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1.
Genes (Basel) ; 12(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202032

RESUMO

Peripheral blood transcriptome is a highly promising area for biomarker development. However, transcript abundances (TA) in these cell mixture samples are confounded by proportions of the component leukocyte subpopulations. This poses a challenge to clinical applications, as the cell of origin of any change in TA is not known without prior cell separation procedure. We developed a framework to develop a cell-type informative TA biomarkers which enable determination of TA of a single cell-type (B lymphocytes) directly in cell mixture samples of peripheral blood (e.g., peripheral blood mononuclear cells, PBMC) without the need for subpopulation separation. It is applicable to a panel of genes called B cell informative genes. Then a ratio of two B cell informative genes (a target gene and a stably expressed reference gene) obtained in PBMC was used as a new biomarker to represent the target gene expression in purified B lymphocytes. This approach, which eliminates the tedious procedure of cell separation and directly determines TA of a leukocyte subpopulation in peripheral blood samples, is called the Direct LS-TA method. This method is applied to gene expression datasets collected in influenza vaccination trials as early predictive biomarkers of seroconversion. By using TNFRSF17 or TXNDC5 as the target genes and TNFRSF13C or FCRLA as the reference genes, the Direct LS-TA B cell biomarkers were determined directly in the PBMC transcriptome data and were highly correlated with TA of the corresponding target genes in purified B lymphocytes. Vaccination responders had almost a 2-fold higher Direct LS-TA biomarker level of TNFRSF17 (log 2 SMD = 0.84, 95% CI = 0.47-1.21) on day 7 after vaccination. The sensitivity of these Direct LS-TA biomarkers in the prediction of seroconversion was greater than 0.7 and area-under curves (AUC) were over 0.8 in many datasets. In this paper, we report a straightforward approach to directly estimate B lymphocyte gene expression in PBMC, which could be used in a routine clinical setting. Moreover, the method enables the practice of precision medicine in the prediction of vaccination response. More importantly, seroconversion could now be predicted as early as day 7. As the acquired immunology pathway is common to vaccination against influenza and COVID-19, these biomarkers could also be useful to predict seroconversion for the new COVID-19 vaccines.


Assuntos
Linfócitos B/fisiologia , Expressão Gênica , Vacinas contra Influenza/imunologia , Soroconversão/genética , Receptor do Fator Ativador de Células B/genética , Biomarcadores/análise , Vacinas contra COVID-19/imunologia , Biologia Computacional/métodos , Bases de Dados Genéticas , Humanos , Leucócitos Mononucleares/fisiologia , Modelos Teóricos , Metanálise em Rede , Isomerases de Dissulfetos de Proteínas/genética , Curva ROC , Receptores Fc/genética , Soroconversão/fisiologia
2.
Recurso na Internet em Português | LIS - Localizador de Informação em Saúde | ID: lis-48237

RESUMO

A Fiocruz Pernambuco está apoiando uma importante pesquisa, envolvendo testes clínicos em humanos, para uma vacina tetravalente contra a gripe.


Assuntos
Vacinas contra Influenza/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Influenza Humana/imunologia
3.
Nat Commun ; 12(1): 3789, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145279

RESUMO

Influenza viruses are a major public health problem. Vaccines are the best available countermeasure to induce effective immunity against infection with seasonal influenza viruses; however, the breadth of antibody responses in infection versus vaccination is quite different. Here, we show that nasal infection controls two sequential processes to induce neutralizing IgG antibodies recognizing the hemagglutinin (HA) of heterotypic strains. The first is viral replication in the lung, which facilitates exposure of shared epitopes that are otherwise hidden from the immune system. The second process is the germinal center (GC) response, in particular, IL-4 derived from follicular helper T cells has an essential role in the expansion of rare GC-B cells recognizing the shared epitopes. Therefore, the combination of exposure of the shared epitopes and efficient proliferation of GC-B cells is critical for generating broadly-protective antibodies. These observations provide insight into mechanisms promoting broad protection from virus infection.


Assuntos
Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Hemaglutininas Virais/imunologia , Interleucina-4/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Anticorpos Antivirais/sangue , Anticorpos Amplamente Neutralizantes/sangue , Epitopos/imunologia , Feminino , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H2N2/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Células T Auxiliares Foliculares/imunologia , Vacinação
4.
Nat Commun ; 12(1): 2691, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976217

RESUMO

How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/ß cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8+ or CD4+ T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.


