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1.
Cancer Immunol Immunother ; 68(7): 1211-1222, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31069460

RESUMO

Human tumor cells express antigens that serve as targets for the host cellular immune system. This phase 1 dose-escalating study was conducted to assess safety and tolerability of G305, a recombinant NY-ESO-1 protein vaccine mixed with glucopyranosyl lipid A (GLA), a synthetic TLR4 agonist adjuvant, in a stable emulsion (SE). Twelve patients with solid tumors expressing NY-ESO-1 were treated using a 3 + 3 design. The NY-ESO-1 dose was fixed at 250 µg, while GLA-SE was increased from 2 to 10 µg. Safety, immunogenicity, and clinical responses were assessed prior to, during, and at the end of therapy. G305 was safe and immunogenic at all doses. All related AEs were Grade 1 or 2, with injection site soreness as the most commonly reported event (100%). Overall, 75% of patients developed antibody response to NY-ESO-1, including six patients with increased antibody titer ( ≥ 4-fold rise) and three patients with seroconversion from negative (titer < 100) to positive (titer ≥ 100). CD4 T-cell responses were observed in 44.4% of patients; 33.3% were new responses and 1 was boosted ( ≥ 2-fold rise). Following treatment, 8 of 12 patients had stable disease for 3 months or more; at the end of 1 year, three patients had stable disease and nine patients were alive. G305 is a potent immunotherapeutic agent that can stimulate NY-ESO-1-specific antibody and T-cell responses. The vaccine was safe at all doses of GLA-SE (2-10 µg) and showed potential clinical benefit in this population of patients.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Glucosídeos/administração & dosagem , Lipídeo A/administração & dosagem , Proteínas de Membrana/administração & dosagem , Neoplasias/terapia , Adjuvantes Imunológicos/efeitos adversos , Adulto , Idoso , Antígenos de Neoplasias/efeitos adversos , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Feminino , Glucosídeos/efeitos adversos , Glucosídeos/imunologia , Humanos , Imunogenicidade da Vacina , Injeções Intramusculares , Lipídeo A/efeitos adversos , Lipídeo A/imunologia , Masculino , Proteínas de Membrana/efeitos adversos , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/imunologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/imunologia , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia , Adulto Jovem
2.
Vaccine ; 36(1): 148-154, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29174683

RESUMO

BACKGROUND: In phase III trials, 2 doses of a herpes zoster (HZ) subunit vaccine (HZ/su; 50 µg varicella-zoster virus glycoprotein E [gE] and AS01B Adjuvant System) administered 2-months apart in older adults (≥50 and ≥70 years) demonstrated >90% efficacy in preventing HZ and had a clinically acceptable safety profile. Here we report immunogenicity, reactogenicity and safety following administration of 2 HZ/su doses at intervals longer than 2 months. METHODS: In this Phase III, open-label trial conducted in the US and Estonia, 354 adults ≥50 years were randomized 1:1:1 to receive 2 HZ/su doses 2, 6, or 12 months apart. gE-specific humoral immune responses were evaluated at pre-vaccination, 1 and 12 months post-dose 2. Co-primary objectives were to compare immune responses to HZ/su 1 month post-dose 2 when given 6-months or 12-months apart to those administered 2-months apart. For each participant, safety information was collected from dose 1 to 12 months post-dose 2. RESULTS: 346 participants completed the study and 343 were included in the according-to-protocol cohort for immunogenicity. One month post-dose 2, vaccine response rates were 96.5% (97.5% confidence interval [CI]: 90.4; 99.2) and 94.5% (97.5% CI: 87.6; 98.3) for the 0, 6- and 0, 12-month schedules, respectively, both schedules meeting the pre-defined criterion. Non-inferiority of anti-gE geometric mean concentrations was demonstrated for HZ/su administered on 0, 6-month compared to a 0, 2-month schedule; however, HZ/su administered on a 0, 12-month schedule did not meet the non-inferiority criterion. Injection site pain was the most commonly reported solicited adverse event (AE). 26 participants each reported at least 1 serious AE; none were assessed as related to vaccination. CONCLUSIONS: Immune responses to HZ/su administered at 0, 6-month were non-inferior to those elicited by a 0, 2-month schedule. HZ/su exhibited a clinically acceptable safety profile for all dosing intervals. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov (NCT01751165).


Assuntos
Vacina contra Herpes Zoster/efeitos adversos , Vacina contra Herpes Zoster/imunologia , Herpes Zoster/prevenção & controle , Imunogenicidade da Vacina , Vacinação/métodos , Idoso , Anticorpos Antivirais/imunologia , Estônia/epidemiologia , Feminino , Herpes Zoster/epidemiologia , Vacina contra Herpes Zoster/administração & dosagem , Herpesvirus Humano 3/imunologia , Humanos , Esquemas de Imunização , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Lipídeo A/análogos & derivados , Lipídeo A/imunologia , Masculino , Pessoa de Meia-Idade , Saponinas/administração & dosagem , Saponinas/efeitos adversos , Saponinas/imunologia , Estados Unidos/epidemiologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/efeitos adversos , Vacinas de Subunidades/imunologia , Proteínas do Envelope Viral/administração & dosagem , Proteínas do Envelope Viral/efeitos adversos , Proteínas do Envelope Viral/imunologia
3.
Hum Vaccin Immunother ; 13(1): 90-102, 2017 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-27629482

