RESUMO
BACKGROUND: VLA1553 is a live-attenuated vaccine candidate for active immunisation and prevention of disease caused by chikungunya virus. We report safety and immunogenicity data up to day 180 after vaccination with VLA1553. METHODS: This double-blind, multicentre, randomised, phase 3 trial was done in 43 professional vaccine trial sites in the USA. Eligible participants were healthy volunteers aged 18 years and older. Patients were excluded if they had history of chikungunya virus infection or immune-mediated or chronic arthritis or arthralgia, known or suspected defect of the immune system, any inactivated vaccine received within 2 weeks before vaccination with VLA1553, or any live vaccine received within 4 weeks before vaccination with VLA1553. Participants were randomised (3:1) to receive VLA1553 or placebo. The primary endpoint was the proportion of baseline negative participants with a seroprotective chikungunya virus antibody level defined as 50% plaque reduction in a micro plaque reduction neutralisation test (µPRNT) with a µPRNT50 titre of at least 150, 28 days after vaccination. The safety analysis included all individuals who received vaccination. Immunogenicity analyses were done in a subset of participants at 12 pre-selected study sites. These participants were required to have no major protocol deviations to be included in the per-protocol population for immunogenicity analyses. This trial is registered at ClinicalTrials.gov, NCT04546724. FINDINGS: Between Sept 17, 2020 and April 10, 2021, 6100 people were screened for eligibility. 1972 people were excluded and 4128 participants were enrolled and randomised (3093 to VLA1553 and 1035 to placebo). 358 participants in the VLA1553 group and 133 participants in the placebo group discontinued before trial end. The per-protocol population for immunogenicity analysis comprised 362 participants (266 in the VLA1553 group and 96 in the placebo group). After a single vaccination, VLA1553 induced seroprotective chikungunya virus neutralising antibody levels in 263 (98·9%) of 266 participants in the VLA1553 group (95% CI 96·7-99·8; p<0·0001) 28 days post-vaccination, independent of age. VLA1553 was generally safe with an adverse event profile similar to other licensed vaccines and equally well tolerated in younger and older adults. Serious adverse events were reported in 46 (1·5%) of 3082 participants exposed to VLA1553 and eight (0·8%) of 1033 participants in the placebo arm. Only two serious adverse events were considered related to VLA1553 treatment (one mild myalgia and one syndrome of inappropriate antidiuretic hormone secretion). Both participants recovered fully. INTERPRETATION: The strong immune response and the generation of seroprotective titres in almost all vaccinated participants suggests that VLA1553 is an excellent candidate for the prevention of disease caused by chikungunya virus. FUNDING: Valneva, Coalition for Epidemic Preparedness Innovation, and EU Horizon 2020.
Assuntos
Febre de Chikungunya , Vírus Chikungunya , Humanos , Idoso , Febre de Chikungunya/prevenção & controle , Vacinas Atenuadas , Anticorpos Antivirais , Vacinação , Método Duplo-CegoRESUMO
OBJECTIVE: To report on the surgical safety and quality of pelvic lymph node dissection (PLND) in patients treated with radical cystectomy (RC) and PLND for muscle-invasive bladder cancer (MIBC) after neoadjuvant chemo-immunotherapy. PATIENTS AND METHODS: The Swiss Group for Clinical Cancer Research (SAKK) 06/17 was an open-label single-arm phase II trial including 61 cisplatin-fit patients with clinical stage (c)T2-T4a cN0-1 operable urothelial MIBC or upper urinary tract cancer. Patients received neoadjuvant cisplatin/gemcitabine and durvalumab followed by surgery. Prospective quality assessment of surgeries was performed via central review of intraoperative photographs. Postoperative complications were assessed using the Clavien-Dindo Classification. Data were analysed descriptively. RESULTS: A total of 50 patients received RC and PLND. All patients received neoadjuvant chemo-immunotherapy. The median (interquartile range) number of lymph nodes removed was 29 (23-38). No intraoperative complications were registered. Grade ≥III postoperative complications were reported in 12 patients (24%). Complete nodal dissection (100%) was performed at the level of the obturator fossa (bilaterally) and of the left external iliac region; in 49 patients (98%) at the internal iliac region and at the right external iliac region; in 39 (78%) and 38 (76%) patients at the right and left presacral level, respectively. CONCLUSION: This study supports the surgical safety of RC and PLND following neoadjuvant chemo-immunotherapy in patients with MIBC. The extent and completeness of protocol-defined PLND varies between patients, highlighting the need to communicate and monitor the surgical template.
Assuntos
Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Cistectomia , Desoxicitidina , Gencitabina , Excisão de Linfonodo , Terapia Neoadjuvante , Neoplasias da Bexiga Urinária , Humanos , Cistectomia/métodos , Excisão de Linfonodo/métodos , Masculino , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Feminino , Idoso , Pessoa de Meia-Idade , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pelve , Estudos ProspectivosRESUMO
Cytomegalovirus (CMV) genome is highly variable and heterosubtypic immunity should be considered in vaccine development since it can enhance protection in a cross-reactive manner. Here, we developed a protein array to evaluate heterosubtypic immunity to CMV glycoprotein B (gB) in natural infection and vaccination. DNA sequences of four antigenic domains (AD1, AD2, AD4/5, and AD5) of gB were amplified from six reference and 12 clinical CMV strains, and the most divergent genotypes were determined by phylogenetic analysis. Assigned genotypes were in vitro translated and immobilized on protein array. Then, we tested immune response of variable serum groups (primarily infected patients, reactivated CMV infections and healthy individuals with latent CMV infection, as well gB-vaccinated rabbits) with protein in situ array (PISA). Serum antibodies of all patient cohorts and gB-vaccinated rabbits recognized many genetic variants of ADs on protein array, including but not limited to the subtype of infecting strain. High-grade cross-reactivity was observed. In several patients, we observed none or neglectable immune response to AD1 and AD2, while the same patients showed high antibody response to AD4/5 and AD5. Among the primary infected patients, AD5 was the predominant AD, in antibody response. The most successful CMV vaccine to date contains gB and demonstrates only 50% efficacy. In this study, we showed that heterosubtypic and cross-reactive immunity to CMV gB is extensive. Therefore, the failure of CMV gB vaccines cannot be explained by a highly, strain-specific immunity. Our observations suggest that other CMV antigens should be addressed in vaccine design.
