Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 12.234
Filtrar
1.
Gut ; 69(2): 343-354, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30926653

RESUMO

OBJECTIVE: This study aimed to develop a novel therapeutic vaccine based on a unique B cell epitope and investigate its therapeutic potential against chronic hepatitis B (CHB) in animal models. METHODS: A series of peptides and carrier proteins were evaluated in HBV-tolerant mice to obtain an optimised therapeutic molecule. The immunogenicity, therapeutic efficacy and mechanism of the candidate were investigated systematically. RESULTS: Among the HBsAg-aa119-125-containing peptides evaluated in this study, HBsAg-aa113-135 (SEQ13) exhibited the most striking therapeutic effects. A novel immunoenhanced virus-like particle carrier (CR-T3) derived from the roundleaf bat HBV core antigen (RBHBcAg) was created and used to display SEQ13, forming candidate molecule CR-T3-SEQ13. Multiple copies of SEQ13 displayed on the surface of this particulate antigen promote the induction of a potent anti-HBs antibody response in mice, rabbits and cynomolgus monkeys. Sera and purified polyclonal IgG from the immunised animals neutralised HBV infection in vitro and mediated efficient HBV/hepatitis B virus surface antigen (HBsAg) clearance in the mice. CR-T3-SEQ13-based vaccination induced long-term suppression of HBsAg and HBV DNA in HBV transgenic mice and eradicated the virus completely in hydrodynamic-based HBV carrier mice. The suppressive effects on HBsAg were strongly correlated with the anti-HBs level after vaccination, suggesting that the main mechanism of CR-T3-SEQ13 vaccination therapy was the induction of a SEQ13-specific antibody response that mediated HBV/HBsAg clearance. CONCLUSIONS: The novel particulate protein CR-T3-SEQ13 suppressed HBsAg effectively through induction of a humoural immune response in HBV-tolerant mice. This B cell epitope-based therapeutic vaccine may provide a novel immunotherapeutic agent against chronic HBV infection in humans.


Assuntos
Epitopos de Linfócito B/imunologia , Antígenos de Superfície da Hepatite B/sangue , Vacinas contra Hepatite B/imunologia , Hepatite B Crônica/imunologia , Adjuvantes Imunológicos , Animais , Antivirais/uso terapêutico , Terapia Combinada , DNA Viral/sangue , Relação Dose-Resposta Imunológica , Feminino , Anticorpos Anti-Hepatite B/biossíntese , Vacinas contra Hepatite B/uso terapêutico , Vírus da Hepatite B/genética , Hepatite B Crônica/terapia , Hepatite B Crônica/virologia , Imunidade Humoral/imunologia , Imunoterapia/métodos , Macaca fascicularis , Masculino , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Coelhos
2.
Allergol. immunopatol ; 47(6): 564-569, nov.-dic. 2019. graf, tab
Artigo em Inglês | IBECS | ID: ibc-186549

RESUMO

Introduction: Sickle cell disease (SCD) children are at increased risk of invasive pneumococcal disease and rely on penicillin prophylaxis and vaccination for infection prevention. Post-vaccination antibody levels in SCD may wane overtime. HbSC are believed to have better immunological response than HbSS. Objective: To compare antibody response to 23-valent pneumococcal polysaccharide vaccine (PPSV-23) between HbSS and HbSC. Methods: Patients with HbSS (n = 33) and HbSC (n = 11), aged 7-18 years, were prospectively recruited. Luminex pneumococcal antibody levels were measured for 23-serotypes, after two PPSV-23 doses. Results: Absolute median titer for 20 of the 23 serotypes was higher in HbSC than HbSS and significantly higher for serotypes 22 (3.9 vs. 1.6mcg/ml; p=0.039) and 43 (2.9 vs. 0.8mcg/ml; p = 0.007). HbSC mounted a better immune anti-pneumococcal response compared to HbSS (≥ 1.3 mcg/ml) for 18 of 23 serotypes, albeit not significant for any of the serotypes. More HbSC (64%) than HbSS (42%) were good vaccine responders (p = 0.303). Two of 21 (10%) good vaccine responders and nine of 23 (39%) poor vaccine responders SCD participants subsequently developed acute chest syndrome or pneumonia (p = 0.036). None of the HbSC patients developed ACS after receiving PPSV-23. HbSS poor vaccine responders were at increased future recurrence risk for ACS (p = 0.003), pneumonia (p = 0.036) or both (p = 0.011), compared to good vaccine responders. Conclusion: HbSC possess better pneumococcal vaccine response than HbSS. Poor vaccine response is concerning for future acute pulmonary events. Current vaccination strategy for SCD sub-types are lacking, therefore further study to evaluate utility of vaccine boosters is necessary


