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1.
J Hematol Oncol ; 15(1): 3, 2022 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-35000597

RESUMO

BACKGROUND: Immune suppression is a clinical feature of chronic lymphocytic leukaemia (CLL), and patients show increased vulnerability to SARS-CoV-2 infection and suboptimal antibody responses. METHOD: We studied antibody responses in 500 patients following dual COVID-19 vaccination to assess the magnitude, correlates of response, stability and functional activity of the spike-specific antibody response with two different vaccine platforms. RESULTS: Spike-specific seroconversion post-vaccine was seen in 67% of patients compared to 100% of age-matched controls. Amongst responders, titres were 3.7 times lower than the control group. Antibody responses showed a 33% fall over the next 4 months. The use of an mRNA (n = 204) or adenovirus-based (n = 296) vaccine platform did not impact on antibody response. Male gender, BTKi therapy, prophylactic antibiotics use and low serum IgA/IgM were predictive of failure to respond. Antibody responses after CD20-targeted immunotherapy recovered 12 months post treatment. Post-vaccine sera from CLL patients with Spike-specific antibody response showed markedly reduced neutralisation of the SARS-CoV-2 delta variant compared to healthy controls. Patients with previous natural SARS-CoV-2 infection showed equivalent antibody levels and function as healthy donors after vaccination. CONCLUSIONS: These findings demonstrate impaired antibody responses following dual COVID-19 vaccination in patients with CLL and further define patient risk groups. Furthermore, humoural protection against the globally dominant delta variant is markedly impaired in CLL patients and indicates the need for further optimisation of immune protection in this patient cohort.


Assuntos
Anticorpos Neutralizantes/imunologia , Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , Leucemia Linfocítica Crônica de Células B/complicações , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Formação de Anticorpos , COVID-19/complicações , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , Feminino , Células HEK293 , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Pessoa de Meia-Idade
2.
J Exp Med ; 219(2)2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35015026

RESUMO

Inflammatory monocytes are key mediators of acute and chronic inflammation; yet, their functional diversity remains obscure. Single-cell transcriptome analyses of human inflammatory monocytes from COVID-19 and rheumatoid arthritis patients revealed a subset of cells positive for CD127, an IL-7 receptor subunit, and such positivity rendered otherwise inert monocytes responsive to IL-7. Active IL-7 signaling engaged epigenetically coupled, STAT5-coordinated transcriptional programs to restrain inflammatory gene expression, resulting in inverse correlation between CD127 expression and inflammatory phenotypes in a seemingly homogeneous monocyte population. In COVID-19 and rheumatoid arthritis, CD127 marked a subset of monocytes/macrophages that retained hypoinflammatory phenotypes within the highly inflammatory tissue environments. Furthermore, generation of an integrated expression atlas revealed unified features of human inflammatory monocytes across different diseases and different tissues, exemplified by those of the CD127high subset. Overall, we phenotypically and molecularly characterized CD127-imprinted functional heterogeneity of human inflammatory monocytes with direct relevance for inflammatory diseases.


Assuntos
Artrite Reumatoide/imunologia , COVID-19/imunologia , Epigênese Genética/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Monócitos/imunologia , SARS-CoV-2/imunologia , Feminino , Humanos , Inflamação/imunologia , Interleucina-7/imunologia , Masculino
3.
BMC Pregnancy Childbirth ; 22(1): 33, 2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35030996