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Anticorpos Antivirais , Infecções por Citomegalovirus , Animais , Citomegalovirus , Humanos , Filogenia , Coelhos , Proteínas do Envelope Viral/genéticaRESUMO
INTRODUCTION: The safety of first-line (1L) durvalumab in patients with advanced nonsmall-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (PS2) is unknown. This is an interim unplanned safety analysis of the study SAKK 19/17 for patients with metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression in ≥ 25% of tumor cells and an ECOG PS2 treated with 1L durvalumab. This safety analysis was triggered by the SAKK data and safety monitoring board due to a high mortality rate observed after the recruitment of the first 21 patients. METHODS: This single-arm phase II study recruited patients with metastatic NSCLC with PD-L1 in ≥ 25% and ECOG PS2. Patients received durvalumab 1500 mg every four weeks. The trial aims to recruit 48 patients in total. This report includes safety analyses only. Adverse events (AEs) were assessed using National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 5.0. Efficacy data including the primary endpoint overall survival at 6 months and secondary endpoints (objective response rate, progression-free survival, and quality of life) will be reported at a later time point. RESULTS: The data from 21 patients were available at this interim safety analysis. Among these, 13 deaths (13/21; 62%) were reported, including one treatment-related fatal colonic perforation at 9 months after treatment initiation (1/13; 8%). Twelve deaths were not treatment-related (12/13; 92%), and mostly attributed to tumor progression (10/13; 77%). Of note, seven deaths (7/13; 54%) occurred during the first 5 weeks (range 0.6-4.7 weeks) after treatment initiation. Four (4/7; 57%) were respiratory failures attributed to tumor progression. One of these patients (25%) had pre-existing COPD, and three (75%) had baseline dyspnea grade 2-3 related to the tumor. Grade ≥ 3 treatment-related AEs (TRAEs) included colonic perforation (grade 5), abdominal pain, and colitis (grade 3 each) in one patient, and fatigue (grade 3) in another. Other Grade ≥ 3 AEs unrelated to treatment were all of pulmonary origin: lung infections (19%), dyspnea (24%), cough (5%), and bronchial obstruction (5%). CONCLUSIONS: 1L durvalumab in patients with ECOG PS2 and metastatic NSCLC with PD-L1 expression ≥ 25% resulted in an unexpectedly high number of fatal early events due to rapid tumor progression. We recommend to avoid treatment with 1 L durvalumab of patients who are highly symptomatic from the tumor, particularly those with respiratory symptoms. The study is continuing its accrual after an amendment excluding these patients.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/metabolismo , Carcinogênese , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Perfuração Intestinal/etiologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/mortalidade , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Insuficiência Respiratória/etiologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Gremlin-1 is a cystine knot protein and is expressed in organs developing fibrosis. Transient ischaemia leads to myocardial fibrosis, a major determinant of impaired myocardial function. MATERIALS AND METHODS: Expression of Gremlin-1 was investigated in infarcted myocardium by real-time PCR, Western blot analysis, histological and immunohistochemistry staining. We further elaborated the colocalization of Gremlin-1 and TGF-ß proteins by confocal microscopy and co-immunoprecipitation experiments. The interaction between Gremlin-1 and TGF-ß was analysed by photon correlation spectroscopy. Gremlin-1 modulation of the TGF-ß-dependent collagen I synthesis in fibroblasts was investigated using ELISA and immunohistochemistry experiments. The effect of prolonged administration of recombinant Gremlin-1 on myocardial function following ischaemia/reperfusion was accessed by echocardiography and immunohistochemistry. RESULTS: Gremlin-1 is expressed in myocardial tissue and infiltrating cells after transient myocardial ischaemia (P < .05). Gremlin-1 colocalizes with the pro-fibrotic cytokine transforming growth factor-ß (TGF-ß) expressed in fibroblasts and inflammatory cell infiltrates (P < .05). Gremlin-1 reduces TGF-ß-induced collagen production of myocardial fibroblasts by approximately 20% (P < .05). We found that Gremlin-1 binds with high affinity to TGF-ß (KD = 54 nmol/L) as evidenced by photon correlation spectroscopy and co-immunoprecipitation. intravenous administration of m Gremlin-1-Fc, but not of equivalent amount of Fc control, significantly reduced infarct size by approximately 20%. In the m Gremlin-1-Fc group, infarct area was reduced by up to 30% in comparison with mice treated with Fc control (I/LV: 4.8 ± 1.2% vs 6.0 ± 1.2% P < .05; I/AaR: 15.2 ± 1.5% vs 21.1 ± 5%, P < .05). CONCLUSIONS: The present data disclose Gremlin-1 as an antagonist of TGF-ß and presume a role for Gremlin-1/TGF-ß interaction in myocardial remodelling following myocardial ischaemia.
