RESUMO
BACKGROUND: Influenza A virus (IAV) causes respiratory disease in pigs and is a major concern for public health. Vaccination of pigs is the most successful measure to mitigate the impact of the disease in the herds. Influenza-based virosome is an effective immunomodulating carrier that replicates the natural antigen presentation pathway and has tolerability profile due to their purity and biocompatibility. METHODS: This study aimed to develop a polyvalent virosome influenza vaccine containing the hemagglutinin and neuraminidase proteins derived from the swine IAVs (swIAVs) H1N1, H1N2 and H3N2 subtypes, and to investigate its effectiveness in mice as a potential vaccine for swine. Mice were immunized with two vaccine doses (1 and 15 days), intramuscularly and intranasally. At 21 days and eight months later after the second vaccine dose, mice were euthanized. The humoral and cellular immune responses in mice vaccinated intranasally or intramuscularly with a polyvalent influenza virosomal vaccine were investigated. RESULTS: Only intramuscular vaccination induced high hemagglutination inhibition (HI) titers. Seroconversion and seroprotection (> 4-fold rise in HI antibody titers, reaching a titer of ≥ 1:40) were achieved in 80% of mice (intramuscularly vaccinated group) at 21 days after booster immunization. Virus-neutralizing antibody titers against IAV were detected at 8 months after vaccination, indicating long-lasting immunity. Overall, mice immunized with the virosome displayed greater ability for B, effector-T and memory-T cells from the spleen to respond to H1N1, H1N2 and H3N2 antigens. CONCLUSIONS: All findings showed an efficient immune response against IAVs in mice vaccinated with a polyvalent virosome-based influenza vaccine.
Assuntos
Vacinas contra Influenza , Influenza Humana , Vacinas Virossomais , Lavagem Broncoalveolar , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H1N2 , Vírus da Influenza A Subtipo H3N2 , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Baço/citologia , Baço/imunologia , Vacinas Combinadas/administração & dosagem , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/imunologia , Virossomos/ultraestrutura , Humanos , Animais , CamundongosRESUMO
The highly pathogenic avian influenza H5N1 viruses constantly evolve and give rise to novel variants that have caused widespread zoonotic outbreaks and sporadic human infections. Therefore, vaccines capable of eliciting broadly protective antibody responses are desired and under development. We here investigated the magnitude, kinetics and protective efficacy of the multi-faceted humoral immunity induced by vaccination in healthy adult volunteers with a Matrix M adjuvanted virosomal H5N1 vaccine. Vaccinees were given escalating doses of adjuvanted vaccine (1.5µg, 7.5µg, or 30µg), or a non-adjuvanted vaccine (30µg). An evaluation of sera from vaccinees against pseudotyped viruses covering all (sub)clades isolated from human H5N1 infections demonstrated that the adjuvanted vaccines (7.5µg and 30µg) could elicit rapid and robust increases of broadly cross-neutralizing antibodies against all clades. In addition, the adjuvanted vaccines also induced multifaceted antibody responses including hemagglutinin stalk domain specific, neuraminidase inhibiting, and antibody-dependent cellular cytotoxicity inducing antibodies. The lower adjuvanted dose (1.5µg) showed delayed kinetics, whilst the non-adjuvanted vaccine induced overall lower levels of antibody responses. Importantly, we demonstrate that human sera post vaccination with the adjuvanted (30µg) vaccine provided full protection against a lethal homologous virus challenge in mice. Of note, when combining our data from mice and humans we identified the neutralizing and neuraminidase inhibiting antibody titers as correlates of in vivo protection.
