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2.
J Med Virol ; 93(12): 6813-6817, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: covidwho-1530183

RESUMO

Vaccination for SARS-CoV-2 is necessary to overcome coronavirus disease 2019 (COVID-19). However, the time-dependent vaccine-induced immune response is not well understood. This study aimed to investigate the dynamics of SARS-CoV-2 antispike immunoglobulin G (IgG) response. Medical staff participants who received two sequential doses of the BNT162b2 vaccination on days 0 and 21 were recruited prospectively from the Musashino Red Cross Hospital between March and May 2021. The quantitative antispike receptor-binding domain (RBD) IgG antibody responses were measured using the Abbott SARS-CoV-2 IgGII Quant assay (cut off ≥50 AU/ml). A total of 59 participants without past COVID-19 history were continuously tracked with serum samples. The median age was 41 (22-75) years, and 14 participants were male (23.7%). The median antispike RBD IgG and seropositivity rates were 0 (0-31.1) AU/ml, 0.3 (0-39.5) AU/ml, 529.1 (48.3-8711.4) AU/ml, 18,836.9 (742.2-57,260.4) AU/ml, and 0%, 0%, 98.3%, and 100% on days 0, 3, 14, and 28 after the first vaccination, respectively. The antispike RBD IgG levels were significantly increased after day 14 from vaccination (p < 0.001) The BNT162b2 vaccination led almost all participants to obtain serum antispike RBD IgG 14 days after the first dose.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Imunoglobulina G/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , COVID-19/virologia , Feminino , Humanos , Testes Imunológicos/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vacinação/métodos , Adulto Jovem
3.
J Gen Virol ; 102(11)2021 11.
Artigo em Inglês | MEDLINE | ID: covidwho-1522470

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide as a severe pandemic, and a significant portion of the infected population may remain asymptomatic. Given this, five surveys were carried out between May and September 2020 with a total of 3585 volunteers in the municipality of Foz do Iguaçu, State of Paraná, a triple border region between Brazil/Argentina/Paraguay. Five months after the first infection, volunteers were re-analysed for the production of IgG anti-Spike and anti-RBD-Spike, in addition to analyses of cellular immunity. Seroconversion rates ranged from 4.4 % to a peak of 37.21 % followed by a reduction in seroconversion to 21.1 % in September, indicating that 25 % of the population lost their circulating anti-SARS-CoV-2 antibodies 3 months after infection. Analyses after 5 months of infection showed that only 17.2 % of people still had anti-RBD-Spike antibodies, however, most volunteers had some degree of cellular immune response. The strategy of letting people become naturally infected with SARS-CoV-2 to achieve herd immunity is flawed, and the first contact with the virus may not generate enough immunogenic stimulus to prevent a possible second infection.


Assuntos
COVID-19/imunologia , Portador Sadio/imunologia , Imunidade Coletiva , SARS-CoV-2/imunologia , Anticorpos Antivirais/imunologia , Argentina/epidemiologia , Brasil/epidemiologia , COVID-19/epidemiologia , COVID-19/virologia , Portador Sadio/epidemiologia , Portador Sadio/virologia , Humanos , Imunidade Celular , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/imunologia
4.
Microbiol Spectr ; 9(2): e0135221, 2021 10 31.
Artigo em Inglês | MEDLINE | ID: covidwho-1526454

