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1.
J Exp Med ; 218(7)2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-33909009

RESUMO

Safe and effective coronavirus disease-19 (COVID-19) vaccines are urgently needed to control the ongoing pandemic. While single-dose vaccine regimens would provide multiple advantages, two doses may improve the magnitude and durability of immunity and protective efficacy. We assessed one- and two-dose regimens of the Ad26.COV2.S vaccine candidate in adult and aged nonhuman primates (NHPs). A two-dose Ad26.COV2.S regimen induced higher peak binding and neutralizing antibody responses compared with a single dose. In one-dose regimens, neutralizing antibody responses were stable for at least 14 wk, providing an early indication of durability. Ad26.COV2.S induced humoral immunity and T helper cell (Th cell) 1-skewed cellular responses in aged NHPs that were comparable to those in adult animals. Aged Ad26.COV2.S-vaccinated animals challenged 3 mo after dose 1 with a SARS-CoV-2 spike G614 variant showed near complete lower and substantial upper respiratory tract protection for both regimens. Neutralization of variants of concern by NHP sera was reduced for B.1.351 lineages while maintained for the B.1.1.7 lineage independent of Ad26.COV2.S vaccine regimen.


Assuntos
Adenoviridae/imunologia , Envelhecimento/imunologia , /imunologia , /imunologia , Animais , Anticorpos Neutralizantes/imunologia , Temperatura Corporal , Lavagem Broncoalveolar , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , /virologia , Relação Dose-Resposta Imunológica , Feminino , Imunidade Humoral , Cinética , Pulmão/patologia , Pulmão/virologia , Macaca mulatta , Masculino , Glicoproteína da Espícula de Coronavírus/metabolismo , Resultado do Tratamento , Vacinação , Carga Viral
2.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806315

RESUMO

Systemic injection of a nerve growth factor (NGF) antibody has been proven to have a significant relevance in relieving osteoarthritis (OA) pain, while its adverse effects remain a safety concern for patients. A local low-dose injection is thought to minimize adverse effects. In this study, OA was induced in an 8-week-old male Sprague-Dawley (SD) rat joint by monoiodoacetate (MIA) injection for 2 weeks, and the effect of weekly injections of low-dose (1, 10, and 100 µg) NGF antibody or saline (control) was evaluated. Behavioral tests were performed, and at the end of week 6, all rats were sacrificed and their knee joints were collected for macroscopic and histological evaluations. Results showed that 100 µg NGF antibody injection relieved pain in OA rats, as evidenced from improved weight-bearing performance but not allodynia. In contrast, no significant differences were observed in macroscopic and histological scores between rats from different groups, demonstrating that intra-articular treatment does not worsen OA progression. These results suggest that local administration yielded a low effective NGF antibody dose that may serve as an alternative approach to systemic injection for the treatment of patients with OA.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Experimental/terapia , Fator de Crescimento Neural/antagonistas & inibidores , Osteoartrite/terapia , Manejo da Dor/métodos , Animais , Artrite Experimental/patologia , Artrite Experimental/fisiopatologia , Cartilagem Articular/patologia , Relação Dose-Resposta Imunológica , Hiperalgesia/fisiopatologia , Hiperalgesia/terapia , Injeções Intra-Articulares , Ácido Iodoacético/toxicidade , Masculino , Fator de Crescimento Neural/imunologia , Osteoartrite/patologia , Osteoartrite/fisiopatologia , Ratos , Ratos Sprague-Dawley , Suporte de Carga/fisiologia
3.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800950

RESUMO

Male patients with Fabry disease (FD) are at high risk for the formation of antibodies to recombinant α-galactosidase A (AGAL), used for enzyme replacement therapy. Due to the rapid disease progression, the identification of patients at risk is highly warranted. However, currently suitable references and standardized protocols for anti-drug antibodies (ADA) determination do not exist. Here we generate a comprehensive patient-derived antibody mixture as a reference, allowing ELISA-based quantification of antibody titers from individual blood samples. Serum samples of 22 male patients with FD and ADAs against AGAL were pooled and purified by immune adsorption. ADA-affinities against agalsidase-α, agalsidase-ß and Moss-AGAL were measured by quartz crystal microbalance with dissipation monitoring (QCM-D). AGAL-specific immune adsorption generated a polyclonal ADA mixture showing a concentration-dependent binding and inhibition of AGAL. Titers in raw sera and from purified total IgGs (r2 = 0.9063 and r2 = 0.8952, both p < 0.0001) correlated with the individual inhibitory capacities of ADAs. QCM-D measurements demonstrated comparable affinities of the reference antibody for agalsidase-α, agalsidase-ß and Moss-AGAL (KD: 1.94 ± 0.11 µM, 2.46 ± 0.21 µM, and 1.33 ± 0.09 µM, respectively). The reference antibody allows the ELISA-based ADA titer determination and quantification of absolute concentrations. Furthermore, ADAs from patients with FD have comparable affinities to agalsidase-α, agalsidase-ß and Moss-AGAL.


