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1.
Proc Natl Acad Sci U S A ; 119(31): e2204336119, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35858382

RESUMO

The durability of vaccine-mediated immunity to SARS-CoV-2, the durations to breakthrough infection, and the optimal timings of booster vaccination are crucial knowledge for pandemic response. Here, we applied comparative evolutionary analyses to estimate the durability of immunity and the likelihood of breakthrough infections over time following vaccination by BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), ChAdOx1 (Oxford-AstraZeneca), and Ad26.COV2.S (Johnson & Johnson/Janssen). We evaluated anti-Spike (S) immunoglobulin G (IgG) antibody levels elicited by each vaccine relative to natural infection. We estimated typical trajectories of waning and corresponding infection probabilities, providing the distribution of times to breakthrough infection for each vaccine under endemic conditions. Peak antibody levels elicited by messenger RNA (mRNA) vaccines mRNA-1273 and BNT1262b2 exceeded that of natural infection and are expected to typically yield more durable protection against breakthrough infections (median 29.6 mo; 5 to 95% quantiles 10.9 mo to 7.9 y) than natural infection (median 21.5 mo; 5 to 95% quantiles 3.5 mo to 7.1 y). Relative to mRNA-1273 and BNT1262b2, viral vector vaccines ChAdOx1 and Ad26.COV2.S exhibit similar peak anti-S IgG antibody responses to that from natural infection and are projected to yield lower, shorter-term protection against breakthrough infection (median 22.4 mo and 5 to 95% quantiles 4.3 mo to 7.2 y; and median 20.5 mo and 5 to 95% quantiles 2.6 mo to 7.0 y; respectively). These results leverage the tools from evolutionary biology to provide a quantitative basis for otherwise unknown parameters that are fundamental to public health policy decision-making.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunogenicidade da Vacina , SARS-CoV-2 , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Formação de Anticorpos , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/uso terapêutico , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Fatores de Tempo
2.
Front Immunol ; 13: 884248, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844545

RESUMO

The severe autoimmune blistering disease Pemphigus vulgaris (PV) is mainly caused by autoantibodies (IgG) against desmoglein (Dsg) 3 and Dsg1. The mechanisms leading to the development of blisters are not fully understood, but intracellular signaling seems to play an important role. Sheddases ADAM10 and ADAM17 are involved in the turnover of the desmosomal cadherin Dsg2 and ADAM10 has been shown to contribute to acantholysis in a murine pemphigus model. In the present study, we further examined the role of ADAM10 and ADAM17 both in keratinocyte adhesion and in the pathogenesis of PV. First, we found that inhibition of ADAM10 enhanced adhesion of primary human keratinocytes but not of immortalized keratinocytes. In dissociation assays, inhibition of ADAM10 shifted keratinocyte adhesion towards a hyperadhesive state. However, ADAM inhibition did neither modulate protein levels of Dsg1 and Dsg3 nor activation of EGFR at Y1068 and Y845. In primary human keratinocytes, inhibition of ADAM10, but not ADAM17, reduced loss of cell adhesion and fragmentation of Dsg1 and Dsg3 immunostaining in response to a PV1-IgG from a mucocutaneous PV patient. Similarly, inhibition of ADAM10 in dissociation assay decreased fragmentation of primary keratinocytes induced by a monoclonal antibody against Dsg3 and by PV-IgG from two other patients both suffering from mucosal PV. However, such protective effect was not observed in both cultured cells and ex vivo disease models, when another mucocutaneous PV4-IgG containing more Dsg1 autoantibodies was used. Taken together, ADAM10 modulates both hyperadhesion and PV-IgG-induced loss of cell adhesion dependent on the autoantibody profile.


Assuntos
Proteína ADAM10 , Proteína ADAM17 , Queratinócitos , Pênfigo , Proteína ADAM10/imunologia , Proteína ADAM17/imunologia , Secretases da Proteína Precursora do Amiloide , Animais , Autoanticorpos/imunologia , Adesão Celular/imunologia , Desmogleína 1/imunologia , Desmogleína 3/imunologia , Humanos , Imunoglobulina G/imunologia , Queratinócitos/imunologia , Queratinócitos/patologia , Proteínas de Membrana/metabolismo , Camundongos , Pênfigo/imunologia , Pênfigo/patologia
3.
Nature ; 606(7915): 769-775, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35676476

RESUMO

Adaptive immune components are thought to exert non-overlapping roles in antimicrobial host defence, with antibodies targeting pathogens in the extracellular environment and T cells eliminating infection inside cells1,2. Reliance on antibodies for vertically transferred immunity from mothers to babies may explain neonatal susceptibility to intracellular infections3,4. Here we show that pregnancy-induced post-translational antibody modification enables protection against the prototypical intracellular pathogen Listeria monocytogenes. Infection susceptibility was reversed in neonatal mice born to preconceptually primed mothers possessing L. monocytogenes-specific IgG or after passive transfer of antibodies from primed pregnant, but not virgin, mice. Although maternal B cells were essential for producing IgGs that mediate vertically transferred protection, they were dispensable for antibody acquisition of protective function, which instead required sialic acid acetyl esterase5 to deacetylate terminal sialic acid residues on IgG variable-region N-linked glycans. Deacetylated L. monocytogenes-specific IgG protected neonates through the sialic acid receptor CD226,7, which suppressed IL-10 production by B cells leading to antibody-mediated protection. Consideration of the maternal-fetal dyad as a joined immunological unit reveals protective roles for antibodies against intracellular infection and fine-tuned adaptations to enhance host defence during pregnancy and early life.


