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1.
Front Immunol ; 15: 1399960, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38873606

RESUMO

The VH6-1 class of antibodies includes some of the broadest and most potent antibodies that neutralize influenza A virus. Here, we elicit and isolate anti-idiotype antibodies against germline versions of VH6-1 antibodies, use these to sort human leukocytes, and isolate a new VH6-1-class member, antibody L5A7, which potently neutralized diverse group 1 and group 2 influenza A strains. While its heavy chain derived from the canonical IGHV6-1 heavy chain gene used by the class, L5A7 utilized a light chain gene, IGKV1-9, which had not been previously observed in other VH6-1-class antibodies. The cryo-EM structure of L5A7 in complex with Indonesia 2005 hemagglutinin revealed a nearly identical binding mode to other VH6-1-class members. The structure of L5A7 bound to the isolating anti-idiotype antibody, 28H6E11, revealed a shared surface for binding anti-idiotype and hemagglutinin that included two critical L5A7 regions: an FG motif in the third heavy chain-complementary determining region (CDR H3) and the CDR L1 loop. Surprisingly, the chemistries of L5A7 interactions with hemagglutinin and with anti-idiotype were substantially different. Overall, we demonstrate anti-idiotype-based isolation of a broad and potent influenza A virus-neutralizing antibody, revealing that anti-idiotypic selection of antibodies can involve features other than chemical mimicry of the target antigen.


Assuntos
Anticorpos Anti-Idiotípicos , Anticorpos Neutralizantes , Anticorpos Antivirais , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Vírus da Influenza A , Humanos , Vírus da Influenza A/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Anti-Idiotípicos/isolamento & purificação , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Influenza Humana/imunologia , Influenza Humana/virologia , Animais , Cadeias Pesadas de Imunoglobulinas/imunologia , Cadeias Pesadas de Imunoglobulinas/química
2.
Sci Rep ; 14(1): 13417, 2024 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862731

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that gave rise to COVID-19 infection produced a worldwide health crisis. The virus can cause a serious or even fatal disease. Comprehending the complex immunological responses triggered by SARS-CoV-2 infection is essential for identifying pivotal elements that shape the course of the disease and its enduring effects on immunity. The span and potency of antibody responses provide valuable perspicuity into the resilience of post-infection immunity. The analysis of existing literature reveals a diverse controversy, confining varying data about the persistence of particular antibodies as well as the multifaceted factors that impact their development and titer, Within this study we aimed to understand the dynamics of anti-SARS-CoV-2 antibodies against nucleocapsid (anti-SARS-CoV-2 (N)) and spike (anti-SARS-CoV-2 (N)) proteins in long-term immunity in convalescent patients, as well as the factors influencing the production and kinetics of those antibodies. We collected 6115 serum samples from 1611 convalescent patients at different post-infection intervals up to 21 months Study showed that in the fourth month, the anti-SARS-CoV-2 (N) exhibited their peak mean value, demonstrating a 79% increase compared to the initial month. Over the subsequent eight months, the peak value experienced a modest decline, maintaining a relatively elevated level by the end of study. Conversely, anti-SARS-CoV-2 (S) exhibited a consistent increase at each three-month interval over the 15-month period, culminating in a statistically significant peak mean value at the study's conclusion. Our findings demonstrate evidence of sustained seropositivity rates for both anti-SARS-CoV-2 (N) and (S), as well as distinct dynamics in the long-term antibody responses, with anti-SARS-CoV-2 (N) levels displaying remarkable persistence and anti-SARS-CoV-2 (S) antibodies exhibiting a progressive incline.


Assuntos
Anticorpos Antivirais , COVID-19 , Imunidade Humoral , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , COVID-19/imunologia , Humanos , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , SARS-CoV-2/imunologia , Imunidade Humoral/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Fosfoproteínas/imunologia , Idoso , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue
3.
Front Immunol ; 15: 1395684, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38868776

RESUMO

Circulating follicular helper T cells (cTfh) can show phenotypic alterations in disease settings, including in the context of tissue-damaging autoimmune or anti-viral responses. Using severe COVID-19 as a paradigm of immune dysregulation, we have explored how cTfh phenotype relates to the titre and quality of antibody responses. Severe disease was associated with higher titres of neutralising S1 IgG and evidence of increased T cell activation. ICOS, CD38 and HLA-DR expressing cTfh correlated with serum S1 IgG titres and neutralising strength, and interestingly expression of TIGIT by cTfh showed a negative correlation. TIGIT+cTfh expressed increased IFNγ and decreased IL-17 compared to their TIGIT-cTfh counterparts, and showed reduced capacity to help B cells in vitro. Additionally, TIGIT+cTfh expressed lower levels of CD40L than TIGIT-cTfh, providing a potential explanation for their poor B-helper function. These data identify phenotypic changes in polyclonal cTfh that correlate with specific antibody responses and reveal TIGIT as a marker of cTfh with altered function.