Assuntos
Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/imunologia , Influenza Humana/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Estudos de Coortes , Citocinas/metabolismo , Hospitalização/estatística & dados numéricos , Humanos , Vírus da Influenza A/classificação , Vírus da Influenza A/genética , Vírus da Influenza A/fisiologia , Vacinas contra Influenza/imunologia , Influenza Humana/virologia , Pessoa de Meia-Idade , Filogenia , Vacinação/métodos
5.
J Virol ; 95(15): e0053021, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-33952647

RESUMO

Elicitation of lung tissue-resident memory CD8 T cells (TRMs) is a goal of T cell-based vaccines against respiratory viral pathogens, such as influenza A virus (IAV). C-C chemokine receptor type 2 (CCR2)-dependent monocyte trafficking plays an essential role in the establishment of CD8 TRMs in lungs of IAV-infected mice. Here, we used a combination adjuvant-based subunit vaccine strategy that evokes multifaceted (TC1/TC17/TH1/TH17) IAV nucleoprotein-specific lung TRMs to determine whether CCR2 and monocyte infiltration are essential for vaccine-induced TRM development and protective immunity to IAV in lungs. Following intranasal vaccination, neutrophils, monocytes, conventional dendritic cells (DCs), and monocyte-derived dendritic cells internalized and processed vaccine antigen in lungs. We found that basic leucine zipper ATF-like transcription factor 3 (BATF3)-dependent DCs were essential for eliciting T cell responses, but CCR2 deficiency enhanced the differentiation of CD127hi, KLRG-1lo, OX40+ve CD62L+ve, and mucosally imprinted CD69+ve CD103+ve effector and memory CD8 T cells in lungs and airways of vaccinated mice. Mechanistically, increased development of lung TRMs induced by CCR2 deficiency was linked to dampened expression of T-bet but not altered TCF-1 levels or T cell receptor signaling in CD8 T cells. T1/T17 functional programming, parenchymal localization of CD8/CD4 effector and memory T cells, recall T cell responses, and protective immunity to a lethal IAV infection were unaffected in CCR2-deficient mice. Taken together, we identified a negative regulatory role for CCR2 and monocyte trafficking in mucosal imprinting and differentiation of vaccine-induced TRMs. Mechanistic insights from this study may aid the development of T-cell-based vaccines against respiratory viral pathogens, including IAV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). IMPORTANCE While antibody-based immunity to influenza A virus (IAV) is type and subtype specific, lung- and airway-resident memory T cells that recognize conserved epitopes in the internal viral proteins are known to provide heterosubtypic immunity. Hence, broadly protective IAV vaccines need to elicit robust T cell memory in the respiratory tract. We have developed a combination adjuvant-based IAV nucleoprotein vaccine that elicits strong CD4 and CD8 T cell memory in lungs and protects against H1N1 and H5N1 strains of IAV. In this study, we examined the mechanisms that control vaccine-induced protective memory T cells in the respiratory tract. We found that trafficking of monocytes into lungs might limit the development of antiviral lung-resident memory T cells following intranasal vaccination. These findings suggest that strategies that limit monocyte infiltration can potentiate vaccine-induced frontline T-cell immunity to respiratory viruses, such as IAV and SARS-CoV-2.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade nas Mucosas , Memória Imunológica , Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/imunologia , Receptores CCR2/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Vírus da Influenza A/genética , Vacinas contra Influenza/genética , Vacinas contra Influenza/farmacologia , Pulmão/imunologia , Camundongos , Camundongos Knockout , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/prevenção & controle , Receptores CCR2/genética
6.
Nat Commun ; 12(1): 3073, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031386

RESUMO

Follicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate TFH function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying TFH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human TFH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs TFH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of TFH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.