RESUMO

The emerging new lineages of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have marked a new phase of coronavirus disease 2019 (COVID-19). Understanding the recognition mechanisms of potent neutralizing monoclonal antibodies (NAbs) against the spike protein is pivotal for developing new vaccines and antibody drugs. Here, we isolated several monoclonal antibodies (MAbs) against the SARS-CoV-2 spike protein receptor-binding domain (S-RBD) from the B cell receptor repertoires of a SARS-CoV-2 convalescent. Among these MAbs, the antibody nCoV617 demonstrates the most potent neutralizing activity against authentic SARS-CoV-2 infection, as well as prophylactic and therapeutic efficacies against the human angiotensin-converting enzyme 2 (ACE2) transgenic mouse model in vivo. The crystal structure of S-RBD in complex with nCoV617 reveals that nCoV617 mainly binds to the back of the "ridge" of RBD and shares limited binding residues with ACE2. Under the background of the S-trimer model, it potentially binds to both "up" and "down" conformations of S-RBD. In vitro mutagenesis assays show that mutant residues found in the emerging new lineage B.1.1.7 of SARS-CoV-2 do not affect nCoV617 binding to the S-RBD. These results provide a new human-sourced neutralizing antibody against the S-RBD and assist vaccine development. IMPORTANCE COVID-19 is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The COVID-19 pandemic has posed a serious threat to global health and the economy, so it is necessary to find safe and effective antibody drugs and treatments. The receptor-binding domain (RBD) in the SARS-CoV-2 spike protein is responsible for binding to the angiotensin-converting enzyme 2 (ACE2) receptor. It contains a variety of dominant neutralizing epitopes and is an important antigen for the development of new coronavirus antibodies. The significance of our research lies in the determination of new epitopes, the discovery of antibodies against RBD, and the evaluation of the antibodies' neutralizing effect. The identified antibodies here may be drug candidates for the development of clinical interventions for SARS-CoV-2.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , COVID-19/terapia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , Sítios de Ligação/imunologia , Vacinas contra COVID-19/imunologia , Cristalografia por Raios X , Modelos Animais de Doenças , Feminino , Humanos , Imunização Passiva/métodos , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Domínios e Motivos de Interação entre Proteínas/imunologia , Carga Viral/efeitos dos fármacos
5.
Nat Med ; 27(10): 1744-1751, 2021 10.
Artigo em Inglês | MEDLINE | ID: covidwho-1526090

RESUMO

CoronaVac, an inactivated SARS-CoV-2 vaccine, has been approved for emergency use in several countries. However, its immunogenicity in immunocompromised individuals has not been well established. We initiated a prospective phase 4 controlled trial (no. NCT04754698, CoronavRheum) in 910 adults with autoimmune rheumatic diseases (ARD) and 182 age- and sex-frequency-matched healthy adults (control group, CG), who received two doses of CoronaVac. The primary outcomes were reduction of ≥15% in both anti-SARS-CoV-2 IgG seroconversion (SC) and neutralizing antibody (NAb) positivity 6 weeks (day 69 (D69)) after the second dose in the ARD group compared with that in the CG. Secondary outcomes were IgG SC and NAb positivity at D28, IgG titers and neutralizing activity at D28 and D69 and vaccine safety. Prespecified endpoints were met, with lower anti-SARS-Cov-2 IgG SC (70.4 versus 95.5%, P < 0.001) and NAb positivity (56.3 versus 79.3%, P < 0.001) at D69 in the ARD group than in the CG. Moreover, IgG titers (12.1 versus 29.7, P < 0.001) and median neutralization activity (58.7 versus 64.5%, P = 0.013) were also lower at D69 in patients with ARD. At D28, patients with ARD presented with lower IgG frequency (18.7 versus 34.6%, P < 0.001) and NAb positivity (20.6 versus 36.3%, P < 0.001) than that of the CG. There were no moderate/severe adverse events. These data support the use of CoronaVac in patients with ARD, suggesting reduced but acceptable short-term immunogenicity. The trial is still ongoing to evaluate the long-term effectiveness/immunogenicity.


Assuntos
Anticorpos Antivirais/biossíntese , Doenças Autoimunes/complicações , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Doenças Reumáticas/complicações , Adulto , Anticorpos Neutralizantes/biossíntese , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/complicações , COVID-19/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
Front Immunol ; 12: 754127, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1518487

RESUMO

COVID-19 presentations range from mild to moderate through severe disease but also manifest with persistent illness or viral recrudescence. We hypothesized that the spectrum of COVID-19 disease manifestations was a consequence of SARS-CoV-2-mediated delay in the pathogen-associated molecular pattern (PAMP) response, including dampened type I interferon signaling, thereby shifting the balance of the immune response to be dominated by damage-associated molecular pattern (DAMP) signaling. To test the hypothesis, we constructed a parsimonious mechanistic mathematical model. After calibration of the model for initial viral load and then by varying a few key parameters, we show that the core model generates four distinct viral load, immune response and associated disease trajectories termed "patient archetypes", whose temporal dynamics are reflected in clinical data from hospitalized COVID-19 patients. The model also accounts for responses to corticosteroid therapy and predicts that vaccine-induced neutralizing antibodies and cellular memory will be protective, including from severe COVID-19 disease. This generalizable modeling framework could be used to analyze protective and pathogenic immune responses to diverse viral infections.


