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1.
Front Immunol ; 12: 629185, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833755

RESUMO

The WHO declared the COVID-19 outbreak a public health emergency of international concern. The causative agent of this acute respiratory disease is a newly emerged coronavirus, named SARS-CoV-2, which originated in China in late 2019. Exposure to SARS-CoV-2 leads to multifaceted disease outcomes from asymptomatic infection to severe pneumonia, acute respiratory distress and potentially death. Understanding the host immune response is crucial for the development of interventional strategies. Humoral responses play an important role in defending viral infections and are therefore of particular interest. With the aim to resolve SARS-CoV-2-specific humoral immune responses at the epitope level, we screened clinically well-characterized sera from COVID-19 patients with mild and severe disease outcome using high-density peptide microarrays covering the entire proteome of SARS-CoV-2. Moreover, we determined the longevity of epitope-specific antibody responses in a longitudinal approach. Here we present IgG and IgA-specific epitope signatures from COVID-19 patients, which may serve as discriminating prognostic or predictive markers for disease outcome and/or could be relevant for intervention strategies.


Assuntos
/imunologia , Epitopos/imunologia , Proteoma/imunologia , /imunologia , Adulto , Anticorpos Antivirais/imunologia , Feminino , Humanos , Imunidade Humoral , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Masculino
2.
Nat Commun ; 12(1): 2037, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795692

RESUMO

The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.


Assuntos
Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , /imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , /imunologia , Criança , Pré-Escolar , Reações Cruzadas/imunologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Pessoa de Meia-Idade , Receptores de IgG/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto Jovem
3.
Viruses ; 13(4)2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807151

RESUMO

The renal involvement of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported. The etiology of kidney injury appears to be tubular, mainly due to the expression of angiotensin-converting enzyme 2, the key joint receptor for SARS-CoV-2; however, cases with glomerular implication have also been documented. The multifactorial origin of this renal involvement could include virus-mediated injury, cytokine storm, angiotensin II pathway activation, complement dysregulation, hyper-coagulation, and microangiopathy. We present the renal histological findings from a patient who developed acute kidney injury and de novo nephrotic syndrome, highly suggestive of acute IgA-dominant infection-associated glomerulonephritis (IgA-DIAGN) after SARS-CoV-2 infection, as evidenced by the presence of this virus detected in the renal tissue of the patient via immunohistochemistry assay. In summary, we document the first case of IgA-DIAGN associated to SARS-CoV-2. Thus, SARS-CoV-2 S may act as a super antigen driving the development of multisystem inflammatory syndrome as well as cytokine storm in patients affected by COVID-19, reaching the glomerulus and leading to the development of this novel IgA-DIAGN.


Assuntos
/complicações , Glomerulonefrite/etiologia , Glomerulonefrite/imunologia , Imunoglobulina A/imunologia , Idoso de 80 Anos ou mais , Síndrome da Liberação de Citocina , Humanos , Rim/imunologia , Masculino , /fisiologia
4.
PLoS One ; 16(3): e0245424, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33760825

RESUMO

SARS-CoV-2 (Severe Acute Respiratory Syndrome Corona Virus-2), cause of COVID-19 (Coronavirus Disease of 2019), represents a significant risk to people living with pre-existing conditions associated with exacerbated inflammatory responses and consequent dysfunctional immunity. In this paper, we have evaluated the influence of obesity, a condition associated with chronic systemic inflammation, on the secretion of SARS-CoV-2-specific IgG antibodies in the blood of COVID-19 patients. Our hypothesis is that obesity is associated with reduced amounts of specific IgG antibodies. Results have confirmed our hypothesis and have shown that SARS-CoV-2 IgG antibodies are negatively associated with Body Mass Index (BMI) in COVID-19 obese patients, as expected based on the known influence of obesity on humoral immunity. Antibodies in COVID-19 obese patients are also negatively associated with serum levels of pro-inflammatory and metabolic markers of inflammaging and pulmonary inflammation, such as SAA (serum amyloid A protein), CRP (C-reactive protein), and ferritin, but positively associated with NEFA (nonesterified fatty acids). These results altogether could help to identify an inflammatory signature with strong predictive value for immune dysfunction. Inflammatory markers identified may subsequently be targeted to improve humoral immunity in individuals with obesity and in individuals with other chronic inflammatory conditions.


