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1.
Emerg Microbes Infect ; 11(1): 2724-2734, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36287714

RESUMO

The development of safe and effective vaccines to respond to COVID-19 pandemic/endemic remains a priority. We developed a novel subunit protein-peptide COVID-19 vaccine candidate (UB-612) composed of: (i) receptor binding domain of SARS-CoV-2 spike protein fused to a modified single-chain human IgG1 Fc; (ii) five synthetic peptides incorporating conserved helper and cytotoxic T lymphocyte (Th/CTL) epitopes derived from SARS-CoV-2 structural proteins (three from S2 subunit, one from membrane and one from nucleocapsid), and one universal Th peptide; (iii) aluminum phosphate as adjuvant. The immunogenicity and protective immunity induced by UB-612 vaccine were evaluated in four animal models: Sprague-Dawley rats, AAV-hACE2 transduced BALB/c mice, rhesus and cynomolgus macaques. UB-612 vaccine induced high levels of neutralizing antibody and T-cell responses, in all animals. The immune sera from vaccinated animals neutralized the SARS-CoV-2 original wild-type strains and multiple variants of concern, including Delta and Omicron. The vaccination significantly reduced viral loads, lung pathology scores, and disease progression after intranasal and intratracheal challenge with SARS-CoV-2 in mice, rhesus and cynomolgus macaques. UB-612 has been tested in primary regimens in Phase 1 and Phase 2 clinical studies and is currently being evaluated in a global pivotal Phase 3 clinical study as a single dose heterologous booster.


Assuntos
COVID-19 , Vacinas Virais , Ratos , Camundongos , Humanos , Animais , SARS-CoV-2 , Vacinas contra COVID-19 , Anticorpos Amplamente Neutralizantes , Pandemias/prevenção & controle , COVID-19/prevenção & controle , Ratos Sprague-Dawley , Glicoproteína da Espícula de Coronavírus , Anticorpos Neutralizantes , Vacinas de Subunidades Antigênicas/genética , Camundongos Endogâmicos BALB C , Macaca mulatta , Anticorpos Antivirais
2.
J Infect Dis ; 226(8): 1401-1406, 2022 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-35723969

RESUMO

The highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has caused high rates of breakthrough infections in those previously vaccinated with ancestral strain coronavirus disease 2019 (COVID-19) vaccines. Here, we demonstrate that a booster dose of UB-612 vaccine candidate delivered 7-9 months after primary vaccination increased neutralizing antibody levels by 131-, 61-, and 49-fold against ancestral SARS-CoV-2 and the Omicron BA.1 and BA.2 variants, respectively. Based on the receptor-binding domain protein binding antibody responses, the UB-612 third-dose booster may lead to an estimated approximately 95% efficacy against symptomatic COVID-19 caused by the ancestral strain. Our results support UB-612 as a potential potent booster against current and emerging SARS-CoV-2 variants.


Assuntos
COVID-19 , Vacinas Virais , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Humanos , SARS-CoV-2
3.
J Clin Invest ; 132(10)2022 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-35316221

RESUMO

BackgroundThe Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase I/II trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally designed promiscuous peptides representing sarbecovirus conserved helper T cell and cytotoxic T lymphocyte epitopes on the nucleocapsid (N), membrane (M), and spike (S2) proteins.MethodWe conducted a phase I primary 2-dose (28 days apart) trial of 10, 30, or 100 µg UB-612 in 60 healthy young adults 20 to 55 years old, and 50 of them were boosted with 100 µg of UB-612 approximately 7 to 9 months after the second dose. A separate placebo-controlled and randomized phase II study was conducted with 2 doses of 100 µg of UB-612 (n = 3,875, 18-85 years old). We evaluated interim safety and immunogenicity of phase I until 14 days after the third (booster) dose and of phase II until 28 days after the second dose.ResultsNo vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were long-lasting virus-neutralizing antibodies and broad T cell immunity against SARS-CoV-2 variants of concern (VoCs), including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron VoCs.ConclusionUB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B and broad T cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines.Trial RegistrationClinicalTrials.gov: NCT04545749, NCT04773067, and NCT04967742.FundingUBI Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , COVID-19/terapia , Humanos , Imunização Passiva , Pessoa de Meia-Idade , SARS-CoV-2 , Linfócitos T , Adulto Jovem , Soroterapia para COVID-19
4.
J Biol Chem ; 287(14): 11037-48, 2012 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-22334673