Assuntos
Imunidade Materno-Adquirida , Imunoglobulina G , Espaço Intracelular , Listeria monocytogenes , Mães , Gravidez , Acetilesterase , Animais , Animais Recém-Nascidos , Linfócitos B , Feminino , Imunidade Materno-Adquirida/imunologia , Imunoglobulina G/imunologia , Interleucina-10/biossíntese , Espaço Intracelular/imunologia , Espaço Intracelular/microbiologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Listeriose/prevenção & controle , Camundongos , Ácido N-Acetilneuramínico/metabolismo , Gravidez/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Linfócitos T
4.
Arch Toxicol ; 96(10): 2785-2797, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35763063

RESUMO

Occupational exposure to trichloroethylene (TCE) causes a systemic skin disorder with hepatitis known as TCE hypersensitivity syndrome (TCE-HS). Human Leukocyte Antigen (HLA)-B*13:01 is its susceptibility factor; however, the immunological pathogenesis of TCE-HS remains unknown. We herein examined the hypothesis that autoantibodies to CYP2E1 are primarily involved in TCE-HS. A case-control study of 80 TCE-HS patients, 186 TCE-tolerant controls (TCE-TC), and 71 TCE-nonexposed controls (TCE-nonEC) was conducted to measure their serum anti-CYP2E1 antibody (IgG) levels. The effects of TCE exposure indices, such as 8-h time-weighted-average (TWA) airborne concentrations, urinary metabolite concentrations, and TCE usage duration; sex; smoking and drinking habits; and alanine aminotransferase (ALT) levels on the antibody levels were also analyzed in the two control groups. There were significant differences in anti-CYP2E1 antibody levels among the three groups: TCE-TC > TCE-HS patients > TCE-nonEC. Antibody levels were not different between HLA-B*13:01 carriers and noncarriers in TCE-HS patients and TCE-TC. The serum CYP2E1 measurement suggested increased immunocomplex levels only in patients with TCE-HS. Multiple regression analysis for the two control groups showed that the antibody levels were significantly higher by the TCE exposure. Women had higher antibody levels than men; however, smoking, drinking, and ALT levels did not affect the anti-CYP2E1 antibody levels. Anti-CYP2E1 antibodies were elevated at concentrations lower than the TWA concentration of 2.5 ppm for TCE exposure. Since HLA-B*13:01 polymorphism was not involved in the autoantibody levels, the possible mechanism underlying the pathogenesis of TCE-HS is that TCE exposure induces anti-CYP2E1 autoantibody production, and HLA-B*13:01 is involved in the development of TCE-HS.


Assuntos
Citocromo P-450 CYP2E1 , Síndrome de Hipersensibilidade a Medicamentos , Exposição Ocupacional , Tricloroetileno , Autoanticorpos/sangue , Autoanticorpos/genética , Autoanticorpos/imunologia , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Citocromo P-450 CYP2E1/sangue , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/imunologia , Síndrome de Hipersensibilidade a Medicamentos/sangue , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Síndrome de Hipersensibilidade a Medicamentos/imunologia , Feminino , Antígenos HLA-B/sangue , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Hepatite Autoimune/sangue , Hepatite Autoimune/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Masculino , Exposição Ocupacional/efeitos adversos , Polimorfismo Genético , Tricloroetileno/imunologia , Tricloroetileno/toxicidade
5.
Proc Natl Acad Sci U S A ; 119(28): e2204607119, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35759653

RESUMO

Messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective at inducing protective immunity. However, weak antibody responses are seen in some individuals, and cellular correlates of immunity remain poorly defined, especially for B cells. Here we used unbiased approaches to longitudinally dissect primary antibody, plasmablast, and memory B cell (MBC) responses to the two-dose mRNA-1273 vaccine in SARS-CoV-2-naive adults. Coordinated immunoglobulin A (IgA) and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses but earlier and more intensely after dose 2. While antibody and B cell cellular responses were generally robust, they also varied within the cohort and decreased over time after a dose-2 peak. Both antigen-nonspecific postvaccination plasmablast frequency after dose 1 and their spike-specific counterparts early after dose 2 correlated with subsequent antibody levels. This correlation between early plasmablasts and antibodies remained for titers measured at 6 months after vaccination. Several distinct antigen-specific MBC populations emerged postvaccination with varying kinetics, including two MBC populations that correlated with 2- and 6-month antibody titers. Both were IgG-expressing MBCs: one less mature, appearing as a correlate after the first dose, while the other MBC correlate showed a more mature and resting phenotype, emerging as a correlate later after dose 2. This latter MBC was also a major contributor to the sustained spike-specific MBC response observed at month 6. Thus, these plasmablasts and MBCs that emerged after both the first and second doses with distinct kinetics are potential determinants of the magnitude and durability of antibodies in response to mRNA-based vaccination.