RESUMO

An increased risk of narcolepsy following administration of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine (Pandemrix™) was described in children and adolescents in certain European countries. We investigated the potential effects of administration of the AS03-adjuvanted vaccine, non-adjuvanted vaccine antigen and AS03 Adjuvant System alone, on the central nervous system (CNS) in one-month-old cotton rats. Naïve or A(H1N1)pdm09 virus-primed animals received 2 or 3 intramuscular injections, respectively, of test article or saline at 2-week intervals. Parameters related to systemic inflammation (hematology, serum IL-6/IFN-γ/TNF-α) were assessed. Potential effects on the CNS were investigated by histopathological evaluation of brain sections stained with hematoxylin-and-eosin, or by immunohistochemical staining of microglia, using Iba1 and CD68 as markers for microglia identification/activation, albumin as indicator of vascular leakage, and hypocretin. We also determined cerebrospinal fluid (CSF) hypocretin levels and hemagglutination-inhibiting antibody titers. Immunogenicity of the AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine was confirmed by the induction of hemagglutination-inhibiting antibodies. Both AS03-adjuvanted vaccine and AS03 alone activated transient innate (neutrophils/eosinophils) immune responses. No serum cytokines were detected. CNS analyses revealed neither microglia activation nor inflammatory cellular infiltrates in the brain. No differences between treatment groups were detected for albumin extravascular leakage, CSF hypocretin levels, numbers of hypocretin-positive neuronal bodies or distributions of hypocretin-positive axonal/dendritic projections. Consequently, there was no evidence that intramuscular administration of the test articles promoted inflammation or damage in the CNS, or blood-brain barrier disruption, in this model.


Assuntos
Encéfalo/efeitos dos fármacos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Lipídeo A/análogos & derivados , Saponinas/administração & dosagem , Saponinas/efeitos adversos , Animais , Anticorpos Antivirais/sangue , Encéfalo/patologia , Combinação de Medicamentos , Testes de Inibição da Hemaglutinação , Histocitoquímica , Imuno-Histoquímica , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Injeções Intramusculares , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Lipídeo A/imunologia , Orexinas/líquido cefalorraquidiano , Saponinas/imunologia , Sigmodontinae
4.
Hum Vaccin Immunother ; 12(12): 3177-3185, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27841725

RESUMO

This community-randomized controlled trial was initiated to assess the overall and herd effects of 2 different human papillomavirus (HPV) immunization strategies in over 80,000 girls and boys aged 12-15 y in 33 communities in Finland (ClinicalTrials.gov NCT00534638). Overall, 14,838 adolescents received HPV-16/18 vaccine (2,440 boys and 12,398 girls) and 17,338 received hepatitis-B virus (HBV) vaccine (9,221 boys and 8,117 girls). In an interim analysis, vaccine safety was assessed by active monitoring and surveillance via health registry linkage. Active monitoring showed that the HPV-16/18 vaccine has acceptable safety and reactogenicity in boys. In all study participants, the observed incidences (per 100,000 person-years) of serious adverse events (SAEs) possibly related to vaccination were 54.3 (95% Confidence Interval [CI]: 34.0-82.1) in the HPV-16/18 group and 64.0 (95% CI: 43.2-91.3) in the HBV group. During the follow-up period for this interim analysis, the most common new-onset autoimmune diseases (NOADs; with incidence rate ≥15 per 100,000) in any group based on hospital discharge registry (HILMO) download were ulcerative colitis, juvenile arthritis, celiac disease, insulin-dependent diabetes mellitus (IDDM) and Crohn's disease. No increased NOAD incidences were observed in HPV-16/18 vaccine recipients compared to HBV vaccine recipients. In both the SAE possibly related- and HILMO-analyses, a lower incidence of IDDM was observed in HPV-16/18 vaccinees compared to HBV vaccinees (relative risks, 0.26 [95% CI: 0.03-1.24] and 0.16 [95% CI: 0.03-0.55], respectively).


Assuntos
Hidróxido de Alumínio/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Lipídeo A/análogos & derivados , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversos , Adolescente , Hidróxido de Alumínio/administração & dosagem , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/epidemiologia , Criança , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Finlândia , Vacinas contra Hepatite B/administração & dosagem , Vacinas contra Hepatite B/efeitos adversos , Humanos , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Masculino , Vacinas contra Papillomavirus/administração & dosagem
5.
Hum Vaccin Immunother ; 12(11): 2862-2871, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27428517

RESUMO

To assess the risk of autoimmune disease (AD) in 9-25 year-old women within 1 year after the first AS04-HPV-16/18vaccine dose, a retrospective, observational database cohort study was conducted using CPRD GOLD. From CPRD GOLD 4 cohorts (65,000 subjects each) were retrieved: 1 exposed female cohort (received ≥1 AS04-HPV-16/18 vaccine dose between Sep2008-Aug2010) and 3 unexposed cohorts: historical female (Sep2005-Aug2007), concurrent male, and historical male. Co-primary endpoints were confirmed neuroinflammatory/ophthalmic AD and other AD, secondary endpoints were confirmed individual AD. Risk of new onset of AD was compared between cohorts (reference: historical cohort) using Poisson regression. The main analysis using confirmed cases showed no neuroinflammatory/ophthalmic AD cases in the female exposed cohort. Incidence rate ratio (IRR) (95% CI) of other AD was 1.41 (0.86 to 2.31) in female and 1.77 (0.94 to 3.35) in male cohorts when compared to the female and male historical cohort, respectively. Secondary endpoints were evaluated for diseases with >10 cases, which were Crohn's disease (IRR: 1.21 [0.37 to 3.95] for female and 4.22 [0.47 to 38.02] for male cohorts), autoimmune thyroiditis (IRR: 3.75 [1.25 to 11.31] for female and no confirmed cases for male cohorts) and type 1 diabetes (IRR: 0.30 [0.11 to 0.83] for female and 2.46 [1.08 to 5.60] for male cohorts). Analysis using confirmed and non-confirmed cases showed similar results, except for autoimmune thyroiditis in females, IRR: 1.45 (0.79 to 2.64). There was no evidence of an increased risk of AD in women aged 9 to 25 years after AS04-HPV-16/18 vaccination.