Assuntos
Fibroblastos/metabolismo , Coração/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Infarto do Miocárdio/genética , Traumatismo por Reperfusão Miocárdica/genética , Miocárdio/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Colágeno Tipo I/metabolismo , Ecocardiografia , Células Endoteliais/metabolismo , Fibroblastos/efeitos dos fármacos , Fibrose , Coração/diagnóstico por imagem , Coração/efeitos dos fármacos , Humanos , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Camundongos , Microscopia Confocal , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Proteínas Recombinantes , Fator de Crescimento Transformador beta/efeitos dos fármacos , Remodelação Ventricular/genéticaRESUMO
Viruses shape a diversity of ecosystems by modulating their microbial, eukaryotic, or plant host metabolism. The complexity of virus-host interaction networks is progressively fathomed by novel metagenomic approaches. By using a novel metagenomic method, we explored the virome in mammalian cell cultures and clinical samples to identify an extensive pool of mobile genetic elements in all of these ecosystems. Despite aseptic treatment, cell cultures harbored extensive and diverse phage populations with a high abundance of as yet unknown and uncharacterized viruses (viral dark matter). Unknown phages also predominated in the oropharynx and urine of healthy individuals and patients infected with cytomegalovirus despite demonstration of active cytomegalovirus replication. The novelty of viral sequences correlated primarily with the individual evaluated, whereas relative abundance of encoded protein functions was associated with the ecologic niches probed. Together, these observations demonstrate the extensive presence of viral dark matter in human and artificial ecosystems.-Thannesberger, J., Hellinger, H.-J., Klymiuk, I., Kastner, M.-T., Rieder, F. J. J., Schneider, M., Fister, S., Lion, T., Kosulin, K., Laengle, J., Bergmann, M., Rattei, T., Steininger, C. Viruses comprise an extensive pool of mobile genetic elements in eukaryote cell cultures and human clinical samples.
Assuntos
Células Eucarióticas/virologia , Genoma Viral/genética , Células Cultivadas , DNA Viral/genética , Células Eucarióticas/citologia , Humanos , Sequências Repetitivas Dispersas/genética , Metagenoma/genética , Metagenômica/métodos , Análise de Sequência de DNA/métodosRESUMO
Protein phosphorylation has important regulatory functions in cell homeostasis and is tightly regulated by kinases and phosphatases. The tegument of human cytomegalovirus (CMV) contains not only several proteins reported to be extensively phosphorylated but also cellular protein phosphatases (PP1 and PP2A). To investigate this apparent inconsistency, we evaluated the phosphorylation status of the tegument proteins pUL32 and pp65 by enzymatic dephosphorylation and MS. Enzymatic dephosphorylation with bacterial λ phosphatase, but not with PP1, shifted the pUL32-specific signal on reducing SDS-PAGE from ~150 to ~148 kDa, a mass still much larger than the ~118 kDa obtained from our diffusion studies and from the calculated protein mass of ~113 kDa. Remarkably, inhibition of phosphatases through treatment with the phosphatase inhibitors calyculin A and okadaic acid resulted in a shift to ~190 or ~180 kDa, respectively, indicating that a considerable number of potential phosphorylated residues on pUL32 are not phosphorylated under normal conditions. MS revealed a general state of hypophosphorylation of CMV phosphoproteins with only 17 phosphorylated residues detected on pUL32 and 19 on pp65, respectively. Moreover, bioinformatics analysis shows that the C-terminal two-thirds of pUL32 are intrinsically disordered and that most phosphorylations map to this region. In conclusion, we show that important CMV tegument proteins are indeed phosphorylated, though to a lesser extent than previously reported, and the difference in mobility on SDS-PAGE and calculated mass of pUL32 may not be attributed to phosphorylation but more likely due to the partially intrinsically disordered nature of pUL32.
Assuntos
Citomegalovirus/metabolismo , Fosfoproteínas/metabolismo , Proteínas da Matriz Viral/metabolismo , Eletroforese em Gel de Poliacrilamida , Inibidores Enzimáticos/farmacologia , Humanos , Toxinas Marinhas , Ácido Okadáico/farmacologia , Oxazóis/farmacologia , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosforilação , Processamento de Proteína Pós-TraducionalRESUMO
Protocadherins represent the biggest subgroup within the cadherin superfamily of transmembrane glycoproteins. In contrast to classical type I cadherins, protocadherins in general exhibit only moderate adhesive activity. During embryogenesis, they are involved in cell signaling and regulate diverse morphogenetic processes, including morphogenetic movements during gastrulation and neural crest migration. The two protocadherins paraxial protocadherin (PAPC) and axial protocadherin (AXPC) are indispensable for proper gastrulation movements in Xenopus and zebrafish. The closest relative PCNS instead, is required for neural crest and somite formation. Here, we show that cranial neural crest (CNC) cells in addition to PCNS express PAPC, but not AXPC. Overexpression of PAPC resulted in comparable migration defects as knockdown of PCNS. Moreover, reconstitution experiments revealed that PAPC is able to replace PCNS in CNC cells, indicating that both protocadherins can regulate CNC migration.