Assuntos
Vacina de mRNA-1273 contra 2019-nCoV , Formação de Anticorpos , Linfócitos B , COVID-19 , RNA Mensageiro , SARS-CoV-2 , Vacina de mRNA-1273 contra 2019-nCoV/administração & dosagem , Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Linfócitos B/imunologia , COVID-19/prevenção & controle , Humanos , Imunidade Celular , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , RNA Mensageiro/administração & dosagem , RNA Mensageiro/imunologia , SARS-CoV-2/imunologia , Vacinação
6.
Lancet Infect Dis ; 22(9): 1374-1387, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35772449

RESUMO

BACKGROUND: Australian First Nations children are at very high risk of early, recurrent, and persistent bacterial otitis media and respiratory tract infection. With the PREVIX randomised controlled trials, we aimed to evaluate the immunogenicity of novel pneumococcal conjugate vaccine (PCV) schedules. METHODS: PREVIX_BOOST was a parallel, open-label, outcome-assessor-blinded, randomised controlled trial. Aboriginal children living in remote communities of the Northern Territory of Australia were eligible if they had previously completed the three-arm PREVIX_COMBO randomised controlled trial of the following vaccine schedules: three doses of a 13-valent PCV (PCV13; PPP) or a ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; SSS) given at 2, 4, and 6 months, or SSS given at 1, 2, and 4 months followed by PCV13 at 6 months (SSSP). At age 12 months, eligible children were randomly assigned by a computer-generated random sequence (1:1, stratified by primary group allocation) to receive either a PCV13 booster or a PHiD-CV10 booster. Analyses used intention-to-treat principles. Co-primary outcomes were immunogenicity against protein D and serotypes 3, 6A, and 19A. Immunogenicity measures were geometric mean concentrations (GMC) and proportion of children with IgG concentrations of 0·35 µg/mL or higher (threshold for invasive pneumococcal disease), and GMCs and proportion of children with antibody levels of 100 EU/mL or higher against protein D. Standardised assessments of otitis media, hearing impairment, nasopharyngeal carriage, and developmental outcomes are reported. These trials are registered with ClinicalTrials.gov (NCT01735084 and NCT01174849). FINDINGS: Between April 10, 2013, and Sept 4, 2018, 261 children were randomly allocated to receive a PCV13 booster (n=131) or PHiD-CV10 booster (n=130). Adequate serum samples for pneumococcal serology were obtained from 127 (95%) children in the PCV13 booster group and 126 (97%) in the PHiD-CV10 booster group; for protein D, adequate samples were obtained from 126 (96%) children in the PCV13 booster group and 123 (95%) in the PHiD-CV10 booster group. The proportions of children with IgG concentrations above standard thresholds in PCV13 booster versus PHiD-CV10 booster groups were the following: 71 (56%) of 126 versus 81 (66%) of 123 against protein D (difference 10%, 95% CI -2 to 22), 85 (67%) of 127 versus 59 (47%) of 126 against serotype 3 (-20%, -32 to -8), 119 (94%) of 127 versus 91 (72%) of 126 against serotype 6A (-22%, -31 to -13), and 116 (91%) of 127 versus 108 (86%) of 126 against serotype 19A (-5%, -13 to 3). Infant PCV13 priming mitigated differences between PCV13 and PHiD-CV10 boosters. In both groups, we observed a high prevalence of otitis media (about 90%), hearing impairment (about 75%), nasopharyngeal carriage of pneumococcus (about 66%), and non-typeable H influenzae (about 57%). Of 66 serious adverse events, none were vaccine related. INTERPRETATION: Low antibody concentrations 6 months post-booster might indicate increased risk of pneumococcal infection. The preferred booster was PCV13 if priming did not have PCV13, otherwise either PCV13 or PHiD-CV10 boosters provided similar immunogenicity. Mixed schedules offer flexibility to regional priorities. Non-PCV13 serotypes and non-typeable H influenzae continue to cause substantial disease and disability in Australian First Nation's children. FUNDING: National Health and Medical Research Council (NHMRC).