Assuntos
Formação de Anticorpos/imunologia , Vacinas contra Influenza/imunologia , Leptina/metabolismo , Animais , Anticorpos Antivirais/imunologia , Diferenciação Celular , Feminino , Homeostase , Humanos , Imunização , Influenza Humana/prevenção & controle , Leptina/deficiência , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Vacinação/métodos
7.
Sci Rep ; 11(1): 11025, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34040014

RESUMO

The coronavirus disease of 2019 (COVID-19) has caused a global pandemic and led to nearly three million deaths globally. As of April 2021, there are still many countries that do not have COVID-19 vaccines. Before the COVID-19 vaccines were developed, some evidence suggested that an influenza vaccine may stimulate nonspecific immune responses that reduce the risk of COVID-19 infection or the severity of COVID-19 illness after infection. This study evaluated the association between influenza vaccination and the risk of COVID-19 infection. We conducted a retrospective cross-sectional study with data from July 1, 2019, to June 30, 2020 with the Claims data from Symphony Health database. The study population was adults age 65 years old or older who received influenza vaccination between September 1 and December 31 of 2019. The main outcomes and measures were odds of COVID-19 infection and severe COVID-19 illness after January 15, 2020. We found the adjusted odds ratio (aOR) of COVID-19 infection risk between the influenza-vaccination group and no-influenza-vaccination group was 0.76 (95% confidence interval (CI), 0.75-0.77). Among COVID-19 patients, the aOR of developing severe COVID-19 illness was 0.72 (95% CI, 0.68-0.76) between the influenza-vaccination group and the no-influenza-vaccination group. When the influenza-vaccination group and the other-vaccination group were compared, the aOR of COVID-19 infection was 0.95 (95% CI, 0.93-0.97), and the aOR of developing a severe COVID-19 illness was 0.95 (95% CI, 0.80-1.13). The influenza vaccine may marginally protect people from COVID-19 infection.


Assuntos
COVID-19/imunologia , Vírus da Influenza A/fisiologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , SARS-CoV-2/fisiologia , Idoso , Idoso de 80 Anos ou mais , COVID-19/epidemiologia , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Masculino , Razão de Chances , Pandemias , Estudos Retrospectivos , Risco , Estados Unidos/epidemiologia , Vacinação
8.
Med Sci Monit ; 27: e929572, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-33994536

RESUMO

BACKGROUND Obesity is associated with susceptibility to severe influenza infection and several disturbances of the immune response to the influenza vaccine. However, the effect of obesity on the immunogenicity of the influenza vaccine is not fully understood. Our objective here was to assess the immunogenicity of the split, inactivated quadrivalent influenza vaccine (QIV) in Polish adults with obesity. MATERIAL AND METHODS Fifty-three subjects with obesity aged 21-69 years were vaccinated with the QIV in 2017/2018 season. Antibody titers against the 4 vaccine strains were measured using the hemagglutination inhibition (HI) assay. The mean fold antibody increase (MFI), seroprotection rate (protection rate, PR), and seroconversion rate (response rate, RR) were calculated to assess vaccine immunogenicity. RESULTS The vaccine elicited a significant increase in the anti-HI titers against the QIV antigens. The MFI, PR, and RR for the QIV antigens also reached the required age-specific values, indicating the QIV meets current immunogenicity criteria. Individuals with class I and class II/III obesity had similar anti-HI titers, MFI, PR, and RR to each of the vaccine strains. Adults aged <60 years had similar anti-HI titers, MFI, PR, and RR to the QIV strains to those aged ≥60 years. CONCLUSIONS Our results indicate that the split virion, inactivated QIV is immunogenic in adults with obesity regardless of their degree of obesity and age (ie, <60 and ≥60 years).


Assuntos
Imunogenicidade da Vacina/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Obesidade/imunologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , Feminino , Humanos , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Obesidade/virologia , Estações do Ano , Soroconversão/fisiologia , Adulto Jovem
9.
Recurso na Internet em Português | LIS - Localizador de Informação em Saúde | ID: lis-48179

RESUMO

A Organização Pan-Americana da Saúde (OPAS) participou nesta segunda-feira (12) do lançamento da campanha de vacinação contra a gripe no Brasil. O Ministério da Saúde do país vai distribuir 80 milhões de doses da vacina influenza trivalente, produzida pelo Instituto Butantan, para imunizar um público-alvo de 79,7 milhões de pessoas. A campanha vai até o dia 9 de julho.