Assuntos
Alarminas/imunologia , COVID-19 , Modelos Biológicos , SARS-CoV-2 , Corticosteroides/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19 , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Carga Viral
7.
Cell Rep ; 37(3): 109869, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: covidwho-1517084

RESUMO

The dramatically expanding coronavirus disease 2019 (COVID-19) needs multiple effective countermeasures. Neutralizing nanobodies (Nbs) are a potential therapeutic strategy for treating COVID-19. Here, we characterize several receptor binding domain (RBD)-specific Nbs isolated from an Nb library derived from an alpaca immunized with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S); among them, three Nbs exhibit picomolar potency against SARS-CoV-2 live virus, pseudotyped viruses, and circulating SARS-CoV-2 variants. To improve their efficacy, various configurations of Nbs are engineered. Nb15-NbH-Nb15, a trimer constituted of three Nbs, is constructed to be bispecific for human serum albumin (HSA) and RBD of SARS-CoV-2. Nb15-NbH-Nb15 exhibits single-digit ng/ml neutralization potency against the wild-type and Delta variants of SARS-CoV-2 with a long half-life in vivo. In addition, we show that intranasal administration of Nb15-NbH-Nb15 provides effective protection for both prophylactic and therapeutic purposes against SARS-CoV-2 infection in transgenic hACE2 mice. Nb15-NbH-Nb15 is a potential candidate for both the prevention and treatment of SARS-CoV-2 through respiratory administration.


Assuntos
Administração Intranasal , Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Biespecíficos/imunologia , COVID-19/imunologia , SARS-CoV-2 , Animais , Anticorpos Monoclonais/química , Anticorpos Neutralizantes , Anticorpos Antivirais/imunologia , Camelídeos Americanos , Epitopos/química , Feminino , Humanos , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Testes de Neutralização , Ligação Proteica , Domínios Proteicos , Engenharia de Proteínas/métodos , Albumina Sérica Humana/química , Anticorpos de Domínio Único , Glicoproteína da Espícula de Coronavírus/imunologia
8.
Cell Rep ; 37(3): 109838, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: covidwho-1517083

RESUMO

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads, variants with enhanced virulence and transmissibility have emerged. Although in vitro systems allow rapid characterization, they do not fully recapitulate the dynamic interaction of virions and neutralizing antibodies in the airway. Here, we demonstrate that the N501Y variant permits respiratory infection in unmodified mice. We utilize N501Y to survey in vivo pseudovirus infection dynamics and susceptibility to reinfection with the L452R (Los Angeles), K417N + E484K (South Africa), and L452R + K417N + E484Q (India) variants. Human coronavirus disease 2019 (COVID-19)+ or vaccinated antibody isotypes, titers, variant receptor binding domain (RBD) binding, and neutralization potential are studied, revealing numerous significant correlations. Immune escape of the K417N + E484K variant is observed because infection can be appreciated in the nasopharynx, but not lungs, of mice transferred with low-antibody-tier plasma. Conversely, near-complete protection is observed in animals receiving high-antibody-tier plasma, a phenomenon that can only be appreciated in vivo.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/terapia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Linhagem Celular , Cricetinae , Variação Genética , Células HEK293 , Humanos , Sistema Imunitário , Imunização Passiva/métodos , Técnicas In Vitro , Camundongos , Mutação , Nasofaringe/virologia , Ligação Proteica , Proteínas Recombinantes/metabolismo , Glicoproteína da Espícula de Coronavírus/genética
9.
Nat Commun ; 12(1): 6405, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: covidwho-1505001