Assuntos
Anticorpos Antivirais/sangue , Anticorpos Amplamente Neutralizantes/sangue , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , Adulto , Animais , Reações Cruzadas , Feminino , Humanos , Imunização Passiva , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Neuraminidase/antagonistas & inibidores , Neuraminidase/imunologia , Saponinas de Quilaia/administração & dosagem , Saponinas de Quilaia/imunologia , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/imunologia , Adulto JovemRESUMO
PURPOSE: Characterization of virosomes, in late stage preclinical development as vaccines for Respiratory Syncytial Virus (RSV), with a membrane-incorporated synthetic monophosphoryl lipid A, 3D-PHAD® adjuvant. METHODS: Virosomes were initially formed by contacting a lipid film containing 3D-PHAD® with viral membranes solubilized with the short chain phospholipid DCPC, followed by dialysis, later by adding solubilized 3D-PHAD to viral membranes, or to preformed virosomes from DMSO. RESULTS: Virosomes formed from lipid films contained the membrane glycoproteins G and F, at similar F to G ratios but lower concentrations than in virus, and the added lipids, but only a fraction of the 3D-PHAD®. By single particle tracking (SPT), the virosome size distribution resembled that seen by cryo-electron microscopy, but dynamic light scattering showed much larger particles. These differences were caused by small virosome aggregates. Measured by SPT, virosomes were stable for 300 days. 3DPHAD ® incorporation in virosomes could be enhanced by providing the adjuvant from DCPC solubilized stock, but also by adding DMSO dissolved adjuvant to pre-formed virosomes. Virosomes with 0.1 mg/mg of 3D-PHAD®/viral protein from DMSO induced antibody titers similar to those by virosomes containing 0.2 mg/mg of DCPC-solubilized 3D-PHAD®. CONCLUSIONS: Stable 3D-PHAD® adjuvanted RSV virosomes can be formulated.
Assuntos
Adjuvantes Imunológicos/química , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/química , Vírus Sinciciais Respiratórios/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Animais , Chlorocebus aethiops , Composição de Medicamentos , Feminino , Humanos , Imunização , Camundongos Endogâmicos BALB C , Infecções por Vírus Respiratório Sincicial/imunologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/farmacologia , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/química , Vacinas Virossomais/farmacologia , Células VeroRESUMO
BACKGROUND: Influenza remains a significant problem in elderly despite widespread vaccination coverage. This randomized, phase-I study in elderly compared different strategies of improving vaccine immunogenicity. METHODS: A total of 370 healthy participants (⩾65years) were randomized equally 1:1:1:1:1:1 to six influenza vaccine treatments (approximately 60-63 participants per treatment arm) at day 1 that consisted of three investigational virosomal vaccine formulations at doses of 7.5, 15, and 45µg HA antigen/strain administered intradermally (ID) by MicronJet600™ microneedle device (NanoPass Technologies) or intramuscularly (IM), and three comparator registered seasonal vaccines; Inflexal V™ (Janssen) and MF59 adjuvanted Fluad™ (Novartis) administered IM and Intanza™ (Sanofi Pasteur) administered ID via Soluvia™ prefilled microinjection system (BD). Serological evaluations were performed at days 22 and 90 and safety followed-up for 6months. RESULTS: Intradermal delivery of virosomal vaccine using MicronJet600™ resulted in significantly higher immunogenicity than the equivalent dose of virosomal Inflexal V™ administered intramuscularly across most of the parameters and strains, as well as in some of the readouts and strains as compared with the 45µg dose of virosomal vaccine formulation. Of 370 participants, 300 (81.1%) reported ⩾1 adverse event (AE); more participants reported solicited local AEs (72.2%) than solicited systemic AEs (12.2%). CONCLUSIONS: Intradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery. Triple dose (45µg) virosomal vaccine did not demonstrate any benefit on vaccine's immunogenicity over 15µg commercial presentation. All treatments were generally safe and well-tolerated.