Assuntos
Hidróxido de Alumínio/efeitos adversos , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/epidemiologia , Lipídeo A/análogos & derivados , Vacinas contra Papillomavirus/efeitos adversos , Adolescente , Adulto , Hidróxido de Alumínio/administração & dosagem , Criança , Feminino , Humanos , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Vacinas contra Papillomavirus/administração & dosagem , Estudos Retrospectivos , Medição de Risco , Reino Unido/epidemiologia , Adulto Jovem
6.
Vaccine ; 34(6): 714-22, 2016 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-26740250

RESUMO

INTRODUCTION: New adjuvants such as the AS- or the MF59-adjuvants improve vaccine efficacy and facilitate dose-sparing. Their use in influenza and malaria vaccines has resulted in a large body of evidence on their clinical safety in children. METHODS: We carried out a systematic search for safety data from published clinical trials on newly adjuvanted vaccines in children ≤10 years of age. Serious adverse events (SAEs), solicited AEs, unsolicited AEs and AEs of special interest were evaluated for four new adjuvants: the immuno-stimulants containing adjuvant systems AS01 and AS02, and the squalene containing oil-in-water emulsions AS03 and MF59. Relative risks (RR) were calculated, comparing children receiving newly adjuvanted vaccines to children receiving other vaccines with a variety of antigens, both adjuvanted and unadjuvanted. RESULTS: Twenty-nine trials were included in the meta-analysis, encompassing 25,056 children who received at least one dose of the newly adjuvanted vaccines. SAEs did not occur more frequently in adjuvanted groups (RR 0.85, 95%CI 0.75-0.96). Our meta-analyses showed higher reactogenicity following administration of newly adjuvanted vaccines, however, no consistent pattern of solicited AEs was observed across adjuvant systems. Pain was the most prevalent AE, but often mild and of short duration. No increased risks were found for unsolicited AEs, febrile convulsions, potential immune mediated diseases and new onset of chronic diseases. CONCLUSIONS: Our meta-analysis did not show any safety concerns in clinical trials of the newly adjuvanted vaccines in children ≤10 years of age. An unexplained increase of meningitis in one Phase III AS01-adjuvanted malaria trial and the link between narcolepsy and the AS03-adjuvanted pandemic vaccine illustrate that continued safety monitoring is warranted.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Adjuvantes Imunológicos/química , Vacinas/química , Adolescente , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Humanos , Lactente , Funções Verossimilhança , Lipídeo A/efeitos adversos , Lipídeo A/análogos & derivados , Lipídeo A/química , Polissorbatos/efeitos adversos , Polissorbatos/química , Risco , Saponinas/efeitos adversos , Saponinas/química , Esqualeno/efeitos adversos , Esqualeno/química , Vacinas/efeitos adversos , alfa-Tocoferol/efeitos adversos , alfa-Tocoferol/química
7.
Hum Vaccin Immunother ; 12(1): 20-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26176261

RESUMO

In this randomized, partially-blind study ( clinicaltrials.gov ; NCT00541970), the licensed formulation of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (20 µg each of HPV-16/18 antigens) was found highly immunogenic up to 4 y after first vaccination, whether administered as a 2-dose (2D) schedule in girls 9-14 y or 3-dose (3D) schedule in women 15-25 y. This end-of-study analysis extends immunogenicity and safety data until Month (M) 60, and presents antibody persistence predictions estimated by piecewise and modified power law models. Healthy females (age stratified: 9-14, 15-19, 20-25 y) were randomized to receive 2D at M0,6 (N = 240 ) or 3D at M0,1,6 (N = 239). Here, results are reported for girls 9-14 y (2D) and women 15-25 y (3D). Seropositivity rates, geometric mean titers (by enzyme-linked immunosorbent assay) and geometric mean titer ratios (GMRs; 3D/2D; post-hoc exploratory analysis) were calculated. All subjects seronegative pre-vaccination in the according-to-protocol immunogenicity cohort were seropositive for anti-HPV-16 and -18 at M60. Antibody responses elicited by the 2D and 3D schedules were comparable at M60, with GMRs close to 1 (anti-HPV-16: 1.13 [95% confidence interval: 0.82-1.54]; anti-HPV-18: 1.06 [0.74-1.51]). Statistical modeling predicted that in 95% of subjects, antibodies induced by 2D and 3D schedules could persist above natural infection levels for ≥ 21 y post-vaccination. The vaccine had a clinically acceptable safety profile in both groups. In conclusion, a 2D M0,6 schedule of the HPV-16/18 AS04-adjuvanted vaccine was immunogenic for up to 5 y in 9-14 y-old girls. Statistical modeling predicted that 2D-induced antibodies could persist for longer than 20 y.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Esquemas de Imunização , Lipídeo A/análogos & derivados , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Adolescente , Hidróxido de Alumínio/efeitos adversos , Anticorpos Antivirais/sangue , Criança , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
8.
Kidney Blood Press Res ; 40(6): 584-92, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26566033