Assuntos
Anticorpos Neutralizantes/imunologia , Terapia de Reposição de Enzimas , Ensaio de Imunoadsorção Enzimática , Doença de Fabry/imunologia , alfa-Galactosidase/imunologia , alfa-N-Acetilgalactosaminidase/imunologia , Anticorpos Neutralizantes/biossíntese , Afinidade de Anticorpos , Relação Dose-Resposta Imunológica , Doença de Fabry/sangue , Doença de Fabry/tratamento farmacológico , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/imunologia , Masculino , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Padrões de Referência , alfa-Galactosidase/sangue , alfa-Galactosidase/uso terapêutico , alfa-N-Acetilgalactosaminidase/sangue , alfa-N-Acetilgalactosaminidase/uso terapêutico
4.
JAMA Netw Open ; 4(2): e2035693, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33560425

RESUMO

Importance: Low-dose intradermal influenza vaccines could be a suitable alternative to full intramuscular dose during vaccine shortages. Objective: To compare the immunogenicity and safety of the influenza vaccine at reduced or full intradermal doses with full intramuscular doses to inform policy design in the event of vaccine shortages. Data Sources: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies published from 2010 until June 5, 2020. Study Selection: All comparative studies across all ages assessing the immunogenicity or safety of intradermal and intramuscular influenza vaccinations were included. Data Extraction and Synthesis: Data were extracted by a single reviewer and verified by a second reviewer. Discrepancies between reviewers were resolved through consensus. Random-effects meta-analysis was conducted. Main Outcomes and Measures: Primary outcomes included geometric mean titer, seroconversion, seroprotection, and adverse events. Results: A total of 30 relevant studies were included; 29 studies were randomized clinical trials with 13 759 total participants, and 1 study was a cohort study of 164 021 participants. There was no statistically significant difference in seroconversion rates between the 3-µg, 6-µg, 7.5-µg, and 9-µg intradermal vaccine doses and the 15-µg intramuscular vaccine dose for each of the H1N1, H3N2, and B strains, but rates were significantly higher with the 15-µg intradermal dose compared with the 15-µg intramuscular dose for the H1N1 strain (rate ratio [RR], 1.10; 95% CI, 1.01-1.20) and B strain (RR, 1.40; 95% CI, 1.13-1.73). Seroprotection rates for the 9-µg and 15-µg intradermal doses did not vary significantly compared with the 15-µg intramuscular dose for all the 3 strains, except for the 15-µg intradermal dose for the H1N1 strain, for which rates were significantly higher (RR, 1.05; 95% CI, 1.01-1.09). Local adverse events were significantly higher with intradermal doses than with the 15-µg intramuscular dose, particularly erythema (3-µg dose: RR, 9.62; 95% CI, 1.07-86.56; 6-µg dose: RR, 23.79; 95% CI, 14.42-39.23; 9-µg dose: RR, 4.56; 95% CI, 3.05-6.82; 15-µg dose: RR, 3.68; 95% CI, 3.19-4.25) and swelling (3-µg dose: RR, 20.16; 95% CI, 4.68-86.82; 9-µg dose: RR, 5.23; 95% CI, 3.58-7.62; 15-µg dose: RR, 3.47 ; 95% CI, 2.21-5.45). Fever and chills were significantly more common with the 9-µg intradermal dose than the 15-µg intramuscular dose (fever: RR, 1.36; 95% CI, 1.03-1.80; chills: RR, 1.24; 95% CI, 1.03-1.50) while all other systemic adverse events were not statistically significant for all other doses. Conclusions and Relevance: These findings suggest that reduced-dose intradermal influenza vaccination could be a reasonable alternative to standard dose intramuscular vaccination.


Assuntos
Anticorpos Antivirais/imunologia , 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/prevenção & controle , Calafrios/epidemiologia , Relação Dose-Resposta Imunológica , Febre/epidemiologia , Testes de Inibição da Hemaglutinação , Humanos , Imunogenicidade da Vacina , Reação no Local da Injeção/epidemiologia , Injeções Intradérmicas , Injeções Intramusculares , Soroconversão
5.
Nutrients ; 13(2)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578927