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Caderinas/metabolismo , Crista Neural/metabolismo , Precursores de Proteínas/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus/embriologia , Animais , Região Branquial/fisiologia , Caderinas/genética , Movimento Celular , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Precursores de Proteínas/genética , Protocaderinas , Xenopus/metabolismo , Proteínas de Xenopus/genéticaRESUMO
Xenopus cadherin-11 (Xcadherin-11) is an exceptional cadherin family member, which is predominantly expressed in cranial neural crest cells (NCCs). Apart from mediating cell-cell adhesion it promotes cranial NCC migration by initiating filopodia and lamellipodia formation. Here, we demonstrate an unexpected function of Xcadherin-11 in NCC specification by interfering with canonical Wnt/ß-catenin signaling. Loss-of-function experiments, using a specific antisense morpholino oligonucleotide against Xcadherin-11, display a nuclear ß-catenin localization in cranial NCCs and a broader expression domain of the proto-oncogene cyclin D1 which proceeds c-myc up-regulation. Additionally, we observe an enhanced NCC proliferation and an expansion of specific NCC genes like AP2 and Sox10. Thereby, we could allocate NCC proliferation and specification to different gene functions. To clarify which domain in Xcadherin-11 is required for early NCC development we tested different deletion mutants for their rescue ability in Xcadherin-11 morphants. We identified the cytoplasmic tail, specifically the ß-catenin binding domain, to be necessary for proper NCC development. We propose that Xcadherin-11 is necessary for controlled NCC proliferation and early NCC specification in tuning the expression of the canonical Wnt/ß-catenin target genes cyclin D1 and c-myc by regulating the concentration of the nuclear pool of ß-catenin.
Assuntos
Caderinas/deficiência , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Crista Neural/citologia , Crista Neural/metabolismo , Via de Sinalização Wnt/fisiologia , Xenopus laevis/embriologia , beta Catenina/metabolismo , Transporte Ativo do Núcleo Celular/fisiologia , Animais , Caderinas/genética , Movimento Celular/fisiologia , Proliferação de Células , Ciclina D1/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Imuno-Histoquímica , Luciferases , Crista Neural/embriologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Via de Sinalização Wnt/genéticaRESUMO
Monocyte infiltration and macrophage formation are pivotal steps in atherosclerosis and plaque vulnerability. Gremlin-1/Drm is crucial in embryo-/organogenesis and has been shown to be expressed in the adult organism at sites of arterial injury and to inhibit monocyte migration. The purpose of the present study was to evaluate and characterize the role of Gremlin-1 in atherosclerosis. Here we report that Gremlin-1 is highly expressed primarily by monocytes/macrophages in aortic atherosclerotic lesions of ApoE(-/-) mice and is secreted from activated monocytes and during macrophage development in vitro. Gremlin-1 reduces macrophage formation by inhibiting macrophage migration inhibitory factor (MIF), a cytokine critically involved in atherosclerotic plaque progression and vulnerability. Gremlin-1 binds with high affinity to MIF (KD = 54 nm), as evidenced by surface plasmon resonance analysis and co-immunoprecipitation, and reduces MIF-induced release of TNF-α from macrophages. Treatment of ApoE(-/-) mice with a dimeric recombinant fusion protein, mGremlin1-Fc, but not with equimolar control Fc or inactivated mGremlin1-Fc, reduced TNF-α expression, the content of monocytes/macrophages of atherosclerotic lesions, and attenuated atheroprogression. The present data disclose that Gremlin-1 is an endogenous antagonist of MIF and define a role for Gremlin-1/MIF interaction in atherosclerosis.
Assuntos
Apolipoproteínas E , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Oxirredutases Intramoleculares/biossíntese , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/biossíntese , Fatores Inibidores da Migração de Macrófagos/genética , Macrófagos/patologia , Camundongos , Camundongos Knockout , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND: The global spread of the chikungunya virus (CHIKV) increases the exposure risk for individuals travelling to or living in endemic areas. This Phase 3 study was designed to demonstrate manufacturing consistency between three lots of the single shot live-attenuated CHIKV vaccine VLA1553, and to confirm the promising immunogenicity and safety data obtained in previous trials. METHODS: This randomized, double-blinded, lot-to-lot consistency, Phase 3 study, assessed immunogenicity and safety of VLA1553 in 408 healthy adults (18-45 years) in 12 sites across the USA. The primary endpoint was a comparison of the geometric mean titre (GMT) ratios of CHIKV-specific neutralizing antibodies between three VLA1553 lots at 28 days post-vaccination. Secondary endpoints included immunogenicity and safety over 6 months post-vaccination. RESULTS: GMTs were comparable between the lots meeting the acceptance criteria for equivalence. The average GMT (measured by 50% CHIKV micro plaque neutralization test; µPRNT50) peaked with 2643 at 28 days post-vaccination and decreased to 709 at 6 months post-vaccination. An excellent seroresponse rate (defined as µPRNT50 titre ≥ 150 considered protective) was achieved in 97.8% of participants at 28 days post-vaccination and still persisted in 96% at 6 months after vaccination. Upon VLA1553 immunization, 72.5% of participants experienced adverse events (AEs), without significant differences between lots (related solicited systemic AE: 53.9% of participants; related solicited local AE: 19.4%). Overall, AEs were mostly mild or moderate and resolved without sequela, usually within 3 days. With 3.9% of participants experiencing severe AEs, 2.7% were classified as related, whereas none of the six reported serious adverse events was related to the administration of VLA1553. CONCLUSIONS: All three lots of VLA1553 recapitulated the safety and immunogenicity profiles of a preceding Phase 3 study, fulfilling pre-defined consistency requirements. These results highlight the manufacturability of VLA1553, a promising vaccine for the prevention of CHIKV disease for those living in or travelling to endemic areas.