Assuntos
Perda Auditiva , Imunização Secundária , Povos Indígenas , Nasofaringe , Otite Média , Vacinas Pneumocócicas , Vacinas Conjugadas , Anticorpos Antibacterianos/imunologia , Austrália , Haemophilus influenzae/imunologia , Perda Auditiva/imunologia , Humanos , Imunoglobulina G/imunologia , Lactente , Recém-Nascido , Nasofaringe/imunologia , Nasofaringe/microbiologia , Otite Média/imunologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Infecções Respiratórias , Streptococcus pneumoniae/imunologia , Fatores de Tempo , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/imunologia
7.
Br J Haematol ; 198(4): 668-679, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35655410

RESUMO

Allogeneic haematopoietic stem cell transplant (HSCT) recipients remain at high risk of adverse outcomes from coronavirus disease 2019 (COVID-19) and emerging variants. The optimal prophylactic vaccine strategy for this cohort is not defined. T cell-mediated immunity is a critical component of graft-versus-tumour effect and in determining vaccine immunogenicity. Using validated anti-spike (S) immunoglobulin G (IgG) and S-specific interferon-gamma enzyme-linked immunospot (IFNγ-ELIspot) assays we analysed response to a two-dose vaccination schedule (either BNT162b2 or ChAdOx1) in 33 HSCT recipients at ≤2 years from transplant, alongside vaccine-matched healthy controls (HCs). After two vaccines, infection-naïve HSCT recipients had a significantly lower rate of seroconversion compared to infection-naïve HCs (25/32 HSCT vs. 39/39 HCs no responders) and had lower S-specific T-cell responses. The HSCT recipients who received BNT162b2 had a higher rate of seroconversion compared to ChAdOx1 (89% vs. 74%) and significantly higher anti-S IgG titres (p = 0.022). S-specific T-cell responses were seen after one vaccine in HCs and HSCT recipients. However, two vaccines enhanced S-specific T-cell responses in HCs but not in the majority of HSCT recipients. These data demonstrate limited immunogenicity of two-dose vaccination strategies in HSCT recipients, bolstering evidence of the need for additional boosters and/or alternative prophylactic measures in this group.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Transplante de Células-Tronco Hematopoéticas , Fatores Etários , Anticorpos Antivirais/imunologia , Vacina BNT162/imunologia , Vacina BNT162/uso terapêutico , Transplante de Medula Óssea/efeitos adversos , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/farmacologia , Vacinas contra COVID-19/uso terapêutico , ChAdOx1 nCoV-19/imunologia , ChAdOx1 nCoV-19/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Imunidade Humoral/efeitos dos fármacos , Imunidade Humoral/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Soroconversão , Transplante Homólogo/efeitos adversos , Vacinação/efeitos adversos
8.
J Virol ; 96(13): e0014322, 2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35658531

RESUMO

Differentiation of infected from vaccinated hosts (DIVH) is a critical step in virus eradication programs. DIVH-compatible vaccines, however, take years to develop, and are therefore unavailable for fighting the sudden outbreaks that typically drive pandemics. Here, we establish a protocol for the swift and efficient development of DIVH assays, and show that this approach is compatible with any type of vaccines. Using porcine circovirus 2 (PCV2) as the experimental model, the first step is to use Immunoglobin G (IgG) sero-dynamics (IsD) curves to aid epitope discovery (IsDAED): PCV2 Cap peptides were categorized into three types: null interaction, nonspecific interaction (NSI), and specific interaction (SI). We subsequently compared IsDAED approach and traditional approach, and demonstrated identifying SI peptides and excluding NSI peptides supports efficient diagnostic kit development, specifically using a protein-peptide hybrid microarray (PPHM). IsDAED directed the design of a DIVH protocol for three types of PCV2 vaccines (while using a single PPHM). Finally, the DIVH protocol successfully differentiated infected pigs from vaccinated pigs at five farms. This IsDAED approach is almost certainly extendable to other viruses and host species. IMPORTANCE Sudden outbreaks of pandemics caused by virus, such as SARS-CoV-2, has been determined as a public health emergency of international concern. However, the development of a DIVH-compatible vaccine is time-consuming and full of uncertainty, which is unsuitable for an emergent situation like the ongoing COVID-19 pandemic. Along with the development and public health implementation of new vaccines to prevent human diseases, e.g., human papillomavirus vaccines for cervical cancer; enterovirus 71 vaccines for hand, foot, and mouth disease; and most recently SARS-CoV-2, there is an increasing demand for DIVH. Here, we use the IsDAED approach to confirm SI peptides and to exclude NSI peptides, finally to direct the design of a DIVH protocol. It is plausible that our IsDAED approach is applicable for other infectious disease.