RESUMO

BACKGROUND: COVID-19 vaccines are advised for pregnant women in the United Kingdom (UK) however COVID-19 vaccine uptake among pregnant women is inadequate. METHODS: An online survey and semi-structured interviews were used to investigate pregnant women's views on COVID-19 vaccine acceptability for themselves when pregnant, not pregnant and for their babies. One thousand one hundred eighty-one women, aged over 16 years, who had been pregnant since 23rd March 2020, were surveyed between 3rd August-11th October 2020. Ten women were interviewed. RESULTS: The majority of women surveyed (81.2%) reported that they would 'definitely' or were 'leaning towards' accepting a COVID-19 vaccine when not pregnant. COVID-19 vaccine acceptance was significantly lower during pregnancy (62.1%, p < 0.005) and for their babies (69.9%, p < 0.005). Ethnic minority women were twice as likely to reject a COVID-19 vaccine for themselves when not pregnant, pregnant and for their babies compared to women from White ethnic groups (p < 0.005). Women from lower-income households, aged under 25-years, and from some geographic regions were more likely to reject a COVID-19 vaccine when not pregnant, pregnant and for their babies. Multivariate analysis revealed that income and ethnicity were the main drivers of the observed age and regional differences. Women unvaccinated against pertussis in pregnancy were over four times more likely to reject COVID-19 vaccines when not pregnant, pregnant and for their babies. Thematic analysis of the survey freetext responses and interviews found safety concerns about COVID-19 vaccines were common though wider mistrust in vaccines was also expressed. Trust in vaccines and the health system were also reasons women gave for accepting COVID-19 vaccines. CONCLUSION: Safety information on COVID-19 vaccines must be clearly communicated to pregnant women to provide reassurance and facilitate informed pregnancy vaccine decisions. Targeted interventions to promote COVID-19 vaccine uptake among ethnic minority and lower-income women may be needed.


Assuntos
Vacinas contra COVID-19 , COVID-19/prevenção & controle , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Complicações Infecciosas na Gravidez/prevenção & controle , Vacinação/psicologia , Adulto , /estatística & dados numéricos , Feminino , Humanos , Renda , Mães/psicologia , Gravidez , Gestantes/psicologia , SARS-CoV-2/imunologia , Inquéritos e Questionários , Reino Unido/epidemiologia
4.
J Hematol Oncol ; 15(1): 5, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35012610

RESUMO

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) blunts the broad inflammatory response induced by damage-associated molecular patterns via binding to extracellular high mobility group box 1 and heat shock proteins, as well as regulating the downstream Siglec10-Src homology 2 domain-containing phosphatase 1 pathway. A recent randomized phase III trial evaluating CD24Fc for patients with severe COVID-19 (SAC-COVID; NCT04317040) demonstrated encouraging clinical efficacy. METHODS: Using a systems analytical approach, we studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial to discern the impact of CD24Fc treatment on immune homeostasis. We performed high dimensional spectral flow cytometry and measured the levels of a broad array of cytokines and chemokines to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19. RESULTS: Twenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found that patients with severe COVID-19 had systemic hyper-activation of multiple cellular compartments, including CD8+ T cells, CD4+ T cells, and CD56+ natural killer cells. Treatment with CD24Fc blunted this systemic inflammation, inducing a return to homeostasis in NK and T cells without compromising the anti-Spike protein antibody response. CD24Fc significantly attenuated the systemic cytokine response and diminished the cytokine coexpression and network connectivity linked with COVID-19 severity and pathogenesis. CONCLUSIONS: Our data demonstrate that CD24Fc rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19.


Assuntos
Antígeno CD24/uso terapêutico , COVID-19/prevenção & controle , Síndrome da Liberação de Citocina/prevenção & controle , Inflamação/prevenção & controle , SARS-CoV-2/efeitos dos fármacos , Idoso , Alarminas/imunologia , Alarminas/metabolismo , Antígeno CD24/química , COVID-19/imunologia , COVID-19/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/metabolismo , Método Duplo-Cego , Feminino , Proteína HMGB1/imunologia , Proteína HMGB1/metabolismo , Proteínas de Choque Térmico/imunologia , Proteínas de Choque Térmico/metabolismo , Homeostase/efeitos dos fármacos , Homeostase/imunologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/virologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Solubilidade , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Resultado do Tratamento
5.
Proc Natl Acad Sci U S A ; 119(3)2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35012976