Assuntos
Anticorpos Antivirais , Linfócitos B , COVID-19 , Receptores Imunológicos , SARS-CoV-2 , Células T Auxiliares Foliculares , Humanos , COVID-19/imunologia , Receptores Imunológicos/imunologia , SARS-CoV-2/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Masculino , Células T Auxiliares Foliculares/imunologia , Linfócitos B/imunologia , Feminino , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Pessoa de Meia-Idade , Adulto , Ativação Linfocitária/imunologia , Idoso , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue
4.
Sci Transl Med ; 16(751): eado7588, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38865483

RESUMO

Immune responses from prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 vaccination mitigate disease severity, but they do not fully prevent subsequent infections, especially from genetically divergent strains. We examined the incidence of and immune differences against human endemic coronaviruses (eCoVs) as a proxy for response against future genetically heterologous coronaviruses (CoVs). We assessed differences in symptomatic eCoV and non-CoV respiratory disease incidence among those with known prior SARS-CoV-2 infection or previous COVID-19 vaccination but no documented SARS-CoV-2 infection or neither exposure. Retrospective cohort analyses suggest that prior SARS-CoV-2 infection, but not previous COVID-19 vaccination alone, associates with a lower incidence of subsequent symptomatic eCoV infection. There was no difference in non-CoV incidence, implying that the observed difference was eCoV specific. In a second cohort where both cellular and humoral immunity were measured, those with prior SARS-CoV-2 spike protein exposure had lower eCoV-directed neutralizing antibodies, suggesting that neutralization is not responsible for the observed decreased eCoV disease. The three groups had similar cellular responses against the eCoV spike protein and nucleocapsid antigens. However, CD8+ T cell responses to the nonstructural eCoV proteins nsp12 and nsp13 were higher in individuals with previous SARS-CoV-2 infection as compared with the other groups. This association between prior SARS-CoV-2 infection and decreased incidence of eCoV disease may therefore be due to a boost in CD8+ T cell responses against eCoV nsp12 and nsp13, suggesting that incorporation of nonstructural viral antigens in a future pan-CoV vaccine may improve vaccine efficacy.


Assuntos
Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/epidemiologia , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Incidência , SARS-CoV-2/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Vacinação , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Adulto , Glicoproteína da Espícula de Coronavírus/imunologia , Imunidade Humoral/imunologia , Idoso , Anticorpos Neutralizantes/imunologia
5.
J Gen Virol ; 105(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38861287

RESUMO

Increased human-to-human transmission of monkeypox virus (MPXV) is cause for concern, and antibodies directed against vaccinia virus (VACV) are known to confer cross-protection against Mpox. We used 430 serum samples derived from the Scottish patient population to investigate antibody-mediated cross-neutralization against MPXV. By combining electrochemiluminescence immunoassays with live-virus neutralization assays, we show that people born when smallpox vaccination was routinely offered in the United Kingdom have increased levels of antibodies that cross-neutralize MPXV. Our results suggest that age is a risk factor of Mpox infection, and people born after 1971 are at higher risk of infection upon exposure.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Monkeypox virus , Mpox , Vacina Antivariólica , Humanos , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Vacina Antivariólica/imunologia , Vacina Antivariólica/administração & dosagem , Adulto , Pessoa de Meia-Idade , Monkeypox virus/imunologia , Adulto Jovem , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Mpox/imunologia , Mpox/prevenção & controle , Feminino , Adolescente , Idoso , Masculino , Proteção Cruzada/imunologia , Escócia , Fatores Etários , Testes de Neutralização , Criança , Vacinação , Varíola/prevenção & controle , Varíola/imunologia , Pré-Escolar , Reações Cruzadas , Idoso de 80 Anos ou mais
6.
J Med Virol ; 96(6): e29732, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38874202

RESUMO

Neutralizing antibodies (NAbs) are considered the primary mechanism of vaccine-mediated protection against human papillomaviruses (HPV), the causative agent of cervical cancer. However, the minimum level of NAb needed for protection is currently unknown. The HPV pseudovirion-based neutralization assay (PBNA) is the gold standard method for assessing HPV antibody responses but is time-consuming and labor-intensive. With the development of higher valency HPV vaccines, alternative serological assays with the capacity for multiplexing would improve efficiency and output. Here we describe a multiplex bead-based immunoassay to characterize the antibody responses to the seven oncogenic HPV types (HPV16/18/31/33/45/52/58) contained in the current licensed nonavalent HPV vaccine. This assay can measure antibody isotypes and subclasses (total IgG, IgM, IgA1-2, IgG1-4), and can be adapted to measure other antibody features (e.g., Fc receptors) that contribute to vaccine immunity. When tested with serum samples from unvaccinated and vaccinated individuals, we found high concordance between HPV-specific IgG using this multiplex assay and NAbs measured with PBNA. Overall, this assay is high-throughput, sample-sparing, and time-saving, providing an alternative to existing assays for the measurement and characterization of HPV antibody responses.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Imunoglobulina G , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Humanos , Anticorpos Antivirais/sangue , Imunoensaio/métodos , Feminino , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/imunologia , Vacinas contra Papillomavirus/administração & dosagem , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Imunoglobulina G/sangue , Papillomaviridae/imunologia , Papillomavirus Humano
7.
J Immunol Methods ; 530: 113698, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38823574