Assuntos
Anticorpos Antivirais , Infecções por Circoviridae , Epitopos , Imunoglobulina G , Vacinas Virais , Animais , Anticorpos Antivirais/sangue , COVID-19 , Infecções por Circoviridae/imunologia , Circovirus , Modelos Animais de Doenças , Epitopos/análise , Epitopos/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Peptídeos , SARS-CoV-2 , Suínos , Doenças dos Suínos/imunologia , Vacinas Virais/imunologia
9.
Haemophilia ; 28(5): 737-744, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35654086

RESUMO

INTRODUCTION: Presence of von Willebrand factor (VWF) in FVIII concentrates offers protection against neutralizing inhibitors in haemophilia A (HA). Whether this protection is more evident in plasma-derived (pd) FVIII/VWF or recombinant (r) FVIII concentrates remains controversial. AIM: We investigated the protection exerted by VWF against FVIII inhibitors in an in vivo mouse model of HA exposed to pdFVIII/VWF or to various rFVIII concentrates. METHODS: Haemophilia A mice received the different FVIII concentrates after administration of vehicle or an inhibitory IgG purified from a commercial pool of HA plasma with inhibitors and FVIII:C recoveries were measured. Furthermore, using a novel clinically oriented ex vivo approach, Bethesda inhibitory activities (BU) of a commercial pool of HA plasma with inhibitors were assessed using normal plasma, or plasma from severe HA patients, without inhibitors, after treatment with the same concentrates. RESULTS: in vivo studies showed that pdFVIII/VWF offers markedly higher protection against inhibitors when compared with any of the FVIII products without VWF. More importantly, in the ex vivo studies, plasma from patients treated with pdFVIII/VWF showed higher protection against inhibitors (P values ranging .05-.001) in comparison with that observed in plasma from patients who received FVIII products without VWF, regardless of the type of product evaluated. CONCLUSION: Data indicate that FVIII+VWF complexes assembled in the circulation after rFVIII infusion are not equivalent to the naturally formed complex in pdFVIII/VWF. Therefore, rFVIII infused into HA patients with inhibitors would be less protected by VWF than the FVIII in pdFVIII/VWF concentrates.


Assuntos
Fator VIII , Hemofilia A , Fator de von Willebrand , Animais , Modelos Animais de Doenças , Fator VIII/administração & dosagem , Fator VIII/imunologia , Fator VIII/isolamento & purificação , Hemofilia A/terapia , Imunoglobulina G/imunologia , Camundongos , Proteínas Recombinantes/administração & dosagem , Fator de von Willebrand/administração & dosagem , Fator de von Willebrand/isolamento & purificação
10.
Int J Mol Sci ; 23(10)2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35628640

RESUMO

Anti-citrullinated protein antibodies (ACPAs) are involved in the pathogenesis of rheumatoid arthritis. N-glycosylation pattern of ACPA-IgG and healthy IgG Fc differs. The aim of this study is to determine the relative sialylation and galactosylation level of ACPAs and control IgG to assess their capability of inducing TNFα production, and furthermore, to analyze the correlations between the composition of Fc glycans and inflammatory markers in RA. We isolated IgG from sera of healthy volunteers and RA patients, and purified ACPAs on a citrulline-peptide column. Immunocomplexes (IC) were formed by adding an F(ab)2 fragment of anti-human IgG. U937 cells were used to monitor the binding of IC to FcγR and to trigger TNFα release determined by ELISA. To analyze glycan profiles, control IgG and ACPA-IgG were digested with trypsin and the glycosylation patterns of glycopeptides were analyzed by determining site-specific N-glycosylation using nano-UHPLC-MS/MS. We found that both sialylation and galactosylation levels of ACPA-IgG negatively correlate with inflammation-related parameters such as CRP, ESR, and RF. Functional assays show that dimerized ACPA-IgG significantly enhances TNFα release in an FcγRI-dependent manner, whereas healthy IgG does not. TNFα production inversely correlates with the relative intensities of the G0 glycoform, which lacks galactose and terminal sialic acid moieties.


Assuntos
Artrite Reumatoide , Imunoglobulina G , Fator de Necrose Tumoral alfa , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Glicosilação , Humanos , Imunoglobulina G/imunologia , Receptores Fc/imunologia , Espectrometria de Massas em Tandem , Fator de Necrose Tumoral alfa/imunologia
11.
Sci Rep ; 12(1): 8890, 2022 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-35614113