Assuntos
Programas de Imunização , Vacinação , Brasil , Vacinas contra Influenza/imunologia
10.
Biochem Biophys Res Commun ; 554: 166-172, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33798943

RESUMO

Although influenza vaccines are effective for reducing viral transmission and the severity of clinical symptoms, influenza viruses still induce considerable morbidity and mortality worldwide. Seasonal influenza viruses infect the upper respiratory tract initially but then often induce severe pulmonary complications in the lower respiratory tract. Therefore, influenza vaccines that prevent viral infection at both the upper and lower respiratory tracts are highly anticipated. Here, we examined whether using different vaccination routes for priming and boosting achieved protection in both regions of the respiratory tract. To this end, we used inactivated whole-virion influenza vaccines to immunize mice either subcutaneously or intranasally for both priming and boosting. Regardless of the route used for boosting, the levels of virus-specific IgG in plasma were higher in mice primed subcutaneously than those in control mice, which received PBS only. In addition, intranasal priming followed by subcutaneous boosting induced higher levels of virus-specific IgG in plasma than those in control mice. The levels of virus-specific nasal IgA were higher in mice that were primed intranasally than in control mice or in mice primed subcutaneously. Furthermore, intranasal priming but not subcutaneous priming provided protection against viral challenge in the upper respiratory tract. In addition, when coupled with subcutaneous boosting, both subcutaneous and intranasal priming protected against viral challenge in the lower respiratory tract. These results indicate that intranasal priming followed by subcutaneous boosting induces both virus-specific IgG in plasma and IgA in nasal washes and protects against virus challenge in both the upper and lower respiratory tracts. Our results will help to develop novel vaccines against influenza viruses and other respiratory viruses.


Assuntos
Anticorpos Neutralizantes/imunologia , Vacinas contra Influenza/administração & dosagem , Infecções por Orthomyxoviridae/prevenção & controle , Orthomyxoviridae/imunologia , Infecções Respiratórias/prevenção & controle , Administração Intranasal , Animais , Anticorpos Antivirais/sangue , Modelos Animais de Doenças , Vacinas contra Influenza/imunologia , Injeções Subcutâneas/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Orthomyxoviridae/isolamento & purificação , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Infecções Respiratórias/patologia , Infecções Respiratórias/virologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia
11.
Scand J Immunol ; 94(2): e13045, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33891354

RESUMO

There is limited knowledge of influenza-specific immune responses and their kinetics in critically ill patients. We investigated humoral and cellular immune responses after critical influenza A/H1N1 infection and hypothesized that dysfunctionality or absence of immune responses could contribute to more severe illness. We followed 12 patients hospitalized with severe influenza infection; the majority admitted to intensive care unit (ICU). Blood samples were collected at days 10 and 19 and at 5 months. Antibody responses to surface glycoproteins haemagglutinin (HA) and neuraminidase (NA) of A/H1N1pdm09 were quantified by haemagglutination inhibition (HAI), microneutralization (MN), Enzyme-linked immunosorbent assay (ELISA) and Enzyme-linked lectin assay (ELLA). Influenza-specific antibody levels and avidity were measured separately for head and stalk domains of H1. Cytokine secreting CD4+ and CD8+ T cell responses to conserved influenza epitopes (M1, NP and PB1) were analysed by FluoroSpot. Overall, the patients retained a high level of functional HA- and NA-specific antibodies over the study period. During the acute phase (up to 3 weeks from symptom onset), antibodies specific to H1 stalk increased earlier and were present in higher amount compared with H1 head-specific antibodies. The NA-specific antibodies and the non-neutralizing HA-specific antibody response for H1 head and H1 full-length showed a significant decline from acute to convalescent phase. Despite high total IgG concentrations, avidity to H1 head and H1 full-length protein remained low at all time points. Similarly, CD8+ T cell responses were continuously measured at low levels. In conclusion, our study found that critically ill patients were characterized by low HA-specific antibody avidity and CD8+ T cell response.