RESUMO

Detailed information about the amount of allergenic protein ingested by the patient prior to an allergic reaction yields valuable information for the diagnosis, guidance and management of food allergy. However, the exact amount of ingredients is often not declared on the label. In this study the feasibility was studied for estimating the amount of allergenic protein from milk, eggs, peanuts and hazelnuts in frequently consumed composite and non-composite foods and per bite or sip size in different age groups in the Netherlands. Foods containing milk, egg, peanut or hazelnut most frequently consumed were selected for the age groups 2-3, 4-6 and 19-30 years. If the label did not yield clear information, the amount of allergenic protein was estimated based on food labels. Bite or sip sizes were determined in these age groups in 30 different foods. The amount of allergenic protein could be estimated in 47/70 (67%) of composite foods, which was complex. Estimated protein content of milk, egg, peanut and hazelnut was 2-3 g for most foods but varied greatly from 3 to 8610 mg and may be below threshold levels of the patient. In contrast, a single bite or sip can contain a sufficient amount of allergenic protein to elicit an allergic reaction. Bite and sip sizes increased with age. In every day practice it is hard to obtain detailed and reliable information about the amount of allergenic protein incorporated in composite foods. We encourage companies to disclose the amount of common allergenic foods on their labels.


Assuntos
Alérgenos/análise , Proteínas na Dieta/análise , Hipersensibilidade Alimentar/imunologia , Rotulagem de Alimentos , Adolescente , Adulto , Alérgenos/imunologia , Animais , Arachis/química , Arachis/imunologia , Criança , Pré-Escolar , Corylus/química , Corylus/imunologia , Dieta , Proteínas na Dieta/imunologia , Relação Dose-Resposta Imunológica , Ovos/análise , Feminino , Hipersensibilidade Alimentar/diagnóstico , Humanos , Masculino , Leite/química , Leite/imunologia , Países Baixos , Inquéritos e Questionários , Adulto Jovem
7.
Euro Surveill ; 26(6)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33573712

RESUMO

The BNT162b2 mRNA COVID-19 vaccine showed high efficacy in clinical trials but observational data from populations not included in trials are needed. We describe immunogenicity 21 days post-dose 1 among 514 Israeli healthcare workers by age, ethnicity, sex and prior COVID-19 infection. Immunogenicity was similar by ethnicity and sex but decreased with age. Those with prior infection had antibody titres one magnitude order higher than naïve individuals regardless of the presence of detectable IgG antibodies pre-vaccination.


Assuntos
/imunologia , Imunogenicidade da Vacina , Adulto , Fatores Etários , Idoso , /administração & dosagem , Relação Dose-Resposta Imunológica , Grupos Étnicos/estatística & dados numéricos , Feminino , Pessoal de Saúde/estatística & dados numéricos , Humanos , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia
8.
Nat Med ; 27(2): 270-278, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33335323

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed1. Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses2 and might reduce the potential for disease enhancement3. Cytotoxic T cells clear virus-infected host cells and contribute to control of infection4. Studies of patients infected with SARS-CoV-2 have suggested a protective role for both humoral and cell-mediated immune responses in recovery from COVID-19 (refs. 5,6). ChAdOx1 nCoV-19 (AZD1222) is a candidate SARS-CoV-2 vaccine comprising a replication-deficient simian adenovirus expressing full-length SARS-CoV-2 spike protein. We recently reported preliminary safety and immunogenicity data from a phase 1/2 trial of the ChAdOx1 nCoV-19 vaccine (NCT04400838)7 given as either a one- or two-dose regimen. The vaccine was tolerated, with induction of neutralizing antibodies and antigen-specific T cells against the SARS-CoV-2 spike protein. Here we describe, in detail, exploratory analyses of the immune responses in adults, aged 18-55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1 nCoV-19 in this trial, demonstrating an induction of a Th1-biased response characterized by interferon-γ and tumor necrosis factor-α cytokine secretion by CD4+ T cells and antibody production predominantly of IgG1 and IgG3 subclasses. CD8+ T cells, of monofunctional, polyfunctional and cytotoxic phenotypes, were also induced. Taken together, these results suggest a favorable immune profile induced by ChAdOx1 nCoV-19 vaccine, supporting the progression of this vaccine candidate to ongoing phase 2/3 trials to assess vaccine efficacy.


Assuntos
Formação de Anticorpos/imunologia , Linfócitos T/imunologia , Adolescente , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , /virologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunidade Celular , Imunidade Humoral , Imunoglobulina A/imunologia , Imunoglobulina M/imunologia , Interferon gama/metabolismo , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Subunidades Proteicas/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Adulto Jovem
9.
Nat Commun ; 11(1): 6402, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328475

RESUMO

The COVID-19 pandemic caused by SARS-CoV-2 imposes an urgent need for rapid development of an efficient and cost-effective vaccine, suitable for mass immunization. Here, we show the development of a replication competent recombinant VSV-∆G-spike vaccine, in which the glycoprotein of VSV is replaced by the spike protein of SARS-CoV-2. In-vitro characterization of this vaccine indicates the expression and presentation of the spike protein on the viral membrane with antigenic similarity to SARS-CoV-2. A golden Syrian hamster in-vivo model for COVID-19 is implemented. We show that a single-dose vaccination results in a rapid and potent induction of SARS-CoV-2 neutralizing antibodies. Importantly, vaccination protects hamsters against SARS-CoV-2 challenge, as demonstrated by the abrogation of body weight loss, and  alleviation of the extensive tissue damage and viral loads in lungs and nasal turbinates. Taken together, we suggest the recombinant VSV-∆G-spike as a safe, efficacious and protective vaccine against SARS-CoV-2.


