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1.
Int Arch Allergy Immunol ; 181(2): 94-102, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31865326

RESUMO

Only few data on safety during high-dose, accelerated escalation schedules during subcutaneous allergen immunotherapy (AIT) are available. The aim of this study was to assess the safety and tolerability of an accelerated dose escalation schedule of AIT in adult patients with moderate to severe seasonal rhinoconjunctivitis in a multicenter, open-label, randomized phase II trial. The dose escalation scheme for patients in Group I (1 strength) included 3 injections with 1 strength, B (10,000 TU/mL), whereas the dose escalation scheme for Group II (standard) included 7 injections with 2 strengths, A (1,000 TU/mL) and B (10,000 TU/mL), of an aluminum hydroxide-adsorbed allergoid grass pollen preparation. Overall, 72 of 87 randomized patients (83.7%) reported at least 1 treatment-emergent adverse event (TEAE; 82.2 [Group I] vs. 85.4% [Group II]); 58.8% of all reported TEAEs were assessed as being related to AIT (60.0 vs. 48.8%). The most frequently reported AIT-related TEAEs were swelling (46.7 vs. 34.1%), erythema (28.9 vs. 36.6%), and pruritus (31.1 vs. 17.1%) at the site of the injection. Systemic allergic reactions occurred in 5 (5.8%) patients overall, with more being reported in the 1-strength group (4 [8.9%] vs. 1 [2.4%]). All systemic allergic reactions were classified as World Allergy Organization (WAO) Grade 1 or Grade 2 reactions. Accelerated high-dose escalation with an aluminum hydroxide-adsorbed grass pollen allergoid can be initiated with a safety and tolerability profile comparable to the standard dose escalation schedule in patients with allergic rhinitis with or without asthma.


Assuntos
Alergoides/química , Alergoides/imunologia , Hidróxido de Alumínio/química , Poaceae/imunologia , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica/imunologia , Adulto , Alérgenos/imunologia , Alergoides/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/imunologia , Antígenos de Plantas/imunologia , Asma/imunologia , Conjuntivite Alérgica/imunologia , Dessensibilização Imunológica/métodos , Feminino , Humanos , Masculino , Pólen/imunologia
2.
Int J Pharm ; 571: 118704, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31536763

RESUMO

Only few adjuvants are licensed for use in humans and there is a need to develop safe and improved vaccine adjuvants. In this study, we report the one-pot synthesis of antigen ovalbumin (OVA)-conjugated gold nanoparticles (OVA@GNPs). A systematical study was performed by comparing OVA@GNPs with the simple mixture of OVA and gold nanoparticles (OVA+GNPs), including their physiochemical properties through spectrometric and electrophoretic analysis, in vitro stability, cytotoxicity and cellular uptake, and in vivo humoral immune responses following subcutaneous and transcutaneous immunization in mice. The results demonstrate a much stronger interaction between protein and GNPs in OVA@GNPs than OVA+GNPs, which makes OVA@GNPs more stable under in vitro conditions than OVA+GNPs with the ability to induce 4 times higher OVA-specific serum IgG titers following subcutaneous immunization. We also show the dose sparing of OVA@GNPs, as the dosage for aluminum adjuvant required to reach to an equivalent OVA-specific antibody titer was almost five times higher than OVA@GNPs. However, we found that the co-administration of small-sized GNPs had a limited ability for the transcutaneous delivery of OVA. These results demonstrate the potential application of one-pot synthesis approach for producing antigen protein-conjugated gold nanoparticles for vaccine delivery.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Técnicas de Química Sintética/métodos , Nanopartículas Metálicas/química , Nanoconjugados/química , Ovalbumina/administração & dosagem , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacocinética , Administração Cutânea , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/imunologia , Hidróxido de Alumínio/farmacocinética , Animais , Química Farmacêutica , Coloides , Relação Dose-Resposta Imunológica , Feminino , Ouro/química , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Injeções Subcutâneas , Camundongos , Modelos Animais , Ovalbumina/química , Ovalbumina/imunologia , Ovalbumina/farmacocinética , Permeabilidade , Pele/metabolismo
3.
Pediatr Infect Dis J ; 38(10): 1061-1067, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31469776

RESUMO

BACKGROUND: The burden of human papillomavirus (HPV) diseases is high in Latin America. HPV vaccines licensed from 2006 onwards offer protection against most HPV-related cancers, especially when introduced into national immunization programs. Barriers to optimal vaccine uptake are, however, lowering the impact of adolescent HPV vaccination programs. Immunization of children might overcome these barriers and be a strategy of choice for some countries. METHODS: This multicenter phase III randomized, controlled, single-blind study (NCT01627561) was conducted in Colombia, Mexico and Panama to assess safety and immunogenicity of 2-dose vaccination with AS04-adjuvanted HPV-16/18 vaccine in girls 4-6 years of age. We report safety outcomes and anti-HPV-16/18 antibody titers measured by enzyme-linked immunosorbent assay in HPV-vaccinated girls that were followed over a 36-month period. RESULTS: Over 36 months (ie, 30 months after the second vaccine dose), among 74 girls included in the HPV group, 1 serious adverse event unrelated to vaccination has been reported. No withdrawal because of (serious) adverse events has been reported. At month 36, all girls in the per-protocol-cohort were still seropositive for anti-HPV-16 and anti-HPV-18 with geometric mean concentrations of 1680.6 and 536.4 enzyme-linked immunosorbent assay units/mL, respectively. CONCLUSIONS: The AS04-adjuvanted HPV-16/18 vaccine administered according to a 2-dose schedule to girls 4-6 years of age induced a high and sustained immunologic response with an acceptable safety profile during the 30 months following vaccination.