No disponible


Assuntos
Humanos , Feminino , Criança , Adolescente , Doença da Hemoglobina SC/imunologia , Vacinas Pneumocócicas/imunologia , Anemia Falciforme , Relação Dose-Resposta Imunológica , Streptococcus pneumoniae/imunologia , Estudos Prospectivos
3.
Vet Parasitol ; 276: 108956, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31706235

RESUMO

Turkeys and chickens were orally infected with tissue cysts (one mouse brain) or oocysts (103, 105 or 106 oocysts) of three T. gondii strains of the clonal types II and III (ME49, CZ-Tiger, NED) to investigate the influence of the applied T. gondii strain and infective doses on the distribution of T. gondii in several organs and tissues and the serologic response of chickens and turkeys. Organ samples from 16 different tissues, including heart, brain, muscles and gizzard were analyzed by PCR. Brain and heart were found most frequently positive for T. gondii DNA in both species, followed by gizzard. Serological analysis with kinetic ELISA for turkey samples and IFAT for chicken samples were performed once a week. In both species a dose-depending serological response was found. Turkeys seroconverted one week after infection with CZ-Tiger strain and medium and high doses of ME49 oocysts. In chickens, infection with medium and high doses of CZ-Tiger led to seroconversion one week p.i. Frequency of T. gondii positive organs showed a trend of a dose-effect in both species after infection with the type II strains. The NED strain showed low virulence in chickens and turkeys, demonstrated by clearly less T. gondii positive organs. Infection with tissue cysts of all three strains revealed T. gondii stages in tissues of turkeys and chickens. In conclusion, our data show a risk for human infection with T. gondii due to consumption of chicken and turkey meat.


Assuntos
Galinhas/parasitologia , Modelos Animais de Doenças , Doenças das Aves Domésticas/parasitologia , Toxoplasmose Animal/parasitologia , Perus/parasitologia , Animais , Anticorpos Antiprotozoários/sangue , Encéfalo/parasitologia , Gatos , DNA de Protozoário/análise , Relação Dose-Resposta Imunológica , Moela das Aves/parasitologia , Coração/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Músculos/parasitologia , Organismos Livres de Patógenos Específicos , Toxoplasma/genética , Toxoplasma/imunologia
4.
Nat Med ; 25(10): 1560-1565, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591593

RESUMO

Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups of three participants received a single peripheral infusion of 107, 108 or up to 109 cells. Leukapheresis and macrophage infusion were well tolerated with no transfusion reactions, dose-limiting toxicities or macrophage activation syndrome. All participants were alive and transplant-free at one year, with only one clinical event recorded, the occurrence of minimal ascites. The primary outcomes of safety and feasibility were met. This study informs and provides a rationale for efficacy studies in cirrhosis and other fibrotic diseases.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Doença Hepática Terminal/terapia , Cirrose Hepática/terapia , Macrófagos/transplante , Idoso , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Relação Dose-Resposta Imunológica , Doença Hepática Terminal/imunologia , Doença Hepática Terminal/patologia , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Regeneração Hepática , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade
5.
Immunobiology ; 224(5): 645-648, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31402150

RESUMO

Mugwort pollen allergy is frequent in parts of Europe. As mugwort pollen contains only one major allergen, Art v 1, which harbors only one T cell epitope, we employed mugwort pollen allergy as a model to study allergen-specific T cell responses. However, after 2004, we noticed a drastic decrease in the T cell responses to Art v 1 and eventually it became almost impossible to detect allergen-specific responses at the T cell level in mugwort-allergic individuals. To explain this observation, we retrospectively investigated the local exposure to mugwort pollen and its possible correlation to the frequency and reactivity of allergen-specific T cells. The total annual pollen indices dramatically dropped after 2004 and never reached previous levels again. Local sensitization to mugwort pollen and serum IgE antibodies specific for Art v 1 remained unchanged until 2015. Our mugwort pollen model shows that specific IgE-levels are maintained for extremely long time periods in spite of a long-term reduction of natural allergen exposure to levels that are too low to boost specific T cells.


