.ResultsUnsupervised clustering analyses delineated predominant 34-myeloid cell clusters (~75%) over 28-lymphoid cell clusters (~25%) reflecting enormous heterogeneity within and across glioma subtypes. The glioma immune diversity spanned functionally imprinted phagocytic, antigen-presenting, hypoxia, angiogenesis and, tumoricidal myeloid to classical cytotoxic lymphoid subpopulations. Specifically, IDH-mutant gliomas were predominantly enriched for brain-resident microglial subpopulations in contrast to enriched bone barrow-derived infiltrates in IDH-wild type especially in a recurrent setting. Microglia attrition in IWP and IWR gliomas were concomitant with invading monocyte-derived cells with semblance to dendritic cell and macrophage like transcriptomic features. Additionally, microglial functional diversification was noted with disease severity and mostly converged to inflammatory states in IWR gliomas. Beyond dendritic cells, multiple antigen-presenting cellular states expanded with glioma severity especially in IWP and IWR gliomas. Furthermore, we noted differential microglia and dendritic cell inherent antigen presentation axis viz, osteopontin, and classical HLAs in IDH subtypes and, glioma-wide non-PD1 checkpoints associations in T cells like Galectin9 and Tim-3. As a general utility, our immune cell deconvolution approach with single-cell-matched bulk RNA sequencing data faithfully resolved 58-cell states which provides glioma specific immune reference for digital cytometry application to genomics datasets.ConclusionsAltogether, we identified prognosticator immune cell-signatures from TCGA cohorts as one of many potential immune responsiveness applications of the curated signatures for basic and translational immune-genomics efforts. Thus, we not only provide an unprecedented insight of glioma TIME but also present an immune data resource that can be exploited for immunotherapy applications.Ethics ApprovalThe brain tumor/tissue samples were collected as per MD Anderson internal review board (IRB)-approved protocol numbers LAB03-0687 and, LAB04-0001. One non-tumor brain tissue sample was collected from patient undergoing neurosurgery for epilepsy as per Baylor College of Medicine IRB-approved protocol number H-13798. All experiments were compliant with the review board of MD Anderson Cancer Center, USA.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal

scholarly journals Multi-Omic Data Integration Allows Baseline Immune Signatures to Predict Hepatitis B Vaccine Response in a Small Cohort

2020 ◽  
Vol 11 ◽  
Author(s):  
Casey P. Shannon ◽  
Travis M. Blimkie ◽  
Rym Ben-Othman ◽  
Nicole Gladish ◽  
Nelly Amenyogbe ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Vaccine Development ◽  
Effective Means ◽  
Interaction Network ◽  
Effective Vaccine ◽  
Molecular Characteristics ◽  
Vaccine Response ◽  
Hbv Vaccine ◽  
Fecal Microbiome ◽  
Vaccine Responses

BackgroundVaccination remains one of the most effective means of reducing the burden of infectious diseases globally. Improving our understanding of the molecular basis for effective vaccine response is of paramount importance if we are to ensure the success of future vaccine development efforts.MethodsWe applied cutting edge multi-omics approaches to extensively characterize temporal molecular responses following vaccination with hepatitis B virus (HBV) vaccine. Data were integrated across cellular, epigenomic, transcriptomic, proteomic, and fecal microbiome profiles, and correlated to final HBV antibody titres.ResultsUsing both an unsupervised molecular-interaction network integration method (NetworkAnalyst) and a data-driven integration approach (DIABLO), we uncovered baseline molecular patterns and pathways associated with more effective vaccine responses to HBV. Biological associations were unravelled, with signalling pathways such as JAK-STAT and interleukin signalling, Toll-like receptor cascades, interferon signalling, and Th17 cell differentiation emerging as important pre-vaccination modulators of response.ConclusionThis study provides further evidence that baseline cellular and molecular characteristics of an individual’s immune system influence vaccine responses, and highlights the utility of integrating information across many parallel molecular datasets.

scholarly journals Single-dose SARS-CoV-2 vaccine in a prospective cohort of COVID-19 patients

2021 ◽  
Author(s):  
Marit J. van Gils ◽  
Hugo D.G. Willegen ◽  
Elke Wynberg ◽  
Alvin X. Han ◽  
Karlijn van der Straten ◽  
...  
Keyword(s):  
Single Dose ◽  
Prospective Cohort ◽  
Serum Antibody ◽  
Neutralizing Antibody ◽  
Credible Interval ◽  
Time Interval ◽  
Vaccine Response ◽  
Vaccine Strategy ◽  
Igg Antibody ◽  
Antibody Titers