RESUMO

BACKGROUND/AIMS: Patients undergoing maintenance dialysis have an unsatisfactory response to vaccination, including to hepatitis B vaccine. A recombinant HB vaccine containing a new adjuvant system AS04 (HBV-AS04) has been recently developed; a few data exist on the immunogenicity and safety of HBV-AS04 among patients undergoing regular dialysis. All hepatitis B virus-seronegative patients with undetectable antibody against HBsAg undergoing maintenance dialysis at two units were prospectively included. METHODS: Patients received four 20-mcg doses of HBV-AS04 by intramuscular route (deltoid muscle) at months 0,1,2, and 3. Anti-HB surface antibody concentrations were measured at intervals of 1, 2, 3, 4, and 12 months. Univariate and multivariate analyses determined which parameters predicted immunologic response to HBV-AS04 vaccine. RESULTS: 102 patients were enrolled and 91 completed the study. At completion of the vaccination schedule, using per-protocol analysis, 76 of 91 (84%) had antibody titers ≥10 mIU/mL with anti-HBs geometric antibody concentrations (GMCs) of 385.25 mIU/mL. The sero-protection rate at month 12 was 84% (48/57) with lower GMCs (62.74 mIU/mL, P<0.0001). Multivariate analysis revealed a detrimental role of age on the immune response to HB-AS04 vaccine (F Ratio, 4.04; P<0.04). Tolerance to HBV-AS04 was good and only minor side-effects were observed. CONCLUSIONS: HBV-AS04 vaccine was highly immunogenic in our cohort of patients on maintenance dialysis even if a significant number of non-responders is still present. Prospective studies with HBV-AS04 on larger study groups and with longer follow-ups are under way.


Assuntos
Vacinas contra Hepatite B/imunologia , Lipídeo A/análogos & derivados , Diálise Renal , Adjuvantes Imunológicos , Adulto , Idoso , Envelhecimento/imunologia , Estudos de Coortes , Feminino , Antígenos de Superfície da Hepatite B/sangue , Vacinas contra Hepatite B/administração & dosagem , Vacinas contra Hepatite B/efeitos adversos , Humanos , Esquemas de Imunização , Injeções Intramusculares , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Lipídeo A/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Segurança , Vacinas Sintéticas
9.
Curr Opin Allergy Clin Immunol ; 15(6): 568-74, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26418475

RESUMO

PURPOSE OF REVIEW: Toll-like receptors (TLRs) are novel and promising targets for allergen immunotherapy. Bench studies suggest that TLR agonists reduce Th2 responses and ameliorate airway hyper-responsiveness. In addition, clinical trials are at initial phases to evaluate the safety and efficacy of TLR agonists for the allergen immunotherapy of patients with allergic rhinitis and asthma. (Figure is included in full-text article.) RECENT FINDINGS: To date, two allergy vaccine-containing TLR agonists have been investigated in clinical trials; Pollinex Quattro and AIC. The former contains monophosphoryl lipid, a TLR4 agonist and the latter contains, CpG motifs activating the TLR9 cascade. Preseasonal subcutaneous injection of both of these allergy vaccines has been safe and efficacious in control of nasal symptoms of patients with allergic rhinitis. CRX-675 (a TLR4 agonist), AZD8848 (a TLR7 agonist), VTX-1463 (a TLR8 agonist) and 1018 ISS and QbG10 (TLR9 agonists) are currently in clinical development for allergic rhinitis and asthma. SUMMARY: TLR agonists herald promising results for allergen immunotherapy of patients with allergic rhinitis and asthma. Future research should be directed at utilizing these agents for immunotherapy of food allergy (for instance, peanut allergy) as well.


Assuntos
Antialérgicos/uso terapêutico , Asma/terapia , Dessensibilização Imunológica/métodos , Rinite Alérgica/terapia , Receptores Toll-Like/imunologia , Adenosina/administração & dosagem , Adenosina/efeitos adversos , Adenosina/análogos & derivados , Animais , Antialérgicos/farmacologia , Asma/imunologia , Ensaios Clínicos como Assunto , Humanos , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Lipídeo A/análogos & derivados , Terapia de Alvo Molecular , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/efeitos adversos , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/efeitos adversos , Fenilacetatos/administração & dosagem , Fenilacetatos/efeitos adversos , Rinite Alérgica/imunologia , Receptores Toll-Like/agonistas , Vacinas/administração & dosagem , Vacinas/efeitos adversos
10.
Vaccine ; 33(48): 6884-91, 2015 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-26206268

RESUMO

BACKGROUND: We assessed the risk of spontaneous abortion (SA) after inadvertent exposure to HPV-16/18-vaccine during pregnancy using an observational cohort design. METHODS: The study population included women aged 15-25 years registered with the Clinical Practice Research Datalink General Practice OnLine Database in the United Kingdom (UK), who received at least one HPV-16/18-vaccine dose between 1st September 2008 and 30th June 2011. Exposed women had the first day of gestation between 30 days before and 45 days (90 days for the extended exposure period) after any HPV-16/18-vaccine dose. Non-exposed women had the first day of gestation 120 days-18 months after the last dose. SA defined as foetal loss between weeks 1 and 23 of gestation (UK definition). RESULTS: The frequency of SA was 11.6% (among 207 exposed) and 9.0% (632 non-exposed), women: hazard ratio (HR) adjusted for age at first day of gestation 1.30 (95% confidence interval: 0.79-2.12). Sensitivity analysis per number of doses administered (-30 to +45-day risk period) showed a HR for SA of 1.11 (0.64-1.91) for 18/178 women with one dose during the risk period versus 2.55 (1.09-5.93) in 6/29 women with two doses within a 4-5 weeks period. The proportion of pre-term/full-term/postterm deliveries, small/large for gestational age infants, and birth defects was not significantly different between exposed and non-exposed women. Results were consistent using a (United States) SA definition of foetal loss between weeks 1-19 and/or the extended risk period. CONCLUSION: There was no evidence of an increased risk of SA and other adverse pregnancy outcomes in young women inadvertently HPV-16/18-vaccinated around gestation. Nevertheless, women who are pregnant or trying to become pregnant are advised to postpone vaccination until completion of pregnancy.