Assuntos
Alérgenos/imunologia , Imunoglobulina E/imunologia , Pólen/imunologia , Rinite Alérgica Sazonal/imunologia , Linfócitos T/imunologia , Relação Dose-Resposta Imunológica , Exposição Ambiental/efeitos adversos , Epitopos de Linfócito T/imunologia , Humanos , Rinite Alérgica Sazonal/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T/metabolismo
6.
PLoS One ; 14(8): e0219040, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31469853

RESUMO

BACKGROUND: In April 2016, an emergency vaccination campaign using one dose of Oral Cholera Vaccine (OCV) was organized in response to a cholera outbreak that started in Lusaka in February 2016. In December 2016, a second round of vaccination was conducted, with the objective of increasing the duration of protection, before the high-risk period for cholera transmission. We assessed vaccination coverage for the first and second rounds of the OCV campaign. METHODS: Vaccination coverage was estimated after each round from a sample selected from targeted-areas for vaccination using a cross-sectional survey in to establish the vaccination status of the individuals recruited. The study population included all individuals older than 12 months residing in the areas targeted for vaccination. We interviewed 505 randomly selected individuals after the first round and 442 after the second round. Vaccination status was ascertained either by vaccination card or verbal reporting. Households were selected using spatial random sampling. RESULTS: The vaccination coverage with two doses was 58.1% (25/43; 95%CI: 42.1-72.9) in children 1-5 years old, 59.5% (69/116; 95%CI: 49.9-68.5) in children 5-15 years old and 19.9% (56/281; 95%CI: 15.4-25.1) in adults above 15 years old. The overall dropout rate was 10.9% (95%CI: 8.1-14.1). Overall, 69.9% (n = 309/442; 95%CI: 65.4-74.1) reported to have received at least one OCV dose. CONCLUSIONS: The areas at highest risk of suffering cholera outbreaks were targeted for vaccination obtaining relatively high vaccine coverage after each round. However, the long delay between doses in areas subject to considerable population movement resulted in many individuals receiving only one OCV dose. Additional vaccination campaigns may be required to sustain protection over time in case of persistence of risk. Further evidence is needed to establish a maximum optimal interval time of a delayed second dose and variations in different settings.


Assuntos
Vacinas contra Cólera/administração & dosagem , Cólera/prevenção & controle , Cólera/transmissão , Vacinação/métodos , Administração Oral , Adolescente , Adulto , Criança , Cólera/epidemiologia , Vacinas contra Cólera/imunologia , Surtos de Doenças/prevenção & controle , Relação Dose-Resposta Imunológica , Feminino , Humanos , Masculino , Risco , Fatores de Tempo , Adulto Jovem , Zâmbia/epidemiologia
7.
Inhal Toxicol ; 31(5): 192-202, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31345048

RESUMO

Background: Increasing evidence from rodent studies indicates that inhaled multi-walled carbon nanotubes (MWCNTs) have harmful effects on the lungs. In this study, we examined the effects of inhalation exposure to MWCNTs on allergen-induced airway inflammation and fibrosis. We hypothesized that inhalation pre-exposure to MWCNTs would render mice susceptible to developing allergic lung disease induced by house dust mite (HDM) allergen. Methods: Male B6C3F1/N mice were exposed by whole-body inhalation for 6 h a day, 5 d a week, for 30 d to air control or 0.06, 0.2, and 0.6 mg/m3 of MWCNTs. The exposure atmospheres were agglomerates (1.4-1.8 µm) composed of MWCNTs (average diameter 16 nm; average length 2.4 µm; 0.52% Ni). Mice then received 25 µg of HDM extract by intranasal instillation 6 times over 3 weeks. Necropsy was performed at 3 and 30 d after the final HDM dose to collect serum, bronchoalveolar lavage fluid (BALF), and lung tissue for histopathology. Results: MWCNT exposure at the highest dose inhibited HDM-induced serum IgE levels, IL-13 protein levels in BALF, and airway mucus production. However, perivascular and peribronchiolar inflammatory lesions were observed in the lungs of mice at 3 d with MWCNT and HDM, but not MWCNT or HDM alone. Moreover, combined HDM and MWCNT exposure increased airway fibrosis in the lungs of mice. Conclusions: Inhalation pre-exposure to MWCNTs inhibited HDM-induced TH2 immune responses, yet this combined exposure resulted in vascular inflammation and airway fibrosis, indicating that MWCNT pre-exposure alters the immune response to allergens.


Assuntos
Antígenos de Dermatophagoides/imunologia , Hipersensibilidade/fisiopatologia , Exposição por Inalação/efeitos adversos , Pulmão/fisiologia , Nanotubos de Carbono/toxicidade , Animais , Líquido da Lavagem Broncoalveolar , Relação Dose-Resposta Imunológica , Fibrose , Imunoglobulina E/sangue , Interleucina-13/análise , Masculino , Camundongos , Células Th2/imunologia
8.
PLoS One ; 14(6): e0216533, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166987