RESUMO

Hematopoietic progenitor kinase 1 (HPK1) is a Ste20-like serine/threonine kinase that suppresses immune responses and autoimmunity. B cell receptor (BCR) signaling activates HPK1 by inducing BLNK/HPK1 interaction. Whether HPK1 can reciprocally regulate BLNK during BCR signaling is unknown. Here, we show that HPK1-deficient B cells display hyper-proliferation and hyper-activation of IκB kinase and MAPKs (ERK, p38, and JNK) upon the ligation of BCR. HPK1 attenuates BCR-induced cell activation via inducing BLNK threonine 152 phosphorylation, which mediates BLNK/14-3-3 binding. Furthermore, threonine 152-phosphorylated BLNK is ubiquitinated at lysine residues 37, 38, and 42, leading to attenuation of MAPK and IκB kinase activation in B cells during BCR signaling. These results reveal a novel negative feedback regulation of BCR signaling by HPK1-mediated phosphorylation, ubiquitination, and subsequent degradation of the activated BLNK.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linfócitos B/metabolismo , Regulação para Baixo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Antígenos de Linfócitos B/antagonistas & inibidores , Transdução de Sinais , Ubiquitinação , Proteínas 14-3-3/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Animais , Linfócitos B/citologia , Sítios de Ligação , Ativação Enzimática , Células HEK293 , Humanos , Camundongos , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Receptores de Antígenos de Linfócitos B/fisiologia
5.
Cancer Res ; 67(24): 11914-23, 2007 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-18089822

RESUMO

B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor that plays an important role during plasmacytic differentiation and is expressed in normal and transformed plasma cells. We here investigated the importance of continuous Blimp-1 expression. We found that knockdown of Blimp-1 expression by lentiviral vector-delivered short hairpin RNA causes apoptosis in multiple myeloma cell lines and plasmacytoma cells, indicating that continued expression of Blimp-1 is required for cell survival. We examined the mechanism underlying Blimp-1 knockdown-mediated apoptosis and found that the Blimp-1 knockdown neither reversed the phenotypic markers of plasma cells nor caused cell cycle arrest. Instead, our results show that knockdown of Blimp-1 induced the proapoptotic protein Bim, reduced the antiapoptotic protein Mcl-1, and activated caspase-9 and caspase-3. We further link apoptosis in transformed plasma cells mediated by proteasome inhibitors, the effective therapeutic agent for multiple myeloma patients, with reduced expression of Blimp-1. Lastly, we show that Blimp-1-dependent cell survival may act downstream of IFN regulatory factor 4 (IRF4) because IRF4 knockdown leads to down-regulation of Blimp-1 and apoptosis in multiple myeloma cells and plasmacytoma cells. Together, our data suggest that Blimp-1 ensures the survival of transformed plasma cells.


Assuntos
Apoptose/fisiologia , Linfócitos B/fisiologia , Plasmócitos/citologia , Plasmócitos/fisiologia , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Regiões 3' não Traduzidas/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Sobrevivência Celular , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Mieloma Múltiplo , Plasmocitoma , Fator 1 de Ligação ao Domínio I Regulador Positivo , RNA Neoplásico/genética , RNA Neoplásico/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa
6.
J Immunol ; 178(11): 6984-93, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17513748

RESUMO

Some polyacetylenes from the plant Bidens pilosa have been reported to treat diabetes. In this study, we report that the cytopiloyne from B. pilosa, which is structurally different from the above-mentioned polyacetylenes and inhibits CD4(+) T cell proliferation, effectively prevents the development of diabetes in nonobese diabetic mice as evidenced by a normal level of blood glucose and insulin and normal pancreatic islet architecture. Cytopiloyne also suppresses the differentiation of type 1 Th cells but promotes that of type 2 Th cells, which is consistent with it enhancing GATA-3 transcription. Also, long-term application of cytopiloyne significantly decreases the level of CD4(+) T cells inside pancreatic lymph nodes and spleens but does not compromise total Ab responses mediated by T cells. Coculture assays imply that this decrease in CD4(+) T cells involves the Fas ligand/Fas pathway. Overall, our results suggest that cytopiloyne prevents type 1 diabetes mainly via T cell regulation.