Assuntos
Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Estado Terminal , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Vacinas contra Influenza/imunologia , Masculino , Pessoa de Meia-Idade
12.
J Virol ; 95(12)2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-33827939

RESUMO

Currently, immunization with inactivated influenza virus vaccines is the most prevalent method to prevent infections. However, licensed influenza vaccines provide only strain-specific protection and need to be updated and administered yearly; thus, new vaccines that provide broad protection against multiple influenza virus subtypes are required. In this study, we demonstrated that intradermal immunization with gp96-adjuvanted seasonal influenza monovalent H1N1 split vaccine could induce cross-protection against both group 1 and group 2 influenza A viruses in BALB/c mouse models. Vaccination in the presence of gp96 induced an apparently stronger antigen-specific T cell response than split vaccine alone. Immunization with the gp96-adjuvanted vaccine also elicited an apparent cross-reactive CD8+ T cell response that targeted the conserved epitopes across different influenza virus strains. These cross-reactive CD8+ T cells might be recalled from a pool of memory cells established after vaccination and recruited from extrapulmonary sites to facilitate viral clearance. Of note, six highly conserved CD8+ T epitopes from the viral structural proteins hemagglutinin (HA), M1, nucleoprotein (NP), and PB1 were identified to play a synergistic role in gp96-mediated cross-protection. Comparative analysis showed that most of conservative epitope-specific cytotoxic T lymphocytes (CTLs) apparently induced by heterologous virus infection were also activated by gp96-adjuvanted vaccine, thus resulting in broader protective CD8+ T cell responses. Our results demonstrated the advantage of adding gp96 to an existing seasonal influenza vaccine to improve its ability to provide better cross-protection.IMPORTANCE Owing to continuous mutations in hemagglutinin (HA) or neuraminidase (NA) or recombination of the gene segments between different strains, influenza viruses can escape the immune responses developed by vaccination. Thus, new strategies aimed to efficiently activate immune response that targets to conserved regions among different influenza viruses are urgently needed in designing broad-spectrum influenza vaccine. Heat shock protein gp96 is currently the only natural T cell adjuvant with special ability to cross-present coupled antigen to major histocompatibility complex class I (MHC-I) molecule and activate the downstream antigen-specific CTL response. In this study, we demonstrated the advantages of adding gp96 to monovalent split influenza virus vaccine to improve its ability to provide cross-protection in the BALB/c mouse model and proved that a gp96-activated cross-reactive CTL response is indispensable in our vaccine strategy. Due to its unique adjuvant properties, gp96 might be a promising adjuvant for designing new broad-spectrum influenza vaccines.


Assuntos
Adjuvantes Imunológicos , Linfócitos T CD8-Positivos/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Glicoproteínas de Membrana/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Animais , Anticorpos Antivirais/sangue , Proteção Cruzada , Reações Cruzadas , Epitopos/imunologia , Epitopos de Linfócito T/imunologia , Testes de Inibição da Hemaglutinação , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Imunidade Heteróloga , Imunoglobulina G/sangue , Vírus da Influenza A Subtipo H3N2/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neuraminidase/imunologia , Proteínas do Nucleocapsídeo/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Proteínas da Matriz Viral/imunologia , Proteínas Virais/imunologia
13.
Nat Commun ; 12(1): 2283, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863907

RESUMO

Narcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with HLA-DQB1*0602, thereby suggesting an immunological origin. Increased risk of NT1 has been reported among children or adolescents vaccinated with AS03 adjuvant-supplemented pandemic H1N1 influenza A vaccine, Pandemrix. Here we show that pediatric Pandemrix-associated NT1 patients have enhanced T-cell immunity against the viral epitopes, neuraminidase 175-189 (NA175-189) and nucleoprotein 214-228 (NP214-228), but also respond to a NA175-189-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1675-689). A pathogenic role of influenza virus-specific T-cells and T-cell cross-reactivity in NT1 are supported by the up-regulation of IFN-γ, perforin 1 and granzyme B, and by the converging selection of T-cell receptor TRAV10/TRAJ17 and TRAV10/TRAJ24 clonotypes, in response to stimulation either with peptide NA175-189 or POMT1675-689. Moreover, anti-POMT1 serum autoantibodies are increased in Pandemrix-vaccinated children or adolescents. These results thus identify POMT1 as a potential autoantigen recognized by T- and B-cells in NT1.