RESUMO

BACKGROUND: New influenza vaccines eliciting more effective protection are needed, particularly for the elderly who paid a large and disproportional toll of hospitalization and dead during seasonal influenza epidemics. Low (≤15 µg/strain) doses of a new plant-derived virus-like-particle (VLP) vaccine candidate have been shown to induce humoral and cellular responses against both homologous and heterologous strains in healthy adults 18-64 years of age. The two clinical trials reported here addressed the safety and immunogenicity of higher doses (≥15 µg/strain) of quadrivalent VLP candidate vaccine on 18-49 years old and ≥50 years old subjects. We also investigated the impact of alum on the immunogenicity induced by lower doses of the vaccine candidate. METHOD: In the first Phase II trial reported here (NCT02233816), 18-49 year old subjects received 15, 30 or 60 µg/strain of a hemagglutinin-bearing quadrivalent virus-like particle (QVLP) vaccine or placebo. In the second trial (NCT02236052), ≥50 years old subjects received QVLP as above or placebo with additional groups receiving 7.5 or 15 µg/strain with alum. Along with safety recording, the humoral and cell-mediated immune responses were analyzed. RESULTS: Local and systemic side-effects were similar to those reported previously. The QVLP vaccine induced significant homologous and heterologous antibody responses at the two higher doses, the addition of alum having little-to-no effect. Serologic outcomes tended to be lower in ≥50 years old subjects previously vaccinated. The candidate vaccine also consistently elicited both homologous and heterologous antigen-specific CD4+ T cells characterized by their production of interferon-gamma (IFN-γ), interleukine-2 (IL-2) and/or tumor-necrosis factor alpha (TNF-α) upon ex vivo antigenic restimulation. CONCLUSION: Overall, the 30 µg dose produced the most consistent humoral and cellular responses in both 18-49 and ≥50 years old subjects, strongly supporting the clinical development of this candidate vaccine. That particular dose was chosen to test in the ongoing Phase III clinical trial.


Assuntos
Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/imunologia , Plantas , Segurança , Vacinas de Partículas Semelhantes a Vírus/efeitos adversos , Vacinas de Partículas Semelhantes a Vírus/imunologia , Adolescente , Adulto , Idoso , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Int J Nanomedicine ; 14: 3129-3143, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118627

RESUMO

Background: Bacillus Calmette-Guérin, the attenuated strain of Mycobacterium bovis, remains the only available vaccine against tuberculosis (TB). However, its ineffectiveness in adults against pulmonary TB and varied protective efficacy (0-80%) speak to an urgent need for the development of an improved and efficient TB vaccine. In this milieu, poly(lactic-co-glycolic acid) (PLGA), is a preferential candidate, due to such properties as biocompatibility, targeted delivery, sustained antigen release, and atoxic by-products. Methods: In this study, we formulated PLGA nanoparticles (NPs) encapsulating the bivalent H1 antigen, a fusion of Mycobacterium tuberculosis (Mtb) Ag85B and ESAT6 proteins, and investigated its role in immunomodulation and protection against Mtb challenge. Using the classical water-oil-water solvent-evaporation method, H1-NPs were prepared, with encapsulation efficiency of 86.1%±3.2%. These spherical NPs were ~244.4±32.6 nm in diameter, with a negatively charged surface (ζ-potential -4±0.6 mV). Results: Under physiological conditions, NPs degraded slowly and the encapsulated H1 antigen was released over a period of weeks. As a proof-of-concept vaccine candidate, H1 NPs were efficiently internalized by the THP-1 human macrophages. Six weeks after a single-dose vaccination, H1 NP-immunized C57BL/6J mice showed significant increase in the production of total serum IgG (P<0.0001) and its isotypes compared to H1 alone, IgG2a being the predominant one, followed by IgG1. Further, the cytokine-release profile of antigen-stimulated splenocyteculture supernatant indicated a strong TH1-biased immunoresponse in H1 NP-vaccinated mice, with ~6.03- and ~2.8-fold increase in IFNγ and TNFα cytokine levels, and ~twofold and 1.6 fold increase in IL4 and IL10 cytokines, respectively, compared to H1 alone-immunized mice. In protection studies, H1 NP-vaccinated mice displayed significant reductions in lung and spleen bacillary load (P<0.05) at 5-week post-Mtb H37Rv challenge and prolonged survival, with a mean survival time of 177 days, compared to H1 alone-vaccinated mice (mean survival time 80 days). Conclusion: Altogether, our findings highlight the significance of the H1-PLGA nanoformulation in terms of providing long-term protection in mice with a single dose.