Assuntos
Hidróxido de Alumínio/efeitos adversos , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Lipídeo A/análogos & derivados , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/imunologia , Hidróxido de Alumínio/administração & dosagem , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Ensaios Clínicos Fase III como Assunto , Colômbia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Seguimentos , Humanos , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , México , Panamá , Vacinas contra Papillomavirus/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego
4.
Eur J Pharm Biopharm ; 136: 213-220, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30703544

RESUMO

No United States Food and Drug Administration-licensed vaccines protective against Ebola virus (EBOV) infections are currently available. EBOV vaccine candidates currently in development, as well as most currently licensed vaccines in general, require transport and storage under a continuous cold chain in order to prevent potential decreases in product efficacy. Cold chain requirements are particularly difficult to maintain in developing countries. To improve thermostability and reduce costly cold chain requirements, a subunit protein vaccine against EBOV was formulated as a glassy solid using lyophilization. Formulations of the key antigen, Ebola glycoprotein (EBOV-GP), adjuvanted with microparticulate aluminum hydroxide were prepared in liquid and lyophilized forms, and the vaccines were incubated at 40 °C for 12 weeks. Aggregation and degradation of EBOV-GP were observed in liquid formulations during the 12-week incubation period, whereas changes were minimal in lyophilized formulations. Antibody responses against EBOV-GP following three intramuscular immunizations in BALB/c mice were used to determine vaccine immunogenicity. EBOV-GP formulations were equally immunogenic in liquid and lyophilized forms. After lyophilization and reconstitution, adjuvanted vaccine formulations produced anti-EBOV-GP IgG antibody responses in mice similar to those generated against corresponding adjuvanted liquid vaccine formulations. More importantly, antibody responses in mice injected with reconstituted lyophilized vaccine formulations that had been incubated at 40 °C for 12 weeks prior to injection indicated that vaccine immunogenicity was fully retained after high-temperature storage, showing promise for future vaccine development efforts.


Assuntos
Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/química , Vacinas contra Ebola/administração & dosagem , Vacinas contra Ebola/química , Ebolavirus/efeitos dos fármacos , Doença pelo Vírus Ebola/prevenção & controle , Hidróxido de Alumínio/imunologia , Animais , Composição de Medicamentos , Estabilidade de Medicamentos , Vacinas contra Ebola/imunologia , Ebolavirus/imunologia , Feminino , Liofilização , Doença pelo Vírus Ebola/imunologia , Camundongos , Camundongos Endogâmicos BALB C
5.
Clin Infect Dis ; 68(3): 466-474, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29945169

RESUMO

Background: P27A is an unstructured 104mer synthetic peptide from Plasmodium falciparum trophozoite exported protein 1 (TEX1), the target of human antibodies inhibiting parasite growth. The present project aimed at evaluating the safety and immunogenicity of P27A peptide vaccine in malaria-nonexposed European and malaria-exposed African adults. Methods: This study was designed as a staggered, fast-track, randomized, antigen and adjuvant dose-finding, multicenter phase 1a/1b trial, conducted in Switzerland and Tanzania. P27A antigen (10 or 50 µg), adjuvanted with Alhydrogel or glucopyranosil lipid adjuvant stable emulsion (GLA-SE; 2.5 or 5 µg), or control rabies vaccine (Verorab) were administered intramuscularly to 16 malaria-nonexposed and 40 malaria-exposed subjects on days 0, 28, and 56. Local and systemic adverse events (AEs) as well as humoral and cellular immune responses were assessed after each injection and during the 34-week follow-up. Results: Most AEs were mild to moderate and resolved completely within 48 hours. Systemic AEs were more frequent in the formulation with alum as compared to GLA-SE, whereas local AEs were more frequent after GLA-SE. No serious AEs occurred. Supported by a mixed Th1/Th2 cell-mediated immunity, P27A induced a marked specific antibody response able to recognize TEX1 in infected erythrocytes and to inhibit parasite growth through an antibody-dependent cellular inhibition mechanism. Incidence of AEs and antibody responses were significantly lower in malaria-exposed Tanzanian subjects than in nonexposed European subjects. Conclusions: The candidate vaccine P27A was safe and induced a particularly robust immunogenic response in combination with GLA-SE. This formulation should be considered for future efficacy trials. Clinical Trials Registration: NCT01949909, PACTR201310000683408.


