ABSTRACT
BackgroundUpadacitinib (UPA) is an oral JAK inhibitor (JAKi) approved for the treatment of RA. JAKi have been associated with an elevated risk of herpes zoster (HZ) in patients (pts) with RA. The adjuvanted recombinant zoster vaccine (RZV, Shingrix) was shown to be well-tolerated and effective in preventing HZ in adults aged ≥ 50 years.[1] The efficacy and safety of RZV have not been studied in pts with RA while on UPA in combination with MTX.ObjectivesTo assess the immunogenicity of RZV in pts with RA receiving UPA 15 mg once daily (QD) with background MTX.MethodsEligible adults aged ≥ 50 years with RA enrolled in the ongoing SELECT-COMPARE phase 3 trial (NCT02629159) received two RZV doses, administered at the baseline and week (wk) 12 visits. Pts should have been on stable doses of UPA 15 mg QD and background MTX for ≥ 8 wks before the first vaccination and ≥ 4 wks after the second vaccination. Antibody titers were collected pre-vaccination (baseline), 4 wks post-dose 1 vaccination (wk 4), and 4 wks post-dose 2 vaccination (wk 16). The primary endpoint was the proportion of pts with a humoral response to RZV defined as ≥ 4-fold increase in pre-vaccination concentration of anti-glycoprotein E [gE] titer levels at wk 16. Secondary endpoints included humoral response to RZV at wk 4 and the geometric mean fold rise (GMFR) in anti-gE antibody levels at wks 4 and 16. Cell-mediated immunogenicity to RZV was an exploratory endpoint evaluated by the frequencies of gE-specific CD4+ [2+] T cells (CD4+ T cells expressing ≥ 2 of 4 activation markers: IFN-γ, IL-2, TNF-α, and CD40 ligand) measured by flow cytometry at wks 4 and 16 in a sub-cohort of pts.ResultsOf the 95 pts who received ≥ 1 RZV dose, 93 (98%) received both RZV doses. Pts had a mean (standard deviation) age of 62.4 (7.5) years. The median (range) disease duration was 11.7 (4.9–41.6) years and duration of UPA exposure was 3.9 (2.9–5.8) years. At baseline, all but 2 pts were receiving concomitant MTX and half (50%) were taking an oral corticosteroid (CS) at a median daily dose of 5.0 mg. One pt discontinued UPA by wk 16. Blood samples were available from 90/93 pts. Satisfactory humoral responses to RZV occurred in 64% (95% confidence interval [CI]: 55–74) of pts at wk 4 and 88% (81–95) at wk 16 (Figure 1). Age (50–< 65 years: 85% [95% CI: 75–94];≥ 65 years: 94% [85–100]) and concomitant CS (yes: 87% [77–97];no: 89% [80–98]) use at baseline did not affect humoral responses at wk 16. GMFR in anti-gE antibody levels compared with baseline values were observed at wks 4 (10.2 [95% CI: 7.3–14.3]) and 16 (22.6 [15.9–32.2]). Among the sub-cohort of pts, nearly two-thirds achieved a cell-mediated immune response to RZV (wk 4: n = 21/34, 62% [95% CI: 45–78];wk 16: n = 25/38;66% [51–81]). Within 30 days post-vaccination of either RZV dose, no serious adverse events (AEs) (Table 1) or HZ were reported. AEs that were possibly related to RZV were reported in 17% of pts. One death occurred more than 30 days after wk 16 due to COVID-19 pneumonia.ConclusionMore than three-quarters (88%) of pts with RA receiving UPA 15 mg QD on background MTX achieved a satisfactory humoral response to RZV at wk 16. In a subgroup of pts, two-thirds (66%) achieved a cell-mediated immune response to RZV at wk 16. Age and concomitant CS use did not negatively affect RZV response.Reference[1]Syed YY. Drugs Aging. 2018;35:1031–40.Table 1. Safety Results Through 30-Days Post-RZV Vaccination in UPA-Treated PatientsEvent, n (%)UPA 15 mg QD (N = 95)Any AE38 (40%)AE with reasonable possibility of being related to UPAa13 (14%)AE with reasonable possibility of being related to RZVa16 (17%)Severe AEb1 (1%)Serious AE0AE leading to discontinuation of UPA0Death0AE, adverse event;QD, once daily;RZV, adjuvanted recombinant zoster vaccine;UPA, upadacitinib.aAs assessed by the investigator.bHypersensitivity.AcknowledgementsAbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review, and approval of the . All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Julia Zolotarjova, MSc, MWC, of AbbVie.Disclosure of InterestsKevin Winthrop Consultant of: AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Gilead, GSK, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Gilead, GSK, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Justin Klaff Shareholder of: AbbVie, Employee of: AbbVie, Yanxi Liu Shareholder of: AbbVie, Employee of: AbbVie, CONRADO GARCIA GARCIA: None declared, Eduardo Mysler Speakers bureau: AbbVie, Amgen, AstraZeneca, BMS, Eli Lilly, GlaxoSmithKline, Pfizer, Roche, and Sandoz, Consultant of: AbbVie, Amgen, AstraZeneca, BMS, Eli Lilly, GlaxoSmithKline, Pfizer, Roche, and Sandoz, Alvin F. Wells Consultant of: AbbVie, Amgen, BMS, Eli Lilly, Novartis, Pfizer, and Sanofi, Xianwei Bu Shareholder of: AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: AbbVie, Employee of: AbbVie, Michael Chen Shareholder of: AbbVie, Employee of: AbbVie, Heidi Camp Shareholder of: AbbVie, Employee of: AbbVie, Anthony Cunningham Consultant of: GSK, Merck Sharp & Dohme, and BioCSL/Sequirus.