Assuntos
Anticorpos Antivirais/imunologia , Obesidade/virologia , Adulto , Idoso , Anticorpos/sangue , Anticorpos/imunologia , Anticorpos Antivirais/sangue , Biomarcadores/sangue , Índice de Massa Corporal , /epidemiologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Imunidade Humoral/imunologia , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , /patogenicidade
5.
Front Immunol ; 12: 632814, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763078

RESUMO

Increasing evidence suggests that dysregulated immune responses are associated with the clinical outcome of coronavirus disease 2019 (COVID-19). Nucleocapsid protein (NP)-, spike (S)-, receptor binding domain (RBD)- specific immunoglobulin (Ig) isotypes, IgG subclasses and neutralizing antibody (NAb) were analyzed in 123 serum from 63 hospitalized patients with severe, moderate, mild or asymptomatic COVID-19. Mild to modest correlations were found between disease severity and antigen specific IgG subclasses in serum, of which IgG1 and IgG3 were negatively associated with viral load in nasopharyngeal swab. Multiple cytokines were significantly related with antigen-specific Ig isotypes and IgG subclasses, and IL-1ß was positively correlated with most antibodies. Furthermore, the old patients (≥ 60 years old) had higher levels of chemokines, increased NAb activities and SARS-CoV-2 specific IgG1, and IgG3 responses and compromised T cell responses compared to the young patients (≤ 18 years old), which are related with more severe cases. Higher IgG1 and IgG3 were found in COVID-19 patients with comorbidities while biological sex had no effect on IgG subclasses. Overall, we have identified diseases severity was related to higher antibodies, of which IgG subclasses had weakly negative correlation with viral load, and cytokines were significantly associated with antibody response. Further, advancing age and comorbidities had obvious effect on IgG1 and IgG3.


Assuntos
Anticorpos Antivirais/imunologia , Imunoglobulina G/imunologia , /fisiologia , Adolescente , Adulto , /virologia , Criança , China , Citocinas/imunologia , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Linfócitos T/imunologia , Adulto Jovem
6.
Nat Commun ; 12(1): 1961, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785765

RESUMO

The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-ß, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-ß. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-ß, and is distracted from itself.


Assuntos
Anticorpos Antivirais/imunologia , /imunologia , Fator de Crescimento Transformador beta/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
7.
Virol J ; 18(1): 54, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33706767

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic remains ongoing around the world, including in areas where dengue is endemic. Dengue and COVID-19, to some extent, have similar clinical and laboratory features, which can lead to misdiagnosis, delayed treatment and patient's isolation. The use of rapid diagnostic tests (RDT) is easy and convenient for fast diagnosis, however there may be issues with cross-reactivity with antibodies for other pathogens. METHODS: We assessed the possibility of cross-reactivity between SARS-CoV-2 and dengue antibodies by: (1) testing five brands of COVID-19 IgG / IgM RDTs on 60 RT-PCR-confirmed dengue samples; (2) testing 95 RT-PCR-confirmed COVID-19 samples on dengue RDT; and (3) testing samples positive for COVID-19 IgG and/or IgM on dengue RDT. RESULTS: We observed a high specificity across all five brands of COVID-19 RDTs, ranging from 98.3 to 100%. Out of the confirmed COVID-19 samples, one patient tested positive for dengue IgM only, another tested positive for dengue IgG only. One patient tested positive for dengue IgG, IgM, and NS1, suggesting a co-infection. In COVID-19 IgG and/or IgM samples, 6.3% of COVID-19 IgG-positive samples also tested positive for dengue IgG, while 21.1% of COVID-19 IgM-positive samples also tested positive for dengue IgG. CONCLUSION: Despite the high specificity of the COVID-19 RDT, we observed cross-reactions and false-positive results between dengue and COVID-19. Dengue and COVID-19 co-infection was also found. Health practitioners in dengue endemic areas should be careful when using antibody RDT for the diagnosis of dengue during the COVID-19 pandemic to avoid misdiagnosis.