RESUMO

The origin of SARS-CoV-2 variants of concern remains unclear. Here, we test whether intra-host virus evolution during persistent infections could be a contributing factor by characterizing the long-term SARS-CoV-2 infection dynamics in an immunosuppressed kidney transplant recipient. Applying RT-qPCR and next-generation sequencing (NGS) of sequential respiratory specimens, we identify several mutations in the viral genome late in infection. We demonstrate that a late viral isolate exhibiting genome mutations similar to those found in variants of concern first identified in UK, South Africa, and Brazil, can escape neutralization by COVID-19 antisera. Moreover, infection of susceptible mice with this patient's escape variant elicits protective immunity against re-infection with either the parental virus and the escape variant, as well as high neutralization titers against the alpha and beta SARS-CoV-2 variants, B.1.1.7 and B.1.351, demonstrating a considerable immune control against such variants of concern. Upon lowering immunosuppressive treatment, the patient generated spike-specific neutralizing antibodies and resolved the infection. Our results suggest that immunocompromised patients could be a source for the emergence of potentially harmful SARS-CoV-2 variants.


Assuntos
COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Genoma Viral , Humanos , Evasão da Resposta Imune , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Mutação , Testes de Neutralização , Filogenia , SARS-CoV-2/química , SARS-CoV-2/classificação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
10.
Emerg Microbes Infect ; 10(1): 365-375, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: covidwho-1490458

RESUMO

Concerns about vaccine safety are an important reason for vaccine hesitancy, however, limited information is available on whether common adverse reactions following vaccination affect the immune response. Data from three clinical trials of recombinant vaccines were used in this post hoc analysis to assess the correlation between inflammation-related solicited adverse reactions (ISARs, including local pain, redness, swelling or induration and systematic fever) and immune responses after vaccination. In the phase III trial of the bivalent HPV-16/18 vaccine (Cecolin®), the geometric mean concentrations (GMCs) for IgG anti-HPV-16 and -18 (P<0.001) were significantly higher in participants with any ISAR following vaccination than in those without an ISAR. Local pain, induration, swelling and systemic fever were significantly correlated with higher GMCs for IgG anti-HPV-16 and/or anti-HPV-18, respectively. Furthermore, the analyses of the immunogenicity bridging study of Cecolin® and the phase III trial of a hepatitis E vaccine yielded similar results. Based on these results, we built a scoring model to quantify the inflammation reactions and found that the high score of ISAR indicates the strong vaccine-induced antibody level. In conclusion, this study suggests inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.


Assuntos
Hepatite E/imunologia , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Vacinas Sintéticas/imunologia , Vacinas contra Hepatite Viral/imunologia , Adolescente , Adulto , Idoso , Anticorpos Antivirais/imunologia , Feminino , Hepatite E/prevenção & controle , Hepatite E/virologia , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Imunidade , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/genética , Vacinação/efeitos adversos , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas contra Hepatite Viral/administração & dosagem , Vacinas contra Hepatite Viral/efeitos adversos , Vacinas contra Hepatite Viral/genética , Adulto Jovem
11.
Front Immunol ; 12: 689065, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1502324

RESUMO

Coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The US FDA has approved several therapeutics and vaccines worldwide through the emergency use authorization in response to the rapid spread of COVID-19. Nevertheless, the efficacies of these treatments are being challenged by viral escape mutations. There is an urgent need to develop effective treatments protecting against SARS-CoV-2 infection and to establish a stable effect-screening model to test potential drugs. Polyclonal antibodies (pAbs) have an intrinsic advantage in such developments because they can target rapidly mutating viral strains as a result of the complexity of their binding epitopes. In this study, we generated anti-receptor-binding domain (anti-RBD) pAbs from rabbit serum and tested their safety and efficacy in response to SARS-CoV-2 infection both in vivo and ex vivo. Primary human bronchial epithelial two-dimensional (2-D) organoids were cultured and differentiated to a mature morphology and subsequently employed for SARS-CoV-2 infection and drug screening. The pAbs protected the airway organoids from viral infection and tissue damage. Potential side effects were tested in mouse models for both inhalation and vein injection. The pAbs displayed effective viral neutralization effects without significant side effects. Thus, the use of animal immune serum-derived pAbs might be a potential therapy for protection against SARS-CoV-2 infection, with the strategy developed to produce these pAbs providing new insight into the treatment of respiratory tract infections, especially for infections with viruses undergoing rapid mutation.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Antivirais/administração & dosagem , Sítios de Ligação , Brônquios/citologia , COVID-19/genética , COVID-19/terapia , Células Epiteliais , Perfilação da Expressão Gênica , Humanos , Imunização Passiva , Camundongos , Mutação , Testes de Neutralização , Organoides , Coelhos , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
12.
J Virol ; 95(14): e0040421, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: covidwho-1501539