ABSTRACT
BackgroundFollowing the launch of the global COVID-19 vaccination campaign, there have been increased reports of autoimmune diseases developing de novo following vaccination. These cases include rheumatoid arthritis, autoimmune hepatitis, immune thrombotic thrombocytopenia, and connective tissue diseases. Nevertheless, COVID-19 vaccines are considered safe for patients with autoimmune diseases and are strongly recommended.ObjectivesThe aim of this in silico analysis is to investigate the presence of protein epitopes encoded by the BNT-162b2 mRNA vaccine, one of the most commonly administered COVID-19 vaccines, that could elicit an aberrant adaptive immune response in predisposed individuals.MethodsThe FASTA sequence of the protein encoded by the BNT-162b2 vaccine was retrieved from http://genome.ucsc.edu and used as a key input to the Immune Epitope Database and Analysis Resource (www.iedb.org). Linear peptides with 90% BLAST homology were selected, and T-cell, B-cell, and MHC ligand assays without MHC restriction were searched and evaluated. HLA-disease associations were screened on the HLA-SPREAD platform (https://hla-spread.igib.res.in) by selecting only positive markers.ResultsA total of 183 epitopes were found, corresponding to 178 SARS-CoV-2 and 5 SARS-CoV spike epitopes, respectively. Results were obtained from 22 T-cell assays, 398 B-cell assays, and 2 MHC ligand assays. Complementary receptors included 1080 T-cell receptors and 0 B-cell receptors.Specifically, the IEDB_epitope:1329790 (NATNVVIKVCEFQFCNDPFLGVYY) was shown to bind to HLA-DRB1*15:02 and HLA-DRB1*15:03 alleles, whereas the IEDB_epitope:1392457 (TKCTLKSFTVEKGIYQTSNFRVQPT) was reported to bind to HLA-DRB1*07:01, HLA-DRB1*03:01, HLA-DRB3*01:01, and HLA-DRB4*01:01 alleles. The HLA alleles detected were found to be positively associated with various immunological disorders (Table 1).Table 1.MHC-restricted epitopes of the BNT-162b2 vaccine and potentially associated immunological conditionsEpitopeAssayMHC moleculeAssociated disease (population)NATNVVIKVCEFQFCNDPFLGVYY + OX(C10)cellular MHC/mass spectrometry ligand presentationHLA-DRB1*15:02Takayasu arteritis (Japanese) Arthritis (Taiwanese) Scleroderma (Japanese) Colitis (Japanese)HLA-DRB1*15:03Systemic lupus erythematosus (Mexican American)TKCTLKSFTVEKGIYQTSNFRVQPT + SCM(K2)as aboveHLA-DRB1*07:01Allergy, hypersensitivity (Caucasian)HLA-DRB1*03:01Type 1 diabetes (African) Sarcoidosis, good prognosis (Finnish)HLA-DRB3*01:01Graves' disease (Caucasian) Thymoma (Caucasian) Sarcoidosis (Scandinavian) Autoimmune hepatitis (Caucasian)HLA-DRB4*01:01Vitiligo (Saudi Arabian)ConclusionSimilar to the SARS-CoV-2 spike protein, the protein product of the BNT-162b2 mRNA vaccine contains immunogenic epitopes that may trigger autoimmune phenomena in predisposed individuals. Genotyping for HLA alleles may help identify at-risk individuals. However, further research is needed to elucidate the underlying mechanisms and potential clinical implications.References[1]Vita R, Mahajan S, Overton JA et al. The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Res. 2019 Jan 8;47(D1):D339-D343. doi: 10.1093/nar/gky1006.[2]Dholakia D, Kalra A, Misir BR et al. HLA-SPREAD: a natural language processing based resource for curating HLA association from PubMed s. BMC Genomics 23, 10 (2022). https://doi.org/10.1186/s12864-021-08239-0[3]Parker R, Partridge T, Wormald C et al. Mapping the SARS-CoV-2 spike glycoprotein-derived peptidome presented by HLA class II on dendritic cells. Cell Rep. 2021 May 25;35(8):109179. doi: 10.1016/j.celrep.2021.109179.[4]Knierman MD, Lannan MB, Spindler LJ et al. The Human Leukocyte Antigen Class II Immunopeptidome of the SARS-CoV-2 Spike Glycoprotein. Cell Rep. 2020 Dec 1;33(9):108454. doi: 10.1016/j.celrep.2020.108454.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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BackgroundAnti-MDA5 antibody positive dermatomyositis (MDA5-DM) is characterized by high mortality due to rapid progressive ILD. MDA5 is a cytosolic protein and a family of RIG-I like receptor, which functions as a virus RNA sensor and induces the production of such as type-1 IFN. Although little is known about the pathogenesis of MDA5-DM, it is notable that the similarities were reported between COVID-19 infection and MDA5-DM. It may suggest that there is a common underlying autoinflammatory mechanism. We reported that in MDA5-DM, (1) RIG-I-like receptor signaling is enhanced and (2) antiviral responses such as type 1 IFN signaling are also enhanced as compare with anti-ARS-antibody positive DM, and (3) the key for survival is suppression of RIG-I-like and IFN signaling (EULAR2022, POS0390). We also found that a significant role for uncontrolled macrophage in the pathogenesis of ILD by our autopsy case. Recently, it has been reported that tacrolimus (TAC) and cyclophosphamide (CY) combination therapy (TC-Tx) has improved the prognosis of cases with early onset of the disease, but there are cases that cannot be saved. Therefore, we devised BRT therapy (BRT-Tx). The Tx combines baricitinib (BAR), which inhibits GM-CSF and IFN-mediated signaling and effectively suppresses uncontrolled macrophages, with rituximab (RTX) and TAC, which rapidly inhibits B and T cell interaction and ultimately prevents anti-MDA5 antibody production.ObjectivesTo determine the differences in gene expression between BRT and TC-Tx for MDA5-DM in peripheral blood.MethodsTotal of 6 MDA5-DM (TC: 3, BRT: 3) were included and all of them had multiple poor prognostic factors. Peripheral whole blood was collected at just before and 2-3 months after the treatment. RNA was extracted, and quantified using a next-generation sequencer. Differentially Expressed Genes (DEGs) were identified by pre vs. post treatment. Gene Ontology (GO), clustering and Gene Set Variation Analysis (GSVA) were performed to DEGs. As one BRT case was added since our last year's report, we also reanalyzed the surviving vs. fatal cases. The IFN signature was scored separately for Types 1, 2, and 3, and the changes between pre- and post-treatment were investigated.ResultsTwo of three cases with TC died during treatment, while all three cases on BRT recovered. The cluster analysis of the DEGs separated deaths from survivors, not by type of treatment. Comparing surviving and dead cases, GO analysis revealed that the immune system via immunoglobulins and B cells was significantly suppressed in surviving cases. GO analysis of DEGs in each therapeutic group showed that expression of B cell-related genes such as lymphocyte proliferation and B cell receptor signaling pathway were significantly suppressed in BRT-Tx. On the other hand, TC-Tx significantly suppressed such pathways as cell proliferation and cell surface receptor signaling, and was less specific for the target cells than BRT-Tx. The changes in IFN signature score after treatment showed an increase in type 2 and 3 IFN scores in all fatal cases and an increase in type 1 IFN score in one fatal case.ConclusionBRT-Tx significantly suppressed gene expression associated with B cells, while TC-Tx was characterized by low specificity of therapeutic targets and suppression of total cell proliferation. Comparison of surviving and dead cases revealed that the combination of RTX contributed to the success of treatment, as suppression of the immune system mediated by immunoglobulins and B cells is the key for survival. Analysis of the IFN signature revealed an increase in IFN score after treatment in fatal cases, indicating that the combination of BAR is beneficial. The superiority of BRT-Tx seems clear from the fact that all patients survived with BRT-Tx while only one/three patients survived with TC-Tx.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsMoe Sakamoto: None declared, Yu Nakai: None declared, Yoshiharu Sato: None declared, Yoshinobu Koyama Speakers bureau: Abbvie, Asahikasei, Ayumi, BMS, Esai, Eli-Lilly, Mitsubishi Tanabe, Grant/research support from: Abbvie, GSK.