Assuntos
Anticorpos Antiprotozoários/sangue , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Hidróxido de Alumínio/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Glucosídeos/administração & dosagem , Voluntários Saudáveis , Humanos , Injeções Intramusculares , Lipídeo A/administração & dosagem , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum , Suíça , Tanzânia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia , Adulto Jovem
6.
Eur J Gastroenterol Hepatol ; 31(1): 86-93, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30272584

RESUMO

BACKGROUND: The alginate-antacid Gaviscon Double Action (Gaviscon DA) has a combined acid-neutralizing and reflux-suppressing action. Response to treatment in a symptomatic gastro-oesophageal reflux disease (GERD) population has not yet been tested in a large-scale clinical study. AIM: The aim of this study was to assess the efficacy and safety of Gaviscon DA compared with matched placebo tablets in the reduction of upper gastrointestinal symptoms in patients with GERD. PARTICIPANTS AND METHODS: In this multicentre, randomized, double-blind, placebo-controlled study, adults with GERD symptoms (N=424) received Gaviscon DA or placebo tablets for 7 days. The primary endpoint was a clinically important reduction of at least 1.5 points in the Reflux Disease Questionnaire (RDQ) GERD dimension (combined heartburn/regurgitation) between baseline and the end of the treatment. Secondary endpoints included the change in RDQ score from baseline for individual RDQ dimensions and Overall Treatment Evaluation. RESULTS: A significantly greater proportion of patients treated with Gaviscon DA met the primary endpoint compared with placebo (47.8 vs. 33.2%, respectively, P=0.0031; odds ratio: 1.85, 95% confidence interval: 1.23-2.78). A significant treatment effect was also observed for heartburn, regurgitation and dyspepsia individually. Patients in the Gaviscon DA group rated their overall treatment response greater than patients in the placebo group [mean Overall Treatment Evaluation (SD): 3.2 (3.08) vs. 2.2 (3.34); P<0.001]. No notable differences in the incidence of adverse events were observed between treatments. CONCLUSION: The alginate-antacid combination, Gaviscon DA, is an effective and well-tolerated treatment to reduce reflux symptoms and associated dyspepsia in symptomatic GERD patients.


Assuntos
Alginatos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Antiácidos/administração & dosagem , Refluxo Gastroesofágico/tratamento farmacológico , Azia/tratamento farmacológico , Ácido Silícico/administração & dosagem , Bicarbonato de Sódio/administração & dosagem , Administração Oral , Adulto , Idoso , Alginatos/efeitos adversos , Hidróxido de Alumínio/efeitos adversos , Antiácidos/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Europa (Continente) , Feminino , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/fisiopatologia , Azia/diagnóstico , Azia/fisiopatologia , Humanos , Masculino , Mastigação , Pessoa de Meia-Idade , Satisfação do Paciente , Indução de Remissão , Ácido Silícico/efeitos adversos , Bicarbonato de Sódio/efeitos adversos , Inquéritos e Questionários , Comprimidos , Fatores de Tempo , Resultado do Tratamento
7.
Fish Shellfish Immunol ; 85: 44-51, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29017943

RESUMO

Flavobacterium psychrophilum is the causative agent of Rainbow Trout Fry Syndrome which has had a major impact on global salmonid aquaculture. Recent outbreaks in Atlantic salmon in Scotland and Chile have added to the need for a vaccine to protect both salmon and trout. At present no licensed vaccines are available in Europe, leaving antibiotics as the only course of action to contain disease outbreaks. Outbreaks generally occur in fry at temperatures between 10 and 15 °C. Recently outbreaks in larger fish have given added impetus to the development of a vaccine which can provide long term protection from this highly heterogeneous pathogen. Most fish injectable vaccines are formulated with oil emulsion adjuvants to induce strong and long lasting immunity, but which are known to cause side effects. Alternative adjuvants are currently sought to minimise these adverse effects. The current study was performed to assess the efficacy of a polyvalent, whole cell vaccine containing formalin-inactivated F. psychrophilum to induce protective immunity in Atlantic salmon. The vaccine was formulated with an adjuvant containing squalene and aluminium hydroxide, and was compared to a vaccine formulated with a traditional oil adjuvant, Montanide ISA 760VG, and a non-adjuvanted vaccine. Duplicate groups of salmon (23.5 ± 6.8 g) were vaccinated with each of the vaccine formulations or phosphate buffered saline by intraperitoneal injection. Fish were challenged by intramuscular injection with F. psychrophilum six weeks post-vaccination to test the efficacy of the vaccines. Cumulative mortality reached 70% in the control salmon, while the groups of salmon that received vaccine had significantly lower mortality than the controls (p = 0.0001), with no significant difference in survival between vaccinated groups. The squalene/alum adjuvant was safe, more readily metabolised by the fish and induced less histopathological changes than the traditional oil adjuvant.


