Clinical Research and Public Health
Abstract
BACKGROUND. Vaccine-elicited adaptive immunity is a prerequisite for control of SARS-CoV-2 infection. Multiple sclerosis (MS) disease-modifying therapies (DMTs) differentially target humoral and cellular immunity. A comprehensive comparison of MS DMTs on SARS-CoV-2 vaccine-specific immunity is needed, including quantitative and functional B and T cell responses. METHODS. Spike-specific antibody and T cell responses were measured before and following SARS-CoV-2 vaccination in a cohort of 80 subjects, including healthy controls and MS patients in six DMT groups: untreated, glatiramer acetate (GA), dimethyl fumarate (DMF), natalizumab (NTZ), sphingosine-1-phosphate (S1P) receptor modulators, and anti-CD20 monoclonal antibodies. Anti-spike antibody responses were quantified by Luminex assay, high-resolution spike epitope reactivity was mapped by VirScan, and pseudovirus neutralization was assessed. Spike-specific CD4+ and CD8+ T cell responses were characterized by activation-induced marker (AIM) expression, cytokine production, and tetramer analysis. RESULTS. Anti-spike IgG levels were similar between healthy controls, untreated MS, GA, DMF, and NTZ patients, but were significantly reduced in anti-CD20 and S1P-treated patients. Anti-spike seropositivity in anti-CD20 patients was significantly correlated with CD19+ B cell levels and inversely correlated with cumulative treatment duration. Spike epitope reactivity and pseudovirus neutralization was reduced in anti-CD20 and S1P patients, directly correlating with reduced spike receptor binding domain (RBD) IgG levels. Spike-specific CD4+ and CD8+ T cell reactivity remained robust across all groups except in S1P-treated patients in whom post-vaccine CD4+ T cell responses were attenuated. CONCLUSIONS. These findings from a large MS cohort exposed to a wide spectrum of MS immunotherapies have important implications for treatment-specific COVID-19 clinical guidelines. FUNDING. This work was supported by grants from the NIH 1K08NS107619 (JJS), NMSS TA- 1903-33713 (JJS), K08NS096117 (MRW), Westridge Foundation (MRW), Chan Zuckerberg Biohub (JLD), R01AI159260 (JAH), R01NS092835 (SSZ), R01AI131624 (SSZ), R21NS108159 (SSZ), NMSS RG1701-26628 (SSZ), and the Maisin Foundation (SSZ).
Authors
Joseph J. Sabatino Jr, Kristen Mittl, William M. Rowles, Kira McPolin, Jayant V. Rajan, Matthew T. Laurie, Colin R. Zamecnik, Ravi Dandekar, Bonny D. Alvarenga, Rita P. Loudermilk, Chloe Gerungan, Collin M. Spencer, Sharon A. Sagan, Danillo G. Augusto, Jessa R. Alexander, Joseph L. DeRisi, Jill A. Hollenbach, Michael R. Wilson, Scott S. Zamvil, Riley Bove
Abstract
BACKGROUND. Most subjects with prior COVID-19 disease manifest long–term, protective immune responses against re-infection. Accordingly, we tested the hypothesis that humoral immune and reactogenicity responses to a SARS-CoV-2 mRNA vaccine differ in subjects with and without prior COVID-19. METHODS. Health care workers (n=61) with (n=30) and without (n=31) prior COVID-19 disease received two, 30 µg doses of Pfizer BNT162b2 vaccine 3 weeks apart. Serum IgG antibody against the Spike receptor-binding domain (RBD); serum neutralizing activity; and vaccine reactogenicity were assessed longitudinally every 2 weeks for 56 days after the 1st injection. RESULTS. The COVID group manifested more rapid increases in Spike IgG antibody and serum neutralizing activity post 1st vaccine dose but showed little or no increase after the 2nd dose compared to the infection-naïve group. In fact, Spike IgG was maximum after the 1st dose in 36% of the COVID group versus 0% of the infection-naïve group. Peak IgG antibody was lower but appeared to fall more slowly in the COVID-19 versus the infection-naïve group. Finally, adverse systemic reactions e.g., fever, headache and malaise, were more frequent and lasted longer after both the 1st and 2nd injection in the COVID group than in the infection-naïve group. CONCLUSION. Subjects with prior COVID-19 demonstrate a robust, accelerated humoral immune response to the 1st dose but attenuated response to the 2nd dose of BNT162b2 vaccine compared to controls. The COVID-19 group also experiences greater reactogenicity. Humoral responses and reactogenicity to BNT162b2 differ qualitatively and quantitatively in subjects with prior COVID-19 compared to infection-naive subjects. FUNDING. This work was supported by Institutional Funds.