RESUMO

There is a critical need to understand the effectiveness of serum elicited by different SARS-CoV-2 vaccines against SARS-CoV-2 variants. We describe the generation of reference reagents comprised of post-vaccination sera from recipients of different primary vaccines with or without different vaccine booster regimens in order to allow standardized characterization of SARS-CoV-2 neutralization in vitro. We prepared and pooled serum obtained from donors who received a either primary vaccine series alone, or a vaccination strategy that included primary and boosted immunization using available SARS-CoV-2 mRNA vaccines (BNT162b2, Pfizer and mRNA-1273, Moderna), replication-incompetent adenovirus type 26 vaccine (Ad26.COV2·S, Johnson and Johnson), or recombinant baculovirus-expressed spike protein in a nanoparticle vaccine plus Matrix-M adjuvant (NVX-CoV2373, Novavax). No subjects had a history of clinical SARS-CoV-2 infection, and sera were screened with confirmation that there were no nucleocapsid antibodies detected to suggest natural infection. Twice frozen sera were aliquoted, and serum antibodies were characterized for SARS-CoV-2 spike protein binding (estimated WHO antibody binding units/ml), spike protein competition for ACE-2 binding, and SARS-CoV-2 spike protein pseudotyped lentivirus transduction. These reagents are available for distribution to the research community (BEI Resources), and should allow the direct comparison of antibody neutralization results between different laboratories. Further, these sera are an important tool to evaluate the functional neutralization activity of vaccine-induced antibodies against emerging SARS-CoV-2 variants of concern. IMPORTANCE: The explosion of COVID-19 demonstrated how novel coronaviruses can rapidly spread and evolve following introduction into human hosts. The extent of vaccine- and infection-induced protection against infection and disease severity is reduced over time due to the fall in concentration, and due to emerging variants that have altered antibody binding regions on the viral envelope spike protein. Here, we pooled sera obtained from individuals who were immunized with different SARS-CoV-2 vaccines and who did not have clinical or serologic evidence of prior infection. The sera pools were characterized for direct spike protein binding, blockade of virus-receptor binding, and neutralization of spike protein pseudotyped lentiviruses. These sera pools were aliquoted and are available to allow inter-laboratory comparison of results and to provide a tool to determine the effectiveness of prior vaccines in recognizing and neutralizing emerging variants of concern.


Assuntos
Vacina de mRNA-1273 contra 2019-nCoV , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacina BNT162 , Vacinas contra COVID-19 , COVID-19 , Testes de Neutralização , SARS-CoV-2 , Humanos , SARS-CoV-2/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/prevenção & controle , COVID-19/imunologia , COVID-19/virologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Vacina BNT162/imunologia , Vacina BNT162/administração & dosagem , Glicoproteína da Espícula de Coronavírus/imunologia , Padrões de Referência , Imunização Secundária , Vacinação , Ad26COVS1/imunologia
8.
Int J Biol Macromol ; 272(Pt 1): 132798, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38838896

RESUMO

The emergence of various variants of concern (VOCs) necessitates the development of more efficient vaccines for COVID-19. In this study, we established a rapid and robust production platform for a novel subunit vaccine candidate based on eukaryotic HEK-293 T cells. The immunogenicity of the vaccine candidate was evaluated in pigs. The results demonstrated that the pseudovirus neutralizing antibody (pNAb) titers reached 7751 and 306 for the SARS-CoV-2 Delta and Omicron variants, respectively, after the first boost. Subsequently, pNAb titers further increased to 10,201 and 1350, respectively, after the second boost. Additionally, ELISPOT analysis revealed a robust T-cell response characterized by IFN-γ (171 SFCs/106 cells) and IL-2 (101 SFCs/106 cells) production. Our study demonstrates that a vaccine candidate based on the Delta variant spike protein may provide strong and broad protection against the prototype SARS-CoV-2 and VOCs. Moreover, the strategy for the efficient and stable expression of recombinant proteins utilizing HEK-293 T cells can be employed as a universal platform for future vaccine development.


Assuntos
Anticorpos Neutralizantes , Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Vacinas de Subunidades Antigênicas , Animais , Humanos , Células HEK293 , Vacinas contra COVID-19/imunologia , Vacinas de Subunidades Antigênicas/imunologia , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/imunologia , Suínos , COVID-19/prevenção & controle , COVID-19/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Antivirais/imunologia , Linfócitos T/imunologia , Imunogenicidade da Vacina
9.
Sci Rep ; 14(1): 13499, 2024 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866888