RESUMO

We assessed the feasibility of a highly sensitive immunoassay method based on single molecule array (Simoa) technology to detect IgG and IgA antibodies against SARS-CoV-2 spike protein receptor binding domain (RBD) in saliva from individuals with natural or vaccine-induced COVID-19 immunity. The performance of the method was compared to a laboratory-developed SARS-CoV-2 RBD total antibody enzyme-linked immunosorbent assay (ELISA). Paired serum and saliva specimens were collected from individuals (n = 40) prior to and 2 weeks after receiving an initial prime COVID-19 vaccine dose (Pfizer/BioNTech BNT162b2 or Moderna mRNA-1273). Saliva was collected using a commercially available collection device (OraSure Inc.) and SARS-CoV-2 RBD IgG antibodies were measured by an indirect ELISA using concentrated saliva samples and a Simoa immunoassay using unconcentrated saliva samples. The IgG results were compared with paired serum specimens that were analyzed for total RBD antibodies using the ELISA method. The analytical sensitivity of the saliva-based Simoa immunoassay was five orders of magnitude higher than the ELISA assay: 0.24 pg/mL compared to 15 ng/mL. The diagnostic sensitivity of the saliva ELISA method was 90% (95% CI 76.3-97.2%) compared to 91.7% (95% CI 77.5-98.2%) for the Simoa immunoassay without total IgG-normalization and 100% (95% CI 90.3-100%) for the Simoa immunoassay after total IgG-normalization when compared to the serum ELISA assay. When analyzed using the SARS-CoV-2 RBD IgG antibody ELISA, the average relative increase in antibody index (AI) between the saliva of the post- and pre-vaccinated individuals was 8.7 (AIpost/pre). An average relative increase of 431 pg/mL was observed when the unconcentrated saliva specimens were analyzed using the Simoa immunoassay (SARS-CoV-2 RBD IgGpost/pre). These findings support the suitability of concentrated saliva specimens for the measurement of SARS-CoV-2 RBD IgG antibodies via ELISA, and unconcentrated saliva specimens for the measurement of SARS-CoV-2 RBD IgG and IgA using an ultrasensitive Simoa immunoassay.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunoglobulina G , SARS-CoV-2 , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Vacina BNT162 , COVID-19/diagnóstico , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , Humanos , Imunoglobulina A/química , Imunoglobulina A/imunologia , Imunoglobulina G/química , Imunoglobulina G/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
12.
Cancer Immunol Res ; 10(7): 788-799, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35605261

RESUMO

We applied our computational algorithm TRUST4 to assemble immune receptor (T-cell receptor/B-cell receptor) repertoires from approximately 12,000 RNA sequencing samples from The Cancer Genome Atlas and seven immunotherapy studies. From over 35 million assembled complete complementary-determining region 3 sequences, we observed that the expression of CCL5 and MZB1 is the most positively correlated genes with T-cell clonal expansion and B-cell clonal expansion, respectively. We analyzed amino acid evolution during B-cell receptor somatic hypermutation and identified tyrosine as the preferred residue. We found that IgG1+IgG3 antibodies together with FcRn were associated with complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity or phagocytosis. In addition to B-cell infiltration, we discovered that B-cell clonal expansion and IgG1+IgG3 antibodies are also correlated with better patient outcomes. Finally, we created a website, VisualizIRR, for users to interactively explore and visualize the immune repertoires in this study. See related Spotlight by Liu and Han, p. 786.


Assuntos
Neoplasias , Receptores de Antígenos de Linfócitos T , Humanos , Imunoglobulina G/imunologia , Fatores Imunológicos , Imunoterapia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores Imunológicos/genética
13.
Proc Natl Acad Sci U S A ; 119(10): e2123002119, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35235456

RESUMO

Therapeutic human IgG antibodies are routinely tested in mouse models of oncologic, infectious, and autoimmune diseases. However, assessing the efficacy and safety of long-term administration of these agents has been limited by endogenous anti-human IgG immune responses that act to clear human IgG from serum and relevant tissues, thereby reducing their efficacy and contributing to immune complex­mediated pathologies, confounding evaluation of potential toxicity. For this reason, human antibody treatment in mice is generally limited in duration and dosing, thus failing to recapitulate the potential clinical applications of these therapeutics. Here, we report the development of a mouse model that is tolerant of chronic human antibody administration. This model combines both a human IgG1 heavy chain knock-in and a full recapitulation of human Fc receptor (FcγR) expression, providing a unique platform for in vivo testing of human monoclonal antibodies with relevant receptors beyond the short term. Compared to controls, hIgG1 knock-in mice mount minimal anti-human IgG responses, allowing for the persistence of therapeutically active circulating human IgG even in the late stages of treatment in chronic models of immune thrombocytopenic purpura and metastatic melanoma.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Imunoglobulina G/imunologia , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/toxicidade , Formação de Anticorpos/genética , Doença Crônica , Humanos , Tolerância Imunológica , Imunoglobulina G/administração & dosagem , Imunoglobulina G/genética , Cadeias Pesadas de Imunoglobulinas/genética , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Transgênicos , Modelos Animais , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/terapia
14.
Elife ; 112022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35289271

RESUMO

Preexisting antibodies to endemic coronaviruses (CoV) that cross-react with SARS-CoV-2 have the potential to influence the antibody response to COVID-19 vaccination and infection for better or worse. In this observational study of mucosal and systemic humoral immunity in acutely infected, convalescent, and vaccinated subjects, we tested for cross-reactivity against endemic CoV spike (S) protein at subdomain resolution. Elevated responses, particularly to the ß-CoV OC43, were observed in all natural infection cohorts tested and were correlated with the response to SARS-CoV-2. The kinetics of this response and isotypes involved suggest that infection boosts preexisting antibody lineages raised against prior endemic CoV exposure that cross-react. While further research is needed to discern whether this recalled response is desirable or detrimental, the boosted antibodies principally targeted the better-conserved S2 subdomain of the viral spike and were not associated with neutralization activity. In contrast, vaccination with a stabilized spike mRNA vaccine did not robustly boost cross-reactive antibodies, suggesting differing antigenicity and immunogenicity. In sum, this study provides evidence that antibodies targeting endemic CoV are robustly boosted in response to SARS-CoV-2 infection but not to vaccination with stabilized S, and that depending on conformation or other factors, the S2 subdomain of the spike protein triggers a rapidly recalled, IgG-dominated response that lacks neutralization activity.