Assuntos
Anticorpos Antivirais/imunologia , Reações Cruzadas/imunologia , Vírus da Dengue/imunologia , Dengue/diagnóstico , /imunologia , Adolescente , Adulto , Criança , Diagnóstico Diferencial , Testes Diagnósticos de Rotina , Reações Falso-Positivas , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Indonésia , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Proteínas não Estruturais Virais/imunologia , Adulto Jovem
9.
PLoS One ; 16(2): e0247665, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33621254

RESUMO

BACKGROUND: The novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread across the world. The aim of our study was to characterize mild courses and to determine the antibody status for these patients. METHODS: We initiated an appeal for convalescent plasma donations. 615 people contacted us, and we ultimately included 426 in our analyses, in whom it was possible to assume COVID-19 based on detection of specific SARS-CoV-2 antibodies or virus detection during the disease using RT-PCR. RESULTS: The median duration of the disease was 12 days and the most common symptoms were fatigue, cough and olfactory and gustatory dysfunction. Anti-SARS-CoV-2 IgG was detected in 82.4% of the persons and IgA antibodies were found in 73.9%. In 10.8%, no antibodies were detectable despite a positive RT-PCR result during the disease. Nevertheless, of 24 persons with asymptomatic courses of COVID-19, antibodies against SARS-CoV-2 could be detected in 23 (96%). Furthermore, there was a correlation between the duration of the disease and the detection of IgG antibodies. In addition, a correlation between the determined IgG antibodies and neutralizing antibodies was shown. CONCLUSION: In this study, we were able to describe mild COVID-19 courses and determine antibody statuses for them. It could be shown that, despite SARS-CoV-2 detection during the disease, not all individuals developed antibodies or their level of antibodies had dropped below the detection limit shortly after the end of the disease. The extent to which immunity to re-infection is given in persons with undetectable antibodies (IgG, IgA) needs to be investigated in future studies.


Assuntos
Anticorpos Antivirais/imunologia , /imunologia , Adulto , Anticorpos Neutralizantes/imunologia , Feminino , Humanos , Imunização Passiva , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
Nat Commun ; 12(1): 1221, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33619281

RESUMO

Hospitalized COVID-19 patients often present with a large spectrum of clinical symptoms. There is a critical need to better understand the immune responses to SARS-CoV-2 that lead to either resolution or exacerbation of the clinical disease. Here, we examine longitudinal plasma samples from hospitalized COVID-19 patients with differential clinical outcome. We perform immune-repertoire analysis including cytokine, hACE2-receptor inhibition, neutralization titers, antibody epitope repertoire, antibody kinetics, antibody isotype and antibody affinity maturation against the SARS-CoV-2 prefusion spike protein. Fatal cases demonstrate high plasma levels of IL-6, IL-8, TNFα, and MCP-1, and sustained high percentage of IgA-binding antibodies to prefusion spike compared with non-ICU survivors. Disease resolution in non-ICU and ICU patients associates with antibody binding to the receptor binding motif and fusion peptide, and antibody affinity maturation to SARS-CoV-2 prefusion spike protein. Here, we provide insight into the immune parameters associated with clinical disease severity and disease-resolution outcome in hospitalized patients that could inform development of vaccine/therapeutics against COVID-19.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Afinidade de Anticorpos/imunologia , Imunoglobulina A/imunologia , /imunologia , Adulto , Idoso , /metabolismo , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , /virologia , Estudos de Coortes , Citocinas/sangue , Citocinas/imunologia , Citocinas/metabolismo , Epitopos/imunologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Imunoglobulina A/sangue , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , /fisiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Ressonância de Plasmônio de Superfície
11.
Cell Rep ; 34(9): 108790, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33596407

RESUMO

Characterization of the humoral response to SARS-CoV-2, the etiological agent of COVID-19, is essential to help control the infection. The neutralization activity of plasma from patients with COVID-19 decreases rapidly during the first weeks after recovery. However, the specific role of each immunoglobulin isotype in the overall neutralizing capacity is still not well understood. In this study, we select plasma from a cohort of convalescent patients with COVID-19 and selectively deplete immunoglobulin A, M, or G before testing the remaining neutralizing capacity of the depleted plasma. We find that depletion of immunoglobulin M is associated with the most substantial loss of virus neutralization, followed by immunoglobulin G. This observation may help design efficient antibody-based COVID-19 therapies and may also explain the increased susceptibility to SARS-CoV-2 of autoimmune patients receiving therapies that impair the production of immunoglobulin M (IgM).