Assuntos
Aborto Espontâneo/induzido quimicamente , Aborto Espontâneo/epidemiologia , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Lipídeo A/análogos & derivados , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/efeitos adversos , Resultado da Gravidez , Adolescente , Adulto , Feminino , Humanos , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Gravidez , Medição de Risco , Reino Unido/epidemiologia , Adulto Jovem
11.
Vaccine ; 33(32): 4025-34, 2015 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-26072017

RESUMO

BACKGROUND: Vaccination that prevents tuberculosis (TB) disease, particularly in adolescents, would have the greatest impact on the global TB epidemic. Safety, reactogenicity and immunogenicity of the vaccine candidate M72/AS01E was evaluated in healthy, HIV-negative adolescents in a TB endemic region, regardless of Mycobacterium tuberculosis (M.tb) infection status. METHODS: In a phase II, double-blind randomized, controlled study (NCT00950612), two doses of M72/AS01E or placebo were administered intramuscularly, one month apart. Participants were followed-up post-vaccination, for 6 months. M72-specific immunogenicity was evaluated by intracellular cytokine staining analysis of T cells and NK cells by flow cytometry. RESULTS: No serious adverse events were recorded. M72/AS01E induced robust T cell and antibody responses, including antigen-dependent NK cell IFN-γ production. CD4 and CD8 T cell responses were sustained at 6 months post vaccination. Irrespective of M.tb infection status, vaccination induced a high frequency of M72-specific CD4 T cells expressing multiple combinations of Th1 cytokines, and low level IL-17. We observed rapid boosting of immune responses in M.tb-infected participants, suggesting natural infection acts as a prime to vaccination. CONCLUSIONS: The clinically acceptable safety and immunogenicity profile of M72/AS01E in adolescents living in an area with high TB burden support the move to efficacy trials.


Assuntos
Antígenos de Bactérias/imunologia , Lipídeo A/análogos & derivados , Mycobacterium tuberculosis/imunologia , Saponinas/efeitos adversos , Vacinas contra a Tuberculose/efeitos adversos , Vacinas contra a Tuberculose/imunologia , Tuberculose/epidemiologia , Tuberculose/prevenção & controle , Adolescente , Citocinas/biossíntese , Método Duplo-Cego , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Doenças Endêmicas , Feminino , Citometria de Fluxo , Humanos , Injeções Intramusculares , Células Matadoras Naturais/imunologia , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Masculino , Placebos/administração & dosagem , Saponinas/administração & dosagem , Coloração e Rotulagem , Linfócitos T/imunologia , Resultado do Tratamento , Vacinas contra a Tuberculose/administração & dosagem , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/efeitos adversos , Vacinas de Subunidades/imunologia
12.
Hum Vaccin Immunother ; 10(7): 1795-806, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25424785

RESUMO

Immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine were evaluated in healthy Chinese females aged 9-45 years in 2 phase IIIB, randomized, controlled trials. Girls aged 9-17 years (ClinicalTrials.gov, NCT00996125) received vaccine (n = 374) or control (n = 376) and women aged 26-45 years (NCT01277042) received vaccine (n = 606) or control (n = 606) at months 0, 1, and 6. The primary objective was to show non-inferiority of anti-HPV-16 and -18 immune responses in initially seronegative subjects at month 7, compared with Chinese women aged 18-25 years enrolled in a separate phase II/III trial (NCT00779766). Secondary objectives were to describe the anti-HPV-16 and -18 immune response, reactogenicity and safety. At month 7, immune responses were non-inferior for girls (9-17 years) vs. young women (18-25 years): the upper limit of the 95% confidence interval (CI) for the geometric mean titer (GMT) ratio (women/girls) was below the limit of 2 for both anti-HPV-16 (0.37 [95% CI: 0.32, 0.43]) and anti-HPV-18 (0.42 [0.36, 0.49]). Immune responses at month 7 were also non-inferior for 26-45 year-old women vs. 18-25 year-old women: the upper limit of the 95% CI for the difference in seroconversion (18-25 minus 26-45) was below the limit of 5% for both anti-HPV-16 (0.00% [-1.53, 1.10]) and anti-HPV-18 (0.21% [-1.36, 1.68]). GMTs were 2- to 3-fold higher in girls (9-17 years) as compared with young women (18-25 years). The HPV-16/18 AS04-adjuvanted vaccine had an acceptable safety profile when administered to healthy Chinese females aged 9-45 years.