Assuntos
Febre de Chikungunya , Vírus Chikungunya , Adulto , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , Febre de Chikungunya/prevenção & controle , Método Duplo-Cego , Testes de Neutralização , Vacinas Atenuadas , Adolescente , Adulto Jovem , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: The safety and efficacy of first-line durvalumab in PS2 patients with advanced NSCLC is unknown. Here, we present the primary analysis of first-line durvalumab in PS2 patients, unsuitable for combination chemotherapy. METHODS: In this single-arm, multicenter, phase II trial patients with PD-L1 positive (tumor proportional score ≥25%), advanced NSCLC with PS2, received four-weekly durvalumab 1500 mg. The primary endpoint was overall survival (OS) at 6 months. RESULTS: Forty-eight patients were included. Median follow-up was 23.3 months (95% CI: 14.3-28.6). OS at 6 months was 60% (95% CI: 45-74%). Median OS was 8.5 months (95%CI: 4.4-16.7). Objective response rate and median progression free survival were 17% (95% CI: 8-30%) and 2.5 months (95% CI: 1.8-7.1), respectively. Thirty-three deaths were observed at the time point of the analysis. Seven early fatal events considered not treatment-related occurred during the first 5 weeks of treatment. Four out of the first 7 early fatal events (4/7; 57%) were respiratory failure in patients with advanced symptomatic primary lung tumors. Three more early fatal events occurred after exclusion of patients with grade ≥ 3 dyspnea. Treatment-related AEs ≥G3 were reported in 9 patients (19%) and included colonic perforation in one patient (grade 5), colitis in 4 patients (8%), increased lipase in 3 patients (6%), and hepatitis in 2 patients (4%). CONCLUSIONS: First-line durvalumab in PS2 patients with advanced PD-L1 positive NSCLC results in a high number of early fatal events. When patients with grade ≥ 3 dyspnea are excluded a promising 6-month OS with an acceptable toxicity profile can be observed. Durvalumab could be an option instead of single agent chemotherapy for PS2 patients who are not candidates for platinum doublet chemotherapy provided they are well selected.
Assuntos
Anticorpos Monoclonais , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Antígeno B7-H1/metabolismo , Dispneia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Incidence rates of Lyme borreliosis, a tickborne disease attributed to infection by Borrelia species, are increasing, and limitations to existing treatments potentiate the possibility of severe outcomes. Nevertheless, there are no licensed vaccines for Lyme borreliosis prevention in humans. This study investigated the immunogenicity and safety of a booster dose of VLA15, an investigational outer surface protein A (OspA)-based Lyme borreliosis vaccine that has previously shown safety and immunogenicity when administered as a primary vaccination series, following a primary VLA15 vaccination series. METHODS: We report the results of the booster phase of a randomised, observer-blinded, placebo-controlled, multicentre, phase 2 study that enrolled healthy adults aged 18-65 years from five US clinical study centres to receive 135 µg or 180 µg VLA15 or placebo at months 0, 2, and 6 in the main study phase. Participants who received 180 µg VLA15 in the main study phase and did not have relevant protocol deviations were eligible for the booster phase (months 18-30). Participants were randomly reassigned (2:1) to receive an intramuscular injection of a VLA15 booster or placebo 1 year after the completion of primary vaccination (month 18) via a randomisation list generated by an unmasked statistician with a block size of six. Individuals involved in data safety monitoring, rerandomisation, vaccine handling, and vaccine accountability were unmasked; the study sponsor and statisticians were only unmasked after analysis of data up to 1 month after booster administration. All other individuals remained masked throughout the booster phase. The outcomes for the booster phase were the immunogenicity (evaluated in the booster per-protocol population) and safety (evaluated for all participants who received the booster) of the booster dose up to month 30. The study is registered at ClinicalTrials.gov (NCT03970733) and is completed. FINDINGS: Between Feb 4 and March 23, 2021, 58 participants (28 men and 30 women) were screened, randomly assigned, and received VLA15 (n=39) or placebo (n=19). One participant in the placebo group was lost to follow-up. The IgG geometric mean titres for each OspA serotype (serotypes 1-6) in the VLA15 group peaked at 1 month after the booster dose (1277·0 U/mL [95% CI 861·8-1892·3] to 2194·5 U/mL [1566·8-3073·7] vs 23·6 U/mL [18·1-30·8] to 36·8 U/mL [26·4-51·3] in the placebo group [p<0·0001 for all serotypes]), remained elevated at month 24 (137·4 U/mL [95·8-196·9] to 265·8 U/mL [202·9-348·2] vs 22·3 U/mL [17·7-28·0] to 29·1 U/mL [20·8-40·6] in the placebo group; p<0·0001 for all serotypes), and declined by month 30 (54·1 U/mL [38·6-75·7] to 101·6 U/mL [77·6-133·1] vs 21·9 U/mL [18·0-26·6] to 24·9 U/mL [19·0-32·6] in the placebo group; p<0·0001 for all serotypes except serotype 1 [p=0·0006]). Solicited local adverse events were reported more frequently in the VLA15 group (35 [92%, 95% CI 79-97] of 38 participants) than the placebo group (six [32%, 15-54] of 19 participants; p<0·0001) after booster vaccination. There was no significant difference in the frequency of solicited systemic adverse events between groups (20 [59%, 42-74] of 34 participants in the VLA15 group vs six [38%, 18-61] of 16 participants in the placebo group). Related unsolicited adverse events (none severe) were reported by two (5%, 1-17) of 39 participants in the VLA15 group and none (0%, 0-17) of 19 participants in the placebo group. There were no severe solicited local or systemic adverse events or deaths during the study. INTERPRETATION: A booster dose of VLA15 is safe and induces substantial anamnestic immune responses against all six OspA serotypes. As with previously investigated OspA-based Lyme borreliosis vaccines, waning immune responses were observed with VLA15, and annual boosters might therefore be required. FUNDING: Valneva.