Assuntos
Diabetes Mellitus Tipo 1/prevenção & controle , Glucosídeos/uso terapêutico , Poli-Inos/uso terapêutico , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Feminino , Fator de Transcrição GATA3/biossíntese , Fator de Transcrição GATA3/genética , Glucosídeos/administração & dosagem , Inibidores do Crescimento/administração & dosagem , Inibidores do Crescimento/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Poli-Inos/administração & dosagem , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Timidina/metabolismo , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
7.
J Biol Chem ; 281(34): 24111-23, 2006 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-16798741

RESUMO

The polysaccharides of Ganoderma lucidum (Reishi) possess immunomodulation activities; however, their mode of molecular action in regulating each cellular subset in the immune system is still not clear. Here, we investigate the function of the main polysaccharide fraction of Reishi (Reishi-F3) in B lymphocyte activation/differentiation. We find that Reishi-F3 causes mouse splenic B cell activation and differentiation to IgM-secreting plasma cells, and the process depends on Reishi-F3-mediated induction of Blimp-1, a master regulator capable of triggering the changes of a cascade of gene expression during plasmacytic differentiation. In human peripheral B lymphocytes, although Reishi-F3 fails to induce their activation, it is able to enhance antibody secretion, which is associated with Blimp-1 mRNA induction. The function of Reishi-F3 depends on the Toll-like receptors TLR4/TLR2 as neutralizing antibodies against TLR4/TLR2 block Reishi-F3-mediated induction of Blimp-1 mRNA and Ig secretion. We have shown that interaction of Reishi-F3 with TLR4/TLR2 followed by signaling through p38 MAPK is involved in the induction of Blimp-1 mRNA, whereas signaling through ERK, p38 MAPK, JNK, and IKK complex is involved in Reishi-F3-mediated Ig secretion. Furthermore, the differential mechanism of Reishi-F3 in mouse and human B cell activation is probably due to the presence of Blimp-1 regulatory site in human CD86 promoter. These results establish the signaling and molecular mechanisms of Reishi-F3 on promoting antibody secretion.


Assuntos
Formação de Anticorpos/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Polissacarídeos/farmacologia , Reishi/química , Proteínas Repressoras/biossíntese , Transdução de Sinais/imunologia , Fatores de Transcrição/biossíntese , Animais , Linfócitos B/imunologia , Antígeno B7-2/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Humanos , Fatores Imunológicos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Fator 1 de Ligação ao Domínio I Regulador Positivo , Regiões Promotoras Genéticas , Transdução de Sinais/efeitos dos fármacos , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia
8.
J Biomed Sci ; 12(1): 79-89, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15864741

RESUMO

Bidens pilosa is claimed to be useful for immune or anti-inflammatory disorders; however, little scientific evidence has been published concerning its function. In this paper, immune disease mouse models were used to study the function of a butanol fraction of B.pilosa. We demonstrated treatment with the butanol fraction of B.pilosa ameliorated Th1 cell-mediated autoimmune diabetes in nonobese diabetic (NOD) mice but caused deterioration of Th2 cell-mediated airway inflammation induced by ovalbumin (OVA) in BALB/c mice. We next showed that Th2 cytokines (IL-4 and/or IL-5) increased but Th1 cytokine (IFN-gamma) decreased following injections with the butanol fraction of B.pilosa in both mouse strains. Accordingly, Th2 cytokine-regulated IgE production in mouse serum increased following treatment with this fraction. Finally, we found that the butanol fraction of B.pilosa inhibited Th1 cell differentiation but promoted Th2 cell differentiation. Taken together, the butanol fraction of B.pilosa has a dichotomous effect on helper T cell-mediated immune disorders, plausibly via modulation of T cell differentiation.


Assuntos
Butanóis/farmacologia , Diabetes Mellitus Tipo 1/imunologia , Medicamentos de Ervas Chinesas , Inflamação/imunologia , Pulmão/imunologia , Células Th1 , Células Th2 , Animais , Bidens , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Diferenciação Celular/efeitos dos fármacos , Citocinas/imunologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Imunoglobulina E/sangue , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Pulmão/patologia , Camundongos , Camundongos Endogâmicos NOD , Ovalbumina/toxicidade , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/fisiologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/fisiologia
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