RESUMO

Acute, transient lymphocytopenia, not clinically significant was observed in the CAPRISA 012B phase 1 clinical trial following administration of broadly neutralizing antibodies (bnAb)-CAP256V2LS alone or with VRC07-523LS. Lymphocytopenia was assigned upon a > 50% decline in absolute lymphocyte counts following bnAb administration. We posited that systemic immunoglobulins (Igs), and cytokine profiles of eight women who developed lymphocytopenia were different to the 12 women without lymphocytopenia. Plasma Ig subclasses (IgG)/isotypes (IgM/IgA), and 27 cytokines were measured at enrolment (prior to bnAbs) and at days 1, 7, 28, 56 post-bnAb administration. IgG subclasses, IgM and total lymphocyte counts were significantly lower prior to bnAbs in women with gradable lymphocytopenia than those without. Gradable lymphocytopenia compared to non-lymphocytopenia women had significantly higher MIP-1ß from enrolment up to day 56. TNF-α was significantly lower in gradable lymphocytopenia compared to non-lymphocytopenia women for enrolment, days 7, 28 and 56 except for day 1. Within the gradable and within the non-lymphocytopenia women, from enrolment to day 1, significantly elevated IL-6, IL-8, IP-10, MCP-1, G-CSF and IL-1RA were found. Additionally, within the gradable lymphocytopenia women, 9 additional cytokines (TNF-α, MIP-1α, MIP-1ß, RANTES, Basic FGF, eotaxin, IFN-γ, IL-17A and IL-4) were significantly elevated at day 1 post-bnAbs compared to enrolment. This sub study presents preliminary findings to support the monitoring of baseline immunological markers including lymphocyte counts for assessing the development of transient lymphocytopenia. In high-risk settings conducting clinical trials testing bnAbs for HIV prevention, understanding factors that could amplify rates of lymphocytopenia, even if transient, remain undefined.


Assuntos
Linfopenia , Humanos , Feminino , Linfopenia/imunologia , Linfopenia/sangue , Adulto , Citocinas/sangue , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/sangue , Anticorpos Anti-HIV/sangue , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Imunoglobulinas/sangue , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Pessoa de Meia-Idade
10.
J Clin Immunol ; 44(6): 147, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38856804

RESUMO

PURPOSE: Asymptomatic SARS-CoV-2 infections were widely reported during the COVID-19 pandemic, acting as a hidden source of infection. Many existing studies investigating asymptomatic immunity failed to recruit true asymptomatic individuals. Thus, we conducted a longitudinal cohort study to evaluate humoral- and cell-mediated responses to infection and vaccination in well-defined asymptomatic young adults (the Asymptomatic COVID-19 in Education [ACE] cohort). METHODS: Asymptomatic testing services located at three UK universities identified asymptomatic young adults who were subsequently recruited with age- and sex-matched symptomatic and uninfected controls. Blood and saliva samples were collected after SARS-CoV-2 Wuhan infection, and again after vaccination. 51 participant's anti-spike antibody titres, neutralizing antibodies, and spike-specific T-cell responses were measured, against both Wuhan and Omicron B.1.1.529.1. RESULTS: Asymptomatic participants exhibited reduced Wuhan-specific neutralization antibodies pre- and post-vaccination, as well as fewer Omicron-specific neutralization antibodies post-vaccination, compared to symptomatic participants. Lower Wuhan and Omicron-specific IgG titres in asymptomatic individuals were also observed pre- and post-vaccination, compared to symptomatic participants. There were no differences in salivary IgA levels. Conventional flow cytometry analysis and multi-dimensional clustering analysis indicated unvaccinated asymptomatic participants had significantly fewer Wuhan-specific IL-2 secreting CD4+ CD45RA+ T cells and activated CD8+ T cells than symptomatic participants, though these differences dissipated after vaccination. CONCLUSIONS: Asymptomatic infection results in decreased antibody and T cell responses to further exposure to SARS-CoV-2 variants, compared to symptomatic infection. Post-vaccination, antibody responses are still inferior, but T cell immunity increases to match symptomatic subjects, emphasising the importance of vaccination to help protect asymptomatic individuals against future variants.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Infecções Assintomáticas , COVID-19 , Imunidade Celular , Imunidade Humoral , SARS-CoV-2 , Humanos , COVID-19/imunologia , SARS-CoV-2/imunologia , Masculino , Feminino , Anticorpos Antivirais/sangue , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Adulto Jovem , Adulto , Vacinas contra COVID-19/imunologia , Estudos de Coortes , Estudos Longitudinais , Vacinação , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Reino Unido/epidemiologia , Adolescente , Glicoproteína da Espícula de Coronavírus/imunologia
11.
Sci Rep ; 14(1): 13311, 2024 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858452

RESUMO

African Green (Vervet) monkeys have been extensively studied to understand the pathogenesis of infectious diseases. Using vervet monkeys as pre-clinical models may be an attractive option for low-resourced areas as they are found abundantly and their maintenance is more cost-effective than bigger primates such as rhesus macaques. We assessed the feasibility of using vervet monkeys as animal models to examine the immunogenicity of HIV envelope trimer immunogens in pre-clinical testing. Three groups of vervet monkeys were subcutaneously immunized with either the BG505 SOSIP.664 trimer, a novel subtype C SOSIP.664 trimer, CAP255, or a combination of BG505, CAP255 and CAP256.SU SOSIP.664 trimers. All groups of vervet monkeys developed robust binding antibodies by the second immunization with the peak antibody response occurring after the third immunization. Similar to binding, antibody dependent cellular phagocytosis was also observed in all the monkeys. While all animals developed potent, heterologous Tier 1 neutralizing antibody responses, autologous neutralization was limited with only half of the animals in each group developing responses to their vaccine-matched pseudovirus. These data suggest that the vervet monkey model may yield distinct antibody responses compared to other models. Further study is required to further determine the utility of this model in HIV immunization studies.