Assuntos
Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Reações Cruzadas/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Especificidade de Anticorpos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Testes de Neutralização , Vacinação
15.
Fukushima J Med Sci ; 68(1): 67-70, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35228456

RESUMO

This study investigated the immune response and outcome of BNT162b2 vaccination among 12 staff at a hospital in Fukushima, Japan. Blood samples were collected from participants before their first vaccination, with subsequent sampling performed during the participants' work days for six weeks thereafter. Antibody titers peaked 6-13 days after the second vaccination (days 27-34 after the first), followed by a steady decrease. Six males had significantly lower peak antibody titers than six females (p = 0.016 with t-test); the older six (median age 53 years) had lower antibody titers than the younger six (median age 35 years) but without statistical significance (p value=0.24 with t-test).


Assuntos
Anticorpos Antivirais , Vacina BNT162 , COVID-19 , Imunoglobulina G , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Adulto , Anticorpos Antivirais/imunologia , Vacina BNT162/administração & dosagem , Vacina BNT162/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
16.
PLoS One ; 17(3): e0265016, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35298515

RESUMO

Serological databases represent an important source of information to perceive COVID-19 impact on health professionals involved in combating the disease. This paper describes SerumCovid, a COVID-19 serological database focused on the diagnosis of health professionals, providing a preliminary analysis to contribute to the understanding of the antibody response to the SARS-CoV-2. The study population comprises 321 samples from 236 healthcare and frontline workers fighting COVID-19 in Vitória de Santo Antão, Brazil. Samples were collected from at least six days of symptoms to more than 100 days. The used immunoenzymatic assays were Euroimmun Anti-SARS-CoV-2 ELISA IgG and IgA. The most common gender in SerumCovid is female, while the most common age group is between 30 and 39 years old. However, no statistical differences were observed in either genders or age categories. The most reported symptoms were fatigue, headaches, and myalgia. Still, some subjects presented positive results for IgA after 130 days. Based on a temporal analysis, we have not identified general patterns as subjects presented high and low values of IgA and IgG with different evolution trends. Unexpectedly, for subjects with both serological tests, the outcome of IgA and IgG tests were the same (either positive or negative) for more than 80% of the samples. Therefore, SerumCovid helps better understand how COVID-19 affected healthcare and frontline workers, which increases knowledge about the infection and enables direct prevention actions.


Assuntos
Teste Sorológico para COVID-19 , COVID-19/epidemiologia , Pessoal de Saúde/estatística & dados numéricos , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Brasil/epidemiologia , COVID-19/diagnóstico , COVID-19/imunologia , Teste Sorológico para COVID-19/métodos , Teste Sorológico para COVID-19/estatística & dados numéricos , Bases de Dados como Assunto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Adulto Jovem
17.
Sci Rep ; 12(1): 3351, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35233014

RESUMO

Severe acute respiratory coronavirus 2 (SARS-CoV-2) has spread globally since its emergence in 2019. Most SARS-CoV-2 infections generate immune responses leading to rising levels of immunoglobulins (Ig) M, A and G which can be detected using diagnostic tests including enzyme-linked immunosorbent assays (ELISA). Whilst implying previous SARS-CoV-2 infection, the detection of Ig by ELISA does not guarantee the presence of neutralising antibodies (NAb) that can prevent the virus infecting cells. Plaque reduction neutralisation tests (PRNT) detect NAb, but are not amenable to mass testing as they take several days and require use of SARS-CoV-2 in high biocontainment laboratories. We evaluated the ability of IgG and IgM ELISAs targeting SARS-CoV-2 spike subunit 1 receptor binding domain (S1-RBD), and spike subunit 2 (S2) and nucleocapsid protein (NP), at predicting the presence and magnitude of NAb determined by PRNT. IgG S2 + NP ELISA was 96.8% [95% CI 83.8-99.9] sensitive and 88.9% [95% CI 51.8-99.7] specific at predicting the presence of NAbs (PRNT80 > 1:40). IgG and IgM S1-RBD ELISAs correlated with PRNT titre, with higher ELISA results increasing the likelihood of a robust neutralising response. The IgM S1-RBD assay can be used as a rapid, high throughput test to approximate the magnitude of NAb titre.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Testes de Neutralização , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Idoso , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Cell Rep Med ; 3(2): 100528, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35233549