RESUMO

Emerging SARS-CoV-2 variants of concern that overcome natural and vaccine-induced immunity threaten to exacerbate the COVID-19 pandemic. Increasing evidence suggests that neutralizing antibody (NAb) responses are a primary mechanism of protection against infection. However, little is known about the extent and mechanisms by which natural immunity acquired during the early COVID-19 pandemic confers cross-neutralization of emerging variants. In this study, we investigated cross-neutralization of the B.1.1.7 and B.1.351 SARS-CoV-2 variants in a well-characterized cohort of early pandemic convalescent subjects. We observed modestly decreased cross-neutralization of B.1.1.7 but a substantial 4.8-fold reduction in cross-neutralization of B.1.351. Correlates of cross-neutralization included receptor binding domain (RBD) and N-terminal domain (NTD) binding antibodies, homologous NAb titers, and membrane-directed T cell responses. These data shed light on the cross-neutralization of emerging variants by early pandemic convalescent immune responses. IMPORTANCE Widespread immunity to SARS-CoV-2 will be necessary to end the COVID-19 pandemic. NAb responses are a critical component of immunity that can be stimulated by natural infection as well as vaccines. However, SARS-CoV-2 variants are emerging that contain mutations in the spike gene that promote evasion from NAb responses. These variants may therefore delay control of the COVID-19 pandemic. We studied whether NAb responses from early COVID-19 convalescent patients are effective against the two SARS-CoV-2 variants, B.1.1.7 and B.1.351. We observed that the B.1.351 variant demonstrates significantly reduced susceptibility to early pandemic NAb responses. We additionally characterized virological, immunological, and clinical features that correlate with cross-neutralization. These studies increase our understanding of emerging SARS-CoV-2 variants.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/epidemiologia , COVID-19/imunologia , Pandemias , SARS-CoV-2/imunologia , Adulto , Reações Cruzadas , Humanos , Masculino
13.
Nat Commun ; 12(1): 6304, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: covidwho-1500462

RESUMO

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/química , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/química , Sítios de Ligação , COVID-19/patologia , COVID-19/virologia , Epitopos , Humanos , Camundongos , Camundongos Transgênicos , Mutação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Carga Viral/efeitos dos fármacos , Perda de Peso/efeitos dos fármacos
14.
Signal Transduct Target Ther ; 6(1): 378, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: covidwho-1500450

RESUMO

The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years. The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants. Here we show that the bivalency of an affinity maturated fully human single-domain antibody (n3113.1-Fc) exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus, and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2 (ACE2) humanized mice. The crystal structure of n3113 in complex with the receptor-binding domain (RBD) of SARS-CoV-2, combined with the cryo-EM structures of n3113 and spike ecto-domain, reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2. The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion, expanding our recognition of neutralization by antibodies against SARS-CoV-2. Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) for n3113.1-Fc with Y58L mutation, demonstrating the potential of n3113.1-Fc (Y58L) as a promising candidate for clinical development to treat COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/química , Anticorpos Neutralizantes/química , Anticorpos Antivirais/química , COVID-19 , SARS-CoV-2/química , Anticorpos de Cadeia Única/química , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Cristalografia por Raios X , Epitopos/química , Epitopos/imunologia , Humanos , Camundongos , SARS-CoV-2/imunologia , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/uso terapêutico
15.
Epidemiol Infect ; 149: e237, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: covidwho-1500393

RESUMO

The SARS-CoV-2 virus is rapidly evolving via mutagenesis, lengthening the pandemic, and threatening the public health. Until August 2021, 12 variants of SARS-CoV-2 named as variants of concern (VOC; Alpha to Delta) or variants of interest (VOI; Epsilon to Mu), with significant impact on transmissibility, morbidity, possible reinfection and mortality, have been identified. The VOC Delta (B.1.617.2) of Indian origin is now the dominant and the most contagious variant worldwide as it provokes a strong binding to the human ACE2 receptor, increases transmissibility and manifests considerable immune escape strategies after natural infection or vaccination. Although the development and administration of SARS-CoV-2 vaccines, based on different technologies (mRNA, adenovirus carrier, recombinant protein, etc.), are very promising for the control of the pandemic, their effectiveness and neutralizing activity against VOCs varies significantly. In this review, we describe the most significant circulating variants of SARS-CoV-2, and the known effectiveness of currently available vaccines against them.


Assuntos
Vacinas contra COVID-19/normas , COVID-19/prevenção & controle , SARS-CoV-2/genética , Anticorpos Neutralizantes , Anticorpos Antivirais/imunologia , Humanos , SARS-CoV-2/classificação , SARS-CoV-2/imunologia
16.
Dokl Biochem Biophys ; 496(1): 44-47, 2021 May.
Artigo em Inglês | MEDLINE | ID: covidwho-1495017

RESUMO

The high efficiency of using thermoheliox (inhalation with a high-temperature mixture of helium and oxygen) in the treatment of patients affected by COVID-19 was shown. The dynamics of accumulation of IgG, IgM, and C-reactive protein (CRP) in patients with coronavirus infection in the "working" and control groups was studied experimentally. It was shown that thermoheliox intensifies the synthesis of IgG, IgM, and CRP antibodies, while eliminating the induction period on the kinetic curves of the synthesis of specific antibodies in the IgG form and transfers the synthesis of CRP to a fast phase. The results of experiments confirm the previously obtained data based on the analysis of the kinetic model of the development of coronaviral infection in the human body.


Assuntos
Anticorpos Antivirais/imunologia , Proteína C-Reativa/biossíntese , COVID-19/metabolismo , COVID-19/prevenção & controle , Imunidade/imunologia , Vacinação/métodos , COVID-19/imunologia , Humanos , Cinética , Glicoproteína da Espícula de Coronavírus/imunologia
17.
Microbiol Spectr ; 9(2): e0141621, 2021 10 31.
Artigo em Inglês | MEDLINE | ID: covidwho-1495015

RESUMO

The rapid worldwide spread of SARS-CoV-2 has accelerated research and development for controlling the COVID-19 pandemic. A multi-coronavirus protein microarray was created containing full-length proteins, overlapping protein fragments of various lengths, and peptide libraries from SARS-CoV-2 and four other human coronaviruses. Sera from confirmed COVID-19 patients as well as unexposed individuals were applied to multicoronavirus arrays to identify specific antibody reactivity. High-level IgG, IgM, and IgA reactivity to structural proteins S, M, and N of SARS-CoV-2, as well as accessory proteins such as ORF3a and ORF7a, were observed that were specific to COVID-19 patients. Antibody reactivity against overlapping 100-, 50-, and 30-amino acid fragments of SARS-CoV-2 proteins was used to identify antigenic regions. Numerous proteins of SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), and the endemic human coronaviruses HCoV-NL63 and HCoV-OC43 were also more reactive with IgG, IgM, and IgA in COVID-19 patient sera than in unexposed control sera, providing further evidence of immunologic cross-reactivity between these viruses. Whereas unexposed individuals had minimal reactivity against SARS-CoV-2 proteins that poorly correlated with reactivity against HCoV-NL63 and HCoV-OC43 S2 and N proteins, COVID-19 patient sera had higher correlation between SARS-CoV-2 and HCoV responses, suggesting that de novo antibodies against SARS-CoV-2 cross-react with HCoV epitopes. Array responses were compared with validated spike protein-specific IgG enzyme-linked immunosorbent assays (ELISAs), showing agreement between orthologous methods. SARS-CoV-2 microneutralization titers were low in the COVID-19 patient sera but correlated with array responses against S and N proteins. The multi-coronavirus protein microarray is a useful tool for mapping antibody reactivity in COVID-19 patients. IMPORTANCE With novel mutant SARS-CoV-2 variants of concern on the rise, knowledge of immune specificities against SARS-CoV-2 proteins is increasingly important for understanding the impact of structural changes in antibody-reactive protein epitopes on naturally acquired and vaccine-induced immunity, as well as broader topics of cross-reactivity and viral evolution. A multi-coronavirus protein microarray used to map the binding of COVID-19 patient antibodies to SARS-CoV-2 proteins and protein fragments as well as to the proteins of four other coronaviruses that infect humans has shown specific regions of SARS-CoV-2 proteins that are highly reactive with patient antibodies and revealed cross-reactivity of these antibodies with other human coronaviruses. These data and the multi-coronavirus protein microarray tool will help guide further studies of the antibody response to COVID-19 and to vaccination against this worldwide pandemic.


Assuntos
Anticorpos Antivirais/imunologia , Coronavirus Humano NL63/imunologia , Coronavirus Humano OC43/imunologia , Epitopos/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , SARS-CoV-2/imunologia , Anticorpos Antivirais/sangue , Sítios de Ligação de Anticorpos/imunologia , COVID-19/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Reações Cruzadas/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Fosfoproteínas/imunologia , Análise Serial de Proteínas , Glicoproteína da Espícula de Coronavírus/imunologia , Proteínas Virais/imunologia , Proteínas Viroporinas/imunologia
20.
J Infect Dis ; 224(8): 1305-1315, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: covidwho-1493821

RESUMO

BACKGROUND: A notable feature of coronavirus disease 2019 (COVID-19) is that children are less susceptible to severe disease. Children are known to experience more infections with endemic human coronaviruses (HCoVs) compared to adults. Little is known whether HCoV infections lead to cross-reactive anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. METHODS: We investigated the presence of cross-reactive anti-SARS-CoV-2 IgG antibodies to spike 1 (S1), S1-receptor-binding domain (S1-RBD), and nucleocapsid protein (NP) by enzyme-linked immunosorbent assays, and neutralizing activity by a SARS-CoV-2 pseudotyped virus neutralization assay, in prepandemic sera collected from children (n = 50) and adults (n = 45), and compared with serum samples from convalescent COVID-19 patients (n = 16). RESULTS: A significant proportion of children (up to 40%) had detectable cross-reactive antibodies to SARS-CoV-2 S1, S1-RBD, and NP antigens, and the anti-S1 and anti-S1-RBD antibody levels correlated with anti-HCoV-HKU1 and anti-HCoV-OC43 S1 antibody titers in prepandemic samples (P < .001). There were marked increases of anti-HCoV-HKU1 and - OC43 S1 (but not anti-NL63 and -229E S1-RBD) antibody titers in serum samples from convalescent COVID-19 patients (P < .001), indicating an activation of cross-reactive immunological memory to ß-coronavirus spike. CONCLUSIONS: We demonstrated cross-reactive anti-SARS-CoV-2 antibodies in prepandemic serum samples from children and young adults. Promoting this cross-reactive immunity and memory response derived from common HCoV may be an effective strategy against SARS-COV-2 and future novel coronaviruses.


Assuntos
Anticorpos Antivirais/sangue , COVID-19/imunologia , Imunoglobulina G/sangue , SARS-CoV-2/imunologia , Adolescente , Adulto , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/virologia , Criança , Pré-Escolar , Convalescença , Coronavirus Humano 229E/imunologia , Proteínas do Envelope de Coronavírus/imunologia , Coronavirus Humano OC43/imunologia , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática , Feminino , Células HEK293 , Humanos , Imunoglobulina G/imunologia , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto Jovem
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