Assuntos
/imunologia , /prevenção & controle , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Sintéticas/imunologia , Vírus da Estomatite Vesicular Indiana/imunologia , Animais , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Peso Corporal , Linhagem Celular , Cricetinae , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Genoma Viral , Pulmão/patologia , Pulmão/virologia , Camundongos Endogâmicos C57BL , Mutação/genética , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/ultraestrutura , Vacinação , Carga Viral
11.
Trials ; 21(1): 883, 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106167

RESUMO

OBJECTIVES: General: To assess the safety, efficacy and dose response of convalescent plasma (CP) transfusion in severe COVID-19 patients Specific: a. To identify the appropriate effective dose of CP therapy in severe patients b. To identify the efficacy of the therapy with their end point based on clinical improvement within seven days of treatment or until discharge whichever is later and in-hospital mortality c. To assess the clinical improvement after CP transfusion in severe COVID-19 patients d. To assess the laboratory improvement after CP transfusion in severe COVID-19 patients TRIAL DESIGN: This is a multicentre, multi-arm phase II Randomised Controlled Trial. PARTICIPANTS: Age and sex matched COVID-19 positive (by RT-PCR) severe cases will be enrolled in this trial. Severe case is defined by the World Health Organization (W.H.O) clinical case definition. The inclusion criteria are 1. Respiratory rate > 30 breaths/min; PLUS 2. Severe respiratory distress; or SpO2 ≤ 88% on room air or PaO2/FiO2≤ 300 mm of Hg, PLUS 3. Radiological (X-ray or CT scan) evidence of bilateral lung infiltrate, AND OR 4. Systolic BP < 90 mm of Hg or diastolic BP <60 mm of Hg. AND/OR 5. Criteria 1 to 4 AND or patient in ventilator support Patients' below18 years, pregnant and lactating women, previous history of allergic reaction to plasma, patients who have already received plasma from a different source will be excluded. Patients will be enrolled at Bangabandhu Sheikh Mujib Medical University (BSMMU) hospital, Dhaka medical college hospital (DMCH) and Mugda medical college hospital (MuMCH). Apheretic plasma will be collected at the transfusion medicine department of SHNIBPS hospital, ELISA antibody titre will be done at BSMMU and CMBT and neutralizing antibody titre will be checked in collaboration with the University of Oxford. Patients who have recovered from COVID-19 will be recruited as donors of CP. The recovery criteria are normality of body temperature for more than 3 days, resolution of respiratory symptoms, two consecutively negative results of sputum SARS-CoV-2 by RT-PCR assay (at least 24 hours apart) 22 to 35 days of post onset period, and neutralizing antibody titre ≥ 1:160. INTERVENTION AND COMPARATOR: This RCT consists of three arms, a. standard care, b. standard care and 200 ml CP and c. standard care and 400 ml CP. Patients will receive plasma as a single transfusion. Intervention arms will be compared to the standard care arm. MAIN OUTCOMES: The primary outcome will be time to clinical improvement within seven days of treatment or until discharge whichever is later and in-hospital mortality. The secondary outcome would be improvement of laboratory parameters after therapy (neutrophil, lymphocyte ratio, CRP, serum ferritin, SGPT, SGOT, serum creatinine and radiology), length of hospital stay, length of ICU stay, reduction in proportion of deaths, requirement of ventilator and duration of oxygen and ventilator support. RANDOMISATION: Randomization will be done by someone not associated with the care or assessment of the patients by means of a computer generated random number table using an allocation ratio of 1:1:1. BLINDING (MASKING): This is an open level study; neither the physician nor the patients will be blinded. However, the primary and secondary outcome (oxygen saturations, PaO2/FiO2, BP, day specific laboratory tests) will be recorded using an objective automated method; the study staff will not be able to influence the recording of these data. NUMBER TO BE RANDOMISED (SAMPLE SIZE): No similar study has been performed previously. Therefore no data are available that could be used to generate a sample size calculation. This phase II study is required to provide some initial data on efficacy and safety that will allow design of a larger study. The trial will recruit 60 participants (20 in each arm). TRIAL STATUS: Protocol version 1.4 dated May 5, 2020 and amended version 1.5, dated June 16, 2020. First case was recruited on May 27, 2020. By August 10, 2020, the trial had recruited one-third (21 out of 60) of the participants. The recruitment is expected to finish by October 31, 2020. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT04403477 . Registered 26 May, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trial's website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.