RESUMO

COVID-19 remains a stark health threat worldwide, in part because of minimal levels of targeted vaccination outside high-income countries and highly transmissible variants causing infection in vaccinated individuals. Decades of theoretical and experimental data suggest that nonspecific effects of non-COVID-19 vaccines may help bolster population immunological resilience to new pathogens. These routine vaccinations can stimulate heterologous cross-protective effects, which modulate nontargeted infections. For example, immunization with Bacillus Calmette-Guérin, inactivated influenza vaccine, oral polio vaccine, and other vaccines have been associated with some protection from SARS-CoV-2 infection and amelioration of COVID-19 disease. If heterologous vaccine interventions (HVIs) are to be seriously considered by policy makers as bridging or boosting interventions in pandemic settings to augment nonpharmaceutical interventions and specific vaccination efforts, evidence is needed to determine their optimal implementation. Using the COVID-19 International Modeling Consortium mathematical model, we show that logistically realistic HVIs with low (5 to 15%) effectiveness could have reduced COVID-19 cases, hospitalization, and mortality in the United States fall/winter 2020 wave. Similar to other mass drug administration campaigns (e.g., for malaria), HVI impact is highly dependent on both age targeting and intervention timing in relation to incidence, with maximal benefit accruing from implementation across the widest age cohort when the pandemic reproduction number is >1.0. Optimal HVI logistics therefore differ from optimal rollout parameters for specific COVID-19 immunizations. These results may be generalizable beyond COVID-19 and the US to indicate how even minimally effective heterologous immunization campaigns could reduce the burden of future viral pandemics.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Modelos Teóricos , SARS-CoV-2/imunologia , Estações do Ano , Vacinação/métodos , Algoritmos , Vacina BCG/administração & dosagem , Vacina BCG/imunologia , COVID-19/epidemiologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Pandemias/prevenção & controle , Admissão do Paciente/estatística & dados numéricos , SARS-CoV-2/fisiologia , Taxa de Sobrevida , Estados Unidos/epidemiologia , Vacinação/estatística & dados numéricos
6.
Nat Commun ; 13(1): 155, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013189

RESUMO

Antibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. This emphasizes the need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we describe the isolation of a nanobody that interacts simultaneously with two RBDs from different spike trimers of SARS-CoV-2, rapidly inducing the formation of spike trimer-dimers leading to the loss of their ability to attach to the host cell receptor, ACE2. We show that this nanobody potently neutralizes SARS-CoV-2, including the beta and delta variants, and cross-neutralizes SARS-CoV. Furthermore, we demonstrate the therapeutic potential of the nanobody against SARS-CoV-2 and the beta variant in a human ACE2 transgenic mouse model. This naturally elicited bispecific monomeric nanobody establishes an uncommon strategy for potent inactivation of viral antigens and represents a promising antiviral against emerging SARS-CoV-2 variants.


Assuntos
Anticorpos Biespecíficos/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Anticorpos de Domínio Único/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Biespecíficos/metabolismo , COVID-19/virologia , Chlorocebus aethiops , Microscopia Crioeletrônica , Células HEK293 , Humanos , Camundongos Transgênicos , Testes de Neutralização/métodos , Ligação Proteica , Conformação Proteica , Multimerização Proteica/imunologia , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Anticorpos de Domínio Único/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero
7.
Nat Commun ; 13(1): 153, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013191

RESUMO

Anti-viral immunity continuously declines over time after SARS-CoV-2 infection. Here, we characterize the dynamics of anti-viral immunity during long-term follow-up and after BNT162b2 mRNA-vaccination in convalescents after asymptomatic or mild SARS-CoV-2 infection. Virus-specific and virus-neutralizing antibody titers rapidly declined in convalescents over 9 months after infection, whereas virus-specific cytokine-producing polyfunctional T cells persisted, among which IL-2-producing T cells correlated with virus-neutralizing antibody titers. Among convalescents, 5% of individuals failed to mount long-lasting immunity after infection and showed a delayed response to vaccination compared to 1% of naïve vaccinees, but successfully responded to prime/boost vaccination. During the follow-up period, 8% of convalescents showed a selective increase in virus-neutralizing antibody titers without accompanying increased frequencies of circulating SARS-CoV-2-specific T cells. The same convalescents, however, responded to vaccination with simultaneous increase in antibody and T cell immunity revealing the strength of mRNA-vaccination to increase virus-specific immunity in convalescents.