Assuntos
Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Neoplasia Intraepitelial Cervical/prevenção & controle , Lipídeo A/análogos & derivados , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/imunologia , Adolescente , Adulto , Anticorpos Antivirais/sangue , Grupo com Ancestrais do Continente Asiático , Neoplasia Intraepitelial Cervical/imunologia , Criança , China , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Voluntários Saudáveis , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Humanos , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Pessoa de Meia-Idade , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/administração & dosagem , Resultado do Tratamento , Adulto Jovem
13.
Pediatr Infect Dis J ; 33(12): 1255-61, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24978856

RESUMO

BACKGROUND: Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine were evaluated up to 6 years postvaccination (month 72) in preteen/adolescent girls. METHODS: Participants, who had received 3 HPV-16/18 AS04-adjuvanted vaccine doses at 10-14 years of age in an initial controlled, observer-blinded, randomized study (NCT00196924) and participated in the open 3-year follow-up (NCT00316706), were invited to continue the follow-up for up to 10 years postvaccination (NCT00877877). Anti-HPV-16 and -18 antibody titers were measured by enzyme-linked immunosorbent assays at yearly visits and were used to fit the modified power-law and piecewise models, predicting long-term immunogenicity. Serious adverse events (SAEs) and pregnancy information were recorded. RESULTS: In the according-to-protocol immunogenicity cohort, all participants (N = 505) with data available remained seropositive for anti-HPV-16 and -18 antibodies at month 72. In initially seronegative participants, anti-HPV-16 and -18 antibody geometric mean titers were 65.8- and 33.0-fold higher than those associated with natural infection (NCT00122681) and 5.0- and 2.5-fold higher than those measured at month 69-74 in a study demonstrating vaccine efficacy in women aged 15-25 years (NCT00120848). Exploratory antibody modeling, based on the 6-year data, predicted that vaccine-induced population anti-HPV-16 and -18 antibody geometric mean titers would remain above those associated with natural infection for at least 20 years postvaccination. The HPV-16/18 AS04-adjuvanted vaccine safety profile was clinically acceptable. CONCLUSIONS: In preteen/adolescent girls, the HPV-16/18 AS04-adjuvanted vaccine induced high anti-HPV-16 and -18 antibody levels up to 6 years postvaccination, which were predicted to remain above those induced by natural infection for at least 20 years.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Lipídeo A/análogos & derivados , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/imunologia , Adolescente , Adulto , Anticorpos Antivirais/sangue , Criança , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Recém-Nascido , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Vacinas contra Papillomavirus/administração & dosagem , Gravidez , Método Simples-Cego , Resultado do Tratamento , Neoplasias do Colo do Útero/prevenção & controle , Adulto Jovem
14.
AIDS ; 28(12): 1769-81, 2014 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-24911353

RESUMO

OBJECTIVE: Tuberculosis (TB) is highly prevalent among HIV-infected people, including those receiving combination antiretroviral therapy (cART), necessitating a well tolerated and efficacious TB vaccine for these populations. We evaluated the safety and immunogenicity of the candidate TB vaccine M72/AS01 in adults with well controlled HIV infection on cART. DESIGN: A randomized, observer-blind, controlled trial (NCT00707967). METHODS: HIV-infected adults on cART in Switzerland were randomized 3 : 1 : 1 to receive two doses, 1 month apart, of M72/AS01, AS01 or 0.9% physiological saline (N = 22, N = 8 and N = 7, respectively) and were followed up to 6 months postdose 2 (D210). Individuals with CD4⁺ cell counts below 200 cells/µl were excluded. Adverse events (AEs) including HIV-specific and laboratory safety parameters were recorded. Cell-mediated (ICS) and humoral (ELISA) responses were evaluated before vaccination, 1 month after each dose (D30, D60) and D210. RESULTS: Thirty-seven individuals [interquartile range (IQR) CD4⁺ cell counts at screening: 438-872 cells/µl; undetectable HIV-1 viremia] were enrolled; 73% of individuals reported previous BCG vaccination, 97.3% tested negative for the QuantiFERON-TB assay. For M72/AS01 recipients, no vaccine-related serious AEs or cART-regimen adjustments were recorded, and there were no clinically relevant effects on laboratory safety parameters, HIV-1 viral loads or CD4⁺ cell counts. M72/AS01 was immunogenic, inducing persistent and polyfunctional M72-specific CD4⁺ T-cell responses [medians 0.70% (IQR 0.37-1.07) at D60] and 0.42% (0.24-0.61) at D210, predominantly CD40L⁺IL-2⁺TNF-α⁺, CD40L⁺IL-2⁺ and CD40L⁺IL-2⁺TNF-α⁺IFN-γ⁺]. All M72/AS01 vaccines were seropositive for anti-M72 IgG after second vaccination until study end. CONCLUSION: M72/AS01 was clinically well tolerated and immunogenic in this population, supporting further clinical evaluation in HIV-infected individuals in TB-endemic settings.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Lipídeo A/análogos & derivados , Saponinas/efeitos adversos , Vacinas contra a Tuberculose/efeitos adversos , Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Adolescente , Adulto , Anticorpos Antibacterianos/sangue , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/imunologia , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Infecções por HIV/complicações , Humanos , Imunoglobulina G/sangue , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Saponinas/administração & dosagem , Método Simples-Cego , Suíça , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento , Vacinas contra a Tuberculose/administração & dosagem , Vacinação/efeitos adversos , Vacinação/métodos , Adulto Jovem
15.
Vaccine ; 32(49): 6683-91, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-24950358