RESUMO
BACKGROUND: Chikungunya virus infection can lead to long-term debilitating symptoms. A precursor phase 3 clinical study showed high seroprotection (defined as a 50% plaque reduction of chikungunya virus-specific neutralising antibodies on a micro plaque reduction neutralisation test [µPRNT] titre of ≥150 in baseline seronegative participants) up to 6 months after a single vaccination of the chikungunya virus vaccine VLA1553 (Valneva Austria, Vienna, Austria) and a good safety profile. Here we report antibody persistence and safety up to 2 years. METHODS: In this single-arm, multicentre, phase 3b study, we recruited participants from the precursor phase 3 trial from professional vaccine trial sites in the USA. Participants (aged ≥18 years) were eligible if they had completed the previous study and received VLA1553. Chikungunya virus-specific neutralising antibodies were evaluated at 28 days, 6 months, and 1 year and 2 years after vaccination. The primary outcome was the proportion of seroprotected participants (ie, µPRNT50 titre of ≥150) at 1 and 2 years, assessed in all eligible participants who had at least one post-vaccination immunogenicity sample available, overall and by age group at the time of vaccination (18-64 years and ≥65 years). Adverse events of special interest at the time of transition from the previous study to the current study (ie, at 6 months) and serious adverse events during the current study were recorded (ie, between 6 months and 2 years). All analyses were descriptive. This study is registered with ClinicalTrials.gov, NCT04838444, and immunogenicity follow-up is ongoing. FINDINGS: In the precursor study, participants were screened between Sept 17, 2020, and April 10, 2021; data cutoff for this analysis was March 31, 2023. Of 2724 participants in the precursor study who received one dose of VLA1553, 363 participants were analysed in this study (310 [85%] aged 18-64 years and 53 [15%] aged ≥65 years at enrolment in the precursor study; mean age 47·7 years [SD 14·2], 207 [57%] of 363 participants were female, 156 [43%] were male, 280 [77%] were White, and 314 [87%] were not Hispanic or Latino). Strong seroprotection was observed at 1 year (98·9% [356 of 360 assessable participants; 97·2-99·7]) and 2 years (96·8% [306 of 316; 94·3-98·5]) after vaccination, and was very similar between those aged 18-64 years (at 1 year: 98·7% [303 of 307; 96·7-99·6]; at 2 years: 96·6% [256 of 265; 93·7-98·4]) and those aged 65 years and older (at 1 year: 100% [53 of 53; 93·3-100]; at 2 years: 98·0% [50 of 51; 89·6-100]) at each timepoint. No adverse events of special interest were ongoing at the time of transition. Ten serious adverse events occurred in nine (2%) participants between the 6-month and 2-year timepoints, including one death (due to drug overdose) that was determined to not be related to VLA1553. INTERPRETATION: After a single VLA1553 vaccination, chikungunya virus-neutralising antibodies above the threshold considered to be protective persisted up to 2 years and there were no long-term serious adverse events related to vaccination. VLA1553 is an efficient and safe intervention that offers high seroprotection against chikungunya virus infection, a virus likely to spread globally with an urgent demand for long-lasting prophylaxis. FUNDING: Valneva Austria, Coalition for Epidemic Preparedness Innovation, and EU Horizon 2020.
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BACKGROUND: Rising Lyme borreliosis incidence rates, potential for severe outcomes, and limitations in accurate and timely diagnosis for treatment initiation suggest the need for a preventive vaccine; however, no vaccine is currently available for human use. We performed two studies in adults to optimise the dose level and vaccination schedule for VLA15, an investigational Lyme borreliosis vaccine targeting outer surface protein A (OspA) serotypes 1-6, which are associated with the most common pathogenic Borrelia species in Europe and North America. METHODS: Both randomised, observer-blind, placebo-controlled, multicentre phase 2 studies included participants aged 18-65 years without recent history of Lyme borreliosis or tick bites. Study one was conducted at nine clinical research and study centre sites in the USA (n=6), Germany (n=2), and Belgium (n=1); study two was conducted at five of the study one US sites. Based on a randomisation list created by an unmasked statistician for each study, participants were randomly assigned via an electronic case report form randomisation module to receive 90 µg (study one only), 135 µg, or 180 µg VLA15 or placebo by intramuscular injection at months 0, 1, and 2 (study one) or 0, 2, and 6 (study two). Study one began with a run-in phase to confirm safety, after which the Data Safety Monitoring Board recommended the removal of the 90 µg group and continuation of the study. In the study one run-in phase, randomisation was stratified by study site, whereas in the study one main phase and in study two, randomisation was stratified by study site, age group, and baseline B burgdorferi (sensu lato) serostatus. All individuals were masked, other than staff involved