Assuntos
/imunologia , COVID-19/imunologia , Convalescença , Nucleocapsídeo/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/virologia , Citocinas/imunologia , Citocinas/metabolismo , Citometria de Fluxo/métodos , Seguimentos , Humanos , Imunoglobulina G/imunologia , Interleucina-2/imunologia , Interleucina-2/metabolismo , Cinética , SARS-CoV-2/fisiologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Fatores de Tempo , Vacinação/métodos
8.
Nat Commun ; 13(1): 80, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013199

RESUMO

Cross-reactive immune responses to SARS-CoV-2 have been observed in pre-pandemic cohorts and proposed to contribute to host protection. Here we assess 52 COVID-19 household contacts to capture immune responses at the earliest timepoints after SARS-CoV-2 exposure. Using a dual cytokine FLISpot assay on peripheral blood mononuclear cells, we enumerate the frequency of T cells specific for spike, nucleocapsid, membrane, envelope and ORF1 SARS-CoV-2 epitopes that cross-react with human endemic coronaviruses. We observe higher frequencies of cross-reactive (p = 0.0139), and nucleocapsid-specific (p = 0.0355) IL-2-secreting memory T cells in contacts who remained PCR-negative despite exposure (n = 26), when compared with those who convert to PCR-positive (n = 26); no significant difference in the frequency of responses to spike is observed, hinting at a limited protective function of spike-cross-reactive T cells. Our results are thus consistent with pre-existing non-spike cross-reactive memory T cells protecting SARS-CoV-2-naïve contacts from infection, thereby supporting the inclusion of non-spike antigens in second-generation vaccines.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Busca de Comunicante/métodos , Reações Cruzadas/imunologia , SARS-CoV-2/imunologia , Adulto , COVID-19/epidemiologia , COVID-19/virologia , Coronavirus/imunologia , Coronavirus/fisiologia , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Masculino , /virologia , Pessoa de Meia-Idade , Pandemias/prevenção & controle , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/metabolismo , Adulto Jovem
9.
Nat Commun ; 13(1): 128, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013206

RESUMO

The quality and persistence of children's humoral immune response following SARS-CoV-2 infection remains largely unknown but will be crucial to guide pediatric SARS-CoV-2 vaccination programs. Here, we examine 548 children and 717 adults within 328 households with at least one member with a previous laboratory-confirmed SARS-CoV-2 infection. We assess serological response at 3-4 months and 11-12 months after infection using a bead-based multiplex immunoassay for 23 human coronavirus antigens including SARS-CoV-2 and its Variants of Concern (VOC) and endemic human coronaviruses (HCoVs), and additionally by three commercial SARS-CoV-2 antibody assays. Neutralization against wild type SARS-CoV-2 and the Delta VOC are analysed in a pseudotyped virus assay. Children, compared to adults, are five times more likely to be asymptomatic, and have higher specific antibody levels which persist longer (96.2% versus 82.9% still seropositive 11-12 months post infection). Of note, symptomatic and asymptomatic infections induce similar humoral responses in all age groups. SARS-CoV-2 infection occurs independent of HCoV serostatus. Neutralization responses of children and adults are similar, although neutralization is reduced for both against the Delta VOC. Overall, the long-term humoral immune response to SARS-CoV-2 infection in children is of longer duration than in adults even after asymptomatic infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Imunidade Humoral/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , Antígenos Virais/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Criança , Pré-Escolar , Reações Cruzadas/imunologia , Feminino , Humanos , Lactente , Masculino , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação/métodos
10.
Nat Commun ; 13(1): 21, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013229

RESUMO

While the seroprevalence of SARS-CoV-2 in healthy people does not differ significantly among age groups, those aged 65 years or older exhibit strikingly higher COVID-19 mortality compared to younger individuals. To further understand differing COVID-19 manifestations in patients of different ages, three age groups of ferrets are infected with SARS-CoV-2. Although SARS-CoV-2 is isolated from all ferrets regardless of age, aged ferrets (≥3 years old) show higher viral loads, longer nasal virus shedding, and more severe lung inflammatory cell infiltration, and clinical symptoms compared to juvenile (≤6 months) and young adult (1-2 years) groups. Furthermore, direct contact ferrets co-housed with the virus-infected aged group shed more virus than direct-contact ferrets co-housed with virus-infected juvenile or young adult ferrets. Transcriptome analysis of aged ferret lungs reveals strong enrichment of gene sets related to type I interferon, activated T cells, and M1 macrophage responses, mimicking the gene expression profile of severe COVID-19 patients. Thus, SARS-CoV-2-infected aged ferrets highly recapitulate COVID-19 patients with severe symptoms and are useful for understanding age-associated infection, transmission, and pathogenesis of SARS-CoV-2.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Modelos Animais de Doenças , SARS-CoV-2/imunologia , Eliminação de Partículas Virais/imunologia , Fatores Etários , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , COVID-19/genética , COVID-19/transmissão , Chlorocebus aethiops , Feminino , Furões , Perfilação da Expressão Gênica/métodos , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Células Vero , Virulência
11.
Nat Commun ; 13(1): 19, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013235