Authors
Steven G. Kelsen, Alan S. Braverman, Mark O. Aksoy, Jacob A. Hayman, Puja S. Patel, Charu Rajput, Huaqing Zhao, Susan G. Fisher, Michael R. Ruggieri Sr., Nina T. Gentile
Abstract
BACKGROUND. Adenoviral (Ad)-vectored vaccines are typically administered via intramuscular injection to humans, incapable of inducing respiratory mucosal immunity. However, aerosol delivery of Ad-vectored vaccines remains poorly characterized and its ability to induce mucosal immunity in humans is unknown. This phase 1b trial was to evaluate the safety and immunogenicity of human serotype-5 Ad-vectored tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to humans via inhaled aerosol or intramuscular injection. METHODS. 31 healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb® Solo Nebulizer or by intramuscular (IM) injection. The study consisted of the low dose (LD) aerosol, high dose (HD) aerosol and IM groups. The adverse events were assessed at various times post-vaccination. Immunogenicity data were collected from the peripheral blood and bronchoalveolar lavage samples at baseline and select timepoints post-vaccination. RESULTS. The nebulized aerosol droplets were <5.39µm in size. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and IM injection were safe and well-tolerated. Both aerosol doses, particularly LD, but not IM, vaccination markedly induced airway tissue-resident memory CD4 and CD8 T cells of polyfunctionality. While as expected, IM vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages. CONCLUSIONS. Inhaled aerosol delivery of Ad-vectored vaccine is a safe and superior way to elicit respiratory mucosal immunity. This study warrants further development of aerosol vaccine strategies against respiratory pathogens including TB and COVID-19. TRIAL REGISTRATION. This trial is registered with ClinicalTrial.gov, NCT# 02337270. FUNDING. The Canadian Institutes for Health Research and the Natural Sciences and Engineering Research Council of Canada.
Authors
Mangalakumari Jeyanathan, Dominik K. Fritz, Sam Afkhami, Emilio Aguirre, Karen J. Howie, Anna Zganiacz, Anna Dvorkin-Gheva, Michael R. Thompson, Richard Silver, Ruth P. Cusack, Brian D. Lichty, Paul M. O'Byrne, Martin Kolb, Maria Fe C. Medina, Myrna B. Dolovich, Imran Satia, Gail M Gauvreau, Zhou Xing, Fiona Smaill
Abstract
BACKGROUND. >1,500 variants in the ABCA4 locus underlie a heterogeneous spectrum of retinal disorders ranging from aggressive childhood-onset chorioretinopathy to milder, late-onset macular disease. Genotype-phenotype correlation studies have been limited in clinical applicability as patient cohorts are typically small and seldom capture the full natural history of individual genotypes. To overcome these limitations, we constructed a genotype-phenotype correlation matrix that provides quantifiable probabilities of long-term disease outcomes associated with specific ABCA4 genotypes from a large, age-restricted patient cohort. METHODS. The study included 112 unrelated patients ≥50 years of age in whom 2 pathogenic variants were identified after sequencing of the ABCA4 locus. Clinical characterization was performed using the results of best-corrected visual acuity, retinal imaging and full-field electroretinogram testing. RESULTS. Four distinct prognostic groups were defined according to the spatial severity of disease features across the fundus. Recurring genotypes were observed in milder prognoses including those associated with a newly defined class of rare hypomorphic alleles. PVS1 (predicted null) variants were enriched in the most severe prognoses; however, missense variants comprised a larger than expected fraction of these patients. Analysis of allele combinations and their respective prognostic severity, showed that certain variants such as p.(Gly1961Glu), and both rare and frequent hypomorphic alleles, are “clinically dominant” with respect to patient phenotypes irrespective of the allele in trans. CONCLUSION. These results provide much needed structure to the complex genetic and clinical landscape of ABCA4 disease and adds a tool to the clinical repertoire to quantitatively assess individual genotype-specific prognoses in patients.