in randomisation, vaccine preparation or administration, or safety data monitoring. The primary endpoint for both studies was OspA-specific IgG geometric mean titres (GMTs) at 1 month after the third vaccination and was evaluated in the per-protocol population. Safety endpoints were evaluated in the safety population: all participants who received at least one vaccination. Both studies are registered at ClinicalTrials.gov (study one NCT03769194 and study two NCT03970733) and are completed. FINDINGS: For study one, 573 participants were screened and randomly assigned to treatment groups between Dec 21, 2018, and Sept, 26, 2019. For study two, 248 participants were screened and randomly assigned between June 26 and Sept 3, 2019. In study one, 29 participants were assigned to receive 90 µg VLA15, 215 to 135 µg, 205 to 180 µg, and 124 to placebo. In study two, 97 participants were assigned to receive 135 µg VLA15, 100 to 180 µg, and 51 to placebo. At 1 month after the third vaccination (ie, month 3), OspA-specific IgG GMTs in study one ranged from 74·3 (serotype 1; 95% CI 46·4-119·0) to 267·4 units per mL (serotype 3; 194·8-367·1) for 90 µg VLA15, 101·9 (serotype 1; 87·1-119·4) to 283·2 units per mL (serotype 3; 248·2-323·1) for 135 µg, and 115·8 (serotype 1; 98·8-135·7) to 308·6 units per mL (serotype 3; 266·8-356·8) for 180 µg. In study two, ranges at 1 month after the third vaccination (ie, month 7) were 278·5 (serotype 1; 214·9-361·0) to 545·2 units per mL (serotype 2; 431·8-688·4) for 135 µg VLA15 and 274·7 (serotype 1; 209·4-360·4) to 596·8 units per mL (serotype 3; 471·9-754·8) for 180 µg. Relative to placebo, the VLA15 groups had more frequent reports of solicited local adverse events (study one: 94%, 95% CI 91-96 vs 26%, 19-34; study two: 96%, 93-98 vs 35%, 24-49 after any vaccination) and solicited systemic adverse events (study one: 69%, 65-73 vs 43%, 34-52; study two: 74%, 67-80 vs 51%, 38-64); most were mild or moderate. In study one, unsolicited adverse events were reported by 52% (48-57) of participants in the VLA15 groups and 52% (43-60) of those in the placebo groups; for study two these were 65% (58-71) and 69% (55-80), respectively. Percentages of participants reporting serious unsolicited adverse events (study one: 2%, 1-4; study two: 4%, 2-7) and adverse events of special interest (study one: 1%, 0-2; study two: 1%, 0-3) were low across all groups. A single severe, possibly related unsolicited adverse event was reported (worsening of pre-existing ventricular extrasystoles, which resolved after change of relevant concomitant medication); no related serious adverse events or deaths were reported. INTERPRETATION: VLA15 was safe, well tolerated, and elicited robust antibody responses to all six OspA serotypes. These findings support further clinical development of VLA15 using the 180 µg dose and 0-2-6-month schedule, which was associated with the greatest immune responses. FUNDING: Valneva.
Assuntos
Esquemas de Imunização , Vacinas contra Doença de Lyme , Doença de Lyme , Humanos , Adulto , Masculino , Pessoa de Meia-Idade , Feminino , Doença de Lyme/prevenção & controle , Adulto Jovem , Vacinas contra Doença de Lyme/imunologia , Vacinas contra Doença de Lyme/administração & dosagem , Adolescente , Idoso , Lipoproteínas/imunologia , Lipoproteínas/administração & dosagem , Anticorpos Antibacterianos/sangue , Borrelia burgdorferi/imunologia , Bélgica , Estados Unidos , Proteínas da Membrana Bacteriana Externa/imunologia , Método Simples-Cego , Antígenos de Superfície/imunologia , Antígenos de Superfície/administração & dosagem , Alemanha , Vacinação/métodos , Voluntários Saudáveis , Vacinas BacterianasRESUMO
Prohibitin 1 (phb1), which was initially described as an inhibitor of cell proliferation, is a highly conserved protein found in multiple cellular compartments. In the nucleus it interacts with the transcriptional regulators Rb and E2F1 and controls cell proliferation and apoptosis. Here we unravel an unexpected novel function for phb1 in Xenopus cranial neural crest (CNC) development. Xphb1 is maternally expressed; zygotically expressed neurula stage transcripts accumulate in the CNC and the neural tube. Knockdown of Xphb1 by antisense morpholino injection results in the loss of foxD3, snail2 and twist expression, whereas expression of c-myc, AP-2 and snail1 remains unaffected. Xphb2, its closest relative, cannot substitute for Xphb1, underlining the specificity of Xphb1 function. Epistatic analyses place Xphb1 downstream of c-myc and upstream of foxD3, snail2 and twist. To elucidate which subdomain in Xphb1 is required for neural crest gene regulation we generated deletion mutants and tested their rescue ability in Xphb1 morphants. The E2F1-binding domain was found to be necessary for Xphb1 function in neural crest development. Gain- and loss-of-function experiments reveal that Xphb1 represses E2F1 activity; suppression of E2F1 through Xphb1 is required for twist, snail2 and foxD3 expression in the CNC. With the Xphb1 dependency of a subset of CNC specifiers downstream of c-myc, we have identified a new branching point in the neural crest gene regulatory network.