Assuntos
/terapia , Imunoglobulina M/imunologia , Imunoglobulina M/uso terapêutico , /imunologia , Adulto , Idoso , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , /imunologia , Canadá/epidemiologia , Estudos de Coortes , Feminino , Humanos , Imunidade Humoral/imunologia , Imunização Passiva/métodos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto Jovem
12.
Nat Commun ; 12(1): 844, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558507

RESUMO

There are only few data concerning persistence of neutralizing antibodies (NAbs) among SARS-CoV-2-infected healthcare workers (HCW). These individuals are particularly exposed to SARS-CoV-2 infection and at potential risk of reinfection. We followed 26 HCW with mild COVID-19 three weeks (D21), two months (M2) and three months (M3) after the onset of symptoms. All the HCW had anti-receptor binding domain (RBD) IgA at D21, decreasing to 38.5% at M3 (p < 0.0001). Concomitantly a significant decrease in NAb titers was observed between D21 and M2 (p = 0.03) and between D21 and M3 (p < 0.0001). Here, we report that SARS-CoV-2 can elicit a NAb response correlated with anti-RBD antibody levels. However, this neutralizing activity declines, and may even be lost, in association with a decrease in systemic IgA antibody levels, from two months after disease onset. This short-lasting humoral protection supports strong recommendations to maintain infection prevention and control measures in HCW, and suggests that periodic boosts of SARS-CoV-2 vaccination may be required.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Pessoal de Saúde/estatística & dados numéricos , /imunologia , Adulto , Sítios de Ligação/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Imunoglobulina A/imunologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Fatores de Tempo
14.
Int J Mol Sci ; 22(3)2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33503874

RESUMO

Several studies highlighted that obesity and diabetes reduce immune function. However, changes in the distribution of immunoglobins (Igs), including immunoglobulin-A (IgA), that have an important function in mucosal immunity in the intestinal tract, are unclear. This study aimed to investigate the impaired immune functions in the context of a diet-induced obese murine model via the assessment of the Igs in the intestinal villi. We used mice fed a high-fat diet (HFD) from four to 12 or 20 weeks of age. The distributions of IgA, IgM, and IgG1 were observed by immunohistochemistry. Interestingly, we observed that IgA was immunolocalized in many cells of the lamina propria and that immunopositive cells increased in mice aged 12 to 20 weeks. Notably, mice fed HFD showed a reduced number of IgA-immunopositive cells in the intestinal villi compared to those fed standard chow. Of note, the levels of IgM and IgG1 were also reduced in HFD fed mice. These results provide insights into the impaired mucosal immune function arising from diet-induced obesity and type 2 diabetes.


Assuntos
Dieta Hiperlipídica , Imunidade nas Mucosas , Imunoglobulina A/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Fatores Etários , Animais , Glicemia , Peso Corporal , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Camundongos , Obesidade/etiologia , Obesidade/metabolismo
15.
Microbiome ; 9(1): 33, 2021 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-33516266