RESUMO

In an attempt to improve the efficacy of the candidate malaria vaccine RTS,S/AS02, two studies were conducted in 1999 in healthy volunteers of RTS,S/AS02 in combination with recombinant Plasmodium falciparum thrombospondin-related anonymous protein (TRAP). In a Phase 1 safety and immunogenicity study, volunteers were randomized to receive TRAP/AS02 (N=10), RTS,S/AS02 (N=10), or RTS,S+TRAP/AS02 (N=20) at 0, 1 and 6-months. In a Phase 2 challenge study, subjects were randomized to receive either RTS,S+TRAP/AS02 (N=25) or TRAP/AS02 (N=10) at 0 and 1-month, or to a challenge control group (N=8). In both studies, the combination vaccine had an acceptable safety profile and was acceptably tolerated. Antigen-specific antibodies, lymphoproliferative responses, and IFN-γ production by ELISPOT assay elicited with the combination vaccine were qualitatively similar to those generated by the single component vaccines. However, post-dose 2 anti-CS antibodies in the RTS,S+TRAP/AS02 vaccine recipients were lower than in the RTS,S/AS02 vaccine recipients. After challenge, 10 of 11 RTS,S+TRAP/AS02 vaccinees, 5 of 5 TRAP/AS02 vaccinees, and 8 of 8 infectivity controls developed parasitemia, with median pre-patent periods of 13.0, 11.0, and 12.0 days, respectively. The absence of any prevention or delay of parasitemia by TRAP/AS02 suggests no apparent added value of TRAP/AS02 as a candidate vaccine. The absence of significant protection or delay of parasitemia in the 11 RTS,S+TRAP/AS02 vaccine recipients contrasts with previous 2 dose studies of RTS,S/AS02. The small sample size did not permit identifying statistically significant differences between the study arms. However, we speculate, within the constraints of the challenge study, that the presence of the TRAP antigen may have interfered with the vaccine efficacy previously observed with this regimen of RTS,S/AS02, and that any future TRAP-based vaccines should consider employing alternative vaccine platforms.


Assuntos
Lipídeo A/análogos & derivados , Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Saponinas/efeitos adversos , Adolescente , Adulto , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Proliferação de Células , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , ELISPOT , Feminino , Humanos , Interferon gama/metabolismo , Leucócitos Mononucleares/imunologia , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Vacinas Antimaláricas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Parasitemia/prevenção & controle , Proteínas de Protozoários/imunologia , Saponinas/administração & dosagem , Resultado do Tratamento , Vacinação/efeitos adversos , Vacinação/métodos , Adulto Jovem
16.
Eur Ann Allergy Clin Immunol ; 46(1): 46-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24702876

RESUMO

We described the first case reported in literature of anaphylactic shock after administration of pollen extract vaccine chemically modified (allergoid) adsorbed onto L-Tyrosine depot adjuvanted with monophosphoryl lipid A (Pollinex® Quattro MPL-4).


Assuntos
Anafilaxia/induzido quimicamente , Lipídeo A/análogos & derivados , Vacinas/efeitos adversos , Humanos , Lipídeo A/efeitos adversos , Masculino , Pessoa de Meia-Idade
17.
Vaccine ; 31(48): 5760-5, 2013 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-24075920

RESUMO

BACKGROUND: Expression of recombinant hemagglutinin (rHA) in insect cells represents a technology with proven efficacy in seasonal influenza and with the potential for a rapid response to the emergence of new, pandemic strains. We evaluated the safety and immunogenicity of rHA vaccine (H5/Indonesia/5/05) produced in SF+ insect cells using a baculovirus expression vector system (BEVS). The rHA vaccine was tested with and without the adjuvant glucopyranosyl lipid A/stable emulsion (GLA/SE). METHODS: Healthy adults 18-49 were randomized to two IM doses on Days 0 and 21 of placebo; unadjuvanted rHA 135 µg or 45 µg, or rHA 45 µg, 15 µg, 7.5 µg or 3.8 µg with GLA/SE. A pioneer group was monitored through Day 42 before randomizing remaining subjects. H5-specific antibody was determined by hemagglutination inhibition (HAI) and microneutralization (MN) on Days 0, 21 and 42. RESULTS: 392 subjects were randomized, of whom 380 (97%) received two doses and 386 (98%) completed 12 months of follow-up. Injection site pain and tenderness were seen in 50-70% of rHA+GLA/SE recipients and 4-9% of rHA alone and placebo recipients, but most complaints were mild to moderate in intensity. After two doses, the proportions of subjects with HAI titers ≥1:40 were 32% and 15% in the unadjuvanted 135 µg and 45 µg groups, and 82%, 75%, 66%, and 72% in those receiving 45 µg, 15 µg, 7.5 µg, or 3.8 µg with GLA/SE. The geometric mean titers (GMTs) of HAI antibody on Day 42 were 128, 95, 69, and 72 in the 45 µg, 15 µg, 7.5 µg, or 3.8 µg with GLA/SE groups, respectively. CONCLUSIONS: rHA GLA/SE was well tolerated and immunogenic in healthy adults, and GLA/SE substantially improved the serum antibody response. rHA expressed using BEVS recombinant DNA platform technology represents a promising strategy for pandemic control.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Emulsões/efeitos adversos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/imunologia , Lipídeo A/efeitos adversos , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Animais , Anticorpos Antivirais/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Emulsões/administração & dosagem , Feminino , Voluntários Saudáveis , Testes de Inibição da Hemaglutinação , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Vacinas contra Influenza/administração & dosagem , Lipídeo A/administração & dosagem , Lipídeo A/análogos & derivados , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia , Adulto Jovem
18.
J Nutr Biochem ; 24(8): 1499-507, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23465595