Assuntos
Vacinas contra a AIDS , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Animais , Anticorpos Anti-HIV/imunologia , Chlorocebus aethiops , Anticorpos Neutralizantes/imunologia , Vacinas contra a AIDS/imunologia , Vacinas contra a AIDS/administração & dosagem , HIV-1/imunologia , Formação de Anticorpos/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Modelos Animais de Doenças , Imunização
12.
Hum Vaccin Immunother ; 20(1): 2358570, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38853516

RESUMO

Among all natural and synthetic toxins, botulinum neurotoxins (BoNTs), produced by Clostridium botulinum in an anaerobic environment, are the most toxic polymer proteins. Currently, the most effective modalities for botulism prevention and treatment are vaccination and antitoxin use, respectively. However, these modalities are associated with long response time for active immunization, side effects, and donor limitations. As such, the development of more promising botulism prevention and treatment modalities is warranted. Here, we designed an mRNA encoding B9-hFc - a heavy-chain antibody fused to VHH and human Fc that can neutralize BoNT serotype B (BoNT/B) effectively - and assessed its expression in vitro and in vivo. The results confirmed that our mRNA demonstrates good expression in vitro and in vivo. Moreover, a single mRNA lipid nanoparticle injection effectively prevents BoNT/B intoxication in vivo, with effects comparable to those of protein antibodies. In conclusion, we explored and clarified whether mRNA drugs encoding neutralizing antibodies prevent BoNT/B intoxication. Our results provide an efficient strategy for further research on the prevention and treatment of intoxication by botulinum toxin.


Assuntos
Anticorpos Neutralizantes , Toxinas Botulínicas Tipo A , Botulismo , RNA Mensageiro , Anticorpos Neutralizantes/imunologia , Animais , Botulismo/prevenção & controle , Botulismo/imunologia , Toxinas Botulínicas Tipo A/imunologia , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Camundongos , Humanos , Feminino , Nanopartículas , Camundongos Endogâmicos BALB C , Anticorpos Antibacterianos/imunologia , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/administração & dosagem , Lipossomos
13.
Int J Immunopathol Pharmacol ; 38: 3946320241260633, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38836458

RESUMO

OBJECTIVES: This study aims to assess the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibodies against the spike (S) and nucleocapsid (NP) proteins, as well as neutralizing antibodies against the receptor-binding domain (RBD). Additionally, it aims to detect viral RNA of SARS-CoV-2 in pre-pandemic archival pediatric specimens collected before the announcement of the COVID-19 pandemic spread on March 20th, 2020, in Morocco. The objective is to investigate the existence of pre-pandemic immunity to SARS-CoV-2. METHODS: We conducted a cross-sectional study, to analyze IgG antibody levels in a cohort of 106 pre-pandemic pediatric participants. Using an indirect enzyme-linked immunosorbent assay (ELISA), we measured the IgG levels against the S and NP proteins of SARS-CoV-2. Additionally, we staged a competitive ELISA assay to evaluate the neutralizing capability of these antibodies. We used reverse transcription polymerase chain reaction (rRT-PCR) to detect viral NP and ORF1ab genes of SARS-CoV-2 in oropharyngeal swabs. Moreover, we conducted on the same specimens a multiplexed RT-PCR to detect RNA of the most common 27 pathogens involved in lower respiratory tract infections. RESULTS: Among the 106 serum samples, 13% (nn = =14) tested positive for SARS-CoV-2 IgG antibodies using ELISA. Temporal analysis indicated varying IgG positivity levels across 2019. Neutralizing antibodies were found in 21% of the 28 samples analyzed, including two with high inhibition rates (93%). The SARS-CoV-2 RNA was detected using rRT-PCR in 14 samples. None of the samples tested positive for the other 27 pathogens associated with lower respiratory tract infections, using multiplexed RT-PCR. CONCLUSION: Our study addresses the possibility, that COVID-19 infections occurred in Morocco before the recognized outbreak. On the other hand, some of the cases might reflect cross-reactivity with other coronaviruses or be influenced by previous viral exposures or vaccinations. Understanding these factors is crucial to comprehending pediatric immune responses to newly emerging infectious diseases.