Background The urgent need for, but limited availability of, SARS-CoV-2 vaccines worldwide has led to widespread consideration of dose sparing strategies, particularly single vaccine dosing of individuals with prior SARS-CoV-2 infection. Methods We evaluated SARS-CoV-2 specific antibody responses following a single-dose of BNT162b2 (Pfizer-BioNTech) mRNA vaccine in 155 previously SARS-CoV-2-infected individuals participating in a population-based prospective cohort study of COVID-19 patients. Participants varied widely in age, comorbidities, COVID-19 severity and time since infection, ranging from 1 to 15 months. Serum antibody titers were determined at time of vaccination and one week after vaccination. Responses were compared to those in SARS-CoV-2-naive health care workers after two BNT162b2 mRNA vaccine doses. Results Within one week of vaccination, IgG antibody levels to virus spike and RBD proteins increased 27 to 29-fold and neutralizing antibody titers increased 12-fold, exceeding titers of fully vaccinated SARS-CoV-2-naive controls (95% credible interval (CrI): 0.56 to 0.67 v. control 95% CrI: -0.16 to -0.02). Pre-vaccination neutralizing antibody titers had the largest positive mean effect size on titers following vaccination (95% CrI (0.16 to 0.45)). COVID-19 severity, the presence of comorbidities and the time interval between infection and vaccination had no discernible impact on vaccine response. Conclusion A single dose of BNT162b2 mRNA vaccine up to 15 months after SARS-CoV-2 infection provides neutralizing titers exceeding two vaccine doses in previously uninfected individuals. These findings support wide implementation of a single-dose mRNA vaccine strategy after prior SARS-CoV-2 infection.

scholarly journals Low response rates to hepatitis B vaccine in patients with chronic hepatitis C

2021 ◽  
Vol 8 (11) ◽  
pp. 5189
Author(s):  
Cláudia Alexandra Pontes Ivantes ◽  
Tiago Zibetti Dos Passos ◽  
João Marcelo Marchi Moraes ◽  
Nicole Espindula Mattar ◽  
Tereza Reck ◽  
...  
Keyword(s):  
Immune Response ◽  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Hepatitis B ◽  
Chronic Hepatitis C ◽  
Smoking Status ◽  
Response Rates ◽  
Vaccine Response ◽  
Genotype 3 ◽  
Hbv Vaccine

Background: Hepatitis B is an infectious disease with converging routes of transmission with hepatitis C, making vaccination important in hepatitis C infected people. The objective was to evaluate the vaccine response against hepatitis B virus (HBV) in patients with chronic hepatitis C virus (HCV).Methods: Retrospective observational study was conducted between November 2018 and April 2020. Subjects with anti-HBs levels ≥10 mUI/ml were considered protected against HBV and those with chronic HCV who did not receive at least one dose of the vaccine schedule or with anti-HBc reagent or even with anti-HBs positive prior to the first dose documented in the HBV vaccine record were excluded. The immune response rates to VHB vaccine in patients with HCV was obtained and different variables were analysed.Results: The study group was compound of 370 subjects. The majority (55.7%) were male, with a median age of 55.6±11 years. Regarding present or past smoking, 56.9% of patients reported that were active or past tobacco users. HCV genotype 1 corresponded to 59.7% of the cases, followed by genotype 3 (36.88%). One hundred and fourteen (30.9%) of the patients had liver cirrhosis. The immune response to complete HBV vaccine was 62.3%, whereas the response to a single dose was 57.1% (p=1). Only the age of the patient at first dose (p=0.030), smoking status (p=0.017) and the presence of cirrhosis (p=0.046) influenced the immune response to HBV vaccine.Conclusions: The rate of immune response to standard schedule of HBV vaccination in patients with HCV was low (62.3%).

EFFECT OF TRIVALENT ORAL POLIOVIRUS VACCINE IN AN INSTITUTIONALIZED POPULATION WITH VARYING NATURAL AND ACQUIRED IMMUNITY TO POLIOMYELITIS

PEDIATRICS ◽  
1965 ◽  
Vol 35 (2) ◽  
pp. 236-246
Author(s):  
Martha L. Lepow ◽  
David A. Spence
Keyword(s):  
Single Dose ◽  
Serum Antibody ◽  
Oral Poliovirus Vaccine ◽  
The Other ◽  
Acquired Immunity ◽  
The Past ◽  
Trivalent Vaccine ◽  
Antibody Levels ◽  
Serum Antibody Titer

Ninety-one children in an orphanage, who had varying degrees of natural and acquired immunity to polioviruses, were given three doses of a trivalent poliovirus vaccine at monthly intervals. It was found that among children who lacked protection to one or two types, a single dose of trivalent vaccine resulted in seroconversion to that type. For those who had antibody levels of less than four to all three types, the type 1 component of the vaccine appeared to be less effective than the other two types. An elevation in serum antibody titer was noted more frequently in children who had preimmunization titers of 1:64 or less than in those with high preimmunization titers. Although the mechanism of acquisition of prior immunity was unknown, it must be assumed that many of the subjects had had natural poliovirus infection in the past.

scholarly journals Cost Analysis of Single-Dose Hepatitis B Revaccination Among Infants Born to Hepatitis B Surface Antigen-Positive Mothers and Not Responding to the Initial Vaccine Series