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Padronização Corporal , Fator de Transcrição E2F1/metabolismo , Crista Neural/metabolismo , Proteínas Repressoras/metabolismo , Xenopus/embriologia , Animais , Apoptose , Sequência de Bases , Padronização Corporal/genética , Proliferação de Células , Fator de Transcrição E2F1/genética , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes/genética , Modelos Biológicos , Dados de Sequência Molecular , Crista Neural/citologia , Proibitinas , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/genética , Crânio/citologia , Crânio/embriologia , Crânio/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína 1 Relacionada a Twist/genética , Proteína 1 Relacionada a Twist/metabolismo , Xenopus/genética , Proteínas de Xenopus/genética , Proteínas de Xenopus/metabolismoRESUMO
BACKGROUND: Gremlin-1 (Grem1), an antagonist of bone morphogenetic proteins, is involved in fibrotic tissue formation in kidney and lung. The impact of myocardial Grem1 expression is unknown. We investigated the prognostic value of Grem1 expression in 214 consecutive patients with nonischemic heart failure (HF) undergoing endomyocardial biopsy. METHODS: In all patients, the following risk factors were assessed: Grem1 expression (semiquantitative score scheme ranging from 1 to 4), presence of inflammatory markers, detection of viral genome, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), New York Heart Association functional class (NYHA), troponin I, and B-type natriuretic peptide. Degree of myocardial fibrosis was defined as an index. Study end point was a combination of all-cause death and HF-related rehospitalization within 3 years of follow-up. RESULTS: Grem1 expression significantly correlated with the degree of myocardial fibrosis (correlation coefficient r = 0.619; P < .0001). Patients with the highest Grem1 expression (score 4) showed the most severely impaired LVEF and highest LVEDD (P < .0001 and P = .030, respectively, for comparison of semiquantitative scores). During follow-up, 33 patients (15.4%) reached the study end point. Grem1 expression and NYHA ≥II were independent predictors of the end point (Grem1: hazard ratio [HR] 7.5, 95% confidence interval [CI] 1.8-32.2; P = .006; NYHA ≥II: HR 2.0, 95% CI 1.0-4.1; P = .048). CONCLUSIONS: Grem1 correlates with the degree of myocardial fibrosis and left ventricular dysfunction and is an independent predictor of adverse outcome in patients with nonischemic HF.
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Endocárdio/metabolismo , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Miocárdio/metabolismo , Adulto , Idoso , Biópsia , Endocárdio/patologia , Feminino , Fibrose , Insuficiência Cardíaca/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Valor Preditivo dos Testes , Resultado do TratamentoRESUMO
Engineered nanoparticles have been under increasing scrutiny in recent years. High aspect ratio nanoparticles such as carbon nanotubes and nanowires have raised safety concerns due to their geometrical similarity to asbestos fibers. III-V epitaxial semiconductor nanowires are expected to be utilized in devices such as LEDs and solar cells and will thus be available to the public. In addition, clean-room staff fabricating and characterizing the nanowires are at risk of exposure, emphasizing the importance of investigating their possible toxicity. Here we investigated the effects of gallium phosphide nanowires on the fruit fly Drosophila melanogaster. Drosophila larvae and/or adults were exposed to gallium phosphide nanowires by ingestion with food. The toxicity and tissue interaction of the nanowires was evaluated by investigating tissue distribution, activation of immune response, genome-wide gene expression, life span, fecundity and somatic mutation rates. Our results show that gallium phosphide nanowires applied through the diet are not taken up into Drosophila tissues, do not elicit a measurable immune response or changes in genome-wide gene expression and do not significantly affect life span or somatic mutation rate.
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Drosophila melanogaster/efeitos dos fármacos , Gálio/toxicidade , Nanofios/toxicidade , Fosfinas/toxicidade , Administração Oral , Animais , Drosophila melanogaster/fisiologia , Ingestão de Alimentos , Fertilidade/efeitos dos fármacos , Gálio/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Larva/citologia , Larva/efeitos dos fármacos , Larva/fisiologia , Longevidade/efeitos dos fármacos , Mutação/efeitos dos fármacos , Nanofios/administração & dosagem , Neoplasias/induzido quimicamente , Análise de Sequência com Séries de Oligonucleotídeos , Fosfinas/administração & dosagem , RNA/análise , RNA/metabolismoRESUMO
Volatilization of pesticides from soils under dry conditions (water content below the permanent wilting point) can be significantly influenced by sorption to hydrated mineral surfaces. This sorption process strongly depends on the water activity, expressed as equilibrium relative humidity in the pore space of the soil, and on the available surface area of the hydrated minerals. In this study, the influence of different humidity regimes on the volatilization of two pesticides (triallate and trifluralin) was demonstrated with a bench-scale wind tunnel system that allowed the establishment of well controlled humidity conditions within the soil. In the experiment starting with very dry conditions, increasing the relative humidity in the adjacent air from 60 to 85% resulted in an up to 8 times higher volatilization rate of the pesticides. An additional strong increase in volatilization (up to 3 times higher) was caused by a simulated rain event, which eliminates all sorption sites associated to mineral surfaces. In agreement with this interpretation, the comparison of two soils suggested that mineral surface area was the soil property that governs the volatilization under dry conditions, whereas soil organic matter was the controlling variable under wet conditions. In contrast to expectations, the use of a novel capsulated suspension for triallate showed the same humidity effects and no substantially lower volatilization rates in comparison to the regular formulation. This study demonstrated that humidity effects on pesticide volatilization can be interpreted via the mechanism of sorption to mineral surfaces under dry conditions.
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Solo , Volatilização , Umidade , Praguicidas , Poluentes do SoloRESUMO
INTRODUCTION: The breast is essential to a woman's physical integrity. There are numerous techniques for breast reconstruction, so that the needs and limitations of each patient can be respected. The individual preferences of the patient play an important role in the decision of silicone implants vs. autologous tissue, size, and shape of the breast as well as the timing of the surgery. The only reasons not to perform a reconstruction are a locally incompletely removed tumor or the explicit wish of the patient against reconstruction. The costs for reconstruction are covered by the health insurance for all procedures, including symmetrizing the opposite breast, nipple reconstruction and autologous fat grafting.