RESUMO

T cells play a vital role in combatting SARS-CoV-2 and forming long-term memory responses. Whereas extensive structural information is available on neutralizing antibodies against SARS-CoV-2, such information on SARS-CoV-2-specific T-cell receptors (TCRs) bound to their peptide-MHC targets is lacking. Here we determine the structures of a public and a private TCR from COVID-19 convalescent patients in complex with HLA-A2 and two SARS-CoV-2 spike protein epitopes (YLQ and RLQ). The structures reveal the basis for selection of particular TRAV and TRBV germline genes by the public but not the private TCR, and for the ability of the TCRs to recognize natural variants of RLQ but not YLQ. Neither TCR recognizes homologous epitopes from human seasonal coronaviruses. By elucidating the mechanism for TCR recognition of an immunodominant yet variable epitope (YLQ) and a conserved but less commonly targeted epitope (RLQ), this study can inform prospective efforts to design vaccines to elicit pan-coronavirus immunity.


Assuntos
COVID-19/imunologia , Epitopos de Linfócito T/imunologia , Antígeno HLA-A2/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , COVID-19/virologia , Epitopos de Linfócito T/metabolismo , Antígeno HLA-A2/química , Antígeno HLA-A2/metabolismo , Humanos , Epitopos Imunodominantes/imunologia , Epitopos Imunodominantes/metabolismo , Células Jurkat , Células K562 , Peptídeos/química , Peptídeos/imunologia , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Ressonância de Plasmônio de Superfície/métodos
12.
Sci Rep ; 12(1): 439, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013430

RESUMO

The spread of SARS-CoV-2 led to rapid vaccine development. However, there remains considerable vaccine hesitancy in some countries. We investigate vaccine willingness in three nations with very different vaccine histories: Israel, Japan and Hungary. Employing an ecological-systems approach we analyse associations between health status, individual cognitions, norms, trust in government, COVID-19 myths and willingness to be vaccinated, with data from three nationally representative samples (Israel, Jan. 2021, N = 1011; Japan, Feb. 2021, N = 997; Hungary, April 2021, N = 1130). Vaccine willingness was higher in Israel (74%) than Japan (51%) or Hungary (31%). In all three countries vaccine willingness was greatest amongst who would regret not being vaccinated and respondents who trusted their government. Multi-group latent class analysis identified three groups of COVID myths, with particular concern about alteration of DNA (Israel), allergies (Hungary) and infection from the vaccine (Japan). Intervention campaigns should address such cultural myths while emphasising both individual and social benefits of vaccination.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Vacinação/psicologia , /métodos , Adulto , Idoso , COVID-19/epidemiologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Hungria , Israel , Japão , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pandemias/prevenção & controle , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , SARS-CoV-2/fisiologia , Vacinação/estatística & dados numéricos
13.
Sci Rep ; 12(1): 385, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013457