Assuntos
Envelhecimento/imunologia , Imunogenicidade da Vacina , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Adjuvantes Imunológicos , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Relação Dose-Resposta Imunológica , Vias de Administração de Medicamentos , Feminino , Humanos , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Injeções Intradérmicas , Injeções Intramusculares , Masculino , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/efeitos adversos , Vacinas Virossomais/imunologiaRESUMO
BACKGROUND: The aim of this open-label, active-controlled, parallel group, phase 2 follow-up study was to assess the long-term immunogenicity of Epaxal Junior, the pediatric dose of an aluminum-free virosomal inactivated hepatitis A virus (HAV) vaccine, in children receiving routine childhood vaccines (RCV). METHODS: Healthy children (12-15 months old, ≥8 kg weight) were randomized (1:1:1) to group A: Epaxal Junior + RCV (day 1); group B: Epaxal Junior (day 1) + RCV (day 29) and group C: Havrix 720 + RCV (day 1). All 3 groups received 2 doses of HAV vaccines 6 months apart. Children who completed the primary study were followed up from 18 months to 7.5 years post booster. RESULTS: Of 291/327 randomized children who had completed the primary study, 157 were followed for the 7.5-year analysis (group A: 50; group B: 54; and group C: 53). Of these, 152 children had protective levels of anti-HAV antibodies [≥10 mIU/mL; 98% (group A); 96.3% (group B); 96.2% (group C)]. Anti-HAV geometric mean concentrations were similar in groups A and B at all the time points (1.5-, 2.5-, 3.5-, 5.25- and 7.5-year time point) but slightly lower in group C. Predictions of the median duration of persistence of seroprotective antibody levels, using the linear mixed model were similar in all groups: (group A: 19.1 years, group B: 18.7 years, group C: 17.3 years). CONCLUSIONS: Immunization with Epaxal Junior administered with RCVs at 12 months elicited protective response beyond 7.5 years in almost all children. Assessing the kinetic of anti-HAV antibody titers decline over time, the moment to reach antibody concentrations below the accepted protective level may occur earlier than previously estimated.
Assuntos
Vacinas contra Hepatite A/administração & dosagem , Vacinas contra Hepatite A/sangue , Feminino , Seguimentos , Hepatite A/imunologia , Hepatite A/prevenção & controle , Anticorpos Anti-Hepatite A/sangue , Vacinas contra Hepatite A/efeitos adversos , Vacinas contra Hepatite A/imunologia , Vírus da Hepatite A Humana/imunologia , Humanos , Esquemas de Imunização , Imunização Secundária , Lactente , Masculino , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/sangue , Vacinas de Produtos Inativados/imunologia , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/efeitos adversos , Vacinas Virossomais/sangue , Vacinas Virossomais/imunologiaRESUMO
An optimized VP2 gene from the current prevalent CPV strain (new CPV-2a) in China was expressed in a baculovirus expression system. It was found that the VP2 proteins assembled into virus-like particles (VLPs) with antigenic properties similar to those of natural CPV and with an especially high hemagglutination (HA) titer (1:2(20)). Dogs intramuscularly or orally immunized with VLPs produced antibodies against CPV with >1:80 hemagglutination inhibition (HI) units for at least 3 months. The CPV VLPs could be considered for use as a vaccine against CPV or as a platform for research on chimeric VLP vaccines against other diseases.
Assuntos
Baculoviridae , Vetores Genéticos , Parvovirus Canino/genética , Proteínas Estruturais Virais/metabolismo , Virossomos/metabolismo , Administração Oral , Animais , Anticorpos Antivirais/sangue , China , Cães , Injeções Intramusculares , Multimerização Proteica , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/genética , Vacinas Virossomais/imunologia , Proteínas Estruturais Virais/genética , Vacinas Virais/administração & dosagem , Vacinas Virais/genética , Vacinas Virais/imunologia , Virossomos/genéticaRESUMO
We have previously identified 17 biomarker genes which were upregulated by whole virion influenza vaccines, and reported that gene expression profiles of these biomarker genes had a good correlation with conventional animal safety tests checking body weight and leukocyte counts. In this study, we have shown that conventional animal tests showed varied and no dose-dependent results in serially diluted bulk materials of influenza HA vaccines. In contrast, dose dependency was clearly shown in the expression profiles of biomarker genes, demonstrating higher sensitivity of gene expression analysis than the current animal safety tests of influenza vaccines. The introduction of branched DNA based-concurrent expression analysis could simplify the complexity of multiple gene expression approach, and could shorten the test period from 7 days to 3 days. Furthermore, upregulation of 10 genes, Zbp1, Mx2, Irf7, Lgals9, Ifi47, Tapbp, Timp1, Trafd1, Psmb9, and Tap2, was seen upon virosomal-adjuvanted vaccine treatment, indicating that these biomarkers could be useful for the safety control of virosomal-adjuvanted vaccines. In summary, profiling biomarker gene expression could be a useful, rapid, and highly sensitive method of animal safety testing compared with conventional methods, and could be used to evaluate the safety of various types of influenza vaccines, including adjuvanted vaccine.