Authors
Winston Lee, Jana Zernant, Pei-Yin Su, Takayuki Nagasaki, Stephen H. Tsang, Rando Allikmets
Abstract
BACKGROUND. While most children experience mild COVID-19, high-risk children with underlying conditions may develop severe disease, requiring interventions. Kinetics of antibodies transferred via COVID-19 convalescent plasma early in disease, have not been characterized. METHODS. In this study (NCT04377672), high-risk children were prospectively enrolled to receive high-titer COVID-19 convalescent plasma (>1:320 anti-spike IgG; Euroimmun). Passive transfer of antibodies and endogenous antibody production were serially evaluated for up to 2 months after transfusion. Commercial and research ELISA assays, virus neutralization assays, high-throughput phage-display assay utilizing a coronavirus epitope library and pharmacokinetic analyses were performed. RESULTS. Fourteen high-risk children (median age 7.5 years) received high-titer COVID-19 convalescent plasma, nine children within five days (range 2-7) of symptom onset and five children within 4 days (range 3-5) after exposure to SARS-CoV-2. There were no serious adverse events related to transfusion. Antibodies to SARS-CoV-2 were transferred from the donor to the recipient, but antibody titers declined by 14-21 days with a 15.1-day t½ for spike protein IgG. Donor plasma had significant neutralization capacity which was transferred to the recipient. However, as early as 30 minutes post-transfusion, recipient plasma had low neutralization capacity. CONCLUSIONS. Convalescent plasma transfused to high-risk children appears to be safe with expected antibody kinetics, regardless of weight or age. However, current use of convalescent plasma in high-risk children achieves low neutralizing capacity.
Authors
Oren Gordon, Mary Katherine Brosnan, Steve Yoon, Dawoon Jung, Kirsten Littlefield, Abhinaya Ganesan, Christopher A. Caputo, Maggie Li, William R. Morgenlander, Stephanie N. Henson, Alvaro A. Ordonez, Patricia De Jesus, Elizabeth W. Tucker, Nadine Peart Akindele, Zexu Ma, Jo Wilson, Camilo A. Ruiz-Bedoya, M. Elizabeth M. Younger, Evan M. Bloch, Shmuel Shoham, David Sullivan, Aaron A.R. Tobian, Kenneth R. Cooke, Ben Larman, Jogarao V.S. Gobburu, Arturo Casadevall, Andrew Pekosz, Howard M. Lederman, Sabra L. Klein, Sanjay K. Jain
Abstract
BACKGROUND. Red blood cell (RBC) transfusion effectiveness varies due to donor, component, and recipient factors. Prior studies identified characteristics associated with variation in hemoglobin increments following transfusion. We extended these observations, examining donor genetic and non-genetic factors affecting transfusion effectiveness. METHODS. This is a multicenter retrospective study of 46,705 patients, and 102,043 evaluable RBC transfusions from 2013-2016 across 12 hospitals. Transfusion effectiveness was defined as hemoglobin, bilirubin, or creatinine increments following single RBC unit transfusion. Models incorporated a subset of donors with data on single nucleotide polymorphisms associated with osmotic and oxidative hemolysis in vitro. Mixed modelling accounting for repeated transfusion episodes identified predictors of transfusion effectiveness. RESULTS. Blood donor (sex, Rh status, fingerstick hemoglobin, smoking), component (storage duration, gamma irradiation, leukoreduction, apheresis collection, storage solution), and recipient (sex, body mass index, race, age) characteristics were associated with hemoglobin and bilirubin but not creatinine increments following RBC transfusions. Increased storage duration was associated with increased bilirubin and decreased hemoglobin increments, suggestive of in vivo hemolysis following transfusion. Donor G6PD-deficiency and polymorphisms in SEC14L4, HBA2, and MYO9B genes were associated with decreased hemoglobin increments. Donor G6PD-deficiency and polymorphisms in SEC14L4 were associated with increased transfusion requirements in the subsequent 48 hours. CONCLUSIONS. Donor genetic and other factors, such as RBC storage duration, affect transfusion effectiveness as defined by decreased hemoglobin or increased bilirubin increments. Addressing these factors will provide a precision medicine approach to improve patient outcomes, particularly for chronically-transfused RBC recipients, who would most benefit from more effective transfusion products.