Assuntos
Betacoronavirus/genética , Transfusão de Sangue/métodos , Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Bangladesh/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Relação Dose-Resposta Imunológica , Feminino , Mortalidade Hospitalar/tendências , Humanos , Imunização Passiva/efeitos adversos , Imunização Passiva/métodos , Masculino , Pandemias , Alta do Paciente/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Segurança , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Ventiladores Mecânicos/estatística & dados numéricos
12.
Anticancer Res ; 40(10): 5687-5700, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988894

RESUMO

BACKGROUND: We previously developed a novel technique for expanding highly activated and purified natural killer (NK) cells able to maximize the theoretical activation potential of NK cells; thus, we named this cell population zenithal-NK (ZNK). AIM: To evaluate the safety, feasibility, and preliminary efficacy of autologous ZNK cells in patients with different types of advanced cancer with measurable solid lesions. PATIENTS AND METHODS: In this phase I/IIb first-in-human, open-label, dose-escalation study (trial registration ID: UMIN-000011555), eligible patients received ZNK cells intravenously starting from 106 to 108 cells/patient/dose at 2-week dosing intervals. A maximum of six cycles were allowed. Safety and survival analyses were also carried out for cases that were excluded and never administered ZNK cells. RESULTS: As of April 20, 2017, a total of nine patients were enrolled in this study, with one recruited twice. Overall, neither grade 2 or higher toxicities (Common Terminology Criteria for Adverse Events v5.0) caused by cell administration, nor adverse events causing discontinuation of protocol treatment were found. In four cases, the number of administered ZNK cells was increased to 108 cells/body/dose without any serious dose-limiting toxicity; the maximally tolerated dose was therefore considered to be at least 108 cells. The overall response rate was 40.0% in 10 net cases, one of partial response and three of stable disease, and the patient with partial response is still alive after 4 year's observation. CONCLUSION: These results demonstrate that autologous ZNK cells are safe and well-tolerated in patients with different types of advanced solid tumors. Clinical studies using similarly active ZNK cells from human leukocyte antigen/killer cell immunoglobulin-like receptor-mismatched healthy donors under Good Manufacturing Practice-compliant manufacturing, and with modified treatment regimen, i.e. doses and frequencies, are warranted for further investigation to show the potential of ZNK cells in such patients.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Células Matadoras Naturais/transplante , Neoplasias/terapia , Transplante Autólogo/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/genética , Relação Dose-Resposta Imunológica , Feminino , Humanos , Células Matadoras Naturais/imunologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia
13.
Med Microbiol Immunol ; 209(6): 681-691, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32918599

RESUMO

Chimeric Antigen Receptor (CAR)-redirected T cells show great efficacy in the patient-specific therapy of hematologic malignancies. Here, we demonstrate that a DARPin with specificity for CD4 specifically redirects and triggers the activation of CAR engineered T cells resulting in the depletion of CD4+ target cells aiming for elimination of the human immunodeficiency virus (HIV) reservoir.


Assuntos
Repetição de Anquirina , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/imunologia , HIV/isolamento & purificação , Imunoterapia Adotiva , Depleção Linfocítica/métodos , Peptídeos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Relação Dose-Resposta Imunológica , Avaliação Pré-Clínica de Medicamentos , Gammaretrovirus/genética , Vetores Genéticos/genética , Células HEK293 , Infecções por HIV/virologia , Humanos , Ativação Linfocitária , Peptídeos/química , Anticorpos de Cadeia Única/imunologia , Transdução Genética
14.
Nat Commun ; 11(1): 4207, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826924

RESUMO

The rapid spread of coronavirus SARS-CoV-2 greatly threatens global public health but no prophylactic vaccine is available. Here, we report the generation of a replication-incompetent recombinant serotype 5 adenovirus, Ad5-S-nb2, carrying a codon-optimized gene encoding Spike protein (S). In mice and rhesus macaques, intramuscular injection with Ad5-S-nb2 elicits systemic S-specific antibody and cell-mediated immune (CMI) responses. Intranasal inoculation elicits both systemic and pulmonary antibody responses but weaker CMI response. At 30 days after a single vaccination with Ad5-S-nb2 either intramuscularly or intranasally, macaques are protected against SARS-CoV-2 challenge. A subsequent challenge reveals that macaques vaccinated with a 10-fold lower vaccine dosage (1 × 1010 viral particles) are also protected, demonstrating the effectiveness of Ad5-S-nb2 and the possibility of offering more vaccine dosages within a shorter timeframe. Thus, Ad5-S-nb2 is a promising candidate vaccine and warrants further clinical evaluation.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/administração & dosagem , Adenoviridae/genética , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Infecções por Coronavirus/imunologia , Relação Dose-Resposta Imunológica , Feminino , Células HEK293 , Humanos , Imunidade Celular , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia Viral/imunologia , Sistema Respiratório/patologia , Sistema Respiratório/virologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Sintéticas/administração & dosagem
15.
JAMA ; 324(10): 951-960, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32789505