Assuntos
Anticorpos Antivirais , COVID-19 , Imunoglobulina G , SARS-CoV-2 , Humanos , SARS-CoV-2/imunologia , Criança , Masculino , Feminino , Anticorpos Antivirais/sangue , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/epidemiologia , Estudos Transversais , Pré-Escolar , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Estudos Soroepidemiológicos , Adolescente , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , RNA Viral/sangue , Febre/imunologia , Febre/virologia , Febre/diagnóstico , Marrocos/epidemiologia , Ensaio de Imunoadsorção Enzimática , Fosfoproteínas
14.
PLoS Negl Trop Dis ; 18(6): e0012216, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38848311

RESUMO

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel tick-borne viral pathogen that causes severe fever with thrombocytopenia syndrome (SFTS). The disease was initially reported in central and eastern China, then later in Japan and South Korea, with a mortality rate of 13-30%. Currently, no vaccines or effective therapeutics are available for SFTS treatment. In this study, three monoclonal antibodies (mAbs) targeting the SFTSV envelope glycoprotein Gn were obtained using the hybridoma technique. Two mAbs recognized linear epitopes and did not neutralize SFTSV, while the mAb 40C10 can effectively neutralized SFTSV of different genotypes and also the SFTSV-related Guertu virus (GTV) and Heartland virus (HRTV) by targeting a spatial epitope of Gn. Additionally, the mAb 40C10 showed therapeutic effect in mice infected with different genotypes of SFTSV strains against death by preventing the development of lesions and by promoting virus clearance in tissues. The therapeutic effect could still be observed in mice infected with SFTSV which were administered with mAb 40C10 after infection even up to 4 days. These findings enhance our understanding of SFTSV immunogenicity and provide valuable information for designing detection methods and strategies targeting SFTSV antigens. The neutralizing mAb 40C10 possesses the potential to be further developed as a therapeutic monoclonal antibody against SFTSV and SFTSV-related viruses.


Assuntos
Anticorpos Monoclonais , Anticorpos Antivirais , Camundongos Endogâmicos BALB C , Phlebovirus , Phlebovirus/imunologia , Phlebovirus/genética , Animais , Anticorpos Monoclonais/imunologia , Camundongos , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/imunologia , Feminino , Febre Grave com Síndrome de Trombocitopenia/imunologia , Febre Grave com Síndrome de Trombocitopenia/virologia , Epitopos/imunologia , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/genética , Glicoproteínas/imunologia , Glicoproteínas/genética , Infecções por Bunyaviridae/imunologia , Infecções por Bunyaviridae/virologia , Infecções por Bunyaviridae/prevenção & controle , Humanos
15.
Cancer Med ; 13(11): e7304, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38826094

RESUMO

BACKGROUND: The surge in omicron variants has caused nationwide breakthrough infections in mainland China since the December 2022. In this study, we report the neutralization profiles of serum samples from the patients with breast cancer and the patients with liver cancer who had contracted subvariant breakthrough infections. METHODS: In this real-world study, we enrolled 143 COVID-19-vaccinated (81 and 62 patients with breast and liver cancers) and 105 unvaccinated patients with cancer (58 and 47 patients with breast and liver cancers) after omicron infection. Anti-spike receptor binding domain (RBD) IgGs and 50% pseudovirus neutralization titer (pVNT50) for the preceding (wild type), circulating omicron (BA.4-BA.5, and BF.7), and new subvariants (XBB.1.5) were comprehensively analyzed. RESULTS: Patients with liver cancer receiving booster doses had higher levels of anti-spike RBD IgG against circulating omicron (BA.4-BA.5, and BF.7) and a novel subvariant (XBB.1.5) compared to patients with breast cancer after breakthrough infection. Additionally, all vaccinated patients produced higher neutralizing antibody titers against circulating omicron (BA.4-BA.5, and BF.7) compared to unvaccinated patients. However, the unvaccinated patients produced higher neutralizing antibody against XBB.1.5 than vaccinated patients after Omicron infection, with this trend being more pronounced in breast cancer than in liver cancer patients. Moreover, we found that there was no correlation between anti-spike RBD IgG against wildtype virus and the neutralizing antibody titer, but a positive correlation between anti-spike RBD IgG and the neutralizing antibody against XBB.1.5 was found in unvaccinated patients. CONCLUSION: Our study found that there may be differences in vaccine response and protective effect against COVID-19 infection in patients with liver and breast cancer. Therefore, we recommend that COVID-19 vaccine strategies should be optimized based on vaccine components and immunology profiles of different patients with cancer.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Neoplasias da Mama , Vacinas contra COVID-19 , COVID-19 , Neoplasias Hepáticas , SARS-CoV-2 , Humanos , Feminino , COVID-19/imunologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/virologia , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/epidemiologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/virologia , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Pessoa de Meia-Idade , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , China/epidemiologia , Vacinas contra COVID-19/imunologia , Adulto , Idoso , Glicoproteína da Espícula de Coronavírus/imunologia , Masculino , Surtos de Doenças , Imunoglobulina G/sangue , Imunoglobulina G/imunologia
16.
EBioMedicine ; 104: 105170, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38823088