Assuntos
Imunidade , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Proteínas Recombinantes de Fusão/metabolismo , Tuberculose/imunologia , Tuberculose/prevenção & controle , Animais , Citocinas/metabolismo , Relação Dose-Resposta Imunológica , Liberação Controlada de Fármacos , Endocitose , Epitopos , Feminino , Humanos , Imunidade Humoral , Imunização , Imunoglobulina G/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Baço/citologia , Baço/imunologia , Análise de Sobrevida , Células THP-1 , Células Th1/imunologia , Vacinas contra a Tuberculose/imunologia , Vacinação
11.
Arq. ciências saúde UNIPAR ; 23(2): 145-153, maio-ago. 2019.
Artigo em Português | LILACS, Index Psicologia - Periódicos técnico-científicos | ID: biblio-996728

RESUMO

A coqueluche é uma doença infecciosa aguda, transmissível, com predileção pelo trato respiratório, caracterizada por paroxismos de tosse seca e considerada uma importante causa de morbidade e mortalidade infantil. A resposta imunológica humoral e celular do hospedeiro promove a contenção da infecção, pois essas respostas se caracterizam como importantes linhas de defesa durante a infecção e colonização da bactéria. Dessa forma, esta revisão bibliográfica procurou descrever os mecanismos mais eficazes de resposta imune contra Bordetella pertussis e abordar os mecanismos de evasão utilizados pelo patógeno.


Pertussis is a transmissible infectious disease with a predilection for the respiratory tract characterized by paroxysms of dry cough. It is considered an important cause of child morbidity and mortality. The humoral and cellular immune responses of the host promote the containment of the infection, and these responses are characterized as important lines of defense during infection and colonization of the bacterium. Thus, this literature review sought to describe the most effective immune response mechanisms against Bordetella pertussis and to address the avoidance mechanisms used by the pathogen.


Assuntos
Humanos , Bordetella pertussis , Coqueluche , Vacinas , Doenças Transmissíveis , Relação Dose-Resposta Imunológica , Imunidade
12.
J AOAC Int ; 102(5): 1346-1353, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30940282

RESUMO

Risk-based approaches to managing allergens in foods are being developed by the food industry and regulatory authorities to support food-allergic consumers to avoid ingestion of their problem food, especially in relation to the traces of unintended allergens. The application of such approaches requires access to good quality data from clinical studies to support identification of levels of allergens in foods that are generally safe for most food-allergic consumers as well as analytical tools that are able to quantify allergenic food protein. The ThRAll project aims to support the application of risk-based approaches to food-allergen management in two ways. First, a harmonized quantitative MS-based prototype reference method will be developed for the detection of multiple food allergens in standardized incurred food matrices. This will be undertaken for cow's milk, hen's egg, peanut, soybean, hazelnut, and almond incurred into two highly processed food matrices, chocolate and broth powder. This activity is complemented by a second objective to support the development and curation of data on oral food challenges, which are used to define thresholds and minimum eliciting doses. This will be achieved through the development of common protocols for collection and curation of data that will be applied to allergenic foods for which there are currently data gaps.


Assuntos
Alérgenos/análise , Contaminação de Alimentos/análise , Hipersensibilidade Alimentar/imunologia , Alérgenos/imunologia , Animais , Chocolate/análise , Relação Dose-Resposta Imunológica , Fast Foods/análise , Humanos , Espectrometria de Massas , Leite/química , Leite/imunologia , Nozes/química , Nozes/imunologia , Plantas/química , Plantas/imunologia
13.
BMC Infect Dis ; 19(1): 227, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30836941

RESUMO

BACKGROUND: There is great interest in the use of reduced dosing schedules for pneumococcal conjugate vaccines, a strategy premised on maintaining an acceptable level of protection against disease and carriage of the organism. We asked about the practicality of measuring differential effectiveness against carriage in a population with and without widespread use of the vaccine for infants. METHODS: We adapted an existing transmission-dynamic, individual-based stochastic model fitted to the prevaccine epidemiology of pneumococcal carriage in the United States, and compared the observed vaccine-type carriage prevalence in different arms of a simulated trial with one, two, or three infant doses plus a 12-month booster. Using these simulations, we calculated vaccine efficacy that would be estimated at different times post-enrollment in the trial and calculated required sample sizes to see a difference in carriage prevalence. RESULTS: In a pneumococcal conjugate vaccine (PCV)-naïve population, the difference in vaccine-type (VT) pneumococcal carriage prevalence between trial arms was less than 7% and varied with sampling time. In a population already receiving routine PCV administration, VT pneumococcal prevalence is nearly indistinguishable between trial arms. Relative efficacy of different dosing schedules was strongly dependent on the time between enrollment and sampling, with maximal prevalence differences reached 1-3 years post-enrollment. Moreover, vaccine efficacy estimates were typically slightly higher in trials in communities already receiving vaccination. Despite this, much larger sample sizes-by more than an order of magnitude-are required for a vaccine trial conducted in a population receiving routine PCV administration as compared to in a PCV-naïve population. CONCLUSIONS: These findings highlight some underappreciated aspects of clinical trials of pneumococcal conjugate vaccines with efficacy endpoints, such as the context- and time-dependence of efficacy estimates. They support the wisdom of conducting comparative dose schedule trials of conjugate vaccine effects on carriage in vaccine-naïve populations.