Authors
Nareg H. Roubinian, Sarah E. Reese, Hannah Qiao, Colleen Plimier, Fang Fang, Grier P. Page, Ritchard G. Cable, Brian Custer, Mark T. Gladwin, Ruchika Goel, Bob Harris, Jeanne E. Hendrickson, Tamir Kanias, Steve Kleinman, Alan E. Mast, Steven R. Sloan, Bryan R. Spencer, Steven L. Spitalnik, Michael P. Busch, Eldad A. Hod
Abstract
BACKGROUND. Tight relationships between sleep quality, cognition and amyloid-beta (Aβ) accumulation, a hallmark of Alzheimer’s disease (AD) neuropathology, emerge in the literature. Sleep arousals become more prevalent with ageing and are considered to reflect poorer sleep quality. Yet, heterogeneity in arousals has been suggested while their associations with Aβ and cognition are not established. METHODS. We recorded undisturbed night-time sleep with EEG in 101 healthy individuals in late midlife (50-70y), devoid of cognitive and sleep disorders. We classified spontaneous arousals according to their association with muscular tone increase (M+/M-) and sleep stage transition (T+/T-). We assessed cortical Aβ burden over earliest affected regions via PET imaging, and cognition via extensive neuropsychological testing. RESULTS. Arousal types differed in their oscillatory composition in theta and beta EEG bands. Furthermore, T+M- arousals, which interrupt sleep continuity, were positively linked to Aβ burden (p=.0053, R²β*=0.08). By contrast, more prevalent T-M+ arousals, upholding sleep continuity, were associated with lower Aβ burden (p=.0003, R²β*=0.13), and better cognition, particularly over the attentional domain (p<.05, R²β*≥0.04). CONCLUSION. Contrasting with what is commonly accepted, we provide empirical evidence that arousals are diverse and differently associated with early AD-related neuropathology and cognition. This suggests that sleep arousals, and their coalescence with other brain oscillations during sleep, may actively contribute to the beneficial functions of sleep. This warrants re-evaluation of age-related sleep changes and suggests that spontaneous arousals could constitute a marker of favourable brain and cognitive health trajectories. TRIAL REGISTRATION. EudraCT 2016-001436-35. FUNDING. This work was supported by Fonds National de la Recherche Scientifique (FRS-FNRS, FRSM 3.4516.11, Belgium), Actions de Recherche Concertées (ARC SLEEPDEM 17/27-09) of the Fédération Wallonie-Bruxelles, University of Liège (ULiège), Fondation Simone et Pierre Clerdent, European Regional Development Fund (ERDF, Radiomed Project). [18F]Flutemetamol doses were provided and cost covered by GE Healthcare Ltd (Little Chalfont, UK) as part of an investigator sponsored study (ISS290) agreement. This agreement had no influence on the protocol and results of the study reported here. M.V.E., C.B., F.C., C.P., and G.V. are/were supported by the F.R.S.-FNRS Belgium. C. B., P. B. and M. B. are owners of Physip, the company that analysed the EEG data as part of a collaboration. This ownership and the collaboration had no impact on the design, data acquisition and interpretations of the findings.
Authors
Daphne O. Chylinski, Maxime Van Egroo, Justinas Narbutas, Martin Grignard, Ekaterina Koshmanova, Christian Berthomier, Pierre Berthomier, Marie Brandewinder, Eric Salmon, Mohamed Ali Bahri, Christine Bastin, Fabienne Collette, Christophe Phillips, Pierre Maquet, Vincenzo Muto, Gilles Vandewalle
Abstract
BACKGROUND. Skeletal muscle maladaptation accompanies chronic kidney disease (CKD) and negatively impacts physical function. Emphasis in CKD has historically been placed on muscle fiber intrinsic deficits, such as altered protein metabolism and atrophy. However, targeted treatment of fiber intrinsic dysfunction has produced limited improvement, whereas alterations within the fiber extrinsic environment have scarcely been examined. METHODS. We investigated alterations to the skeletal muscle interstitial environment with deep cellular phenotyping of biopsies from patients with CKD compared to age-matched control participants and performed transcriptome profiling to define the molecular underpinnings of CKD-associated muscle impairments. We further examined changes in the observed muscle maladaptation following initiation of dialysis therapy for kidney failure. RESULTS. Patients with CKD exhibited a progressive fibrotic muscle phenotype, which was associated with impaired regenerative capacity and lower vascular density. The severity of these deficits was strongly associated with the degree of kidney dysfunction. Consistent with these profound deficits, CKD was associated with broad alterations to the muscle transcriptome, including altered extracellular matrix organization, downregulated angiogenesis, and altered expression of pathways related to stem cell self-renewal. Remarkably, despite the seemingly advanced nature of this fibrotic transformation, dialysis treatment rescued these deficits, restoring a healthier muscle phenotype. Furthermore, after accounting for muscle atrophy, strength and endurance improved after dialysis initiation. CONCLUSION. These data identify a dialysis-responsive muscle fibrotic phenotype in CKD and suggest that the early dialysis window presents a unique opportunity of improved muscle regenerative capacity during which targeted interventions may achieve maximal impact. TRIAL REGISTRATION. NCT01452412 FUNDING. NIH
Authors
Camille R. Brightwell, Ameya S. Kulkarni, William Paredes, Kehao Zhang, Jaclyn B. Perkins, Knubian J. Gatlin, Matthew Custodio, Hina Farooq, Bushra Zaidi, Rima Pai, Rupinder S. Buttar, Yan Tang, Michal L. Melamed, Thomas H. Hostetter, Jeffrey E. Pessin, Meredith Hawkins, Christopher S. Fry, Matthew K. Abramowitz
Abstract
Background IL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.Methods We conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6–17 years).Results There was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.Conclusion Tocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.Trial Registration ClinicalTrials.gov NCT02293837.Funding NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.