RESUMO

BACKGROUND: Ebola virus disease (EVD) survivors experience ocular sequelae including retinal lesions, cataracts, and vision loss. While monoclonal antibodies targeting the Ebola virus glycoprotein (EBOV-GP) have shown promise in improving prognosis, their effectiveness in mitigating ocular sequelae remains uncertain. METHODS: We developed and characterized a BSL-2-compatible immunocompetent mouse model to evaluate therapeutics targeting EBOV-GP by inoculating neonatal mice with vesicular stomatitis virus expressing EBOV-GP (VSV-EBOV). To examine the impact of anti-EBOV-GP antibody treatment on acute retinitis and ocular sequelae, VSV-EBOV-infected mice were treated with polyclonal antibodies or monoclonal antibody preparations with antibody-dependent cellular cytotoxicity (ADCC-mAb) or neutralizing activity (NEUT-mAb). FINDINGS: Treatment with all anti-EBOV-GP antibodies tested dramatically reduced viremia and improved survival. Further, all treatments reduced the incidence of cataracts. However, NEUT-mAb alone or in combination with ADCC-mAb reduced viral load in the eyes, downregulated the ocular immune and inflammatory responses, and minimized retinal damage more effectively. INTERPRETATION: Anti-EBOV-GP antibodies can improve survival among EVD patients, but improved therapeutics are needed to reduce life altering sequelae. This animal model offers a new platform to examine the acute and long-term effect of the virus in the eye and the relative impact of therapeutic candidates targeting EBOV-GP. Results indicate that even antibodies that improve systemic viral clearance and survival can differ in their capacity to reduce acute ocular inflammation, and long-term retinal pathology and corneal degeneration. FUNDING: This study was partly supported by Postgraduate Research Fellowship Awards from ORISE through an interagency agreement between the US DOE and the US FDA.


Assuntos
Anticorpos Antivirais , Modelos Animais de Doenças , Ebolavirus , Doença pelo Vírus Ebola , Animais , Camundongos , Ebolavirus/imunologia , Ebolavirus/patogenicidade , Doença pelo Vírus Ebola/virologia , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Humanos , Carga Viral , Glicoproteínas/imunologia , Glicoproteínas/metabolismo , Proteínas do Envelope Viral/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos
17.
Nat Commun ; 15(1): 5025, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38871701

RESUMO

Influenza A viruses in swine have considerable genetic diversity and continue to pose a pandemic threat to humans due to a potential lack of population level immunity. Here we describe a pipeline to characterize and triage influenza viruses for their pandemic risk and examine the pandemic potential of two widespread swine origin viruses. Our analysis reveals that a panel of human sera collected from healthy adults in 2020 has no cross-reactive neutralizing antibodies against a α-H1 clade strain (α-swH1N2) but do against a γ-H1 clade strain. The α-swH1N2 virus replicates efficiently in human airway cultures and exhibits phenotypic signatures similar to the human H1N1 pandemic strain from 2009 (H1N1pdm09). Furthermore, α-swH1N2 is capable of efficient airborne transmission to both naïve ferrets and ferrets with prior seasonal influenza immunity. Ferrets with H1N1pdm09 pre-existing immunity show reduced α-swH1N2 viral shedding and less severe disease signs. Despite this, H1N1pdm09-immune ferrets that became infected via the air can still onward transmit α-swH1N2 with an efficiency of 50%. These results indicate that this α-swH1N2 strain has a higher pandemic potential, but a moderate level of impact since there is reduced replication fitness and pathology in animals with prior immunity.


Assuntos
Furões , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H1N2 , Influenza Humana , Infecções por Orthomyxoviridae , Pandemias , Animais , Furões/virologia , Humanos , Suínos , Influenza Humana/virologia , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Influenza Humana/sangue , Influenza Humana/transmissão , Infecções por Orthomyxoviridae/virologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/epidemiologia , Infecções por Orthomyxoviridae/transmissão , Infecções por Orthomyxoviridae/sangue , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Vírus da Influenza A Subtipo H1N2/genética , Vírus da Influenza A Subtipo H1N2/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Doenças dos Suínos/virologia , Doenças dos Suínos/epidemiologia , Doenças dos Suínos/imunologia , Doenças dos Suínos/transmissão , Doenças dos Suínos/sangue , Feminino , Eliminação de Partículas Virais , Masculino , Adulto , Replicação Viral
18.
J Med Virol ; 96(6): e29738, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38884390

RESUMO

Immunocompromised individuals are at significantly elevated risk for severe courses of coronavirus disease 2019 (COVID-19). In addition to vaccination, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies (nAbs) have been applied throughout the pandemic, with time of treatment onset and potency against the currently prevailing virus variant identified as relevant factors for medical benefit. Using data from the European Society for Immunodeficiencies (ESID) registry, the present study evaluated COVID-19 cases in three groups of patients with inborn errors of immunity (IEI; 981 agammaglobulinemia patients on immunoglobulin replacement therapy (IGRT); 8960 non-agammaglobulinemia patients on IGRT; 14 428 patients without IGRT), and the neutralizing capacity of 1100 immunoglobulin lots against SARS-CoV-2 ("Wuhan" and Omicron strains), throughout 3 years. From the first (2020/2021) to the second (2021/2022) cold season, i.e., during the virus drift to the more contagious Omicron variants, an increase in case numbers was recorded that was comparable (~2- to 3-fold) for all three study groups. During the same period, immunoglobulin lots showed a profound nAb increase against the archetypal SARS-CoV-2 strain, yet only low levels of Omicron nAbs. Notably, shortly before the third (2022/2023) cold season, Omicron-neutralizing capacity of released immunoglobulin lots had plateaued at high levels. From the second to the third cold season, COVID-19 cases dropped markedly. While a ~6-fold case reduction was recorded for the groups of non-agammaglobulinemia patients on IGRT and IEI patients not receiving IGRT, the decline was ~30-fold for the group of agammaglobulinemia patients on IGRT. These findings suggest a substantial COVID-19-protective effect of IGRT, at least for distinct groups of antibody-deficient patients.