Assuntos
Adjuvantes Imunológicos/farmacologia , Vacinas Bacterianas/farmacologia , Doenças dos Peixes/prevenção & controle , Infecções por Flavobacteriaceae/veterinária , Flavobacterium/imunologia , Salmo salar/imunologia , Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/farmacologia , Animais , Vacinas Bacterianas/administração & dosagem , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Infecções por Flavobacteriaceae/imunologia , Infecções por Flavobacteriaceae/microbiologia , Infecções por Flavobacteriaceae/prevenção & controle , Distribuição Aleatória , Esqualeno/administração & dosagem , Esqualeno/farmacologia
8.
Food Chem Toxicol ; 125: 217-224, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30584904

RESUMO

Ox66™ is a novel solid state oxygenating compound. In order to support the use of Ox66™ as a potential oxygenating supplement to injured cells, this study evaluated the safety of Ox66™, its ability to withstand the conditions in the digestive tract, and its potential to increase oxygenation in the mesentery in rats. The toxicity of Ox66™ was evaluated by performing acute (10-day) and chronic (90-day) feeding studies on rats, the stability of the compound in the digestive tract was evaluated via ex vivo simulated digestion and subsequent CFDA viability assay on gut epithelial cells, and its capacity for oxygenation in the mesenteric microcirculation was determined by interstitial fluid pressure (PISF) O2 measurements upon injection into the small intestine of rats. No toxicity was found associated with acute or chronic oral administration of the compound in rats, and the compound was able to withstand the environment of the digestive tract in vitro. Based on the acute animal feeding study, the NOAEL was considered to be 1000 mg/kg/day. This proof-of-concept study further demonstrates the potential of Ox66™ to function as an oxygenating supplement that might be useful for treating either pathological hypoxic-related conditions or to improve oxygenation levels during or after exercise under healthy conditions.


Assuntos
Oxigênio/química , Oxigênio/toxicidade , Administração Oral , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/química , Hidróxido de Alumínio/toxicidade , Animais , Células CACO-2 , Portadores de Fármacos , Feminino , Humanos , Masculino , Mesentério/irrigação sanguínea , Microcirculação/efeitos dos fármacos , Oxigênio/administração & dosagem , Ratos Sprague-Dawley
9.
Elife ; 72018 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-30592459

RESUMO

Pneumococcal whole cell vaccines (WCVs) could cost-effectively protect against a greater strain diversity than current capsule-based vaccines. Immunoglobulin G (IgG) responses to a WCV were characterised by applying longitudinally-sampled sera, available from 35 adult placebo-controlled phase I trial participants, to a panproteome microarray. Despite individuals maintaining distinctive antibody 'fingerprints', responses were consistent across vaccinated cohorts. Seventy-two functionally distinct proteins were associated with WCV-induced increases in IgG binding. These shared characteristics with naturally immunogenic proteins, being enriched for transporters and cell wall metabolism enzymes, likely unusually exposed on the unencapsulated WCV's surface. Vaccine-induced responses were specific to variants of the diverse PclA, PspC and ZmpB proteins, whereas PspA- and ZmpA-induced antibodies recognised a broader set of alleles. Temporal variation in IgG levels suggested a mixture of anamnestic and novel responses. These reproducible increases in IgG binding to a limited, but functionally diverse, set of conserved proteins indicate WCV could provide species-wide immunity.Clinical trial registration: The trial was registered with ClinicalTrials.gov with Identifier NCT01537185; the results are available from https://clinicaltrials.gov/ct2/show/results/NCT01537185.


Assuntos
Anticorpos Antibacterianos/sangue , Formação de Anticorpos , Vacinas Pneumocócicas/imunologia , Proteoma/análise , Vacinas de Produtos Inativados/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adulto , Hidróxido de Alumínio/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Voluntários Saudáveis , Humanos , Imunoglobulina G/sangue , Estudos Longitudinais , Placebos/administração & dosagem , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/efeitos adversos , Análise Serial de Proteínas , Fatores de Tempo , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , Adulto Jovem
10.
J Control Release ; 292: 111-118, 2018 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-30339906

RESUMO

Intranasal vaccination using dry powder vaccine formulation represents an attractive, non-invasive vaccination modality with better storage stability and added protection at the mucosal surfaces. Herein we report that it is feasible to induce specific mucosal and systemic antibody responses by intranasal immunization with a dry powder vaccine adjuvanted with an insoluble aluminum salt. The dry powder vaccine was prepared by thin-film freeze-drying of a model antigen, ovalbumin, adsorbed on aluminum (oxy)hydroxide as an adjuvant. Special emphasis was placed on the characterization of the dry powder vaccine formulation that can be realistically used in humans by a nasal dry powder delivery device. The vaccine powder was found to have "passable" to "good" flow properties, and the vaccine was uniformly distributed in the dry powder. An in vitro nasal deposition study using nasal casts of adult humans showed that around 90% of the powder was deposited in the nasal cavity. Intranasal immunization of rats with the dry powder vaccine elicited a specific serum antibody response as well as specific IgA responses in the nose and lung secretions of the rats. This study demonstrates the generation of systemic and mucosal immune responses by intranasal immunization using a dry powder vaccine adjuvanted with an aluminum salt.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Óxido de Alumínio/administração & dosagem , Vacinas/administração & dosagem , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacocinética , Administração Intranasal , Hidróxido de Alumínio/química , Hidróxido de Alumínio/farmacocinética , Óxido de Alumínio/química , Óxido de Alumínio/farmacocinética , Animais , Antígenos/administração & dosagem , Antígenos/química , Antígenos/imunologia , Encéfalo/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , Feminino , Imunização , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Líquido da Lavagem Nasal/imunologia , Ovalbumina/administração & dosagem , Ovalbumina/química , Ovalbumina/imunologia , Pós , Ratos Sprague-Dawley , Vacinas/química , Vacinas/farmacocinética
11.
Eur Arch Otorhinolaryngol ; 275(10): 2515-2521, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30062580

RESUMO

OBJECTIVES: Management of laryngopharyngeal reflux (LPR) typically comprises alginates and proton pump inhibitors (PPIs) alone or in combination, yet evidence to support any particular treatment regimen is lacking. We sought to evaluate the efficacy of Gaviscon® Advance alone versus co-prescription with a PPI in treating LPR. METHODS: One hundred consecutive LPR patients with a reflux symptom index (RSI) score > 10 attending our joint voice clinic (JVC) were studied prospectively. All were treated with Gaviscon® Advance four times daily. If patients had been started on a PPI prior to their JVC attendance, this was optimised to a twice-daily dosing regimen and continued. RSI scores were recorded at first attendance and 3 months post-treatment via postal questionnaire. Scores were analysed using t tests and Levene's test for equality of variances. RESULTS: Follow-up RSI scores were returned by 72 patients, 39 of whom were treated with Gaviscon® Advance only (group A) and 33 with Gaviscon® Advance + PPI (group B). Mean pre-treatment RSI scores were similar between groups [group A: 19.2, 95% confidence interval (CI) ± 2.4; group B: 21.3, 95% CI ± 3.2 (p = 0.65)]. No significant differences were observed with respect to 3-month post-treatment RSI scores [group A: 9.9, 95% CI ± 2.8; group B: 12.6, 95% CI ± 4.2 (p = 0.82)] and change in RSI scores [group A: 9.3, 95% CI ± 3.0; group B: 8.7, 95% CI ± 2.9 [p = 0.75]). CONCLUSIONS: Gaviscon® Advance alone is effective in treating symptoms of LPR, while co-prescription with a high-dose PPI offers no additional benefit.


Assuntos
Alginatos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Refluxo Laringofaríngeo/tratamento farmacológico , Ácido Silícico/administração & dosagem , Bicarbonato de Sódio/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiácidos/administração & dosagem , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Refluxo Laringofaríngeo/diagnóstico , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Resultado do Tratamento , Voz/efeitos dos fármacos
12.
J Viral Hepat ; 25(9): 1048-1056, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29660190

RESUMO

Approximately 5% of the healthy adult population respond inadequately to the commercial recombinant hepatitis B vaccines. As the recombinant vaccines all have an aluminium-based adjuvant, we tried to enhance the immune response by adding a cytokine-based adjuvant. This new adjuvant AI20, containing 20 µg recombinant human IL-2 attached to 20 µg aluminium hydroxide, was added to HBVaxPro©-10 µg (HBAI20). In a double-blind randomized controlled trial (RCT), 24 naïve subjects were randomized to receive either HBAI20 or commercial HBVaxPro©-10 µg vaccine. In an open-label study, 10 nonresponders received HBAI20 vaccine. All participants received 3 vaccinations (0, 1 and 6 months). In the RCT, the occurrence of any adverse events or severe events was similar between the trial arms. At month 7, all naïve participants were seroprotected; moreover, 92% in the HBAI20 group had protective antibodies 10 days after the second vaccination vs 58% in the HBVaxPro©-10 µg group, P = .16. In the open-label study, no serious adverse events were noted. The HBAI20 vaccine was able to elicit protective anti-HBs titres in 90% of nonresponders, 1 month after the third vaccination. According to these results, the new HBAI20 vaccine seems safe, well-tolerated and may promote more rapid protection against hepatitis B infection.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Vacinas contra Hepatite B/efeitos adversos , Vacinas contra Hepatite B/imunologia , Hepatite B/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Vacinas contra Hepatite B/administração & dosagem , Humanos , Esquemas de Imunização , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Biomaterials ; 167: 32-43, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29554479

RESUMO

Aluminum salt (Alum) is one of the most important immune adjuvants approved for use in humans, however it is not suitable for vaccination against various chronic infectious diseases and cancers for not being able to induce cell-mediated (Th1) immunity. Here, we encapsulated an Alum colloid inside ß-glucan particles (GPs), which are a type of natural particles derived from the yeast glucan shells, to prepare hybrid GP-Alum (GP-Al) adjuvant particles with a very uniform size of 2-4 µm. These hybrid particles can be used to load antigen proteins through a simple mixing procedure, and can be highly specifically targeted to antigen-presenting cells (APCs) and strongly activate dendritic cells (DCs) maturation and cytokine secretion. In an animal model, they elicit a strong Th1-biased immune response and extremely high antibody titer, and cause marked prophylactic and therapeutic effects against tumors. As Alum has been proven to be a safe adjuvant to induce strong humoral responses and ß-glucans are safe for human use, this very uniform hybrid Alum particulate system could have important application as a vaccine carrier to stimulate humoral and cellular immune responses at the same time.


Assuntos
Adjuvantes Imunológicos/farmacologia , Hidróxido de Alumínio/farmacologia , Vacinas Anticâncer/farmacologia , Portadores de Fármacos/química , Glucanos/química , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Saccharomyces cerevisiae/química , Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Animais , Vacinas Anticâncer/administração & dosagem , Células Cultivadas , Humanos , Camundongos Endogâmicos C57BL
14.
J Pharm Sci ; 107(6): 1577-1585, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29421216

RESUMO

Adjuvants are necessary to enable vaccine development against a significant number of challenging pathogens for which effective vaccines are not available. We engineered a novel small-molecule immune potentiator, a benzonaphthyridine agonist targeting toll-like receptor 7 (TLR7), as a vaccine adjuvant. TLR7 agonist (TLR7a) was engineered to be adsorbed onto aluminum hydroxide (AlOH), and the resulting AlOH/TLR7a was evaluated as a vaccine adjuvant. AlOH/TLR7a exploits the flexibility of AlOH formulations, has an application in many vaccine candidates, and induced good efficacy and safety profiles against all tested antigens (bacterial- and viral-derived protein antigens, toxoids, glycoconjugates, and so forth) in many animal models, including nonhuman primates. In this article, we describe the outcome of the physicochemical characterization of AlOH/TLR7a. Reverse-phase ultra performance liquid chromatography, confocal microscopy, flow cytometry, zeta potential, and phosphophilicity assays were used as tools to demonstrate the association of TLR7a to AlOH and to characterize this novel formulation. Raman spectroscopy, nuclear magnetic resonance, and mass spectroscopy were also used to investigate the interaction between TLR7a and AlOH (data not shown). This pivotal work paved the way for AlOH/TLR7a to progress into the clinic for evaluation as an adjuvant platform for vaccines against challenging preventable diseases.


Assuntos
Adjuvantes Imunológicos/química , Hidróxido de Alumínio/química , Naftiridinas/química , Receptor 7 Toll-Like/agonistas , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Adsorção , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/farmacologia , Animais , Humanos , Naftiridinas/administração & dosagem , Naftiridinas/farmacologia
15.
J Control Release ; 275: 12-19, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29432824

RESUMO

Aluminum salts have been used as vaccine adjuvants for >50 years, and they are currently present in at least 146 licensed vaccines worldwide. In this study we examined whether adsorption of Army Liposome Formulation (ALF) to an aluminum salt that already has an antigen adsorbed to it might result in improved immune potency of the aluminum-adsorbed antigen. ALF is composed of a family of anionic liposome-based adjuvants, in which the liposomes contain synthetic phospholipids having dimyristoyl fatty acyl groups, cholesterol and monophosphoryl lipid A (MPLA). For certain candidate vaccines, ALF has been added to aluminum hydroxide (AH) gel as a second adjuvant to form ALFA. Here we show that different methods of preparation of ALF changed the physical structures of both ALF and ALFA. Liposomes containing the saponin QS21 (ALFQ) have also been mixed with AH to form ALFQA as an effective combination. In this study, we first adsorbed one of two different antigens to AH, either tetanus toxoid conjugated to 34 copies of a hapten (MorHap), which has been used in a candidate heroin vaccine, or gp140 protein derived from the envelope protein of HIV-1. We then co-adsorbed ALF or ALFQ to the AH to form ALFA or ALFQA. In each case, the immune potency of the antigen adsorbed to AH was greatly increased by co-adsorbing either ALF or ALFQ to the AH. Based on IgG subtype and cytokine analysis by ELISPOT, ALFA induced predominately a Th2-type response and ALFQ and ALFQA each induced more balanced Th1/Th2 responses.


Assuntos
Adjuvantes Imunológicos , Hidróxido de Alumínio , Antígenos , Saponinas , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Adsorção , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/química , Hidróxido de Alumínio/imunologia , Animais , Antígenos/administração & dosagem , Antígenos/química , Antígenos/imunologia , Feminino , Haptenos/administração & dosagem , Haptenos/química , Haptenos/imunologia , Imunoglobulina G/imunologia , Lipossomos , Camundongos Endogâmicos BALB C , Saponinas/administração & dosagem , Saponinas/química , Saponinas/imunologia , Toxoide Tetânico/administração & dosagem , Toxoide Tetânico/química , Toxoide Tetânico/imunologia , Vacinas/administração & dosagem , Vacinas/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/administração & dosagem , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
16.
Pediatr Infect Dis J ; 37(4): e93-e102, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29424799

RESUMO

BACKGROUND: The burden of cervical cancer caused by human papillomavirus (HPV) is high in Latin America. The suboptimal HPV vaccination coverage in adolescents could be improved by pediatric immunization. HPV vaccination has not yet been reported in girls <9 years of age. METHODS: This ongoing phase III, controlled, randomized, single-blind, multicenter study conducted in Colombia, Mexico and Panama (NCT01627561) evaluated the safety and immunogenicity of AS04-HPV-16/18 vaccine in 4-6-year-old girls. Healthy girls (randomized 1:1) received either 2 doses of AS04-HPV-16/18 vaccine (HPV group, N=74) or 1 dose of each measles-mumps-rubella and diphtheria-tetanus-acellular-pertussis vaccines (control group, N=74) 6 months apart. We report the safety and serum anti-HPV-16 and anti-HPV-18 antibodies (measured by enzyme-linked immunosorbent assay) up to 6 months postvaccination, that is, month (M) 12. RESULTS: Injection site pain was the most frequently reported solicited local symptom in HPV vaccinees. The incidence of other solicited and unsolicited symptoms after each vaccination was similar between the HPV and control group. Until M12, 1 girl in the HPV group and 2 in the control group reported serious adverse events; all serious adverse events were assessed as unrelated to study vaccines. No potential immune-mediated diseases were identified. All girls seroconverted for both antigens after 2 doses of AS04-HPV-16/18. In initially seronegative girls, anti-HPV-16 geometric mean concentrations were 20080.0 enzyme-linked immunosorbent assay units (EU)/mL at M7 and 3246.5 EU/mL at M12; anti-HPV-18 geometric mean concentrations were 10621.8 EU/mL at M7 and 1216.6 EU/mL at M12. CONCLUSIONS: Two-dose vaccination with AS04-HPV-16/18 was well tolerated and induced adequate antibody responses in 4-6-year-old girls.


Assuntos
Hidróxido de Alumínio/efeitos adversos , Hidróxido de Alumínio/imunologia , Lipídeo A/análogos & derivados , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/imunologia , Hidróxido de Alumínio/administração & dosagem , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Colômbia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Voluntários Saudáveis , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Humanos , Esquemas de Imunização , Incidência , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Lipídeo A/imunologia , México , Panamá , Vacinas contra Papillomavirus/administração & dosagem , Método Simples-Cego
17.
Gut ; 67(2): 372-379, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-27797937

RESUMO

OBJECTIVE: Although HCV is a major cause of chronic liver disease worldwide, there is currently no prophylactic vaccine for this virus. Thus, the development of an HCV vaccine that can induce both humoural and cellular immunity is urgently needed. To create an effective HCV vaccine, we evaluated neutralising antibody induction and cellular immune responses following the immunisation of a non-human primate model with cell culture-generated HCV (HCVcc). DESIGN: To accomplish this, 10 common marmosets were immunised with purified, inactivated HCVcc in combination with two different adjuvants: the classically used aluminum hydroxide (Alum) and the recently established adjuvant: CpG oligodeoxynucleotide (ODN) wrapped by schizophyllan (K3-SPG). RESULTS: The coadministration of HCVcc with K3-SPG efficiently induced immune responses against HCV, as demonstrated by the production of antibodies with specific neutralising activity against chimaeric HCVcc with structural proteins from multiple HCV genotypes (1a, 1b, 2a and 3a). The induction of cellular immunity was also demonstrated by the production of interferon-γ mRNA in spleen cells following stimulation with the HCV core protein. These changes were not observed following immunisation with HCVcc/Alum preparation. No vaccination-related abnormalities were detected in any of the immunised animals. CONCLUSIONS: The current preclinical study demonstrated that a vaccine included both HCVcc and K3-SPG induced humoural and cellular immunity in marmosets. Vaccination with this combination resulted in the production of antibodies exhibiting cross-neutralising activity against multiple HCV genotypes. Based on these findings, the vaccine created in this study represents a promising, potent and safe prophylactic option against HCV.


Assuntos
Anticorpos Neutralizantes/sangue , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/sangue , Vacinação , Vacinas contra Hepatite Viral/imunologia , Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/imunologia , Animais , Callithrix , Células HEK293 , Antígenos da Hepatite C/imunologia , Humanos , Imunidade Celular , Interferon gama/genética , Camundongos , RNA Mensageiro/metabolismo , Baço/citologia , Proteínas do Core Viral/imunologia
18.
Vaccine ; 36(1): 98-106, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29174109

RESUMO

This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of two doses (2D) of the HPV-16/18 AS04-adjuvanted vaccine (2D of AS04-HPV-16/18) vs. two or three doses of the 4vHPV vaccine [2D or 3D of 4vHPV] in 1075 healthy girls aged 9-14 years. Girls were randomized (1:1:1) to receive 2D of AS04-HPV-16/18 at months (M) 0, 6 (N = 359), 2D of 4vHPV at M0, 6 (N = 358) or 3D of 4vHPV at M0, 2, 6 (N = 358). 351, 339 and 346 girls, respectively, returned for the concluding visit at M36. Superiority was demonstrated at M7 and M12; comparison of the immune response to both vaccine antigens was made between 2D of AS04-HPV-16/18 and 2D or 3D of 4vHPV at subsequent time points in the according-to-protocol immunogenicity cohort (ATP-I; N = 958 at M36) and the total vaccinated cohort (TVC: N = 1036 at M36). HPV-16/18-specific T-cell- and B-cell-mediated immune responses and safety were also investigated. At M36, anti-HPV-16/18 ELISA responses in the 2D AS04-HPV-16/18 group remained superior to those of the 2D and 3D 4vHPV groups. In the M36 TVC, geometric mean titers were 2.78-fold (HPV-16) and 6.84-fold (HPV-18) higher for 2D of AS04-HPV-16/18 vs. 2D of 4vHPV and 2.3-fold (HPV-16) and 4.14-fold (HPV-18) higher vs. 3D of 4vHPV. Results were confirmed by vaccine pseudovirion-based neutralisation assay. Numbers of circulating CD4+ T cells and B cells appeared similar across groups. Safety was in line with the known safety profiles of both vaccines. In conclusion, superior HPV-16/18 antibody responses were elicited by 2D of the AS04-HPV-16/18 compared with 2D or 3D of the 4vHPV vaccine in girls aged 9-14 years. CLINICAL TRIAL REGISTRATION: NCT0146235.