RESUMO

BACKGROUND: Identifying which taxa are targeted by immunoglobulins can uncover important host-microbe interactions. Immunoglobulin binding of commensal taxa can be assayed by sorting bound bacteria from samples and using amplicon sequencing to determine their taxonomy, a technique most widely applied to study Immunoglobulin A (IgA-Seq). Previous experiments have scored taxon binding in IgA-Seq datasets by comparing abundances in the IgA bound and unbound sorted fractions. However, as these are relative abundances, such scores are influenced by the levels of the other taxa present and represent an abstract combination of these effects. Diversity in the practical approaches of prior studies also warrants benchmarking of the individual stages involved. Here, we provide a detailed description of the design strategy for an optimised IgA-Seq protocol. Combined with a novel scoring method for IgA-Seq datasets that accounts for the aforementioned effects, this platform enables accurate identification and quantification of commensal gut microbiota targeted by host immunoglobulins. RESULTS: Using germ-free and Rag1-/- mice as negative controls, and a strain-specific IgA antibody as a positive control, we determine optimal reagents and fluorescence-activated cell sorting (FACS) parameters for IgA-Seq. Using simulated IgA-Seq data, we show that existing IgA-Seq scoring methods are influenced by pre-sort relative abundances. This has consequences for the interpretation of case-control studies where there are inherent differences in microbiota composition between groups. We show that these effects can be addressed using a novel scoring approach based on posterior probabilities. Finally, we demonstrate the utility of both the IgA-Seq protocol and probability-based scores by examining both novel and published data from in vivo disease models. CONCLUSIONS: We provide a detailed IgA-Seq protocol to accurately isolate IgA-bound taxa from intestinal samples. Using simulated and experimental data, we demonstrate novel probability-based scores that adjust for the compositional nature of relative abundance data to accurately quantify taxon-level IgA binding. All scoring approaches are made available in the IgAScores R package. These methods should improve the generation and interpretation of IgA-Seq datasets and could be applied to study other immunoglobulins and sample types. Video abstract.


Assuntos
Microbioma Gastrointestinal/imunologia , Imunoglobulina A/imunologia , Simbiose , Animais , Bactérias/genética , Bactérias/imunologia , Bactérias/isolamento & purificação , Conjuntos de Dados como Assunto , Feminino , Microbioma Gastrointestinal/genética , Intestinos/imunologia , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
16.
Nature ; 591(7851): 639-644, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33461210

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models1,2. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.


Assuntos
Anticorpos Antivirais/imunologia , Imunidade Humoral/imunologia , /imunologia , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/genética , Antígenos Virais/química , Antígenos Virais/genética , Antígenos Virais/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Biópsia , Estudos de Coortes , Imunofluorescência , Humanos , Imunidade Humoral/genética , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Memória Imunológica/imunologia , Intestinos/imunologia , Pessoa de Meia-Idade , Mutação , Hipermutação Somática de Imunoglobulina , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Fatores de Tempo , Adulto Jovem
17.
Cell Host Microbe ; 29(2): 236-249.e6, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33357418

RESUMO

To develop a vaccine candidate against coronavirus disease 2019 (COVID-19), we generated a lentiviral vector (LV) eliciting neutralizing antibodies against the Spike glycoprotein of SARS-CoV-2. Systemic vaccination by this vector in mice, in which the expression of the SARS-CoV-2 receptor hACE2 has been induced by transduction of respiratory tract cells by an adenoviral vector, confers only partial protection despite high levels of serum neutralizing activity. However, eliciting an immune response in the respiratory tract through an intranasal boost results in a >3 log10 decrease in the lung viral loads and reduces local inflammation. Moreover, both integrative and non-integrative LV platforms display strong vaccine efficacy and inhibit lung deleterious injury in golden hamsters, which are naturally permissive to SARS-CoV-2 replication and closely mirror human COVID-19 physiopathology. Our results provide evidence of marked prophylactic effects of LV-based vaccination against SARS-CoV-2 and designate intranasal immunization as a powerful approach against COVID-19.


Assuntos
Administração Intranasal/métodos , /imunologia , /imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Cricetinae , Feminino , Vetores Genéticos , Imunidade nas Mucosas , Imunização Secundária , Imunoglobulina A/imunologia , Lentivirus/genética , Lentivirus/imunologia , Masculino , Camundongos , Modelos Animais , Sistema Respiratório/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Carga Viral
18.
Nat Med ; 27(2): 270-278, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33335323