Assuntos
Portador Sadio/imunologia , Imunidade Coletiva , Infecções Pneumocócicas/imunologia , Vacinas Pneumocócicas/imunologia , Simulação por Computador , Relação Dose-Resposta Imunológica , Feminino , Humanos , Lactente , Modelos Imunológicos , Infecções Pneumocócicas/prevenção & controle , Prevalência , Tamanho da Amostra , Streptococcus pneumoniae , Vacinas Conjugadas/imunologia
15.
J Microbiol ; 57(2): 163-169, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30706345

RESUMO

To evaluate the efficacy of a non-adjuvant A/H1N1/2009 influenza A vaccine (GC1115), we demonstrated the immunogenicity and protective efficacy of GC1115 in mouse and ferret models. The immunogenicity of GC1115 was confirmed after intramuscular administration of 1.875, 3.75, 7.5, and 15 µg hemagglutinin antigen (HA) in mice and 7.5, 15, and 30 µg HA in ferrets at 3-week intervals. A single immunization with GC1115 at HA doses > 7.5 µg induced detectable seroconversion in most mice, and all mice given a second dose exhibited high antibody responses in a dose-dependent manner. The mice in the mock (PBS) and 1.875 µg HA immunized groups succumbed by 13 days following A/California/ 04/09 infection, while all mice in groups given more than 3.75 µg HA were protected from lethal challenge with the A/California/04/09 virus. In ferrets, although immunization with even a single dose of 15 or 30 µg of HA induced detectable HI antibodies, all ferrets given two doses of vaccine seroconverted and exhibited HI titers greater than 80 units. Following challenge with A/California/04/09, the mock (PBS) immunized ferrets showed influenza-like clinical symptoms, such as increased numbers of coughs, elevated body temperature, and body weight loss, for 7 days, while GC1115- immunized ferrets showed attenuated clinical symptoms only for short time period (3-4 days). Further, GC1115-immunized ferrets displayed significantly lower viral titers in the upper respiratory tract (nasal cavity) than the mock vaccinated group in a dose-dependent manner. Taken together, this study demonstrates the immunogenicity and protective efficacy of GC1115 as a non-adjuvanted vaccine.


Assuntos
Imunogenicidade da Vacina/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Antivirais/sangue , Temperatura Corporal , Peso Corporal , Tosse , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Furões , Testes de Inibição da Hemaglutinação , Vacinas contra Influenza/administração & dosagem , Injeções Intramusculares , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/fisiopatologia , Sistema Respiratório/virologia , Taxa de Sobrevida , Vacinação/métodos , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Carga Viral
16.
J Pharmacol Exp Ther ; 369(1): 26-36, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30643015

RESUMO

Migraine is a debilitating disease that affects almost 15% of the population worldwide and is the first cause of disability in people under 50 years of age, yet its etiology and pathophysiology remain incompletely understood. Recently, small molecules and therapeutic antibodies that block the calcitonin gene-related peptide (CGRP) signaling pathway have reduced migraine occurrence and aborted acute attacks of migraine in clinical trials and provided prevention in patients with episodic and chronic migraine. Heterogeneity is present within each diagnosis and patient's response to treatment, suggesting migraine as a final common pathway potentially activated by multiple mechanisms, e.g., not all migraine attacks respond to or are prevented by anti-CGRP pharmacological interventions. Consequently, other unique mechanisms central to migraine pathogenesis may present new targets for drug development. Pituitary adenylate cyclase-activating peptide (PACAP) is an attractive novel target for treatment of migraines. We generated a specific, high-affinity, neutralizing monoclonal antibody (ALD1910) with reactivity to both PACAP38 and PACAP27. In vitro, ALD1910 effectively antagonizes PACAP38 signaling through the pituitary adenylate cyclase-activating peptide type I receptor, vasoactive intestinal peptide receptor 1, and vasoactive intestinal peptide receptor 2. ALD1910 recognizes a nonlinear epitope within PACAP and blocks its binding to the cell surface. To test ALD1910 antagonistic properties directed against endogenous PACAP, we developed an umbellulone-induced rat model of neurogenic vasodilation and parasympathetic lacrimation. In vivo, this model demonstrates that the antagonistic activity of ALD1910 is dose-dependent, retaining efficacy at doses as low as 0.3 mg/kg. These results indicate that ALD1910 represents a potential therapeutic antibody to address PACAP-mediated migraine.


Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/imunologia , Animais , Especificidade de Anticorpos , Relação Dose-Resposta Imunológica , Epitopos/imunologia , Humanos , Cinética , Masculino , Transtornos de Enxaqueca/imunologia , Transtornos de Enxaqueca/prevenção & controle , Células PC12 , Ratos , Ratos Sprague-Dawley
17.
Nat Med ; 25(2): 255-262, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30664782

RESUMO

Tuberculosis (TB) remains the deadliest infectious disease1, and the widely used Bacillus Calmette-Guérin (BCG) vaccine fails to curb the epidemic. An improved vaccination strategy could provide a cost-effective intervention to break the transmission cycle and prevent antimicrobial resistance2,3. Limited knowledge of the host responses critically involved in protective immunity hampers the development of improved TB vaccination regimens. Therefore, assessment of new strategies in preclinical models to select the best candidate vaccines before clinical vaccine testing remains indispensable. We have previously established in rhesus macaques (Macaca mulatta) that pulmonary mucosal BCG delivery reduces TB disease where standard intradermal injection fails4,5. Here, we show that pulmonary BCG prevents infection by using a repeated limiting-dose Mycobacterium tuberculosis challenge model and identify polyfunctional T-helper type 17 (TH17) cells, interleukin-10 and immunoglobulin A as correlates of local protective immunity. These findings warrant further research into mucosal immunization strategies and their translation to clinical application to more effectively prevent the spread of TB.


Assuntos
Vacina BCG/imunologia , Tuberculose/imunologia , Tuberculose/prevenção & controle , Animais , Carga Bacteriana , Relação Dose-Resposta Imunológica , Imunidade Humoral , Interferon gama/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Macaca mulatta , Masculino , Membrana Mucosa/imunologia , Vacinação
18.
Medicine (Baltimore) ; 98(2): e14042, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30633199

RESUMO

BACKGROUND: Secukinumab has been approved for the treatment of moderate to severe plaque psoriasis. However, safety measures concerning drug administration is vital during treatment. Understanding the right way to administer drugs is important to reduce any serious adverse drug event. In this analysis we aimed to systematically show the risk of adverse drug events which were observed with 150 mg versus (vs) 300 mg secukinumab for the treatment of moderate to severe plaque psoriasis. METHODS: The major online databases: Cochrane Central, MEDLINE, www.ClinicalTrials.com and EMBASE were searched for relevant publications based on the comparison of secukinumab 150 mg vs 300 mg for the treatment of moderate to severe plaque psoriasis. Adverse drug events were considered as the clinical endpoints. Statistical analysis was carried out by the RevMan 5.3 software. Risk ratios (RR) and 95% confidence intervals (CIs) were generated to represent the data following statistical analysis. RESULTS: Seven studies with a total number of 2361 participants were included. Results of this analysis showed that the risk of any adverse event (RR: 1.00, 95% CI: 0.96-1.05; P = .94), the risk of serious adverse events (RR: 1.04, 95% CI: 0.75-1.43; P = .82) and the risk of adverse events leading to drug discontinuation (RR: 0.98, 95% CI: 0.61-1.57; P = .92) were not significantly different between 150 mg vs 300 mg secukinumab for the treatment of moderate to severe plaque psoriasis. When the detailed adverse drug events were studied, the risks of infection or infestation (RR: 1.11, 95% CI: 0.98-1.25; P = .09), naso-pharyngitis (RR: 1.05, 95% CI: 0.90-1.23; P = .55), headache (RR: 0.92, 95% CI: 0.68-1.25; P = .60), diarrhea (RR: 1.14, 95% CI: 0.75-1.73; P = .55), pruritus (RR: 0.82, 95% CI: 0.56-1.22; P = .33), arthralgia (RR: 0.96, 95% CI: 0.67-1.38; P = .83), upper respiratory tract infection (RR: 0.98, 95% CI: 0.70-1.36; P = .89), hypertension (RR: 1.22, 95% CI: 0.83-1.81; P = .31), nausea (RR: 1.39, 95% CI: 0.63-3.04; P = .42), and cough (RR: 1.46, 95% CI: 0.67-3.19; P = .34) were still not significantly different between these 2 dosage regimens. CONCLUSION: Secukinumab 150 mg and 300 mg were both equally tolerable and might safely be used for the treatment of moderate to severe plaque psoriasis. No significant adverse drug events were observed with any of the dosage.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Psoríase/terapia , Anticorpos Monoclonais Humanizados , Relação Dose-Resposta a Droga , Relação Dose-Resposta Imunológica , Humanos
19.
Hum Vaccin Immunother ; 15(3): 549-559, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30689507