RESUMO

The immune response after SARS-CoV-2 vaccine administration appears to be characterized by high inter-individual variation, even in SARS-CoV-2 positive subjects, who could have experienced different post-infection, unresolved conditions. We monitored anti-SARS-CoV-2 IgG levels and kinetics along with circulating biomarkers in a cohort of 175 healthcare workers during early immunization with COVID-19 mRNA-LNP BNT162b2 vaccine, to identify the associated factors. Subjects with a previous SARS-CoV-2 infection were characterized by higher BMI and CRP levels and lower neutrophil count with respect to naïve subjects. Baseline IgG levels resulted associated with CRP independently on BMI and inflammatory diseases. Among 137 subjects undergoing vaccination and monitored after the first and the second dose, three kinetic patterns were identified. The pattern showing a rapid growth was characterized by higher IgG levels at baseline and higher CRP and MCHC levels than negative subjects. Subjects previously exposed to SARS-CoV-2 showed higher levels of CRP, suggesting persistence of unresolved inflammation. These levels are the main determinant of IgG levels at baseline and characterized subjects belonging to the best performing, post-vaccine antibody kinetic pattern.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Pessoal de Saúde/estatística & dados numéricos , Inflamação/imunologia , SARS-CoV-2/imunologia , Adulto , Anticorpos Antivirais/sangue , Biomarcadores/sangue , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , COVID-19/epidemiologia , COVID-19/virologia , Estudos de Coortes , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Inflamação/virologia , Cinética , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pandemias/prevenção & controle , SARS-CoV-2/fisiologia , Vacinação/métodos , Vacinação/estatística & dados numéricos
14.
MAbs ; 14(1): 2014296, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35030985

RESUMO

In this 13th annual installment of the annual 'Antibodies to Watch' article series, we discuss key events in commercial antibody therapeutics development that occurred in 2021 and forecast events that might occur in 2022. Regulatory review of antibody therapeutics that target the SARS-CoV-2 coronavirus proceeded at an unprecedented pace in 2021, resulting in both emergency use authorizations and full approvals for sotrovimab, regdanvimab, REGEN-COV2, as well as others, in numerous countries. As of November 1, a total of 11 antibody therapeutics had been granted first approvals in either the United States or European Union in 2021 (evinacumab, dostarlimab loncastuximab tesirine, amivantamab, aducanumab, tralokinumab, anifrolumab, bimekizumab, tisotumab vedotin, regdanvimab, REGEN-COV2). The first global approvals of seven products, however, were granted elsewhere, including Japan (pabinafusp alfa), China (disitamab vedotin, penpulimab, zimberelimab), Australia (sotrovimab, REGEN-COV2), or the Republic of Korea (regdanvimab). Globally, at least 27 novel antibody therapeutics are undergoing review by regulatory agencies. First actions by the Food and Drug Administration on the biologics license applications for faricimab, sutimlimab, tebentafusp, relatlimab, sintilimab, ublituximab and tezepelumab are expected in the first quarter of 2022. Finally, our data show that, with antibodies for COVID-19 excluded, the late-stage commercial clinical pipeline of antibody therapeutics grew by over 30% in the past year. Of those in late-stage development, marketing applications for at least 22 may occur by the end of 2022.


Assuntos
Anticorpos Monoclonais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Especificidade de Anticorpos , Antígenos Virais/imunologia , Ásia , Austrália , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/terapia , Ensaios Clínicos como Assunto , Ensaios de Uso Compassivo , Aprovação de Drogas , União Europeia , Previsões , Humanos , SARS-CoV-2/imunologia , Estados Unidos , United States Food and Drug Administration
15.
MAbs ; 14(1): 2021601, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35030983

RESUMO

Coronavirus disease 2019, caused by SARS-CoV-2, remains an on-going pandemic, partly due to the emergence of variant viruses that can "break-through" the protection of the current vaccines and neutralizing antibodies (nAbs), highlighting the needs for broadly nAbs and next-generation vaccines. We report an antibody that exhibits breadth and potency in binding the receptor-binding domain (RBD) of the virus spike glycoprotein across SARS coronaviruses. Initially, a lead antibody was computationally discovered and crystallographically validated that binds to a highly conserved surface of the RBD of wild-type SARS-CoV-2. Subsequently, through experimental affinity enhancement and computational affinity maturation, it was further developed to bind the RBD of all concerning SARS-CoV-2 variants, SARS-CoV-1 and pangolin coronavirus with pico-molar binding affinities, consistently exhibited strong neutralization activity against wild-type SARS-CoV-2 and the Alpha and Delta variants. These results identify a vulnerable target site on coronaviruses for development of pan-sarbecovirus nAbs and vaccines.