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BackgroundA 3rd COVID-19 vaccination is currently recommended for patients under immunosuppression. However, a fast decline of antibodies against the SARS-CoV-2 receptor-binding domain (RBD) of the spike protein has been observed.ObjectivesIt remains unclear whether immunosuppressive therapy affects kinetics of humoral and cellular immune responses.Methods50 patients under immunosuppression and 42 healthy controls (HCs) received a 3rd dose of an mRNA-based vaccine and were monitored over a 12-weeks period. Humoral immune response was assessed 4 and 12 weeks after 3rd dose. Antibodies were quantified using the Elecsys Anti-SARS-CoV-2 Spike immunoassay against the receptor-binding domain (RBD) of the spike protein. SARS-CoV-2-specific T cell responses were quantified by IFN-γ ELISpot assays. Adverse events, including SARS-CoV-2 infections, were monitored over a 12-week period.ResultsAt week 12, reduced anti-RBD antibody levels were observed in IMID patients as compared to HCs (median antibody level 5345 BAU/ml [1781 – 10208] versus 9650 BAU/ml [6633 - 16050], p < 0.001). Reduction in relative antibody levels was significantly higher in IMID patients as compared to HCs at week 12 (p < 0.001). Lowest anti-RBD antibody levels were detected in IMID patients who received biological diseases modifying anti-rheumatic drugs (DMARDs) or a combination therapy with conventional synthetic and biological DMARDs. Number of SARS-CoV-2-specific T cells against wildtype and Omicron variants remained stable over 12 weeks in IMID patients. No serious adverse events were reported.ConclusionDue to a fast decline in anti-RBD antibodies in IMID patients an early 4th vaccination should be considered in this vulnerable group of patients.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsDaniel Mrak Consultant of: AstraZeneca, Felix Kartnig: None declared, Daniela Sieghart: None declared, Elisabeth Simader Speakers bureau: Lilly, Helga Radner Speakers bureau: Gilead, Merck Sharp and Pfizer, Peter Mandl: None declared, Lisa Göschl: None declared, Philipp Hofer: None declared, Thomas Deimel: None declared, Irina Gessl: None declared, Renate Kain Speakers bureau: Otsuka, Consultant of: AstraZeneca, Takeda Pharma, MEDahead and Janssen Cilag, Stefan Winkler: None declared, Josef S. Smolen Consultant of: AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celltrion, Gilead-Galapagos, Janssen, Lilly, Pfizer, R-Pharma, Samsung, Sanofi, Chugai, Merck Sharp & Dohme, Novartis-Sandoz Roche, Samsung and UCB, Grant/research support from: Abbvie, AstraZeneca, Lilly, Novartis, and Roche, Thomas Perkmann: None declared, Helmuth Haslacher Grant/research support from: Glock Health, BlueSky Immunotherapies and Neutrolis, Daniel Aletaha Speakers bureau: Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi, Consultant of: Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi, Grant/research support from: Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi, Leonhard Heinz: None declared, Michael Bonelli Consultant of: EliLilly.
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BackgroundAmid the coronavirus disease 2019 (COVID-19) crisis, two messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have benefited most people worldwide. While healthy people can acquire sufficient humoral immunity against COVID-19 even in the elderly by vaccination with three doses of vaccine., recent studies have shown that complex factors other than age, including the type of vaccines and immunosuppressive drugs, are associated with immunogenicity in patients with rheumatic musculoskeletal disease (RMD). Identifying factors that contribute to the vulnerability of those patients to acquire not only humoral but also cellular immunity to SARS-CoV-2 despite multiple vaccinations is crucial for establishing an appropriate booster vaccine strategy.ObjectivesTo assess humoral,and T cell immune responses after third doses of mRNA vaccines against SARS-CoV-2.MethodsThis prospective observational study included consecutive RMD patients treated with immunosuppressant who received three doses of mRNA vaccines including BNT162b2 and mRNA-1273. Blood samples were obtained 2-6 weeks after second and third dose of mRNA vaccines. We measured neutralizing antibody titres, which against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 and seroconversion rates to evaluate the humoral responses. We also assessed T-cell immunity responses using interferon releasing assay against SARS-CoV-2.ResultsA total of 586 patients with RMD treated with mmunosuppressive treatments were enrolled. The mean age was 54 years, and 70% of the patients were female. Seroconversion rates and neutralizing antibody titres after third vaccination of SARS-CoV-2 were significantly higher compared to those after second vaccination (seroconversion rate, 94.5% vs 83.6%, p<0.001;titres of neutralizing antibody, 48.2 IU/mL vs 11.0 IU/mL, p<0.001, respectively). Interferon releasing assay after third vaccinations demonstrated that T cell reaction against SARS-CoV-2 was also increased from that of second vaccination (interferon for antigen 1, 1.11.9 vs 0.61.9, p=0.004,interferon for antigen 2, 1.72.6 vs 0.82.3, p=0.004). Humoral and cellular immunogenicity did not differ between the types of third vaccination including full dose of BNT162 and half dose of mRNA1273.(neutralizing antibody titers, 47.8±76.1 IU/mL vs 49.0±60.1 IU/mL, p<0.001;interferon for antigen 1, 1.12.0 vs 1.01.5, p=0.004, respectively). Attenuated humoral response to third vaccination was associated with BNT162b2 as second vaccination age (>60 years old), glucocorticoid (equivalent to prednisolone > 7.5 mg/day), and immunosuppressant use including mycophenolate, and rituximab. On another front, use of mycophenolate and abatacept or tacrolimus but not rituximab were identified as negative factors for T-cell reactions against SARS-CoV-2. Although 53 patients (9.0%) who had been immunised with third-vaccination contracted COVID-19 during Omicron pandemic phase, no one developed severe pulmonary disease that required corticosteroid therapy.ConclusionOur results demonstrated third mRNA vaccination booster of SARS-CoV-2 contributed to restore both humeral and cellular immunity in RMD patients with immunosuppressants. We also identified that certain immunosuppressive therapy with older RMD patients having BNT162b2 as a second vaccination may need additional booster vaccination.Reference[1]Furer V, Eviatar T, Freund T, et al. Ann Rheum Dis. 2022 Nov;81(11):1594-1602. doi: 10.1136/ard-2022-222550.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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BackgroundVaccine-induced immunity is very important for controlling the COVID-19 infection. The vaccination supports humoral and cellular immunity, and this is one of the main strategy for us. Various vaccines approved in the countries have been shown to reduce infection rates, severity, and mortality.ObjectivesWe aimed to compare humoral and cellular immune responses after homologous or heterologous vaccination among patients with aiRMDs at their third vaccination with BNT162b2 or with two vaccinations followed by COVID-19 infection. We detected the anti-SARS-CoV2 antibody levels and measured the SARS-CoV-2 reactive B-, or T-cell mediated immunity in aiRMDs receiving homologous (Hom.), heterologous (Het.) vaccines or became infected (Inf.).MethodsA single center observational study evaluated immunogenicity and safety of the third dose vaccines or after two-dose regimen of vaccine and COVID infection in patients with aiRMDs. Neutralizing anti-RBD antibodies and specific T-cell response were measured.ResultsWe showed that following 4 months of the booster vaccination with the third dose of mRNA-based vaccine or after COVID infection, the positive (>21.8 BAU/mL) neutralizing anti-RBD IgG antibody response was