RESUMO

Saturated free fatty acids (FFA) can activate inflammatory cascades including the toll-like receptor 4 (TLR4) pathway. TLR4 is expressed by hepatocytes and may help link FFA to altered hepatic gluconeogenesis in type 2 diabetes mellitus. This study examined the role of TLR4 in mediating palmitate effects on the expression of phosphoenolpyruvate carboxykinase (PCK1) and the catalytic subunit of glucose-6-phosphatase (G6PC), rate-determining gluconeogenic enzymes. Human hepatocellular carcinoma cells (HepG2 and HuH7) were incubated in media including 2% bovine serum albumin and 250 to 1000 µM palmitate for 24 h. Signaling mediated by TLR4 was blocked by a TLR4 decoy peptide or small interfering RNA knockdown of TLR4. Palmitate induced dose-dependent increases in PCK1 and G6PC mRNA abundance, which were prevented by the TLR4 decoy peptide. Palmitate doubled PCK1 promoter activity, and TLR4 knockdown ablated this response. Lipopolysaccharide and monophosphoryl lipid A also up-regulated G6PC and PCK1 transcript abundance in a TLR4-dependent manner. Addition of oleate attenuated palmitate-induced increases in G6PC and PCK1 mRNA abundance. Palmitate increased nuclear factor κ-light-chain-enhancer of activated B cells reporter gene activity, which was unaffected by TLR4 blockade, but increased mRNA abundance of hepatocyte-specific cyclic AMP response element binding protein, a transcriptional regulator of PCK1, in a TLR4-dependent manner. Finally, TLR4 activation by palmitate increased subsequent cellular uptake of palmitate, and inhibiting ceramide synthesis ablated palmitate effects on PCK1 mRNA abundance and promoter activity. These results suggest that TLR4 signaling could play a critical role in linking elevated saturated FFA to increased transcription of gluconeogenic genes.


Assuntos
Ácidos Graxos não Esterificados/efeitos adversos , Expressão Gênica , Gluconeogênese/genética , Palmitatos/efeitos adversos , Receptor 4 Toll-Like/metabolismo , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipídeo A/efeitos adversos , Lipídeo A/análogos & derivados , Lipopolissacarídeos/efeitos adversos , Neoplasias Hepáticas/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais , Receptor 4 Toll-Like/genética , Regulação para Cima
19.
Hum Vaccin Immunother ; 9(6): 1254-62, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23434737

RESUMO

Herpes simplex virus (HSV) type 2 (HSV-2) is the main cause of genital and neonatal herpes and is highly prevalent worldwide. Previous phase I and II studies showed the immunogenicity and safety of the candidate prophylactic HSV-2 glycoprotein D-based subunit vaccine (gD2-AS04), containing aluminum hydroxide and 3-O-deacylated monophosphoryl lipid A (MPL) as adjuvant (AS04), in healthy adults. The primary objective of the study presented here was to compare the immunogenicity and safety of five different vaccine formulations: 3 different antigen doses [20, 40 or 80 µg of truncated glycoprotein D from HSV-2 strain (gD-2t)], different aluminum salts [AlPO4 or Al(OH)3], different preservatives or different volumes of vaccine (0.5 or 1 ml). One hundred and fifty healthy men and women aged 18-45 years, with negative serological markers for HSV-1 and HSV-2 infection, were vaccinated with one of 5 formulations of the gD2-AS04 candidate vaccine according to a 0-, 1-, 6-month schedule. No statistically significant difference was observed in humoral or cellular immune responses between different antigen doses or the different aluminum salts, preservatives or volumes of vaccine. The gD2-AS04 vaccine was well tolerated by study participants for the duration of the study period. Local symptoms were more frequently reported than general symptoms, with muscle stiffness and/or injection site redness being the most frequently reported. Overall, the incidence of adverse events was comparable in all groups. Based on these results the gD2-AS04 formulation, containing 20 µg of gD-2t, was selected for evaluation of prophylactic efficacy in further clinical trials.


Assuntos
Hidróxido de Alumínio/efeitos adversos , Herpes Genital/prevenção & controle , Vacinas contra Herpesvirus/efeitos adversos , Vacinas contra Herpesvirus/imunologia , Lipídeo A/análogos & derivados , Proteínas do Envelope Viral/imunologia , Adolescente , Adulto , Hidróxido de Alumínio/administração & dosagem , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Voluntários Saudáveis , Herpes Genital/imunologia , Vacinas contra Herpesvirus/administração & dosagem , Humanos , Imunidade Celular , Imunidade Humoral , Incidência , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Masculino , Vacinação/métodos , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/efeitos adversos , Vacinas de Subunidades/imunologia , Adulto Jovem
20.
Adv Pharmacol ; 66: 81-128, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23433456

RESUMO

The structural core of bacterial lipopolysaccharide, lipid A, has played a role in medicine since the 1890s when William Coley sought to harness its immunostimulatory properties in the form of a crude bacterial extract. Recent decades have brought remarkable clarity to the structure of lipid A and the multicomponent endotoxin receptor system that evolved to detect it. A range of therapeutically useful versions of lipid A now exists, including preparations of detoxified lipid A, synthetic copies of naturally occurring biological intermediates such as lipid IVa, and synthetic mimetics. These agents are finding use as vaccine adjuvants, antagonists and immunostimulants whose structural features have been refined to potentiate efficacy while decreasing the risk of inflammatory side effects.


Assuntos
Sistema Imunitário/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Lipídeo A/análogos & derivados , Receptores de Lipopolissacarídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adjuvantes Imunológicos/efeitos adversos , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/metabolismo , Adjuvantes Imunológicos/farmacologia , Animais , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Lipídeo A/efeitos adversos , Lipídeo A/química , Lipídeo A/farmacologia , Receptores de Lipopolissacarídeos/química , Receptores Imunológicos/agonistas , Receptores Imunológicos/química , Receptores Imunológicos/metabolismo , Receptores de Interleucina-1/agonistas , Receptores de Interleucina-1/química , Receptores de Interleucina-1/metabolismo , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/química , Receptor 4 Toll-Like/metabolismo
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