RESUMO

Importance: A vaccine against coronavirus disease 2019 (COVID-19) is urgently needed. Objective: To evaluate the safety and immunogenicity of an investigational inactivated whole-virus COVID-19 vaccine in China. Interventions: In the phase 1 trial, 96 participants were assigned to 1 of the 3 dose groups (2.5, 5, and 10 µg/dose) and an aluminum hydroxide (alum) adjuvant-only group (n = 24 in each group), and received 3 intramuscular injections at days 0, 28, and 56. In the phase 2 trial, 224 adults were randomized to 5 µg/dose in 2 schedule groups (injections on days 0 and 14 [n = 84] vs alum only [n = 28], and days 0 and 21 [n = 84] vs alum only [n = 28]). Design, Setting, and Participants: Interim analysis of ongoing randomized, double-blind, placebo-controlled, phase 1 and 2 clinical trials to assess an inactivated COVID-19 vaccine. The trials were conducted in Henan Province, China, among 96 (phase 1) and 224 (phase 2) healthy adults aged between 18 and 59 years. Study enrollment began on April 12, 2020. The interim analysis was conducted on June 16, 2020, and updated on July 27, 2020. Main Outcomes and Measures: The primary safety outcome was the combined adverse reactions 7 days after each injection, and the primary immunogenicity outcome was neutralizing antibody response 14 days after the whole-course vaccination, which was measured by a 50% plaque reduction neutralization test against live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results: Among 320 patients who were randomized (mean age, 42.8 years; 200 women [62.5%]), all completed the trial up to 28 days after the whole-course vaccination. The 7-day adverse reactions occurred in 3 (12.5%), 5 (20.8%), 4 (16.7%), and 6 (25.0%) patients in the alum only, low-dose, medium-dose, and high-dose groups, respectively, in the phase 1 trial; and in 5 (6.0%) and 4 (14.3%) patients who received injections on days 0 and 14 for vaccine and alum only, and 16 (19.0%) and 5 (17.9%) patients who received injections on days 0 and 21 for vaccine and alum only, respectively, in the phase 2 trial. The most common adverse reaction was injection site pain, followed by fever, which were mild and self-limiting; no serious adverse reactions were noted. The geometric mean titers of neutralizing antibodies in the low-, medium-, and high-dose groups at day 14 after 3 injections were 316 (95% CI, 218-457), 206 (95% CI, 123-343), and 297 (95% CI, 208-424), respectively, in the phase 1 trial, and were 121 (95% CI, 95-154) and 247 (95% CI, 176-345) at day 14 after 2 injections in participants receiving vaccine on days 0 and 14 and on days 0 and 21, respectively, in the phase 2 trial. There were no detectable antibody responses in all alum-only groups. Conclusions and Relevance: In this interim report of the phase 1 and phase 2 trials of an inactivated COVID-19 vaccine, patients had a low rate of adverse reactions and demonstrated immunogenicity; the study is ongoing. Efficacy and longer-term adverse event assessment will require phase 3 trials. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000031809.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Imunogenicidade da Vacina , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adolescente , Adulto , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus/genética , Infecções por Coronavirus/imunologia , Relação Dose-Resposta Imunológica , Método Duplo-Cego , Feminino , Humanos , Injeções Intramusculares , Masculino , Pneumonia Viral/imunologia , Propiolactona , Vacinas de Produtos Inativados/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversos , Adulto Jovem
16.
Zhonghua Liu Xing Bing Xue Za Zhi ; 41(7): 1138-1144, 2020 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-32741184

RESUMO

Objective: To assess the effectiveness of 1 dose varicella attenuated live vaccine (VarV) for healthy children aged 1-12 years in China and explore the application of the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework in observational studies of vaccine effectiveness (VE). Methods: We searched studies about the VE of 1-dose VarV for children aged 1-12 years in China which published before 2019 and evaluated the quality of the studies by the Newcastle Ottawa Scale (NOS) table. We used Meta-analysis models to obtain the pooled 1-dose VE and that in subgroups by study design, outbreak or not, study quality and age of subjects. The evidences of VEs were rated by means of the GRADE system. Results: Thirty-two studies were included and the pooled 1-dose VE was 75% [95% confidence interval (CI): 68%-80%]. The VE of outbreak studies [VE=66% (95%CI: 57%-73%)] was lower than non-outbreak studies [VE=85% (95%CI: 78%-89%)], and the VE in <6 years old children [VE=84% (95%CI:77%-89%)] was higher than that in ≥6 years old children [VE=60% (95%CI: 51%-68%)]. There was no significant difference in VE among studies with different design and quality. The quality of the evidences of pooled 1-dose VE was"very low", which was downgraded in bias risk and inconsistency and not downgraded in indirectness, imprecision and publication bias. Conclusions: The 1-dose VarV can provide medium level protection for 1-12 years old children in China, but it will decrease significantly for ≥6 years old children, so it is suggested to implement the strategies of two-dose vaccination of VarV in children <6 years old. The GRADE framework can be used in the observational studies of VE and it is suggested that the technical guidelines of observational study should be worked out to improve the overall quality of evidence.