Assuntos
Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Antivirais/genética , Anticorpos Antivirais/metabolismo , Afinidade de Anticorpos , Especificidade de Anticorpos , Reações Antígeno-Anticorpo , Antígenos Virais/química , Antígenos Virais/genética , Anticorpos Amplamente Neutralizantes/genética , Anticorpos Amplamente Neutralizantes/metabolismo , Cristalografia por Raios X , Epitopos/química , Epitopos/imunologia , Humanos , Fragmentos de Imunoglobulinas/imunologia , Simulação de Acoplamento Molecular , Método de Monte Carlo , Testes de Neutralização , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Domínios Proteicos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
16.
Immunohorizons ; 6(1): 1-7, 2022 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-35031581

RESUMO

The perpetuation of the SARS-CoV-2 pandemic has permitted the continued evolution of mutations, many of which appear to promote infectivity, transmission, and immune evasion. Critically, several derivative lineages defined as variants of concern (VOCs) and variants of interest (VOIs) have emerged in the last year that possess a constellation of highly adaptive mutations that have resulted in unprecedented propagation. To better understand the significance of these mutations, we analyzed their molecular and immunological consequences against the immunogenetic profile of the United States population using immunoinformatics to analyze in silico data. Our findings indicate that several evolving mutations in the VOCs and VOIs appear to confer immune evasion properties leading to antigenic drift, specifically for Ab-mediated and Th cell-mediated immune recognition, whereas mutations leading to evasion from innate immune mechanisms are less common in the more successful VOC strains compared with the VOIs. Importantly, several of these mutations raise concerns for the effectiveness of anamnestic responses achieved through natural infection and vaccination as well as for the utility of Ab-based therapeutic interventions. The emergence of such adaptations underscores the need for vaccine enhancements as well as the continued need to for preventative hygiene measures to help minimize transmission.


Assuntos
COVID-19/imunologia , Evasão da Resposta Imune/imunologia , Fenômenos Imunogenéticos/fisiologia , Mutação/imunologia , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , Humanos , Imunidade Inata/imunologia , Pandemias/prevenção & controle , Estados Unidos , Vacinação/métodos
17.
PLoS One ; 17(1): e0262657, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35041700

RESUMO

BACKGROUND: Tests for SARS-CoV-2 immunity are needed to help assess responses to vaccination, which can be heterogeneous and may wane over time. The plaque reduction neutralization test (PRNT) is considered the gold standard for measuring serum neutralizing antibodies but requires high level biosafety, live viral cultures and days to complete. We hypothesized that competitive enzyme linked immunoassays (ELISAs) based on SARS-CoV-2 spike protein's receptor binding domain (RBD) attachment to its host receptor, the angiotensin converting enzyme 2 receptor (ACE2r), would correlate with PRNT, given the central role of RBD-ACE2r interactions in infection and published studies to date, and enable evaluation of vaccine responses. METHODS AND RESULTS: Configuration and development of a competitive ELISA with plate-bound RBD and soluble biotinylated ACE2r was accomplished using pairs of pre/post vaccine serum. When the competitive ELISA was used to evaluate N = 32 samples from COVID-19 patients previously tested by PRNT, excellent correlation in IC50 results were observed (rs = .83, p < 0.0001). When the competitive ELISA was used to evaluate N = 42 vaccinated individuals and an additional N = 13 unvaccinated recovered COVID-19 patients, significant differences in RBD-ACE2r inhibitory activity were associated with prior history of COVID-19 and type of vaccine received. In longitudinal analyses pre and up to 200 days post vaccine, surrogate neutralizing activity increased markedly after primary and booster vaccine doses, but fell substantially, up to <12% maximal levels within 6 months. CONCLUSIONS: A competitive ELISA based on inhibition of RBD-ACE2r attachment correlates well with PRNT, quantifies significantly higher activity among vaccine recipients with prior COVID (vs. those without), and highlights marked declines in surrogate neutralizing activity over a 6 month period post vaccination. The findings raise concern about the duration of vaccine responses and potential need for booster shots.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Vacinas Sintéticas/imunologia , /imunologia , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Vacinas Sintéticas/administração & dosagem , /administração & dosagem
18.
Blood Cancer J ; 12(1): 8, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35042847