outstanding in all three patient groups, 95.5%, 100% and 100% of the homologous and heterologous as well as the SARS-CoV-2 infected groups. Taken together booster vaccinations or SARS-CoV-2 infection after completing 2 doses of the vaccination can lead to the production of neutralizing antibodies still protective in RMD cases after 4 months of the third antigen exposition. The booster vaccination reduces the frequency of hospital admissions and mortality with ai RMDs. The vaccinations are effective independently from the type of vaccine, the SARS-CoV-2 specific memory B-cell populations showed a statistically not significant but lower frequency in the infection group. Clinical activity of aiRMDs was not increased following booster vaccination.ConclusionPatients, who received a heterologous booster vaccine had a higher level of peripheral memory B-cells compared to those who had COVID-19 infection. Biologic therapy decreased the level of B-cells. Patients with a disease duration of more than 10 years had higher level of CD8+TNF-α+ and CD8+IFN-γ+ T-cells compared to patients who were diagnosed less than 10 years ago. The third booster mRNA-based vaccine was as much effective as in the homologous and heterologous patients groups compared who had COVID infection.References[1] Szebeni, G.J.;Gemes, N.;Honfi, D.;Szabo, E.;Neuperger, P.;Balog, J.A.;Nagy, L.I.;Szekanecz, Z.;Puskas, L.G.;Toldi, G.;et al. Humoral and Cellular Immunogenicity and Safety of Five Different SARS-CoV-2 Vaccines in Patients With Autoimmune Rheumatic and Musculoskeletal Diseases in Remission or With Low Disease Activity and in Healthy Controls: A Single Center Study. Front. Immunol. 2022, 13, 846248.[2]Honfi, D.;Gémes, N.;Szabó, E.;Neuperger, P.;Balog, J.Á.;Nagy, L.I.;Toldi, G.;Puskás, L.G.;Szebeni, G.J.;Balog, A. Comparison of Homologous and Heterologous Booster SARS-CoV-2 Vaccination in Autoimmune Rheumatic and Musculoskeletal Patients. Int. J. Mol. Sci. 2022, 23, 11411Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Objectives Human leukocyte antigens (HLA) are highly diverse transmembrane proteins that present viral peptides to T cells and launch pathogen-specific immune responses. We aim to investigate the correlation between HLA evolutionary divergence (HED), a surrogate for the capacity to present different peptides, and the outcomes of SARS-CoV-2 infection in a cohort from the St. Louis Metropolitan area. Methods We enrolled adult patients with SARS-CoV-2 infection confirmed by RT-PCR who were hospitalized at two tertiary hospitals in St. Louis between March and July 2020. Genomic DNA was extracted from peripheral blood and genotyped by next-generation sequencing (NGS). HLA alleles were assigned based on key-exon sequences (G group) and limited to the 2-field resolution. HED was calculated by Grantham distance, which considers the difference in composition, polarity, and molecular volume between each pair of amino acids from maternal and paternal HLA. The HED score was obtained for HLA class I (HLA-A, -B, and -C) genotypes using the HLAdivR package in R. Clinical data were collected retrospectively from electronic medical records. A poor outcome was defined as an admission to the intensive care unit (ICU), a need for mechanical ventilation, or death. A favorable outcome was defined as the absence of the above poor outcomes. Results A total of 234 patients were enrolled in this study, 96 being females (41%). The median age and BMI were 66 years old and 28.30 kg/m2, respectively. African Americans comprised 71.4% of the cohort. Only 19 patients (8.1%) presented with no comorbidity;the rest had one or more comorbidities, with cardiovascular diseases being the most common. A total of 137 (58.5%) patients had poor outcomes from SARS-CoV-2 infection, while 97 (41.5%) patients had a favorable outcome. We detected a significant association between higher HLA-B HED and favorable outcomes, with each 1-point increase in HLA-B HED associated with 8% increased probability for the composite endpoint (OR 1.08, 95% CI=1.01-1.16, P = 0.04). The HED scores calculated for HLA-A or HLA-C were not significantly different between patients with favorable or poor outcomes. In a multivariate logistic regression analysis, increased HLA-B HED score, younger age, and no comorbidity were independently associated with favorable outcomes (P = 0.02, P = 0.01, and P = 0.05, respectively). Conclusion Our study shows a significant correlation between lower HLA-B HED scores and poor outcomes after SARS-CoV-2 infection. This finding suggests that maximizing the presentation of diverse SARS-CoV-2 peptides by HLA-B alleles may improve the clearance of SARS-CoV-2. Further studies are warranted to understand the functional and mechanistic implications of this finding.
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BackgroundVaccination against SARS-CoV2 had a critical role in the fight against COVID19 pandemic.A weaker humoral response to COVID19 vaccine has been found in rheumatic patients treated with Rituximab (RTX) or Mycophenolate Mofetil (MMF)[1]. Despite the evidence that anti-SARS-CoV-2 mRNA vaccines can elicit a T-cell response [2], some data show that even the cellular immunity could be impaired in rheumatic patients [3] but COVID19 serology is the only parameter that is feasible to measure in daily practice.Tixagevimab+cilgavimab are two human-derived monoclonal antibodies administered parenterally and authorized by regulatory agencies in February 2022 for pre-exposure prophylaxis (PrEP) against COVID19 from different virus variants in fragile patients.ObjectivesTo demonstrate safety and effectiveness of tixagevimab+cilgavimab.MethodsPatients with autoimmune rheumatic diseases undergoing immunosuppressive treatment with RTX or MMF during the vaccination campaign were enrolled between April and June 2022. All patients must have anti-spike antibody levels below the protective threshold (defined by anti-spike IgG titre <250 BAU/ml) after receiving at least 2 vaccine doses.Patients were monitored with a questionnaire every month about COVID19 symptoms (including respiratory and gastrointestinal symptoms, anosmia and ageusia, skin rash and potential contact with COVID19+ subjects) and were checked for anti-spike and anti-nucleocapside antibodies titres every 2 months for a total of a 6 month follow-up. MMF dose was reduced at 1 g/die at the time of vaccine administration.ResultsFifteen patients were enrolled: 9 participants had a connective tissue disease (CTD;1 dermatomyositis, 3 anti-syntethase syndrome, 4 systemic sclerosis, 1 systemic lupus erythematosus) and 6 had vasculitis (all granulomatosis with polyangiitis). 12 of them received RTX in the preceding 12 months and 3 were taking MMF.About safety, the therapy was very well tolerated and only 4 patients (26%) reported a non-severe adverse event in the 2 weeks following drug administration (2 myalgia, 1 headache, 1 fatigue), none of them requiring hospitalization nor pharmacologic treatment.Regarding effectiveness, 3/15 patients contracted SARS-Cov2 infection (20%) with mild symptoms and no need for hospitalization nor oxygen therapy. Only 1 of them received an antiviral drug (nirmatrelvir+ritonavir). All infected patients had a CTD diagnosis. No significant correlation was observed between the type of rheumatic disease and the risk of infection or response to tixagevimab+cilgavimab.ConclusionNone of our patients developed severe adverse events after tixagevimab+cilgavimab administration and, among the 3 SARS-CoV2 infected patients, none required hospitalization nor oxygen therapy.We conclude that in our experience tixagevimab+cilgavimab is a safe and useful complementary immunization strategy to vaccination for COVID19 prophylaxis.These data will be implemented in a larger study, comprehending various immunocompromised patients from several departments.References[1] Furer et al., Ann Rheum Dis, 2021[2] Mangalakumari