Assuntos
Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/efeitos adversos , Influenza Humana/prevenção & controle , Manosiltransferases/imunologia , Narcolepsia/imunologia , Adolescente , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoantígenos/imunologia , Linfócitos B/imunologia , Antígenos CD4/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Reações Cruzadas/imunologia , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Feminino , Cadeias beta de HLA-DQ/imunologia , Humanos , Lactente , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Influenza Humana/virologia , Masculino , Camundongos Transgênicos , Narcolepsia/sangue , Narcolepsia/induzido quimicamente , Neuraminidase/imunologia , Linfócitos T/imunologia , Proteínas Virais/imunologia , Adulto Jovem
14.
J Infect Dis ; 224(1): 49-59, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-33755731

RESUMO

BACKGROUND: We investigated frequency of reinfection with seasonal human coronaviruses (HCoVs) and serum antibody response following infection over 8 years in the Household Influenza Vaccine Evaluation (HIVE) cohort. METHODS: Households were followed annually for identification of acute respiratory illness with reverse-transcription polymerase chain reaction-confirmed HCoV infection. Serum collected before and at 2 time points postinfection were tested using a multiplex binding assay to quantify antibody to seasonal, severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins and SARS-CoV-2 spike subdomains and N protein. RESULTS: Of 3418 participants, 40% were followed for ≥3 years. A total of 1004 HCoV infections were documented; 303 (30%) were reinfections of any HCoV type. The number of HCoV infections ranged from 1 to 13 per individual. The mean time to reinfection with the same type was estimated at 983 days for 229E, 578 days for HKU1, 615 days for OC43, and 711 days for NL63. Binding antibody levels to seasonal HCoVs were high, with little increase postinfection, and were maintained over time. Homologous, preinfection antibody levels did not significantly correlate with odds of infection, and there was little cross-response to SARS-CoV-2 proteins. CONCLUSIONS: Reinfection with seasonal HCoVs is frequent. Binding anti-spike protein antibodies do not correlate with protection from seasonal HCoV infection.


Assuntos
Infecções por Coronavirus/epidemiologia , Coronavirus , Características da Família , Vacinas contra Influenza/imunologia , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Síndrome Respiratória Aguda Grave/epidemiologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/epidemiologia , COVID-19/virologia , Coinfecção/epidemiologia , Coronavirus/classificação , Coronavirus/genética , Coronavirus/imunologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Reações Cruzadas/imunologia , Humanos , Vacinas contra Influenza/administração & dosagem , Influenza Humana/virologia , Estimativa de Kaplan-Meier , Michigan/epidemiologia , Modelos de Riscos Proporcionais , Vigilância em Saúde Pública , Reinfecção/epidemiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2 , Estações do Ano , Estudos Soroepidemiológicos , Síndrome Respiratória Aguda Grave/diagnóstico , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Carga Viral
15.
Front Immunol ; 12: 584299, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746943

RESUMO

Parenteral administration of killed/inactivated swine influenza A virus (SwIAV) vaccine in weaned piglets provides variable levels of immunity due to the presence of preexisting virus specific maternal derived antibodies (MDA). To overcome the effect of MDA on SwIAV vaccine in piglets, we developed an intranasal deliverable killed SwIAV antigen (KAg) encapsulated chitosan nanoparticles called chitosan-based NPs encapsulating KAg (CS NPs-KAg) vaccine. Further, to target the candidate vaccine to dendritic cells and macrophages which express mannose receptor, we conjugated mannose to chitosan (mCS) and formulated KAg encapsulated mCS nanoparticles called mannosylated chitosan-based NPs encapsulating KAg (mCS NPs-KAg) vaccine. In MDA-positive piglets, prime-boost intranasal inoculation of mCS NPs-KAg vaccine elicited enhanced homologous (H1N2-OH10), heterologous (H1N1-OH7), and heterosubtypic (H3N2-OH4) influenza virus-specific secretory IgA (sIgA) antibody response in nasal passage compared to CS NPs-KAg vaccinates. In vaccinated upon challenged with a heterologous SwIAV H1N1, both mCS NPs-KAg and CS NPs-KAg vaccinates augmented H1N2-OH10, H1N1-OH7, and H3N2-OH4 virus-specific sIgA antibody responses in nasal swab, lung lysate, and bronchoalveolar lavage (BAL) fluid; and IgG antibody levels in lung lysate and BAL fluid samples. Whereas, the multivalent commercial inactivated SwIAV vaccine delivered intramuscularly increased serum IgG antibody response. In mCS NPs-KAg and CS NPs-KAg vaccinates increased H1N2-OH10 but not H1N1-OH7 and H3N2-OH4-specific serum hemagglutination inhibition titers were observed. Additionally, mCS NPs-KAg vaccine increased specific recall lymphocyte proliferation and cytokines IL-4, IL-10, and IFNγ gene expression compared to CS NPs-KAg and commercial SwIAV vaccinates in tracheobronchial lymph nodes. Consistent with the immune response both mCS NPs-KAg and CS NPs-KAg vaccinates cleared the challenge H1N1-OH7 virus load in upper and lower respiratory tract more efficiently when compared to commercial vaccine. The virus clearance was associated with reduced gross lung lesions. Overall, mCS NP-KAg vaccine intranasal immunization in MDA-positive pigs induced a robust cross-reactive immunity and offered protection against influenza virus.