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused an ongoing global health crisis. Here, we present as a vaccine candidate synthetic SARS-CoV-2 spike (S) glycoprotein-coated lipid vesicles that resemble virus-like particles. Soluble S glycoprotein trimer stabilization by formaldehyde cross-linking introduces two major inter-protomer cross-links that keep all receptor-binding domains in the "down" conformation. Immunization of cynomolgus macaques with S coated onto lipid vesicles (S-LVs) induces high antibody titers with potent neutralizing activity against the vaccine strain, Alpha, Beta, and Gamma variants as well as T helper (Th)1 CD4+-biased T cell responses. Although anti-receptor-binding domain (RBD)-specific antibody responses are initially predominant, the third immunization boosts significant non-RBD antibody titers. Challenging vaccinated animals with SARS-CoV-2 shows a complete protection through sterilizing immunity, which correlates with the presence of nasopharyngeal anti-S immunoglobulin G (IgG) and IgA titers. Thus, the S-LV approach is an efficient and safe vaccine candidate based on a proven classical approach for further development and clinical testing.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação/métodos , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Chlorocebus aethiops , Modelos Animais de Doenças , Células HEK293 , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Lipossomos , Macaca fascicularis , Masculino , Pandemias/prevenção & controle , Células Th1/imunologia , Resultado do Tratamento , Vacinas de Partículas Semelhantes a Vírus/imunologia , Células Vero
19.
Epidemiol Infect ; 150: e39, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-35229710

RESUMO

Diphtheria is a potentially devastating disease whose epidemiology remains poorly described in many settings, including Madagascar. Diphtheria vaccination is delivered in combination with pertussis and tetanus antigens and coverage of this vaccine is often used as a core measure of health system functioning. However, coverage is challenging to estimate due to the difficulty in translating numbers of doses delivered into numbers of children effectively immunised. Serology provides an alternative lens onto immunisation, but is complicated by challenges in discriminating between natural and vaccine-derived seropositivity. Here, we leverage known features of the serological profile of diphtheria to bound expectations for vaccine coverage for diphtheria, and further refine these using serology for pertussis. We measured diphtheria antibody titres in 185 children aged 6-11 months and 362 children aged 8-15 years and analysed them with pertussis antibody titres previously measured for each individual. Levels of diphtheria seronegativity varied among age groups (18.9% of children aged 6-11 months old and 11.3% of children aged 8-15 years old were seronegative) and also among the districts. We also find surprisingly elevated levels of individuals seropositive to diphtheria but not pertussis in the 6-11 month old age group suggesting that vaccination coverage or efficacy of the pertussis component of the DTP vaccine remains low or that natural infection of diphtheria may be playing a significant role in seropositivity in Madagascar.


Assuntos
Anticorpos Antibacterianos/imunologia , Vacina contra Difteria, Tétano e Coqueluche/uso terapêutico , Difteria/prevenção & controle , Programas de Imunização , Imunoglobulina G/imunologia , Coqueluche/prevenção & controle , Adolescente , Bordetella pertussis/imunologia , Criança , Corynebacterium diphtheriae/imunologia , Difteria/epidemiologia , Difteria/imunologia , Feminino , Humanos , Lactente , Madagáscar/epidemiologia , Masculino , Estudos Soroepidemiológicos , Cobertura Vacinal , Coqueluche/epidemiologia , Coqueluche/imunologia
20.
PLoS One ; 17(3): e0265236, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35271669

RESUMO

OBJECTIVE: To determine the seroprevalence of the SARS Cov 2 infection among vaccine naive population in a rural district of South India post-second surge. METHODOLOGY: We conducted a cross-sectional study in the five villages of a randomly chosen sub-district in the Bangalore rural district. We did house to house surveys and recruited 831 vaccine naive adults in July 2021. We tested samples for the presence of antibodies (including IgG & IgM) to SARS CoV-2 using the Roche Elecsys SARS-CoV-2 -S assay that quantifies antibodies against the receptor-binding domain (RBD) of the spike (S) protein. RESULTS: We estimated an overall prevalence of 62.7% (95% CI: 59.3-66.0) and an age-and gender-adjusted seroprevalence of 44.9% (95% CI: 42.5-47.4). When adjusted for test performance, the seroprevalence was 74.64% (95% CI: 70.66-78.47). The case-to-undetected-infected ratio (CIR) was 1: 8.65 (95% CI 1:8.1-1:9.1), and the Infection Fatality Rate (IFR) was 16.27 per 100,00 infections as of 13 July 2021. A history of at least one symptom suggestive of COVID-19 or a positive COVID-19 test of self or a family member in the past were significantly associated with seropositivity. CONCLUSION: We report a high seroprevalence of COVID-19 infection despite the advantages of low population density and well-ventilated landscapes in rural areas. CIR and IFR were higher than the previous serosurvey conducted in the same population during the first surge. The thought of achieving herd immunity comes with relief. However, it's vital to put efforts into building population health and rural health infrastructure to avert future health catastrophes.


Assuntos
COVID-19/epidemiologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Adulto , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19 , Estudos Transversais , Feminino , Humanos , Imunoglobulina G/imunologia , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , RNA Viral/imunologia , População Rural , SARS-CoV-2/patogenicidade , Estudos Soroepidemiológicos
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