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed1. Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses2 and might reduce the potential for disease enhancement3. Cytotoxic T cells clear virus-infected host cells and contribute to control of infection4. Studies of patients infected with SARS-CoV-2 have suggested a protective role for both humoral and cell-mediated immune responses in recovery from COVID-19 (refs. 5,6). ChAdOx1 nCoV-19 (AZD1222) is a candidate SARS-CoV-2 vaccine comprising a replication-deficient simian adenovirus expressing full-length SARS-CoV-2 spike protein. We recently reported preliminary safety and immunogenicity data from a phase 1/2 trial of the ChAdOx1 nCoV-19 vaccine (NCT04400838)7 given as either a one- or two-dose regimen. The vaccine was tolerated, with induction of neutralizing antibodies and antigen-specific T cells against the SARS-CoV-2 spike protein. Here we describe, in detail, exploratory analyses of the immune responses in adults, aged 18-55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1 nCoV-19 in this trial, demonstrating an induction of a Th1-biased response characterized by interferon-γ and tumor necrosis factor-α cytokine secretion by CD4+ T cells and antibody production predominantly of IgG1 and IgG3 subclasses. CD8+ T cells, of monofunctional, polyfunctional and cytotoxic phenotypes, were also induced. Taken together, these results suggest a favorable immune profile induced by ChAdOx1 nCoV-19 vaccine, supporting the progression of this vaccine candidate to ongoing phase 2/3 trials to assess vaccine efficacy.


Assuntos
Formação de Anticorpos/imunologia , Linfócitos T/imunologia , Adolescente , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , /virologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunidade Celular , Imunidade Humoral , Imunoglobulina A/imunologia , Imunoglobulina M/imunologia , Interferon gama/metabolismo , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Subunidades Proteicas/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Adulto Jovem
19.
Front Immunol ; 11: 611337, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329607

RESUMO

The mucosal immune system is the largest component of the entire immune system, having evolved to provide protection at the main sites of infectious threat: the mucosae. As SARS-CoV-2 initially infects the upper respiratory tract, its first interactions with the immune system must occur predominantly at the respiratory mucosal surfaces, during both inductive and effector phases of the response. However, almost all studies of the immune response in COVID-19 have focused exclusively on serum antibodies and systemic cell-mediated immunity including innate responses. This article proposes that there is a significant role for mucosal immunity and for secretory as well as circulating IgA antibodies in COVID-19, and that it is important to elucidate this in order to comprehend especially the asymptomatic and mild states of the infection, which appear to account for the majority of cases. Moreover, it is possible that mucosal immunity can be exploited for beneficial diagnostic, therapeutic, or prophylactic purposes.


Assuntos
Anticorpos Antivirais/imunologia , Imunidade nas Mucosas , Imunoglobulina A/imunologia , /imunologia , /diagnóstico , /patologia , Humanos
20.
PLoS Pathog ; 16(12): e1009103, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33315937

RESUMO

The antibody molecule comprises a variable domain conferring antigen specificity and affinity distinct from the heavy chain constant (CH) domains dictating effector functions. We here interrogate this paradigm by evaluating the unique influence of the CH1α domain on epitope specificity and functions using two mucosal gp41-specific Fab-IgAs (FabA) derived from HIV-1 highly-exposed but persistently seronegative individuals (HESN). These HESN develop selectively affinity-matured HIV-1-specific mucosal IgA that target the gp41 viral envelope and might provide protection although by unclear mechanisms. Isotype-switching FabAs into Fab-IgGs (FabGs) results in a >10-fold loss in affinity for HIV-1 clade A, B, and C gp41, together with reduced neutralization of HIV-1 cross-clade. The FabA conformational epitopes map selectively on gp41 in 6-Helix bundle and pre-fusion conformations cross-clade, unlike FabGs. Finally, we designed in silico, a 12 amino-acid peptide recapitulating one FabA conformational epitope that inhibits the FabA binding to gp41 cross-clade and its neutralizing activity. Altogether, our results reveal that the CH1α domain shapes the antibody paratope through an allosteric effect, thereby strengthening the antibody specificity and functional activities. Further, they clarify the mechanisms by which these HESN IgAs might confer protection against HIV-1-sexual acquisition. The IgA-specific epitope we characterized by reverse vaccinology could help designing a mucosal HIV-1 vaccine.


Assuntos
Especificidade de Anticorpos/imunologia , Sítios de Ligação de Anticorpos/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Imunoglobulina A/imunologia , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Proteína gp41 do Envelope de HIV/imunologia , Soronegatividade para HIV/imunologia , Humanos , Imunoglobulina A/química , Imunoglobulina G/imunologia , Domínios Proteicos/imunologia
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