Assuntos
Quitosana/imunologia , Imunidade/imunologia , Vacinas contra Influenza/imunologia , Manose/imunologia , Infecções por Orthomyxoviridae/imunologia , Doenças dos Suínos/imunologia , Animais , Anticorpos Antivirais/imunologia , Células Cultivadas , Quitosana/metabolismo , Cães , Feminino , Imunidade/efeitos dos fármacos , Vacinas contra Influenza/administração & dosagem , Células Madin Darby de Rim Canino , Manose/metabolismo , Nanopartículas/administração & dosagem , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/virologia , Gravidez , Suínos , Doenças dos Suínos/prevenção & controle , Doenças dos Suínos/virologia , Vacinação/métodos , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia
16.
PLoS Pathog ; 17(3): e1009330, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33662023

RESUMO

Pigs are natural hosts for the same subtypes of influenza A viruses as humans and integrally involved in virus evolution with frequent interspecies transmissions in both directions. The emergence of the 2009 pandemic H1N1 virus illustrates the importance of pigs in evolution of zoonotic strains. Here we generated pig influenza-specific monoclonal antibodies (mAbs) from H1N1pdm09 infected pigs. The mAbs recognized the same two major immunodominant haemagglutinin (HA) epitopes targeted by humans, one of which is not recognized by post-infection ferret antisera that are commonly used to monitor virus evolution. Neutralizing activity of the pig mAbs was comparable to that of potent human anti-HA mAbs. Further, prophylactic administration of a selected porcine mAb to pigs abolished lung viral load and greatly reduced lung pathology but did not eliminate nasal shedding of virus after H1N1pdm09 challenge. Hence mAbs from pigs, which target HA can significantly reduce disease severity. These results, together with the comparable sizes of pigs and humans, indicate that the pig is a valuable model for understanding how best to apply mAbs as therapy in humans and for monitoring antigenic drift of influenza viruses in humans, thereby providing information highly relevant to making influenza vaccine recommendations.


Assuntos
Anticorpos Antivirais/farmacologia , Epitopos/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Influenza Humana/tratamento farmacológico , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Hemaglutininas/imunologia , Hemaglutininas/farmacologia , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/virologia , Suínos
17.
PLoS Pathog ; 17(3): e1009324, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33735218

RESUMO

The development of safe subunit vaccines requires adjuvants that augment immunogenicity of non-replicating protein-based antigens. Current vaccines against infectious diseases preferentially induce protective antibodies driven by adjuvants such as alum. However, the contribution of antibody to host defense is limited for certain classes of infectious diseases such as fungi, whereas animal studies and clinical observations implicate cellular immunity as an essential component of the resolution of fungal pathogens. Here, we decipher the structural bases of a newly identified glycoprotein ligand of Dectin-2 with potent adjuvancy, Blastomyces endoglucanase-2 (Bl-Eng2). We also pinpoint the developmental steps of antigen-specific CD4+ and CD8+ T responses augmented by Bl-Eng2 including expansion, differentiation and tissue residency. Dectin-2 ligation led to successful systemic and mucosal vaccination against invasive fungal infection and Influenza A infection, respectively. O-linked glycans on Bl-Eng2 applied at the skin and respiratory mucosa greatly augment vaccine subunit- induced protective immunity against lethal influenza and fungal pulmonary challenge.