Assuntos
Agamaglobulinemia , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19 , SARS-CoV-2 , Humanos , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , COVID-19/imunologia , COVID-19/terapia , Masculino , SARS-CoV-2/imunologia , Feminino , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Pessoa de Meia-Idade , Adolescente , Idoso , Adulto Jovem , Criança , Pré-Escolar , Resultado do Tratamento , Imunoglobulinas/uso terapêutico , Imunoglobulinas/imunologia
19.
J Med Virol ; 96(6): e29743, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38884419

RESUMO

As one of the most effective measures to prevent seasonal influenza viruses, annual influenza vaccination is globally recommended. Nevertheless, evidence regarding the impact of repeated vaccination to contemporary and future influenza has been inconclusive. A total of 100 subjects singly or repeatedly immunized with influenza vaccines including 3C.2a1 or 3C.3a1 A(H3N2) during 2018-2019 and 2019-2020 influenza season were recruited. We investigated neutralization antibody by microneutralization assay using four antigenically distinct A(H3N2) viruses circulating from 2018 to 2023, and tracked the dynamics of B cell receptor (BCR) repertoire for consecutive vaccinations. We found that vaccination elicited cross-reactive antibody responses against future emerging strains. Broader neutralizing antibodies to A(H3N2) viruses and more diverse BCR repertoires were observed in the repeated vaccination. Meanwhile, a higher frequency of BCR sequences shared among the repeated-vaccinated individuals with consistently boosting antibody response was found than those with a reduced antibody response. Our findings suggest that repeated seasonal vaccination could broaden the breadth of antibody responses, which may improve vaccine protection against future emerging viruses.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Reações Cruzadas , Vírus da Influenza A Subtipo H3N2 , Vacinas contra Influenza , Influenza Humana , Humanos , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Influenza Humana/prevenção & controle , Influenza Humana/imunologia , Influenza Humana/virologia , Adulto , Reações Cruzadas/imunologia , Masculino , Feminino , Vacinação , Pessoa de Meia-Idade , Adulto Jovem , Testes de Neutralização , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/genética , Adolescente
20.
Cell Mol Life Sci ; 81(1): 267, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38884678

RESUMO

Neutralizing antibodies are considered a correlate of protection against severe human respiratory syncytial virus (HRSV) disease. Currently, HRSV neutralization assays are performed on immortalized cell lines like Vero or A549 cells. It is known that assays on these cell lines exclusively detect neutralizing antibodies (nAbs) directed to the fusion (F) protein. For the detection of nAbs directed to the glycoprotein (G), ciliated epithelial cells expressing the cellular receptor CX3CR1 are required, but generation of primary cell cultures is expensive and labor-intensive. Here, we developed a high-throughput neutralization assay based on the interaction between clinically relevant HRSV grown on primary cells with ciliated epithelial cells, and validated this assay using a panel of infant sera. To develop the high-throughput neutralization assay, we established a culture of differentiated apical-out airway organoids (Ap-O AO). CX3CR1 expression was confirmed, and both F- and G-specific monoclonal antibodies neutralized HRSV in the Ap-O AO. In a side-by-side neutralization assay on Vero cells and Ap-O AO, neutralizing antibody levels in sera from 125 infants correlated well, although titers on Ap-O AO were consistently lower. We speculate that these lower titers might be an actual reflection of the neutralizing antibody capacity in vivo. The organoid-based neutralization assay described here holds promise for further characterization of correlates of protection against HRSV disease.


Assuntos
Anticorpos Neutralizantes , Receptor 1 de Quimiocina CX3C , Testes de Neutralização , Organoides , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Humanos , Vírus Sincicial Respiratório Humano/imunologia , Anticorpos Neutralizantes/imunologia , Organoides/metabolismo , Organoides/imunologia , Organoides/virologia , Organoides/citologia , Animais , Testes de Neutralização/métodos , Chlorocebus aethiops , Células Vero , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Receptor 1 de Quimiocina CX3C/metabolismo , Receptor 1 de Quimiocina CX3C/imunologia , Anticorpos Antivirais/imunologia , Proteínas Virais de Fusão/imunologia , Proteínas Virais de Fusão/metabolismo , Lactente , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Células Epiteliais/virologia , Anticorpos Monoclonais/imunologia
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