Authors
Carla J. Greenbaum, Elisavet Serti, Katharina Lambert, Lia J. Weiner, Sai Kanaparthi, Sandra Lord, Stephen E. Gitelman, Darrell M. Wilson, Jason L. Gaglia, Kurt J. Griffin, William E. Russell, Philip Raskin, Antoinette Moran, Steven M. Willi, Eva Tsalikian, Linda A. DiMeglio, Kevan C. Herold, Wayne V. Moore, Robin Goland, Mark Harris, Maria E. Craig, Desmond A. Schatz, David A. Baidal, Henry Rodriguez, Kristina M. Utzschneider, Hendrik J. Nel, Carol L. Soppe, Karen D. Boyle, Karen Cerosaletti, Lynette Keyes-Elstein, S. Alice Long, Ranjeny Thomas, James G. McNamara, Jane H. Buckner, Srinath Sanda, for the ITN058AI EXTEND Study Team
Abstract
BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and life-threatening inherited skin fragility disorder due to a lack of functional type VII collagen, for which no effective therapy exists. ABCB5-positive dermal mesenchymal stem cells (ABCB5+ MSCs) possess immunomodulatory capacities, a favorable skin homing potential and the ability to secrete type VII collagen. In a COL7A1–/– mouse model of RDEB, treatment with ABCB5+ MSCs markedly extended the animals’ lifespans. METHODS. In this international, multicentric, single-arm, phase I/IIa clinical trial, 16 patients (aged 4–36 years) enrolled into four age cohorts received three intravenous infusions of 2×106 ABCB5+ MSCs/kg on days 0, 17 and 35. Patients were followed up for 12 weeks regarding efficacy and 12 months regarding safety. RESULTS. At 12 weeks, statistically significant median (IQR) reductions in the Epidermolysis Bullosa Disease Activity and Scarring Index activity (EBDASI activity) score of 13.0% (2.9%-30%; P = 0.049) and the Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa clinician (iscorEB c) score of 18.2% (4.1%-41.7%; P = 0.037) were observed. Reductions in itch and pain numerical rating scale scores were greatest on day 35, amounting to 37.5% (0.0%-42.9%; P = 0.033) and 25.0% (-8.4%-46.4%; P = 0.168), respectively. Three adverse events were considered related to the cell product, one mild lymphadenopathy and two hypersensitivity reactions. The latter two were serious but resolved without sequelae shortly after withdrawal of treatment. CONCLUSION. This trial demonstrates good tolerability, manageable safety and potential efficacy of intravenous ABCB5+ MSCs as a readily available disease-modifying therapy for RDEB and provides a rationale for further clinical evaluation. TRIAL REGISTRATION. clinicaltrials.gov NCT03529877; EudraCT 2018-001009-98 FUNDING. The trial was sponsored by RHEACELL GmbH & Co. KG, Heidelberg, Germany. Contributions by NY Frank and MH Frank to this work were supported by the National Institutes of Health (NIH)/National Eye Institute (NEI) grants RO1EY025794 and R24EY028767.
Authors
Dimitra Kiritsi, Kathrin Dieter, Elke Niebergall-Roth, Silvia Fluhr, Cristina Daniele, Jasmina Esterlechner, Samar Sadeghi, Seda Ballikaya, Leoni Erdinger, Franziska Schauer, Stella Gewert, Martin Laimer, Johann W. Bauer, Alain Hovnanian, Giovanna Zambruno, May El Hachem, Emmanuelle Bourrat, Maria Papanikolaou, Gabriela Petrof, Sophie Kitzmüller, Christen L. Ebens, Markus H. Frank, Natasha Y. Frank, Christoph Ganss, Anna E. Martinez, John A. McGrath, Jakub Tolar, Mark A. Kluth
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