2018 ◽  
Vol 133 (3) ◽  
pp. 338-346 ◽  
Author(s):  
Eric W. Hall ◽  
Eli S. Rosenberg ◽  
Monica Trigg ◽  
Noele Nelson ◽  
Sarah Schillie
Keyword(s):  
Single Dose ◽  
Hepatitis B ◽  
Cost Analysis ◽  
Surface Antigen ◽  
Lower Cost ◽  
Hepatitis B Surface Antigen ◽  
Sensitivity Analyses ◽  
The Cost ◽  
Antibody Levels ◽  
Lower Cost Option

Objectives: Infants born to mothers who are hepatitis B surface antigen (HBsAg) positive are at risk for perinatal hepatitis B infection. As prevention, these infants receive a series of 3 or 4 doses of hepatitis B vaccine starting at birth and postvaccination serologic testing. Infants with antibody levels <10 mIU/mL are considered vaccine nonresponders and should be revaccinated. The objective of this cost analysis was to assess a single-dose revaccination strategy among infant nonresponders. Methods: We used a decision analytic tree to compare the costs of a single-dose revaccination strategy with the costs of a 3-dose revaccination strategy. The analysis consisted of 3 epidemiologic scenarios that varied levels of previous protection among infants indicated for revaccination. We assumed health outcomes in each strategy were the same, and we evaluated costs from the societal perspective using 2016 US dollars. We conducted sensitivity analyses on key variables, including the minimum required efficacy of a single revaccination dose. Results: In all analyses, the single-dose revaccination strategy was a lower-cost option than the 3-dose revaccination strategy. Under the assumption that all revaccination visits were previously unscheduled, single-dose revaccination reduced the cost per infant by $119.81 to $155.72 (depending on the scenario). Across all scenarios, the most conservative estimate for the threshold efficacy (the minimum efficacy required to result in a lower-cost option) value of single-dose revaccination was 67%. Conclusions: For infants who were born to HBsAg-positive mothers and who were not responding to the initial vaccine series, a single-dose revaccination strategy, compared with a 3-dose revaccination strategy, reduced costs across several scenarios. These results helped inform the Advisory Committee on Immunization Practices’ vote in February 2017 to recommend single-dose revaccination.

scholarly journals CTIM-29. CRUCIAL APPLICATION OF SINGLE CELL GENE EXPRESSION FOR MONITORING CHANGES IN GLIOBLASTOMA PATIENTS WITH SUSTAINED RADIOGRAPHIC RESPONSE TO CMV pp65-LAMP RNA-PULSED DENDRITIC CELL-BASED VACCINES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii39-ii39
Author(s):  
Oleg Yegorov ◽  
Changlin Yang ◽  
Anjelika Dechkovskaia ◽  
Maryam Rahman ◽  
Ashley Ghiaseddin ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Single Cell ◽  
Immune Cell ◽  
Nkt Cells ◽  
Durable Response ◽  
Radiographic Response ◽  
Dc Vaccines

Abstract BACKGROUND The application of single cell sequencing as a novel immune monitoring platform can be used to identify the molecular mechanisms of immune response to dendritic cell- based vaccines, trace the cell types and states involved, and uncover novel biomarkers for immunotherapy. We applied single-cell RNA Seq analysis of longitudinal peripheral blood mononuclear cells (PBMCs) in patients with newly-diagnosed GBM enrolled on the ATTAC II clinical trial (FDA IND BB-16530; Clinicaltrials.gov # NCT02465268) who experienced a sustained radiographic response to autologous CMV pp65-LAMP RNA-pulsed DC vaccines plus GM-CSF and tetanus-diphtheria booster administered during adjuvant cycles of dose-intensified temozolomide. METHODS We constructed 5’ gene expression libraries and T cell receptor enriched libraries for 10x Genomics single-cell 5’ and VDJ sequencing, generated from PBMCs collected prior to and during patient immunization using dendritic cells loaded with messenger ribonucleic acid encoding the human cytomegalovirus (CMV) matrix protein pp65 conjugated with the lysosomal associated membrane protein (LAMP) sequence. RESULTS Overall, we sequenced a total of 189,808 single-cell transcriptomes from 5 patients. We leveraged these transcriptome-wide features to distinguish 15 peripheral immune cell subtypes in tested PBMCs. Analysis revealed dynamic changes in immune cell subsets over the course of first three vaccines, including increases in cytotoxic CD8 T cells, CD4 T cells, and NK cell subsets. Increased markers of T cell activation were observed during vaccination. Surprisingly, we observed a very high-level frequency of natural killer T (NKT) cells in the patient with a complete durable response compared to other patients. After three DC vaccines, the level of NKT cells in PBMC of this patient increased up to 10%. CONCLUSIONS These results emphasize the importance of subset specific profiling to achieve higher resolution in monitoring immune responses compared with bulk expression profiling in patients receiving immunotherapeutic treatment.

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