RESUMO

Understanding antibody-based SARS-CoV-2 immunity in hematologic malignancy (HM) patients following infection is crucial to inform vaccination strategies for this highly vulnerable population. This cross-sectional study documents the anti-SARS-CoV-2 humoral response and serum neutralizing activity in 189 HM patients recovering from a PCR-confirmed infection. The overall seroconversion rate was 85.7%, with the lowest values in patients with lymphoid malignancies or undergoing chemotherapy. Therapy-naive patients in the "watch and wait" status were more likely to seroconvert and display increased anti-s IgG titers. Enhanced serum neutralizing activity was observed in the following SARS-CoV-2-infected HM patient groups: (i) males; (ii) severe COVID-19; and (iii) "watch and wait" or "complete/partial response". The geometric mean (GeoMean) ID50 neutralization titers in patients analyzed before or after 6 months post-infection were 299.1 and 306.3, respectively, indicating that >50% of the patients in either group had a neutralization titer sufficient to provide 50% protection from symptomatic COVID-19. Altogether, our findings suggest that therapy-naive HM patients mount a far more robust immune response to SARS-CoV-2 infection vs. patients receiving anti-cancer treatment, raising the important question as to whether HM patients should be vaccinated before therapy and/or receive vaccine formats capable of better recapitulating the natural infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antineoplásicos/administração & dosagem , COVID-19/imunologia , Neoplasias Hematológicas , Imunidade Humoral , SARS-CoV-2/imunologia , Idoso , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade
19.
Cell Host Microbe ; 30(1): 69-82.e10, 2022 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-34973165

RESUMO

A fraction of COVID-19 convalescent individuals mount a potent antibody response to SARS-CoV-2 with cross-reactivity to SARS-CoV-1. To uncover their humoral response in detail, we performed single B cell analysis from 10 SARS-CoV-2 elite neutralizers. We isolated and analyzed 126 monoclonal antibodies, many of which were sarbecovirus cross-reactive, with some displaying merbecovirus- and embecovirus-reactivity. Several isolated broadly neutralizing antibodies were effective against B.1.1.7, B.1.351, B.1.429, B.1.617, and B.1.617.2 variants and 19 prominent potential escape sites. Furthermore, assembly of 716,806 SARS-CoV-2 sequences predicted emerging escape variants, which were also effectively neutralized. One of these broadly neutralizing potent antibodies, R40-1G8, is a IGHV3-53 RBD-class-1 antibody. Remarkably, cryo-EM analysis revealed that R40-1G8 has a flexible binding mode, targeting both "up" and "down" conformations of the RBD. Given the threat of emerging SARS-CoV-2 variants, we demonstrate that elite neutralizers are a valuable source for isolating ultrapotent antibody candidates to prevent and treat SARS-CoV-2 infection.


Assuntos
Anticorpos Antivirais/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Animais , Anticorpos Monoclonais/imunologia , COVID-19/virologia , Células Cultivadas , Chlorocebus aethiops , Reações Cruzadas/imunologia , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Neutralização/métodos , Glicoproteína da Espícula de Coronavírus/imunologia , Células Vero
20.
Cell Rep ; 38(2): 110237, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-34982967

RESUMO

Recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants Mu and C.1.2 have spike proteins with mutations that may confer resistance to natural and vaccine-elicited antibodies. Analysis of neutralizing antibody titers in the sera of vaccinated individuals without previous history of infection and from convalescent individuals show partial resistance of the viruses. In contrast, sera from individuals with a previous history of SARS-CoV-2 infection who were subsequently vaccinated neutralize variants with titers 4- to 11-fold higher, providing a rationale for vaccination of individuals with previous infection. The heavily mutated C.1.2 spike is the most antibody neutralization-resistant spike to date; however, the avidity of C.1.2 spike protein for angiotensin-converting enzyme 2 (ACE2) is low. This finding suggests that the virus evolved to escape the humoral response but has a decrease in fitness, suggesting that it may cause milder disease or be less transmissible. It may be difficult for the spike protein to evolve to escape neutralizing antibodies while maintaining high affinity for ACE2.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Células A549 , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Humanos , Testes de Neutralização/métodos , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação/métodos
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