et al., Nat Rev Immunol, 2020[3] Picchianti-Diamanti et al., Front Immunol, 2021Charateristic of the cohortIdentificativeAgeDiagnosisRTX/MMFSARS-CoV2 InfectionHospitalizationAntiviral drugs180SScMMF-//270ASSDRTX+nono370ASSDRTX+noyes452GPARTX-//551GPARTX-//649SSc+SSjRTX-//768SScMMF-//847LESRTX-//964ASSDRTX-//1068GPARTX-//1123GPARTX-//1258DMRTX+nono1361SScMMF-//1475GPARTX-//1569GPARTX-//Figure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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BackgroundSARS-Cov2 vaccination has been shown to be effective against severe forms of SARS-Cov2 infection. Several studies investigated the humoral and cellular response to SARS-Cov2 vaccines in patients followed for autoimmune and inflammatory diseases under immunosuppressive or immunomodulatory treatments. It has been shown that patients on immunosuppressive or immunomodulatory therapies have a poor humoral response to the vaccine[1]ObjectivesThe aim of our study was to investigate the humoral response in patients under conventional immunosuppressive and biotherapies compared to healthy controls.MethodsPatients followed for immuno-inflammatory diseases under immunosuppressive or immunomodulatory drugs who received at least one dose of anti- SARS-Cov2 vaccines were included. Quantitative Anti- SARS-Cov2 antibodies (IgM and IgG assay) VIDAS ® were assessed for all patients. Patients were then compared with healthy controls.ResultsWe enrolled 93 blood samples (63 patients with autoimmune and inflammatory disease and 30 healthy controls), the median age was 52 years [Q1 43, Q3 56]. The immuno-inflammatory diseases were: Crohn's disease (n=28), Rheumatoid arthritis (n=9), Hemorrhagic rectocolitis (n=5), Behçet's disease (n=5), Systemic lupus erythematosus (n=4), Sjogren's syndrome (n=3), Sarcoidosis (n=2), Takayasu disease (n=1). All patients continued their treatment during and after vaccination. Nineteen patients were on biotherapies: Infliximab (n=12), Adalimumab (n=3), etanercept (n=2), Ustekinumab (n=1), tocilizimab (n=1). Forty-three patients were on conventional immunosuppressive: azathioprine (n=18), methotrexate (n=16), corticosteroids > 10 mg/d (n=12). All patients had received at least one dose of vaccine: the median number of doses in both groups was 2[1-4] with no statistically significant difference between the 2 groups (p=0.2). The vaccines received in the group of patients were mRNA vaccine (n=35) and other type of vaccine (n=28). In the healthy control group, type of vaccine were mRNA (n=13) other type vaccine (n=17). The patient had a lower mean level of Ig G against SARS-Cov2 antibodies (24.64 IU +/- 16.65) comparing to healthy controls (33.05+/- 10) with statically significant difference (p= 0.014). No difference between the 2 groups was noted in Ig G levels according to the history of SARS-Cov2 infection. No difference was found between conventional immunosuppressive drugs and biotherapies regarding to the level of antibodies.ConclusionOur study highlights that patients with autoimmune disease and under immunosuppressive therapy displayed a decrease of humoral response comparing to healthy controls. This finding was reported in several studies, Geisen et al[2] reported that patients with chronic inflammatory condition and receiving TNF alfa blockers had a decreased protection and a low level Ig A against spike. Based on these data, patients with autoimmune and inflammatory diseases have decreased humoral immunity to SARS-Cov2 and should be encouraged to receive a booster dose of SARS-COv2 vaccine.References[1]Prendecki M, Clarke C, Edwards H, et al. Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression. Ann Rheum Dis 2021;80:1322–9. doi:10.1136/annrheumdis-2021-220626[2]Geisen UM, Sümbül M, Tran F, et al. Humoral protection to SARS-CoV2 declines faster in patients on TNF alpha blocking therapies. RMD Open 2021;7:e002008. doi:10.1136/rmdopen-2021-002008AcknowledgementsMrs Hajer Mediouni.Disclosure of InterestsNone Declared.
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BackgroundChildren infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) usually present minimal symptoms or are asymptomatic. Nevertheless, a subset of children 2-6 weeks after the initial SARS-CoV-2 infection develops a postinfectious SARS-CoV-2-related multisystem inflammatory syndrome in (MIS-C). Recently, transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation, however, the underlying pathophysiology of MIS-C is not fully understood [1].ObjectivesThe purpose of our project is to characterize the complexity of cell populations and capture cellular heterogeneity to uncover the regulatory networks and interactions that are disrupted during MIS-C flare with simultaneous profiling of gene expression and open chromatin regions from the same nuclei.MethodsSamples of peripheral blood mononuclear cells from patients with MIS-C diagnosed at the University Children's Hospital, University Medical Center Ljubljana, were collected during the initial presentation before any treatment and at 6-12 months in remission. The primary aim is to identify which regulatory networks are driving inflammation in MIS-C flare, for which we are performing single cell Multiome ATAC + Gene Expression Sequencing. To enable simultaneous profiling of epigenomic landscape and gene expression from the same nuclei, we are using Chromium Next GEM Single Cell Multiome ATAC + Gene Expression kit from 10X Genomics.ResultsWe included 32 patients with MIS-C from whom we collected paired blood samples during the initial presentation before treatment and at 6-12 months in remission. In single cell multiomic experiment we included 10 patients with paired samples, with the most viable cell count prior cryopreservation. All samples that are included into multiomic single cell analysis have 75% - 99% viability prior cryopreservation. In the protocol the key is to remove remaining granulocytes causing high mitochondrial RNA burden and extensively optimize the dilution factor of lysis buffer and the length of cell lysis step in order to get intact nuclei with no significant blebbing. Afterward, the single cell ATAC libraries as well as single-cell gene expression libraries are constructed and sequenced. Data are undergoing pairwise analysis to compare the cell population heterogeneity, expression profile and open chromatin landscape in the time of the initial presentation of MIS-C and in the remission, with Cell ranger software as well as with R package scREG [2], and custom scripting. In the second step we will inspect if the resulting altered transcriptomic signature from single-cell experiment is present on larger cohort. In that regard, we will perform bulk transcriptomic profiling on all paired collected samples during the initial presentation of MIS-C before treatment and at 6-12 months in remission.ConclusionThe results of this project are expected to enlighten the underlying pathophysiology of MIS-C flare and thus support clinical decision on more targeted treatment. The identified disrupted networks during MIS-C flare could lead the way to establish an early diagnosis and improve long-term outcome, including prevention of myocardial and neuropsychological impairment. Moreover, a better understanding of the disrupted regulatory networks that are driving inflammation in MIS-C, could lead to new insights into diseases with similar clinical presentations as is Kawasaki Disease.References[1]Sacco, K., Castagnoli, R., Vakkilainen, S. et al. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat Med 28, 1050–1062 (2022).[2]Duren, Z., Chang, F., Naqing, F. et al. Regulatory analysis of single cell multiome gene expression and chromatin accessibility data with scREG. Genome Biol 23, 114 (2022).AcknowledgementsThis research was supported by Slovenian research agency grant J3-3061 and Interreg ITA-SLO project Cattedra.Disclosure of InterestsNone Declared.