RESUMO

BACKGROUND: Two new formulations of an investigational 15-valent pneumococcal conjugate vaccine (PCV15-A and PCV15-B) were developed using 2 different protein-polysaccharide conjugation processes and evaluated in separate phase I/II studies (NCT02037984 [V114-004] and NCT02531373 [V114-005]) to assess optimal concentrations of pneumococcal polysaccharide (PnPs) and Aluminum Phosphate Adjuvant. METHODS: Various lots of PCV15-A and PCV15-B containing different concentrations of PnPs and/or adjuvant were compared to PCV13 in young adults and infants. Adults received single dose and infants received 4 doses at 2, 4, 6, and 12-15 months of age. Adverse events (AEs) were collected after each dose. Serotype-specific immunoglobulin G (IgG) concentrations and opsonophagocytic activity (OPA) were measured prior and 30 days postvaccination in adults, at 1 month postdose 3 (PD3), pre-dose4, and postdose 4 (PD4) in infants. RESULTS: Safety profiles were comparable across vaccination groups. At PD3, serotype-specific IgG GMCs were generally lower for either PCV15 formulation than PCV13 for most shared serotypes. PCV15 consistently elicited higher antibody responses to the 2 serotypes unique to the vaccine (22F and 33F) and serotype 3 for which PCV13 was shown to be ineffective. Except for serotypes 6A and 6B, no dose-response effect was observed with increasing concentrations of PnPs and/or adjuvant. CONCLUSION: PCV15 is safe and induces IgG and OPA responses to all 15 serotypes in the vaccine. No significant differences in antibody responses were observed with increases in PnPs and/or Aluminum Phosphate Adjuvant.


Assuntos
Anticorpos Antibacterianos/sangue , Imunogenicidade da Vacina , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Adolescente , Adulto , Relação Dose-Resposta Imunológica , Voluntários Saudáveis , Humanos , Imunoglobulina G/sangue , Lactente , Pessoa de Meia-Idade , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/química , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/química , Vacinas Conjugadas/imunologia , Adulto Jovem
20.
Clin Microbiol Infect ; 25(2): 217-224, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29783025

RESUMO

OBJECTIVES: To compare immunogenicity, reactogenicity and acceptability of high- and standard-dose trivalent inactivated influenza vaccine (HDTIV, SDTIV) in 18- to 64-year-olds. METHODS: We randomized 18- to 64-year-olds to HDTIV or SDTIV in two consecutive years. We collected serum on days 0 and 21, measured haemagglutination inhibition geometric mean titres (GMT) and compared seroconversion, day 21 titres, seroprotection, reactogenicity and acceptability. RESULTS: Immunogenicity was evaluable in 42 of 47 2014 participants, all 33 both-year participants and 87 of 90 2015-only participants. First-dose HDTIV recipients experienced seroconversion more frequently than SDTIV recipients to A(H3N2) in 2014 (13/21, 62% vs. 4/21, 19%, p 0.01) and to all vaccine strains in 2015: (A(H1N1): 24/42, 57% vs. 15/59, 25%; A(H3N2): 42/42, 100% vs. 47/59, 80%; B: 25/42, 60% vs. 13/59, 22%; all p <0.01). Day 21 haemagglutination inhibition GMT were higher in first and two sequential-year HDTIV vs. SDTIV recipients: A(H1N1): GMT 749 and 768 vs. 384 (p <0.0001, p 0.002); A(H3N2): 1238 and 956 vs. 633 (p 0.0003, p 0.1); and B: 1113 and 1086 vs. 556 (p 0.0005, p 0.02). HDTIV was more reactogenic (local pain score 3 vs. 1 of 10 on day 0/1, p 0.0003), but recipients were equally willing to be revaccinated (HDTIV: 76/83 (92%); SDTIV: 76/80 (95%), p 0.54). The ratios of day 21 GMT in SDTIV recipients vaccinated in 0 to 4 prior years to those in SDTIV and HDTIV recipients vaccinated in 15 or more prior years were A(H1N1): 3.73 and 1.38; A(H3N2) 3.07 and 1.16; and B: 2.01 and 1.21. CONCLUSIONS: HDTIV is more immunogenic and reactogenic and as acceptable as SDTIV in 18- to 64-year-olds.


Assuntos
Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Adolescente , Adulto , Relação Dose-Resposta Imunológica , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Vacinas de Produtos Inativados , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA