RESUMO
BACKGROUND: Data suggest that pediatric patients might react differently to influenza vaccination, both in terms of immunity and side effects. We have recently shown that using a whole virion vaccine with aluminum phosphate adjuvants, reduced dose vaccines containing 6 µg of viral hemagglutinin (HA) per strain are immunogenic, and well tolerated in adult and elderly patients. Here we show the results of a multicenter clinical trial of pediatric patients, using reduced doses of a new, whole virion, aluminum phosphate adjuvanted vaccine (FluArt, Budapest, Hungary). METHODS: A total of 120 healthy volunteers were included in two age groups (3-11 years, receiving 3 µg of HA per strain, and 12-18 years, receiving 6 µg of HA per strain). We used hemagglutination inhibition testing to assess immunogenicity, based on EMA and FDA licensing criteria, including post/pre-vaccination geometric mean titer ratios, seroconversion and seropositivity rates. Safety and tolerability were assessed using CHMP guidelines. RESULTS: All subjects entered the study and were vaccinated (ITT population). All 120 subjects attended the control visit on Day 21 (PP population). All immunogenicity licensing criteria were met in both age groups for all three vaccine virus strains. No serious adverse events were detected and the vaccine was well tolerated by both age groups. DISCUSSION: Using a whole virion vaccine and aluminum phosphate adjuvants, a reduction in the amount of the viral hemmaglutinin is possible while maintaining immunogenicity, safety and tolerability in pediatric and adolescent patients.
Assuntos
Adjuvantes Imunológicos , Compostos de Alumínio , Vacinas contra Influenza , Influenza Humana/prevenção & controle , Fosfatos , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adolescente , Compostos de Alumínio/administração & dosagem , Compostos de Alumínio/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Hungria/epidemiologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Masculino , Fosfatos/administração & dosagem , Fosfatos/efeitos adversos , Estudos Prospectivos , Vírion/imunologiaRESUMO
Aluminium (Al) toxicokinetics after intramuscular (IM) injection of Al-adjuvanted vaccines is unknown. Since animal data are required for modeling and extrapolation, a rat study was conducted measuring Al in plasma and tissues after IM injection of either plain Al-hydroxide (pAH) or Al-phosphate (pAP) adjuvant (Al dose 1.25 mg), single human doses of three Al-adjuvanted vaccines (V1, V2, and V3; Al doses 0.5-0.82 mg), or vehicle (saline). A significant increase in Al plasma levels compared to controls was observed after pAP (AUC(0-80 d), mean ± SD: 2424 ± 496 vs. 1744 ± 508 µg/L*d). Percentage of Al dose released from injected muscle until day 80 was higher after pAP (66.9%) and AP-adjuvanted V3 (85.5%) than after pAH and AH-adjuvanted V1 (0 and 22.3%, resp.). Estimated absolute Al release was highest for pAP (836.8 µg per rat). Al concentration in humerus bone was increased in all groups, again strongest in the pAP group [3.35 ± 0.39 vs. 0.05 ± 0.06 µg/g wet weight (ww)]. Extrapolated amounts in whole skeleton corresponded to 5-12% of the released Al dose. Very low brain Al concentrations were observed in all groups (adjuvant group means 0.14-0.29 µg/g ww; control 0.13 ± 0.04 µg/g ww). The results demonstrate systemically available Al from marketed vaccines in rats being mainly detectable in bone. Al release appears to be faster from AP- than AH-adjuvants. Dose scaling to human adults suggests that increase of Al in plasma and tissues after single vaccinations will be indistinguishable from baseline levels.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Compostos de Alumínio/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Fosfatos/administração & dosagem , Vacinas/administração & dosagem , Adjuvantes Imunológicos/farmacocinética , Compostos de Alumínio/farmacocinética , Hidróxido de Alumínio/farmacocinética , Animais , Área Sob a Curva , Humanos , Injeções Intramusculares , Masculino , Fosfatos/farmacocinética , Ratos , Ratos Wistar , Distribuição Tecidual , Vacinas/farmacocinéticaRESUMO
Esophageal variceal bleeding is a common lethal complication of cirrhosis. Endoscopic injection sclerotherapy (EIS) is one of the major endoscopic approaches for treating esophageal variceal bleeding. However, complications may occur after EIS, which mainly include retrosternal discomfort/pain, dysphagia, re-bleeding, esophageal ulcer, esophageal strictures, and esophageal perforation, etc. In this article, we reported a 36-year-old male who developed esophageal ulcer related bleeding after EIS. Currently, there is no consensus on the treatment strategy for esophageal ulcer-related bleeding after EIS. In the present case, the following treatment strategy may be effective for ulcer related bleeding. The first step is to inhibit gastric acid secretion and reduce portal pressure by intravenous infusion of esomeprazole and somatostatin, respectively. The second is local hemostasis by oral norepinephrine and lyophilizing thrombin powder. The third is to protect digestive tract mucosa by oral Kangfuxin Ye and aluminum phosphate.
Assuntos
Varizes Esofágicas e Gástricas/terapia , Hematemese/tratamento farmacológico , Escleroterapia/efeitos adversos , Úlcera/etiologia , Adulto , Compostos de Alumínio/administração & dosagem , Compostos de Alumínio/uso terapêutico , Esomeprazol/administração & dosagem , Esomeprazol/uso terapêutico , Hematemese/etiologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Masculino , Materia Medica/administração & dosagem , Materia Medica/uso terapêutico , Norepinefrina/administração & dosagem , Norepinefrina/uso terapêutico , Fosfatos/administração & dosagem , Fosfatos/uso terapêutico , Somatostatina/administração & dosagem , Somatostatina/uso terapêutico , Trombina/administração & dosagem , Trombina/uso terapêutico , Resultado do Tratamento , Úlcera/complicações , Úlcera/tratamento farmacológicoRESUMO
Objective To investigate the effect of aluminum phosphate (AP) and aluminum hydroxide (AH) as adjuvants on Brucella outer membrane protein 31 (Omp31) in inducing humoral and cellular immune responses and immune protection. Methods AP and AH adjuvants were prepared and separately mixed with Brucella Omp31 protein to measure the adsorption rates. The AP- and AH-absorbed Omp31 protein were intraperitoneally injected into BLAB/c mice at 0, 2, and 4 weeks, and meanwhile, unabsorbed Omp31 protein and PBS were used as controls. The levels of serum IgG, IgG1, IgG2a and genital tract secretion sIgA were determined by ELISA at 0, 2, 4 and 6 weeks. Spleen cells were collected for culture at 6 weeks, and the cells were stimulated by Omp31 for 48 hours followed by the analysis of IFN-γ and IL-10 levels in the supernatants by ELISA, and the determination of lymphocyte proliferation by CCK-8 assay. The mice were challenged with Brucella at 6 weeks, and bacterial content in spleen tissue was determined 1 and 2 weeks later. Results AP and AH could absorb over 70% and 85% of the Omp31 protein, respectively, for solutions at all the tested concentrations. ELISA suggested that serum IgG, IgG1, IgG2a and genital tract sIgA levels peaked 2 weeks after the last immunization for both AP and AH groups, and antibody level was higher in the AP and AH groups than the control groups, and higher in the AH group than in the AP group. CCK-8 assay showed that the proliferating rate of lymphocytes induced by the AH group was significantly higher than that by the AP group, and the AH group also showed significantly higher IFN-γ level in the supernatant than the AP group, but no significant difference in IL-10 level. The AH group had remarkably lower bacterial load in the spleen than the AP group 2 weeks after challenged by Brucella 16M strain. Conclusion Both AP and AH adjuvants effectively enhanced immunogenicity and immune protection of the Brucella Omp31 protein, and AH was superior to AP in this respect.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Proteínas da Membrana Bacteriana Externa/imunologia , Brucella melitensis/imunologia , Brucelose/imunologia , Compostos de Alumínio/administração & dosagem , Compostos de Alumínio/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Proteínas da Membrana Bacteriana Externa/genética , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/genética , Vacinas Bacterianas/imunologia , Brucella melitensis/genética , Brucelose/microbiologia , Brucelose/prevenção & controle , Feminino , Humanos , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Fosfatos/administração & dosagem , Fosfatos/imunologiaRESUMO
Injection site reactions (ISRs; redness, swelling and pain) commonly occur within 1-2 days after vaccination. After administration of toxoid vaccines including diphtheria toxoid, a later onset of ISRs has also been observed. As the serotype capsular polysaccharides in the 13-valent pneumococcal conjugate vaccine (PCV13) are conjugated to cross-reactive material 197 (CRM197), a nontoxic variant of diphtheria toxin, the onset of ISRs over 14 days was explored in 8 adult studies with 19 cohorts. Subjects received PCV13 with aluminum phosphate (AlPO4, n = 5667) or without AlPO4 (n = 304); 1097 subjects received 23-valent pneumococcal polysaccharide vaccine (PPSV23). Late ISRs with onset between days 6-14 were observed in 8/8 cohorts aged ≥65 years after PCV13 with AlPO4 (incidence across cohorts for redness, 2.3%-19.6%; swelling, 0.9%-10.8%; pain, 1.6%-10.0%) and in 1/1 cohort after PCV13 without AlPO4 (redness 10.5%; swelling 7.5%; pain 12.3%); and in 2/4 cohorts aged 50 to 64 years after PCV13 (redness 3.1%-4.8%; swelling 1.0%-3.2%; pain 3.7%-5%). Late ISRs were not generally observed in 1/1 cohort aged 18 to 49 years after PCV13; in 2/2 cohorts aged ≥53 years after PCV13 revaccination; and in 3/3 cohorts aged ≥60 years who received PPSV23, which does not contain CRM197. Post hoc analysis demonstrated numerically higher pneumococcal immune responses in subgroups with late ISRs versus those without. In conclusion, causality of late ISRs is likely multifactorial, with age and the PCV13 carrier protein CRM197 potentially associated. AlPO4, a vaccine adjuvant, did not appear causally related. Observations do not affect the favorable risk-benefit profile of PCV13.
Assuntos
Proteínas de Bactérias/efeitos adversos , Reação no Local da Injeção/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/efeitos adversos , Streptococcus pneumoniae/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adulto , Fatores Etários , Idoso , Compostos de Alumínio/administração & dosagem , Compostos de Alumínio/efeitos adversos , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/imunologia , Estudos Clínicos como Assunto , Estudos de Coortes , Humanos , Imunização Secundária/efeitos adversos , Imunização Secundária/métodos , Incidência , Reação no Local da Injeção/imunologia , Vacinação em Massa/efeitos adversos , Vacinação em Massa/métodos , Pessoa de Meia-Idade , Fosfatos/administração & dosagem , Fosfatos/efeitos adversos , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Medição de Risco , Fatores de Tempo , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/efeitos adversos , Vacinas Conjugadas/imunologia , Adulto JovemRESUMO
INTRODUCTION: This study evaluated the physicochemical, antimicrobial, and biological properties of white mineral trioxide aggregate (MTA) mixed with aqueous and propylene glycol extracts of Arctium lappa L. and Casearia sylvestris Sw. METHODS: The setting-time test was performed according to American Society for Testing and Materials 266/2008 and flowability by American National Standards Institute/American Dental Association 57/2012 standard specifications. The following parameters were assessed: volumetric change by micro-computed tomography; pH level and calcium ion release measured after 3 hours and 1, 3, 7, and 15 days; antimicrobial effect by the dentin decontamination method with intratubular Enterococcus faecalis viability, verified by using confocal laser scanning microscopy; and biocompatibility by histologic-morphometric analyses of inflammatory infiltrate at subcutaneous implant sites after 15, 30, and 60 days. In addition, rat alveolar tissues with implants were processed to measure tumor necrosis factor-alpha and interleukin-10 cytokines by enzyme-linked immunosorbent assay. RESULTS: The plant extracts associated with MTA significantly increased the final setting time; however, they did not influence volumetric change (P > .05) and maintained medium alkalinity and calcium ion release. Propylene glycol extracts showed higher flowability. Casearia sylvestris increased the cementing effect against E. faecalis after 24-hour and 168-hour periods. Histologic evaluation of inflammatory infiltrate showed no significant differences between plant extracts groups and the distilled water group for all periods. Tumor necrosis factor-alpha and interleukin-10 expression was similar among groups (P > .05). CONCLUSIONS: Casearia sylvestris extracts increased the antimicrobial effect of MTA and did not influence biocompatibility but changed some physicochemical properties.
Assuntos
Compostos de Alumínio/farmacologia , Anti-Infecciosos/farmacologia , Arctium , Compostos de Cálcio/farmacologia , Casearia , Óxidos/farmacologia , Veículos Farmacêuticos/uso terapêutico , Extratos Vegetais/uso terapêutico , Silicatos/farmacologia , Compostos de Alumínio/administração & dosagem , Compostos de Alumínio/química , Animais , Anti-Infecciosos/administração & dosagem , Arctium/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Compostos de Cálcio/administração & dosagem , Compostos de Cálcio/química , Casearia/química , Combinação de Medicamentos , Enterococcus faecalis/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Masculino , Óxidos/administração & dosagem , Óxidos/química , Ratos , Ratos Wistar , Silicatos/administração & dosagem , Silicatos/química , Microtomografia por Raio-XRESUMO
We previously reported a 2011/12 study in elderly showing that immunization with the universal influenza vaccine candidate, M-001, three weeks before administering trivalent influenza vaccine (TIV) enhanced seroconversion of Hemagglutination Inhibition (HAI) antibodies against known influenza vaccine strains circulating at that time. We now report that those subjects primed with M-001 prior to TIV in 2011 also showed, in their 2011 sera, significantly more HAI antibodies with improved seroprotection and seroconversion against strain A/Switzerland/9715293/2013(H3N2-like) that caused the 2014/15 influenza epidemic and that wasn't known to circulate in 2011/12. These data indicate that M-001 can provide broadened enhanced immunity extending even to influenza strains destined to circulate in future years. The fact that M-001 stimulates T cell activation and is devoid of HA hypervariable epitopes indicates that such broadened HAI responses effected by M-001 priming is due to extensive T cell priming.
Assuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Imunização/métodos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Compostos de Alumínio/administração & dosagem , Proteção Cruzada , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Esquemas de Imunização , Imunogenicidade da Vacina , Vírus da Influenza A Subtipo H3N2/imunologia , Influenza Humana/imunologia , Influenza Humana/virologia , Masculino , Fosfatos/administração & dosagem , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia , Vacinas de Subunidades AntigênicasRESUMO
BACKGROUND: Broad use of monovalent Haemophilus influenzae type b (Hib) conjugate vaccines based on the capsular polysaccharide polyribosyl-ribitol phosphate (PRP), has significantly reduced invasive Hib disease burden in children worldwide, particularly in children aged <1year. In Japan, PRP conjugated to tetanus toxoid (PRP-T) vaccine has been widely used since the initiation of public funding programs followed by a routine vaccination designation in 2013. METHODS: We compared the immunogenicity and safety of PRP conjugated to a non-toxic diphtheria toxin mutant (PRP-CRM197) vaccine with the PRP-T vaccine when administered subcutaneously to healthy Japanese children in a phase III study. Additionally, we evaluated the immunogenicity and safety profiles of a diphtheria-tetanus acellular pertussis (DTaP) combination vaccine when concomitantly administered with either PRP-CRM197 or PRP-T vaccines. The primary endpoint was the "long-term seroprotection rate", defined as the group proportion with anti-PRP antibody titers ⩾1.0µg/mL, after the primary series. RESULTS: Long-term seroprotection rates were 99.3% in the PRP-CRM197 group and 95.6% in the PRP-T group. The intergroup difference (PRP-CRM197 group - PRP-T group) was 3.7% (95% confidence interval: 0.099-7.336), demonstrating that PRP-CRM197 vaccine was non-inferior to PRP-T vaccine (p<0.0001). Furthermore, the "short-term seroprotection rate" (anti-PRP antibody titer ⩾0.15µg/mL) before booster vaccination was higher in the PRP-CRM197 group than in PRP-T. Concomitant administration of PRP-CRM197 vaccine with DTaP vaccine showed no differences in terms of immunogenicity compared with concomitant vaccination with PRP-T vaccine and DTaP vaccine. Although CRM197 vaccine had higher local reactogenicity, overall, both Hib vaccines had acceptable safety and tolerability profiles. CONCLUSION: The immunogenicity of PRP-CRM197 vaccine administered subcutaneously as a three-dose primary series in children followed by a booster vaccination 1year after the primary series induced protective levels of Hib antibodies with no safety or tolerability concerns. CLINICAL TRIAL REGISTRY: Registered on ClinicalTrials.gov: NCT01379846.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Compostos de Alumínio/administração & dosagem , Proteínas de Bactérias/imunologia , Vacinas Anti-Haemophilus/uso terapêutico , Imunogenicidade da Vacina , Fosfatos/administração & dosagem , Toxoide Tetânico/uso terapêutico , Anticorpos Antibacterianos/sangue , Vacina contra Difteria, Tétano e Coqueluche/administração & dosagem , Feminino , Vacinas Anti-Haemophilus/imunologia , Humanos , Imunização Secundária , Lactente , Japão , Masculino , Toxoide Tetânico/imunologia , Vacinas Conjugadas/imunologia , Vacinas Conjugadas/uso terapêuticoRESUMO
BACKGROUND: Protection of newborns and young infants against RSV disease via maternal immunization mediated by transplacental transfer of antibodies is under evaluation in third-trimester pregnant women with the RSV recombinant F nanoparticle vaccine (RSV F vaccine). Since the hemichorial placental architecture in guinea pigs and humans is similar, the guinea pig model was employed to assess RSV F vaccine immunogenicity in pregnant sows and to compare RSV-specific maternal antibody levels in their pups. METHODS: Thirty (30) presumptive pregnant guinea pigs were immunized on gestational day 25 and 46 with placebo (PBS), 30µg RSV F, or 30µg RSV F+400µg aluminum phosphate. Sera at delivery/birth (sows/pups) and 15 and 30 days post-partum (pups) were analyzed for the presence of anti-F IgG, palivizumab-competitive antibody (PCA) and RSV/A microneutralization (MN). RESULTS: The rates of pregnancy and stillbirth were similar between controls and vaccinees. The vaccine induced high levels of anti-F IgG, PCA and MN in sows, with the highest levels observed in adjuvanted vaccinees. Placental transfer to pups was proportional to the maternal antibody levels, with concentration effects observed for all immune measures. CONCLUSIONS: The RSV F vaccine was safe and immunogenic in pregnant guinea pigs and supported robust transplacental antibody transfer to their pups. Relative concentration of antibodies in the pups was observed even in the presence of high levels of maternal antibody. Guinea pigs may be an important safety and immunogenicity model for preclinical assessment of candidate vaccines for maternal immunization.
Assuntos
Anticorpos Antivirais/sangue , Imunidade Materno-Adquirida , Exposição Materna , Vacinas contra Vírus Sincicial Respiratório/imunologia , Proteínas Virais de Fusão/imunologia , Adjuvantes Imunológicos/administração & dosagem , Compostos de Alumínio/administração & dosagem , Animais , Anticorpos Neutralizantes/sangue , Feminino , Cobaias , Imunoensaio , Imunoglobulina G/sangue , Fosfatos/administração & dosagem , Placebos/administração & dosagem , Gravidez , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/efeitos adversosRESUMO
The two currently available live oral rotavirus vaccines, Rotarix(®) and RotaTeq(®), are highly efficacious in the developed countries. However, the efficacy of such vaccines in resource deprived countries in Africa and Southeast Asia is low. We reported previously that a bacterially-expressed rotavirus P2-P[8] ΔVP8* subunit vaccine candidate administered intramuscularly elicited high-titers of neutralizing antibodies in guinea pigs and mice and significantly shortened the duration of diarrhea in neonatal gnotobiotic pigs upon oral challenge with virulent human rotavirus Wa strain. To further improve its vaccine potential and provide wider coverage against rotavirus strains of global and regional epidemiologic importance, we constructed 2 tandem recombinant VP8* proteins, P2-P[8] ΔVP8*-P[8] ΔVP8* and P2-P[8] ΔVP8*-P[6] ΔVP8* based on Escherichia coli expression system. The two resulting recombinant tandem proteins were highly soluble and P2-P[8] ΔVP8*-P[8] ΔVP8* was generated with high yield. Moreover, guinea pigs immunized intramuscularly by 3 doses of the P2-P[8] ΔVP8*-P[8] ΔVP8* or P2-P[8] ΔVP8*-P[6] ΔVP8* vaccine with aluminum phosphate adjuvant developed high titers of homotypic and heterotypic neutralizing antibodies against human rotaviruses bearing G1-G4, G8, G9 and G12 with P[8], P[4] or P[6] combination. The results suggest that these 2 subunit vaccines in monovalent or bivalent formulation can provide antigenic coverage to almost all the rotavirus G (VP7) types and major P (VP4) types of global as well as regional epidemiologic importance.
Assuntos
Proteínas de Ligação a RNA/imunologia , Vacinas contra Rotavirus/imunologia , Proteínas não Estruturais Virais/imunologia , Adjuvantes Imunológicos/administração & dosagem , Compostos de Alumínio/administração & dosagem , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Escherichia coli/genética , Feminino , Expressão Gênica , Cobaias , Injeções Intramusculares , Proteínas Mutantes/genética , Proteínas Mutantes/imunologia , Fosfatos/administração & dosagem , Proteínas de Ligação a RNA/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/genética , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/genética , Vacinas de Subunidades Antigênicas/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Proteínas não Estruturais Virais/genéticaRESUMO
CIGB-247 is a cancer vaccine that is a formulation of a recombinant protein antigen representative of the human vascular endothelial growth factor (VEGF) with a bacterially-derived adjuvant (VSSP). The vaccine has shown an excellent safety profile in mice, rats, rabbits, not-human primates and in recent clinical trials in cancer patients. Response to the vaccine is characterized by specific antibody titers that neutralize VEGF/VEGFR2 binding and a cytotoxic tumor-specific response. To expand our present anti-VEGF active immunotherapy strategies, we have now studied in mice and non-human primates the effects of vaccination with a formulation of our recombinant VEGF antigen and aluminum phosphate adjuvant (hereafter denominated CIGB-247-A). Administered bi-weekly, CIGB-247-A produces high titers of anti-VEGF IgG blocking antibodies in 2 mice strains. Particularly in BALB/c, the treatment impaired subcutaneous F3II mammary tumor growth and reduced the number of spontaneous lung macro metastases, increasing animals' survival. Spleen cells from specifically immunized mice directly killed F3II tumor cells in vitro. CIGB-247-A also showed to be immunogenic in non-human primates, which developed anti-VEGF blocking antibodies and the ability for specific direct cell cytotoxic responses, all without impairing the healing of deep skin wounds or other side effect. Our results support consideration of aluminum phosphate as a suitable adjuvant for the development of new vaccine formulations using VEGF as antigen.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Compostos de Alumínio/administração & dosagem , Vacinas Anticâncer/imunologia , Química Farmacêutica , Fosfatos/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/imunologia , Animais , Anticorpos Neutralizantes/sangue , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/genética , Chlorocebus aethiops , Citotoxicidade Imunológica , Feminino , Esquemas de Imunização , Leucócitos Mononucleares/imunologia , Masculino , Neoplasias Mamárias Animais/terapia , Neoplasias Mamárias Experimentais/terapia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Metástase Neoplásica/prevenção & controle , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologiaRESUMO
Dysregulation of metal homeostasis has been perceived as one of the key factors in the progression of neurodegeneration. Aluminium (Al) has been considered as a major risk factor, which is linked to several neurodegenerative diseases, especially Alzheimer's disease, whereas zinc (Zn) has been reported as a vital dietary element, which regulates a number of physiological processes in central nervous system. The present study was conducted to explore the protective potential of zinc, if any, in ameliorating neurotoxicity induced by aluminium. Male Sprague Dawley rats received either aluminium chloride (AlCl3) orally (100 mg kg(-1) b.wt. per day), zinc sulphate (ZnSO4) at a dose level of 227 mg L(-1) in drinking water or combined treatment of aluminium and zinc for 8 weeks. Aluminium treatment significantly elevated the levels of lipid peroxidation and reactive oxygen species as well as the activities of catalase, superoxide dismutase and glutathione reductase, which however were decreased following Zn co-treatment of Al-treated rats. In contrast, Al treatment decreased the activities of glutathione-S-transferase as well as the levels of reduced glutathione, oxidised glutathione and total glutathione, but co-administration of Zn to Al-treated animals increased these levels. Furthermore, Al treatment caused a significant increase in the levels of Fe and Mn as well as of Al but decreased the Zn and metallothionein levels. In the Zn-supplemented animals, the levels of Al, Fe, Mn were found to be significantly decreased, whereas the levels of metallothionein as well as Zn were increased. Moreover, histopathological alterations such as vacuolization and loss of Purkinje cells were also evident following Al treatment, which showed improvement upon Zn supplementation. Therefore, zinc has the potential to alleviate aluminium-induced neurodegeneration.
Assuntos
Compostos de Alumínio/toxicidade , Encéfalo/efeitos dos fármacos , Cloretos/toxicidade , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sulfato de Zinco/farmacologia , Cloreto de Alumínio , Compostos de Alumínio/administração & dosagem , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Catalase/metabolismo , Cloretos/administração & dosagem , Glutationa/metabolismo , Glutationa Redutase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Metalotioneína/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Sulfato de Zinco/administração & dosagemRESUMO
Currently available live oral rotavirus vaccines, Rotarix(®) and RotaTeq(®), are highly efficacious in developed countries. However, the immunogenicity and efficacy of such vaccines in some developing countries are low. We reported previously that bacterially-expressed rotavirus ΔVP8* subunit vaccine candidates with P[8], P[4] or P[6] specificity elicited high-titer virus neutralizing antibodies in animals immunized intramuscularly. Of note was the finding that antibodies induced with the P[8]ΔVP8* vaccine neutralized both homotypic P[8] and heterotypic P[4] rotavirus strains to high titer. To further improve its vaccine potential, a tetanus toxoid universal CD4(+) T cell epitope P2 was introduced into P[8] or P[6]ΔVP8* construct. The resulting recombinant fusion proteins expressed in Escherichia coli were of high solubility and were produced with high yield. Two doses (10 or 20 µg/dose) of the P2-P[8]ΔVP8* vaccine or P2-P[6]ΔVP8* vaccine with aluminum phosphate adjuvant elicited significantly higher geometric mean homologous neutralizing antibody titers than the vaccines without P2 in intramuscularly immunized guinea pigs. Interestingly, high levels of neutralizing antibody responses induced in guinea pigs with 3 doses of the P2-P[8]ΔVP8* vaccine persisted for at least 6 months. Furthermore, in the gnotobiotic piglet challenge study, three intramuscular doses (50 µg/dose) of the P2-P[8]ΔVP8* vaccine with aluminum phosphate adjuvant significantly delayed the onset of diarrhea and significantly reduced the duration of diarrhea and the cumulative diarrhea score after oral challenge with virulent human rotavirus Wa (G1P[8]) strain. The P2-P[8]ΔVP8* vaccine induced serum virus neutralizing antibody and VP4-specific IgG antibody production prechallenge, and primed the pigs for higher antibody and intestinal and systemic virus-specific IFN-γ producing CD4(+) T cell responses postchallenge. These two subunit vaccines could be used at a minimum singly or preferably in bivalent formulation to provide antigenic coverage of most of the G types of global importance.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Proteínas de Ligação a RNA/imunologia , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/imunologia , Toxoide Tetânico/imunologia , Proteínas não Estruturais Virais/imunologia , Adjuvantes Imunológicos/administração & dosagem , Compostos de Alumínio/administração & dosagem , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Diarreia/imunologia , Diarreia/prevenção & controle , Modelos Animais de Doenças , Feminino , Cobaias , Imunoglobulina G/sangue , Injeções Intramusculares , Fosfatos/administração & dosagem , Proteínas de Ligação a RNA/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Infecções por Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/genética , Suínos , Vacinação/métodos , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/genética , Vacinas de Subunidades Antigênicas/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Proteínas não Estruturais Virais/genéticaRESUMO
AIMS: The aim of this study was to determine the effects of sub-chronic aluminum chloride (AlCl3) on spermatogenesis and testicular enzymatic activity in male rats. MAIN METHODS: Forty Wistar male rats were randomly divided into four groups: control group (CG, 0), low-dose group (LG, 64.18 mg/kg BW AlCl3), mid-dose group (MG, 128.36 mg/kg BW AlCl3) and high-dose group (HG, 256.72 mg/kg BW AlCl3). The rats were orally administered with AlCl3 for 120 days. At the end of the experiment, the contents of Al, Fe, Cu and Zn, the enzyme activities of testicular acid phosphatase (ACP), succinate dehydrogenase (SDH), lactate dehydrogenase (LDH), lactate dehydrogenase isoenzyme (LDH-x), the sperm count and the sperm malformation rate were examined. KEY FINDINGS: The results showed that the Al and Cu contents, sperm count and the enzyme activities of testicular ACP, SDH, LDH and LDH-x decreased, while the Zn and Fe contents and sperm malformation rate increased in AlCl3-treated rats. SIGNIFICANCE: It suggests that sub-chronic AlCl3 disorders the balance of trace element and decreases the spermatogenesis and the activities of testicular enzymes, indicating that AlCl3 has adverse effect on the testicular function in male rats.
Assuntos
Compostos de Alumínio/toxicidade , Cloretos/toxicidade , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Administração Oral , Cloreto de Alumínio , Compostos de Alumínio/administração & dosagem , Animais , Cloretos/administração & dosagem , Cobre/metabolismo , Relação Dose-Resposta a Droga , Ferro/metabolismo , Masculino , Ratos , Ratos Wistar , Contagem de Espermatozoides , Testículo/enzimologia , Fatores de Tempo , Zinco/metabolismoRESUMO
There is a need for novel rabies vaccines suitable for short course, pre- and post-exposure prophylactic regimens which require reduced doses of antigen to address the current worldwide supply issue. We evaluated in rhesus macaques the immunogenicity of a quarter-dose of a standard rabies vaccine formulated with Merck's amorphous aluminum hydroxylphosphate sulfate adjuvant, the saponin-based ISCOMATRIX™ adjuvant, or a synthetic TLR9 agonist. All adjuvants significantly increased the magnitude and durability of the humoral immune response as measured by rapid fluorescent focus inhibition test (RFFIT). Several three-dose vaccine regimens resulted in adequate neutralizing antibody of ≥ 0.5 IU/ml earlier than the critical day seven post the first dose. Rabies vaccine with ISCOMATRIX™ adjuvant given at days 0 and 3 resulted in neutralizing antibody titers which developed faster and were up to one log10 higher compared to WHO-recommended intramuscular and intradermal regimens and furthermore, passive administration of human rabies immunoglobulin did not interfere with immunogenicity of this reduced dose, short course vaccine regimen. Adjuvantation of whole-killed rabies vaccine for intramuscular injection may therefore be a viable alternative to intradermal application of non-adjuvanted vaccine for both pre- and post-exposure regimens.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Compostos de Alumínio/administração & dosagem , Colesterol/administração & dosagem , Fosfolipídeos/administração & dosagem , Vacina Antirrábica/administração & dosagem , Vacina Antirrábica/imunologia , Saponinas/administração & dosagem , Receptor Toll-Like 9/agonistas , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Combinação de Medicamentos , Feminino , Injeções Intramusculares , Macaca mulatta , Masculino , Testes de Neutralização , Fosfatos/administração & dosagem , Raiva/prevenção & controle , Sulfatos/administração & dosagem , Receptor Toll-Like 9/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologiaRESUMO
OBJECTIVE: This study was designed to review the effect of chronic aluminium exposure on interleukin-6 (IL-6) secretion in the posterior brain and test the putative modulating effect of fenugreek seeds. METHODS: Female Wistar rats were divided into four groups: control; AlCl3 during 5 months (500 mg/kg body weight, intragastric for 1 month then 1600 ppm via the drinking water); AlCl3 plus fenugreek seed powder (FSP) (5%) during the last 2 months and FSP alone. RESULTS: Oral administration of aluminium chloride during 5 months caused hypoproduction of IL-6 together with a decrease in GFAP reactivity and an alteration of antioxidant status in the posterior brain. On the other hand, fenugreek seeds supplementation was able to enhance IL-6 expression, re-increase GFAP reactivity, and modulate the pro-oxidant-related effect. DISCUSSION: In the context of recent researches, IL-6 hypoproduction in the posterior brain could be a novel mechanism of Al chronic toxicity with a direct effect on glial cells. Using FSP as a diet supplement could offer a neuroprotective effect against Al toxicity. This could be mediated by astroglial cells protection, antioxidant and immunomodulatory actions.
Assuntos
Compostos de Alumínio/toxicidade , Encéfalo/efeitos dos fármacos , Cloretos/toxicidade , Proteína Glial Fibrilar Ácida/análise , Interleucina-6/análise , Extratos Vegetais/administração & dosagem , Cloreto de Alumínio , Compostos de Alumínio/administração & dosagem , Animais , Antioxidantes/análise , Química Encefálica , Cloretos/administração & dosagem , Feminino , Ratos , Ratos Wistar , TrigonellaRESUMO
We have previously demonstrated that vaccination with a subunit dengue vaccine containing a consensus envelope domain III with aluminum phosphate elicits neutralizing antibodies against all four serotypes of dengue virus in mice. In this study, we evaluated the immunogenicity of the subunit dengue vaccine in non-human primates. After vaccination, monkeys that received the subunit vaccine with aluminum phosphate developed a significantly strong and long-lasting antibody response. A specific T cell response with cytokine production was also induced, and this correlated with the antibody response. Additionally, neutralizing antibodies against serotype 2 were detected in two of three monkeys. The increase in serotype-2-specific antibody titers and avidity observed in these two monkeys suggested that a serotype-2-biased antibody response occurs. These data provide evidence that a protective neutralizing antibody response was successfully elicited in non-human primates by the dengue subunit vaccine with aluminum phosphate adjuvant.
Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacinas contra Dengue/imunologia , Vírus da Dengue/imunologia , Proteínas do Envelope Viral/imunologia , Adjuvantes Imunológicos/administração & dosagem , Compostos de Alumínio/administração & dosagem , Animais , Afinidade de Anticorpos , Citocinas/metabolismo , Vacinas contra Dengue/administração & dosagem , Vacinas contra Dengue/genética , Vírus da Dengue/genética , Haplorrinos , Fosfatos/administração & dosagem , Linfócitos T/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/genética , Vacinas de Subunidades Antigênicas/imunologia , Proteínas do Envelope Viral/genéticaRESUMO
The aim of the present study was to test a pellet formulation of Monacrosporium thaumasium in a sodium alginate matrix in the biological control of goat gastrointestinal helminthiasis in a semi-arid region of northeastern Brazil. An area of 2.4 ha was divided into three paddocks, with seven goats kept on each paddock, during the months of March to August 2011: group 1 received 3 g/10 kg live weight of M. thaumasium pellets (NF34a) twice a week; group 2 was given 0.2 mg/kg of 0.2 % moxidectin orally every 30 days; and group 3 received 3 g/10 kg live weight of pellets without fungus twice per week. Each month, two tracer goats was placed in each group for 30 days and then killed and necropsied. The M. thaumasium group showed a 34 % reduction in eggs per gram, higher packed cell volume rates and a lower parasitic load in the tracers compared with the other groups. The 0.2 % moxidectin group had weight gain of 5.7 kg; the M. thaumasium group, 3.6 kg; and the control group had an average reduction in weight of 1.1 kg. The use of M. thaumasium pellets may be effective as an alternative method to control goat gastrointestinal helminthiasis in the semi-arid region of northeastern Brazil.
Assuntos
Ascomicetos/crescimento & desenvolvimento , Terapia Biológica/métodos , Doenças das Cabras/terapia , Helmintíase Animal/terapia , Enteropatias Parasitárias/veterinária , Compostos de Alumínio/administração & dosagem , Animais , Peso Corporal , Brasil , Clima Desértico , Portadores de Fármacos/administração & dosagem , Feminino , Doenças das Cabras/parasitologia , Cabras , Helmintíase Animal/parasitologia , Enteropatias Parasitárias/parasitologia , Enteropatias Parasitárias/terapia , Masculino , Carga Parasitária , Compostos de Sódio/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Avian H5N1 influenza has caused human infections globally and has a high mortality rate. Rapid production of effective vaccines is needed. METHODS: A phase 1, randomized, observer-blinded clinical trial was conducted to examine the safety and immunogenicity of an inactivated whole virion vaccine against the influenza A/H5N1 virus produced from the Madin-Darby canine kidney (MDCK) cell line. Participants were randomized to four groups and administered two intramuscular doses of vaccine containing 3 µg hemagglutinin (HA), 3 µg HA with 300 µg aluminum phosphate (AlPO4), 6 µg HA, and 6 µg HA with 300 µg AlPO4, respectively, at two visits, 21 days apart. Serum hemagglutination inhibition (HAI) and neutralizing antibody levels were determined at baseline and on Days 21 and 42. RESULTS: Sixty healthy individuals were enrolled. The neutralization assay showed a significant immune response in the 6 µg with ALPO4 group on Day 42 compared to pre-vaccination levels (11.32±9.77 vs. 4.00±0, p=0.02). The adjuvant effect in neutralization assay was also significant on Day 42 in the 6 µg group (4.52±1.94 without adjuvant vs. 11.32±9.77 with adjuvant, p=0.02). HAI assay also showed an aluminum adjuvant-induced increasing trend in HAI geometric mean titer on Day 42 in the 3 µg and 6 µg groups (6.02 versus 8.20, p=0.05 and 5.74 versus 8.21, p=0.14). The most frequent adverse event was local pain (20% to 60%). There were no vaccine-related severe adverse effects. CONCLUSION: MDCK cell line-derived H5N1 vaccine was well tolerated. It is necessary to investigate further the immunogenicity of higher antigen doses and the role of aluminum adjuvant in augmenting the effect of the vaccine.
Assuntos
Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Adulto , Compostos de Alumínio/administração & dosagem , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Cães , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Voluntários Saudáveis , Testes de Inibição da Hemaglutinação , Humanos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/isolamento & purificação , Injeções Intramusculares , Células Madin Darby de Rim Canino , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Fosfatos/administração & dosagem , Estudos Prospectivos , Método Simples-Cego , Taiwan , Vacinação/métodos , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/isolamento & purificação , Cultura de Vírus/métodos , Adulto JovemRESUMO
OBJECTIVE: We performed a Phase 1 randomized, observer-blinded, placebo-controlled trial to evaluate the safety and immunogenicity of a recombinant respiratory syncytial virus (RSV) fusion (F) protein nanoparticle vaccine. METHODS: Six formulations with (5, 15, 30 and 60 µg) and without (30 and 60 µg) aluminum phosphate (AdjuPhos) were administered intramuscularly on day 0 and 30 in a dose escalating fashion to healthy adults 18-49 years of age. Solicited and unsolicited events were collected through day 210. Immunogenicity measures taken at day 0, 30 and 60 included RSV A and B microneutralization, anti-F IgG, antigenic site II peptide and palivizumab competitive antibodies. RESULTS: The vaccine was well-tolerated, with no evident dose-related toxicity or attributable SAEs. At day 60 both RSV A and B microneutralization was significantly increased in vaccinees versus placebo. Across all vaccinees there was a 7- to 19-fold increase in the anti-F IgG and a 7- to 24-fold increase in the antigenic site II binding and palivizumab competitive antibodies. CONCLUSIONS: The RSV F nanoparticle vaccine candidate was well tolerated without dose-related increases in adverse events. Measures of immunity indicate that neutralization, anti-RSV F IgG titers and palivizumab competing antibodies were induced at levels that have been associated with decreased risk of hospitalization. NCT01290419.