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BackgroundTreatment with Rituximab (RTX) in patients with rheumatic diseases (RD) has presented a challenge during the COVID-19 pandemic, as RTX leads to markedly reduced and often undetectable antibody responses after COVID-19 vaccination (1).ObjectivesTo investigate the effect of COVID-19 mRNA revaccination (two doses) on the antibody response in patients with RD who were initial vaccine non-responders. Further, to examine if B-cell levels or T-cell responses before revaccination predicted seroconversion.MethodsFrom a RD cohort (COPANARD) vaccinated with the standard two-dose COVID-19 vaccinations, we enrolled cases without detectable antibody responses (n=17) and controls with detectable antibody response (n=29). Blood donors (n=32) were included as additional controls. Samples were collected before and six weeks after completed revaccination. Total antibodies (abs) and specific IgG, IgA, and IgM against SARS-CoV-2 spike protein, SARS-CoV-2 neutralizing abs, and SARS-CoV-2 reacting CD4+ and CD8+ T-cells were measured before and after revaccination. B-cells (CD19+CD45+) were quantified before revaccination. This study was funded by the Danish Rheumatism Association.ResultsPatient demographics are given in Table 1. Forty-seven percent of cases had detectable total SARS-CoV-2 abs and neutralizing abs after revaccination. However, antibody levels were significantly lower than in controls and blood donors (p<0.008), Figure 1A+B. Revaccination induced an antibody class switch in cases with a decrease in detectable IgM abs (Baseline 11/17, Followup 3/17) and increase in IgG. No significant difference was observed in T-cell responses before and after revaccination between the three groups, Figure 1C. The proportion of cases with detectable CD4+ T cells increased from 69% to 88% (p=0.25), and for CD8+ T cells, the proportion decreased from 88% to 82% (p=1.00). Only 29% of cases had measurable B-cells compared to 100% of controls and blood donors, Figure 1D. Fifty percent of revaccinated cases who seroconverted had measurable B-cells before revaccination, Figure 1D.Univariate logistic regression analysis was performed to analyze if active RTX treatment, the presence of B-cells, or a positive T-cell response prior to revaccination predicted seroconversion of total SARS-CoV-2-abs in the patient cohort. We did not find a significant explanatory effect of either variable in the univariate logistic models, data not shown.Table 1.DemographicsCases Revaccination, n=17Controls Boost, n=29Female sex, no(%)1482%2172%Age, median (IQR)6549 - 706762 - 72Disease duration, years1510 - 18229 - 31Rheumatoid Arthritis/SLE13/410/19None DMARD529%828%Prednisone424%13%Methotrexate741%1241%Hydroxychloroquine212%414%None biologic treatment424%931%Rituximab1271%0TNF-inhibitors16%724%JAK-inhibitors0621%IL-6-inhibitors, Abatacept, Benlysta0724%Previous rituximab treatmentAny rituximab treatment1694%13%RTX within the last 15 months, no1488%0Cumulative total dose, mg134-242Time from RTX to revaccination, months95-1249Figure 1.ConclusionIn conclusion, forty-seven percent of initial non-responders were able to seroconvert after two-dose revaccination. However, plasma concentrations of the antibodies against SARS-COV-2 and the levels of neutralizing capacity remained significantly lower than in immunocompetent blood donors. B-cell levels or T-cell responses before revaccination did not predict seroconversion. Our study suggests that patients with RDs who did not mount a detectable serological response to a COVID-19 mRNA vaccine have a T cell response similar to immunocompetent controls. Future studies should establish the antibody levels that identify RD patients without sufficient protection against SARS-CoV-2 infection.References[1]Troldborg A, et al. Time Since Rituximab Treatment Is Essential for Developing a Humoral Response to COVID-19 mRNA Vaccines in Patients With Rheumatic Diseases. J Rheumatol. 2022.AcknowledgementsThe Danish Rheumatism Association [grant number R203-A7217]. We acknowledge all patients and blood donors contributing to the stud for their invaluable participation. The authors would like to thank Sif Kaas Nielsen and Mads Engelhardt Knudsen, the Laboratory of Molecular Medicine at Rigshospitalet, for their excellent technical assistance in analyzing the samples.Disclosure of InterestsNone Declared.
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BackgroundData on cellular and humoral immunogenicity triggered by SARS-CoV-2 vaccines in patients with autoimmune rheumatic diseases (ARDs) are limited. While current vaccine efforts have focused on the induction of neutralizing antibodies against SARS-CoV-2, T-cell immunity may also provide protection against infection. Experimental data suggest that CD8+ T cell responses may have a protective role in the presence of decreasing or sub protective antibody titers [1].ObjectivesThe aim of this project is to describe the serological and T cell responses to the third dose of vaccine (either with BNT162b2 mRNA or ChAdOx1 nCoV-19 replication-deficient adenoviral vector vaccines) in a cohort of patients with ARDs (rheumatoid arthritis and spondyloarthropathies) treated with biologic therapies, to describe the impact of these treatments on vaccine response in this patient population. As a second objective, we will describe the characteristics of patients who did not present an adequate immunogenic response.MethodsCase-control study. We studied in 79 patients with ARDs and in 31 healthy controls, anti-SARS-CoV-2 specific interferon-gamma (IFN-γ) production measured by IGRA between 8-12 weeks after the third dose of anti-SARS-CoV-2 vaccine. In addition, humoral response was measured by anti-S1 IgG antibody production measured by chemiluminescent microparticle immunoassay. Statistical comparison between categorical variables was performed by Fisher's or χ2 test. For quantitative variables by Kruskal-Wallis test or Mann-Whitney test.Results79 patients with ARDs (48 women, 31 men;mean age 58±11.4) 43 (54%), with rheumatoid arthritis and 36 (45.6%) with spondyloarthropathies. 32 (49.5%) of them were on glucocorticoid treatment (mean dose 4.92 mg/day), 25 (31.6%) on methotrexate and 56 (70.9%) on anti-TNF. Post-vaccination results showed positive T-cell immune responses in 68 of 79 (86.1%) ARDs patients with mean IFN- γ anti-SARS-CoV-2 titers of 1,606.85 mUI/ml. 7 (8.9%) of ARDs patients showed negative IFN-γ SARS-CoV-2 levels, while 4 (5%) had borderline titers. 100% of patients with previous COVID 19 disease had positive cellular responses. Within the group of negative or borderline cellular responses, 7 of 10 were men (70%), with no significant differences in terms of diagnosis, comorbidities or immunosuppressive treatments used. In the control group, 100% presented positive cellular responses. Anti-Spike IgG antibodies were detectable in all patients with ARDs as in the control group.ConclusionOur preliminary data show that most patients with ARD were able to generate an adequate specific cellular response after vaccination against SARS-CoV-2, emphasizing the relevance of vaccination in this group. Specific antibody responses secondary to anti-SARS-CoV-2 vaccination were detected in all patients with ARD. Our data could support the relevance of these immune responses to personalize prevention, vaccination decision-making and treatment in this subgroup of patients.References[1]Sieiro Santos C, Calleja Antolin S, Moriano Morales C, Garcia Herrero J, Diez Alvarez E, Ramos Ortega F, et al. Immune responses to mRNA vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory rheumatic diseases. RMD Open. 2022 Jan 5;8(1).Figure 1.Specific anti-SARS-CoV-2-IFN- γ responses measured by IGRA. Dotted lines represent positivity cut-off: ≥200mUI/ml. HC: Healthy controls. AIRDs: Autoimmune rheumatic diseases.[Figure omitted. See PDF]Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Peptide vaccines have advantages in easy fabrication and high safety, but their effectiveness is hampered by the poor immunogenicity of the epitopes themselves. Herein, we constructed a series of framework nucleic acids (FNAs) with regulated rigidity and size to precisely organize epitopes in order to reveal the influence of epitope spacing and carrier rigidity on the efficiency of peptide vaccines. We found that assembling epitopes on rigid tetrahedral FNAs (tFNAs) with the appropriate size could efficiently enhance their immunogenicity. Further, by integrating epitopes from SARS‐CoV‐2 on preferred tFNAs, we constructed a COVID‐19 peptide vaccine which could induce high titers of IgG against the receptor binding domain (RBD) of SARS‐CoV‐2 spike protein and increase the ratio of memory B and T cells in mice. Considering the good biocompatibility of tFNAs, our research provides a new idea for developing efficient peptide vaccines against viruses and possibly other diseases.