Assuntos
Anticorpos Antivirais/sangue , Esquemas de Imunização , Imunogenicidade da Vacina , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversos , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adolescente , Hidróxido de Alumínio/administração & dosagem , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Criança , Estudos de Coortes , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/imunologia , Humanos , Imunidade Celular , Imunização/métodos , Imunização/estatística & dados numéricos , Testes de Neutralização , Papillomaviridae/imunologia , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/administração & dosagem
19.
Eur J Med Chem ; 143: 419-425, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29202404

RESUMO

A series of novel α-terpineol derivatives were designed and synthesized through structural derivatization of the tertiary hydroxyl moiety or reduction of the double bond. Of the resulting compounds, eight compounds enhanced relaxation of airway smooth muscle (ASM) compared to the α-terpineol precursor, and four compounds (4a, 4d, 4e, and 4i)were superior or comparable to aminophylline at a concentration of 0.75 mmol/L. Assays for 3'-5'-Cyclic adenosine monophpsphate (cAMP) activation revealed that some representative α-terpineol derivatives in this series were capable of upregulating the level of cAMP in ASM cells. Further in vivo investigation using the asthmatic rat model, illustrated that treatment with the compounds 4a and 4e resulted in significantly lowered lung resistance (RL) and enhanced dynamic lung compliance (Cldyn), two important parameters for lung fuction. Moreover, treatment with 4e downregulated the levels of both IL-4 and IL-17. Due to its several favorable physiological functions, including ASM relaxation activity, cAMP activation capability, and in vivo anti-asthmatic efficacy, 4e is a promising remedy for bronchial asthma, meriting extensive development.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Cicloexenos/uso terapêutico , Descoberta de Drogas , Monoterpenos/uso terapêutico , Administração Oral , Hidróxido de Alumínio/administração & dosagem , Animais , Antiasmáticos/administração & dosagem , Antiasmáticos/química , Asma/induzido quimicamente , Monoterpenos Cicloexânicos , Cicloexenos/administração & dosagem , Cicloexenos/química , Relação Dose-Resposta a Droga , Cobaias , Injeções Intraperitoneais , Masculino , Estrutura Molecular , Monoterpenos/administração & dosagem , Monoterpenos/química , Ovalbumina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
20.
J Inorg Biochem ; 181: 96-103, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29221615

RESUMO

BACKGROUND: Our group has shown that significant correlations exist between rates of Autism Spectrum Disorder (ASD) and total aluminum adjuvants given to children through vaccines in several Western countries. These correlations satisfied eight out of nine Hill criteria for causality. Experimental studies have demonstrated a range of behavioural abnormalities in young mice after postnatal exposure to aluminium. To build on our previous work, the current study will investigate the effect of aluminium adjuvants on social behaviour in mice. Anomalies in social interaction are a key characteristic of those with ASD. METHODS: Neonatal CD-1 mice pups were injected with either a total of 550µg of aluminum hydroxide gel (experimental group) or saline (control) spread out during the first two weeks of postnatal life. The mice were then subjected to behavioural tests for social interest and social novelty at postnatal week 8, 17 and 29. p-Values were calculated using the Mann-Whitney and Kruskal Wallis tests. RESULTS: Aluminum injected mice showed diminished social interest compared to controls at week 8 (p=0.016) and 17 (p=0.012). They also demonstrated abnormal social novelty from controls at week 8 (p=0.002) and week 29 (p=0.042). CONCLUSION: This is the first experimental study, to our knowledge, to demonstrate that aluminum adjuvants can impair social behaviour if applied in the early period of postnatal development. The study, however, is insufficient to make any assertive claims about the link between aluminium adjuvants and ASD in humans.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Hidróxido de Alumínio/efeitos adversos , Transtorno do Espectro Autista/etiologia , Modelos Animais de Doenças , Síndromes Neurotóxicas/fisiopatologia , Transtornos do Comportamento Social/etiologia , Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Animais , Animais Recém-Nascidos , Animais não Endogâmicos , Comportamento Animal/efeitos dos fármacos , Feminino , Esquemas de Imunização , Injeções Subcutâneas , Masculino , Camundongos , Pescoço , Projetos Piloto , Distribuição Aleatória , Reprodutibilidade dos Testes , Caracteres Sexuais , Comportamento Social , Estados Unidos
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