Assuntos
Vacina contra Varicela/administração & dosagem , Vacina contra Varicela/imunologia , Varicela/prevenção & controle , Surtos de Doenças/prevenção & controle , Varicela/epidemiologia , Criança , Pré-Escolar , China/epidemiologia , Relação Dose-Resposta Imunológica , Humanos , Lactente , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia
17.
N Engl J Med ; 383(16): 1544-1555, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32722908

RESUMO

BACKGROUND: Vaccines to prevent coronavirus disease 2019 (Covid-19) are urgently needed. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines on viral replication in both upper and lower airways is important to evaluate in nonhuman primates. METHODS: Nonhuman primates received 10 or 100 µg of mRNA-1273, a vaccine encoding the prefusion-stabilized spike protein of SARS-CoV-2, or no vaccine. Antibody and T-cell responses were assessed before upper- and lower-airway challenge with SARS-CoV-2. Active viral replication and viral genomes in bronchoalveolar-lavage (BAL) fluid and nasal swab specimens were assessed by polymerase chain reaction, and histopathological analysis and viral quantification were performed on lung-tissue specimens. RESULTS: The mRNA-1273 vaccine candidate induced antibody levels exceeding those in human convalescent-phase serum, with live-virus reciprocal 50% inhibitory dilution (ID50) geometric mean titers of 501 in the 10-µg dose group and 3481 in the 100-µg dose group. Vaccination induced type 1 helper T-cell (Th1)-biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses. Viral replication was not detectable in BAL fluid by day 2 after challenge in seven of eight animals in both vaccinated groups. No viral replication was detectable in the nose of any of the eight animals in the 100-µg dose group by day 2 after challenge, and limited inflammation or detectable viral genome or antigen was noted in lungs of animals in either vaccine group. CONCLUSIONS: Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. (Funded by the National Institutes of Health and others.).


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus/fisiologia , Antígenos CD4 , Infecções por Coronavirus/patologia , Infecções por Coronavirus/terapia , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Imunização Passiva , Pulmão/patologia , Pulmão/virologia , Macaca mulatta , Pneumonia Viral/patologia , Pneumonia Viral/terapia , Glicoproteína da Espícula de Coronavírus , Linfócitos T/imunologia , Carga Viral , Vacinas Virais/administração & dosagem , Replicação Viral
18.
Anticancer Res ; 40(7): 3865-3872, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620626

RESUMO

BACKGROUND/AIM: Ovarian cancer (OC) is typically diagnosed at an advanced stage with limitations for cure. Cytokine-induced killer (CIK) T cell therapy exerts significant cytotoxic effects against cancer cells and reduces the adverse effects of chemotherapy. Herein, we performed a flow cytometry-based method to evaluate the cytotoxicity of peripheral blood mononuclear cells-derived CIK cells against OC cells. MATERIALS AND METHODS: The CIK cells were induced and expanded using an interferon-γ/IL-2-based xeno-free medium system. The cytotoxicity of CIK cells or carboplatin against OC cells was examined. RESULTS: The CIK cells showed an NK-like phenotypic characteristic and dose-dependently increased cytotoxicity against OC cells. We found that the number of advanced OC cells, which were more resistant to carboplatin, was dramatically decreased by an additional one-shot CIK treatment. CONCLUSION: CIK cells have a potent cytotoxic ability that would be explored as an alternative strategy for cancer treatment in the near future.


Assuntos
Carboplatina/farmacologia , Células Matadoras Induzidas por Citocinas/imunologia , Células Matadoras Induzidas por Citocinas/transplante , Imunoterapia Adotiva/métodos , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Antineoplásicos/farmacologia , Células Cultivadas , Terapia Combinada , Células Matadoras Induzidas por Citocinas/efeitos dos fármacos , Relação Dose-Resposta Imunológica , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Humanos , Interferon gama/imunologia , Interferon gama/farmacologia , Interleucina-1alfa/imunologia , Interleucina-1alfa/farmacologia , Interleucina-2/imunologia , Interleucina-2/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Neoplasias Ovarianas/tratamento farmacológico
19.
Lancet Child Adolesc Health ; 4(10): 728-739, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32702315

RESUMO

BACKGROUND: Peanut allergy is the leading cause of food-related anaphylaxis. Current management options can negatively affect food allergy-related quality of life. We aimed to investigate the efficacy of an investigational oral biologic drug (AR101). METHODS: The AR101 Trial in Europe Measuring Oral Immunotherapy Success in peanut-allergic children (ARTEMIS) trial was a multicentre, double-blind, randomised, placebo-controlled phase 3 trial done at 18 hospitals in Ireland, France, Germany, Italy, Spain, Sweden, and the UK. Children and adolescents with peanut allergy, aged 4-17 years, who developed dose-limiting symptoms to 300 mg or less peanut protein (equivalent to approximately one peanut kernel) during a double-blind placebo-controlled food challenge test at study entry were enrolled. Participants were randomly assigned (3:1) to receive daily doses of either AR101 oral immunotherapy (AR101 group) or a taste-masked placebo (placebo group). All participants, investigators, and care providers were masked to treatment allocation until the study was completed. Doses were increased every 2 weeks over 6 months until a dose of 300 mg was reached and maintained for 3 months. The primary endpoint was the proportion of participants in the intention-to-treat or safety population (defined as those participants who had been randomly assigned and had received at least one dose of the assigned drug) who could consume a single dose of 1000 mg (cumulative dose 2043 mg) peanut protein without developing dose-limiting allergic symptoms at an exit double-blind placebo-controlled food challenge after 9 months of treatment. Additional endpoints included safety (ie, the frequency and severity of adverse events) and changes in food allergy-related quality of life, assessed by use of age-appropriate Food Allergy Quality of Life Questionnaires (FAQLQs) and the Food Allergy Independent Measure (FAIM). The study is registered with ClinicalTrials.gov, NCT03201003, and is completed. FINDINGS: Between June 12, 2017, and Feb 15, 2018, 227 patients were screened, of whom 175 were randomly assigned to the AR101 group (n=132) and the placebo group (n=43). All primary and secondary endpoints were met. 77 (58%) of 132 participants in the AR101 group tolerated 1000 mg peanut protein at the exit food challenge versus one (2%) of 43 participants in the placebo group (AR101-placebo treatment difference 56·0% [95% CI 44·1-65·2], p<0·0001). Adverse events were reported by almost all participants. The maximum severity of adverse events reported was mild or moderate for most participants who received AR101 (mild, 66 [50%] of 132 participants; moderate, 63 [48%]; and severe, one [1%]) or placebo (mild, 24 [56%] of 43 participants; moderate, 18 [42%]; severe, none). Participants aged 8-12 years in the AR101 group reported improvements that exceeded the minimum clinically important difference between the two groups across all FAQLQ domains. Additionally, participants in the AR101 group and their caregivers reported improvements that exceeded the minimum clinically important difference in FAIM domains related to the perceived likelihood and outcomes of a severe allergic reaction. INTERPRETATION: AR101 oral immunotherapy treatment led to rapid desensitisation to peanut protein, with a predictable safety profile that improved with treatment, and an associated improvement in self-reported and caregiver-reported food allergy-related quality of life. These patient-oriented outcomes provide invaluable data to help physicians, patients, and caregivers make informed, shared decisions on the management of peanut allergy. FUNDING: Aimmune Therapeutics.


Assuntos
Alérgenos/administração & dosagem , Produtos Biológicos/administração & dosagem , Dessensibilização Imunológica/métodos , Hipersensibilidade a Amendoim/terapia , Administração Oral , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta Imunológica , Método Duplo-Cego , Europa (Continente) , Feminino , Humanos , Masculino , Hipersensibilidade a Amendoim/imunologia , Testes Cutâneos , Resultado do Tratamento
20.
Science ; 369(6499): 77-81, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32376603

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. Because of the novelty of the virus, there are currently no SARS-CoV-2-specific treatments or vaccines available. Therefore, rapid development of effective vaccines against SARS-CoV-2 are urgently needed. Here, we developed a pilot-scale production of PiCoVacc, a purified inactivated SARS-CoV-2 virus vaccine candidate, which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats, and nonhuman primates. These antibodies neutralized 10 representative SARS-CoV-2 strains, suggesting a possible broader neutralizing ability against other strains. Three immunizations using two different doses, 3 or 6 micrograms per dose, provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without observable antibody-dependent enhancement of infection. These data support the clinical development and testing of PiCoVacc for use in humans.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais , Animais , Anticorpos Neutralizantes/biossíntese , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/imunologia , Betacoronavirus/isolamento & purificação , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Relação Dose-Resposta Imunológica , Feminino , Imunogenicidade da Vacina , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Projetos Piloto , Pneumonia Viral/virologia , Ratos , Ratos Wistar , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/imunologia , Células Vero , Carga Viral , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversos , Vacinas Virais/imunologia
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