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OBJECTIVES/GOALS: Despite highly effective antiretroviral therapy, people living with HIV (PLWH) experience chronic immune activation and inflammation which may influence the progression of infections such as SARS-CoV-2. Here, we explore the immune response and clinical outcomes in HIV(+) and HIV(-) individuals experiencing acute COVID-19 and long COVID (LC). METHODS/STUDY POPULATION: We performed flow cytometric analyses on peripheral blood mononuclear cells from the following: 1) HIV(-) individuals experiencing acute COVID-19, 2) PLWH experiencing acute COVID-19, and 3) pre-COVID-19 pandemic PLWH. Additionally, we will perform similar analyses for the following: 1) PLWH experiencing LC, 2) PLWH previously infected with SARS-CoV-2 who recovered, 3) pre-COVID-19 pandemic PLWH, and 4) HIV(-) individuals experiencing LC. Flow cytometry panels include surface markers for immune cell populations, activation and exhaustion surface markers (with and without SARS-CoV-2-specific antigen stimulation), and intracellular cytokine staining. We will also analyze how chronic HIV infection and other clinical and demographic factors (e.g., age, CD4 %) impact persistent symptomatic burden. RESULTS/ANTICIPATED RESULTS: Acute COVID-19 results–Overall, PLWH had higher baseline expression of activation markers OX40 and CD137 on CD4+ and CD8+ T cells, along with increased levels of TNFa producing CD8+ T cells. Interestingly, PLWH had increased expression of exhaustion markers PD1 and TIGIT but decreased expression of TIM3 on CD4+ and CD8+ T cells. Additionally, PLWH had decreased levels of IL-2 and IFNg producing CD4+ T cells which suggests functional exhaustion. Long COVID-19 expected results–we hypothesize that the activation and inflammation seen in chronic HIV infection will lead to more immune dysregulation and subsequently worsened symptomatic burden. Additionally, we hypothesize that PLWH may have different frequencies of certain LC manifestations, such as increased rates of neurocognitive impairment. DISCUSSION/SIGNIFICANCE: Our findings suggest that chronic HIV infection influences acute immune response during SARS-CoV-2 infection, and that PLWH have variable expression of exhaustion markers which warrants further study. Additionally, our findings in the LC cohort will aid in characterizing clinical manifestations and immunologic mechanisms of LC in PLWH.
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When a pathogen activates B cells and T cells, memory B cells and memory T cells form, and the major immune response happens as a result. These memory cells "remember" every unique pathogen an animal encounters over the course of its lifetime and can develop a potent secondary response if the pathogen is discovered again. Due to the immune system's proactive self-preparation, this sort of immunity is both active and adaptable. The innate immune system and both the cell-mediated and humoral components of immunity are frequently involved in active immunity. Here, Maiorino discusses the naturally and artificially acquired active immunity.
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Objective: To observe early laboratory indicators in peripheral blood of patients infected with SARSCoV- 2 Delta variant and the protective effects of COVID-19 vaccine on patients infected with SARS-CoV-2 Delta variant, in order to provide reference for epidemic prevention and control. Methods: Twenty-five Chengdu local confirmed nonsevere COVID-19 patients over 18 years old who were infected with COVID-19 caused by Delta variant in November 2021 were included as the research group, 22 cases of whom were vaccinated with COVID-19 vaccine before infection, and 3(2 cases over 80 years old)were unvaccinated. In addition, 71 non-severe COVID-19 patients at the age of over 18 years diagnosed in Chengdu from January 2020 to February 2020 were included as the control group. Peripheral blood was collected for laboratory examination in all cases on the first or second days after admission, and peripheral blood was collected for laboratory examination again in patients on day 4 to 8 after admission in the research group. Laboratory indicators included the blood routine, C-reactive protein, procalcitonin, liver function, myocardial enzyme profile, coagulation routine, T lymphocyte subsets, SARS-CoV-2 IgG antibody, and total antibody, etc. The first peripheral blood laboratory test results: of the two groups were compared to observe the protective effect of COVID-19 vaccine on patients infected with SARS-CoV- 2 Delta variant. Results Among the first time of laboratory indicators after admission, the lymphocyte count, lactate dehydrogenase, and D-dimer in the research group were all lower than those in the control group(all P < 0.05), and the procalcitonin and aspartate aminotransferase were higher than those in the control group(all P < 0.05). Among the 22 cases who had gotten vaccine before infection in the research group, there were 5 cases with positive result of SARS-CoV-2 IgG antibody in the first time of peripheral blood, 22 cases with positive result of SARS-CoV-2 IgG antibody in the second time of peripheral blood, and none of them became severe cases. During 3 unvaccinated cases, twice of the SARS-CoV-2 IgG antibody were both negative among the 2 cases over 80 years who had not vaccinated in the research group, then they became severe cases on day 6-8 during hospitalization, and the rest one had negative result of SARS-CoV-2 IgG antibody in the second time of peripheral blood. Among the 22 vaccinated cases in the research group, the lymphocyte count, CD4+T cell count, CD8+T cell count, SARS-CoV-2 specific antibodies in the second time peripheral blood were all higher than those in the first time of peripheral blood(all P < 0.05), and platelet count, hemoglobin, total protein, creatine kinase were all lower than those in the first time of peripheral blood(all P < 0.05). Conclusions: Lymphocyte count at early admission in COVID-19 patients infected with Delta variant may be lower than that infected with wild strain. COVID-19 vaccine can reduce the risk of infection of SARS-CoV-2 Delta variant by preventing the emergence of inflammatory storms and producing a large number of specific antibodies.
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The lumpy skin disease (LSD) virus of the Poxviridae family is a serious threat that mostly affects cattle and causes significant economic loss. LSD has the potential to spread widely and its rapidly across borders. Despite the availability of information, there is still no competitive vaccine available for LSD. Therefore, the current study was conducted to develop an epitope-based LSD vaccine that is efficient, secure, and biocompatible and stimulates both innate and adaptive immune responses using immunoinformatics techniques. Initially, putative virion core proteins were manipulated;B-cell and T-cell epitopes have been predicted and connected with the help of adjuvants and linkers. Numerous bioinformatics methods, including antigenicity testing, transmembrane topology screening, allergenicity assessment, conservancy analysis, and toxicity evaluation, were employed to find superior epitopes. Based on promising vaccine candidates and immunogenic potential, the vaccine design was selected. Strong interactions between TLR4 and TLR9 and the anticipated vaccine design were revealed by molecular docking. Finally, based on the high docking score, computer simulations were performed in order to assess the stability, efficacy, and compactness of the constructed vaccine. The simulation outcomes showed that the polypeptide vaccine design was remarkably stable, with high expression, stability, immunogenic qualities, and considerable solubility. Additionally, computer-based research shows that the constructed vaccine provides adequate population coverage, making it a promising candidate for use in the design of vaccines against other viruses within the Poxviridae family and potentially other virus families as well. These outcomes suggest that the epitope-based vaccine developed in this study will be a significant candidate against LSD to control and prevent LSDV-related disorders if further investigated experimentally.
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The introduction of Chimeric Antigen Receptor (CAR)-T cells in the clinics has been a real milestone in the management of some malignant haematological diseases of poor prognosis by enabling complete and sustained remissions. The principle is to use lymphocytes (currently autologous in most cases) and to genetically engineer them ex vivo to make them co-express an antibody specific for a tumour-associated antigen and an activation signal triggering the production of cytotoxic factors and therefore allowing to neutralize the tumour cell upon recognition of the relevant antigen. The successful outcomes of CAR-T cells have led to broaden their indications to solid tumours and to consider now their possible extension beyond oncology, particularly to the cardiology area. Namely, the identification in fibrosis, a major hallmark of late-stage cardiomyopathies and a predictive factor of their worsening, of a highly expressed protein (Fibroblast Activation Protein) has led to investigate the effects of CAR-T cells directed against this protein. The initial experimental results in a murine model of hypertensive cardiomyopathy validate the efficacy of this approach for ablating myocardial fibrosis and concomitantly improving cardiac function. It now becomes mandatory to confirm these encouraging data, to check for the absence of toxicity and to streamline the current ex vivo production process which is still too time-consuming, complex and costly. This might be possible by leveraging the technology which has allowed the successful development of anti-Covid-19 vaccines and relies on lipid nanoparticles targeting T lymphocytes for in vivo delivery of the messenger RNA encoding the target protein. © 2022 l'Académie nationale de médecine;L'introduction des Chimeric Antigen Receptor (CAR)-T cells en clinique a représenté un véritable tournant dans la prise en charge de certaines hémopathies malignes de mauvais pronostic en permettant des rémissions complètes et durables. Le principe est d'utiliser des lymphocytes (à ce jour le plus souvent autologues) et de les modifier génétiquement ex vivo pour leur faire co-exprimer un anticorps spécifique d'un antigène tumoral et un signal d'activation déclenchant une production de molécules cytotoxiques et permettant ainsi de neutraliser la cellule maligne une fois cet antigène reconnu. L'efficacité des CAR-T cells explique que l'on cherche à élargir leurs indications aux tumeurs solides et fait maintenant envisager des applications extra-oncologiques, notamment dans le domaine cardiaque. En effet, l'identification dans la fibrose, composante majeure et aggravante des cardiopathies parvenues à un stade avancé, d'une protéine fortement sur-exprimée (la Fibroblast Activation Protein) a conduit à explorer les effets de CAR-T cells dirigés contre cette protéine. Les premiers résultats expérimentaux dans un modèle murin de cardiopathie hypertensive valident l'efficacité de cette stratégie pour diminuer la fibrose myocardique et améliorer en parallèle la fonction cardiaque. Il faut maintenant conforter ces résultats encourageants, vérifier l'absence de toxicité et envisager une simplification de la procédure de production ex vivo actuelle, encore trop longue, complexe et coûteuse. Cela pourrait être possible en capitalisant sur la technologie qui s'est révélée efficace pour développer des vaccins anti-Covid 19 et repose sur l'utilisation de nanoparticules lipidiques ciblant les lymphocytes T pour leur transférer in vivo l'ARN messager codant pour la protéine ciblée. © 2022 l'Académie nationale de médecine
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Currently, the novel and major life-threatening cause all over the world is COVID-19 (Coronavirus disease 2019) which is started at the end of 2019 in Wuhan, China, and spread all over the world today. The infection of COVID-19 severity is variable which affects all ages' people and especially elderly persons whose immune system is very weak. Fatigue, fever, respiratory illness, dry cough, loss of appetite, olfactory dysfunction are the most common symptoms of this disease along with the decrease of certain cells of the immune system like helper T cells, monocytes/macrophages, etc. and an increase in pro-inflammatory cytokines are some of the major characteristics of this disease. Some natural herbal products are a successive option to combat SARS-Cov-2 disease. Herbs have various potential compound which is used as a dietary product that strongly influences immunity and maintenance of the homeostasis of inflammatory/anti-inflammatory. In the present review, we describe the potential of three herbal products as Turmeric (Haldi), Heart-leaved moonseed (Giloy), and Black cumin (Kalonji) that can be used for preventative or nutritional therapy of COVID-19.
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Through the emeigence of new viral infectious diseases, epidemics and pandemics have brought great impacts on public health in recent decades. In this review, we sought to understand the association between the neurological outcomes of two relevant infectious diseases, Zika and COVID-19. Zika can trigger neurological and ophthalmic damage in children born from infected mothers, as well as, Guillain-Barré syndrome, encephalitis, and myelitis in adults. On the other hand, the SARS-CoV-2 virus has great potential to trigger an inflammatory process in the optic nerve, with optic neuritis as the most reported pathology. Although Zika and SARS-CoV-2 infections are associated with different clinical manifestations, both may trigger similar pathogenic processes, through the induction of pro-inflammatory chemokines and cytokines release, triggering neurological and ophthalmological damage in infected patients. Elements in common have been found in both infections, such as antibodies against myelin oligodendrocyte glycoprotein, and the production of CXCL10, a chemokine responsible for the activation of several cellular types (T cells, eosinophils, monocytes and NK cells) in which are responsible to the induction of a cytokine cascade in the body. Based on these last findings, we suggest that both infections have similar activation characteristics as well as common pathogenic mechanisms associated with central nervous system involvement.