Assuntos
Anticorpos Antivirais/imunologia , Blastomyces/imunologia , Vacinas Fúngicas/imunologia , Infecções por Orthomyxoviridae/imunologia , Adjuvantes Imunológicos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Celulase/imunologia , Vacinas contra Influenza/imunologia
18.
Nat Commun ; 12(1): 1722, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741916

RESUMO

Broadly neutralizing antibodies (bnAbs) have been developed as potential countermeasures for seasonal and pandemic influenza. Deep characterization of these bnAbs and polyclonal sera provides pivotal understanding for influenza immunity and informs effective vaccine design. However, conventional virus neutralization assays require high-containment laboratories and are difficult to standardize and roboticize. Here, we build a panel of engineered influenza viruses carrying a reporter gene to replace an essential viral gene, and develop an assay using the panel for in-depth profiling of neutralizing antibodies. Replication of these viruses is restricted to cells expressing the missing viral gene, allowing it to be manipulated in a biosafety level 2 environment. We generate the neutralization profile of 24 bnAbs using a 55-virus panel encompassing the near-complete diversity of human H1N1 and H3N2, as well as pandemic subtype viruses. Our system offers in-depth profiling of influenza immunity, including the antibodies against the hemagglutinin stem, a major target of universal influenza vaccines.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vírus da Influenza A/imunologia , Influenza Humana/virologia , Antígenos Virais/imunologia , Perfilação da Expressão Gênica , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Hemaglutininas , Humanos , Imunidade , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A/genética , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/virologia , Filogenia
19.
J Food Sci ; 86(4): 1410-1417, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33768522

RESUMO

Immunosenescence can negatively affect cytokine production in elderly and may impair poor antibody responses to influenza vaccination and infection. Herein, the effects of Banafine® administration on influenza vaccine antibody titer in elderly patients (average age ∼80 years) receiving gastrostomy tube feeding were examined. In the double-blind, single-center, randomized clinical studies, 30 elderly bedridden patients were administered Banafine® or placebo for 8 weeks. At week 4, all patients received influenza vaccination against H1N1, H3N2, B/Yamagata, or B/Victoria. Blood biochemical indices and serum antibody titers were assessed. Banafine® administration significantly increased hemagglutination inhibition titers in response to vaccination against H1N1, H3N2, and B/Yamagata in the elderly patients (P < 0.05). Moreover, the seroconversion rate against H1N1 (47.1%) and H3N2 (29.4%) and seroprotection rate against H1N1 (71.4%) and both B strains (31.3% and 12.5%, respectively) were increased for the Banafine® group. These results suggest that Banafine® administration can increase antibody responses to influenza vaccination in bedridden hospitalized patients, and potentially modulate immune function in the elderly. PRACTICAL APPLICATION: Literature review suggested that most of the synbiotics are based on innate immunity, strain specific (probiotics), and are not consistently observed. Herein, in clinical studies we demonstrate that administration of Banafine® , a plant-based glycoconjugate, can increase antibody levels in bedridden hospitalized elderly patients following influenza vaccination.


Assuntos
Anticorpos Antivirais/sangue , Formação de Anticorpos/imunologia , Nutrição Enteral/métodos , Glicoconjugados/administração & dosagem , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Musa/imunologia , Idoso , Idoso de 80 Anos ou mais , Formação de Anticorpos/efeitos dos fármacos , Método Duplo-Cego , Feminino , Fermentação , Gastrostomia , Glicoconjugados/imunologia , Testes de Inibição da Hemaglutinação , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Masculino , Musa/química , Probióticos/administração & dosagem
20.
Sci Transl Med ; 13(583)2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658355

RESUMO

Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus-associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vacinas contra Influenza/imunologia , Primatas/imunologia , Animais , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/química , Complexo Antígeno-Anticorpo/química , Anticorpos Amplamente Neutralizantes/biossíntese , Anticorpos Amplamente Neutralizantes/química , COVID-19 , Ferritinas/química , Ferritinas/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/química , Influenza Humana/imunologia , Influenza Humana/virologia , Macaca fascicularis , Modelos Moleculares , Nanopartículas/química , Pandemias , Primatas/virologia , Estrutura Quaternária de Proteína , SARS-CoV-2 , Pesquisa Médica Translacional
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