Assuntos
Adjuvantes Imunológicos/farmacologia , Vacinas contra Influenza/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Animais , Ensaio de Amplificação de Sinal de DNA Ramificado/métodos , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos , Humanos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Masculino , Controle de Qualidade , Ratos , Ratos Wistar , Segurança , Regulação para Cima , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/efeitos adversos , Vacinas Virossomais/farmacologiaRESUMO
BACKGROUND: The pediatric dose of the virosomal hepatitis A vaccine Epaxal, Epaxal Junior, is safe and immunogenic in children from 1 to 17 years of age. The present study investigated the long-term immunogenicity of Epaxal Junior. The standard doses of Epaxal and aluminum-adsorbed hepatitis A vaccine (Havrix Junior) were used as comparators. METHODS: A total of 271 children who had completed a 0/6-month immunization schedule (priming and booster dose) participated in this follow-up study. Anti-hepatitis A virus (HAV) antibody levels were measured using a microparticle enzyme immunoassay (HAVAB 2.0 Quantitative; Abbott Diagnostics, Wiesbaden, Germany) starting at 18 months following the second dose, and then yearly until 66 months (ie, 5.5 years) after the second dose. RESULTS: All subjects tested at Month 66 still had protective anti-HAV antibodies (≥10 mIU/mL). Antibody titers were generally lower in subjects 1-7 years old than in subjects 8-17 years old and higher in females 11-17 years old than in males 11-17 years old. In addition, an age-dependent decay was observed, that is, antibody decreased more rapidly in younger than in older children. CONCLUSIONS: Vaccination of children with two doses of Epaxal Junior confers a real-time protection of at least 5.5 years. This protection is estimated to last approximately 25 years. Younger children showed lower antibody titers and a faster antibody decline than older children. Additional follow-up studies are needed beyond 5.5 years to further assess the long-term immunogenicity of Epaxal Junior.
Assuntos
Anticorpos Anti-Hepatite A/sangue , Vacinas contra Hepatite A/administração & dosagem , Vacinas contra Hepatite A/imunologia , Vacinação/métodos , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Imunoensaio , Lactente , Estudos Longitudinais , Fatores de TempoRESUMO
PURPOSE: Influenza CD8(+) T-cell epitopes are conserved amongst influenza strains and can be recognized by influenza-specific cytotoxic T-cells (CTLs), which can rapidly clear infected cells. An influenza peptide vaccine that elicits these CTLs would therefore be an alternative to current influenza vaccines, which are not cross-reactive. However, peptide antigens are poorly immunogenic due to lack of delivery to antigen presenting cells, and therefore need additional formulation with a suitable delivery system. In this study, the potential of virosomes as a delivery system for an influenza T-cell peptide was investigated. METHODS: The conserved human HLA-A2.1 influenza T-cell epitope M158-66 was formulated with virosomes. The immunogenicity and protective effect of the peptide-loaded virosomes was assessed in HLA-A2 transgenic mice. Delivery properties of the virosomes were studied in mice and in in vitro dendritic cell cultures. RESULTS: Immunization of HLA-A2.1 transgenic C57BL/6 mice with peptide-loaded virosomes in the presence of the adjuvant CpG-ODN 1826 increased the number of peptide-specific CTLs. Vaccination with adjuvanted peptide-loaded virosomes reduced weight loss in mice after heterologous influenza infection. Association with fusion-active virosomes was found to be crucial for antigen uptake by dendritic cells, and subsequent induction of CTLs in mice. CONCLUSIONS: These results show that influenza virosomes loaded with conserved influenza epitopes could be the basis of a novel cross-protective influenza vaccine.
Assuntos
Adjuvantes Imunológicos/química , Epitopos de Linfócito T/imunologia , Antígeno HLA-A2/imunologia , Vacinas contra Influenza/administração & dosagem , Oligodesoxirribonucleotídeos/química , Animais , Antígeno HLA-A2/genética , Humanos , Vacinas contra Influenza/química , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/imunologia , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/química , Proteínas da Matriz Viral/imunologia , VirossomosRESUMO
Acute disseminated encephalomyelitis (ADEM) is an inflammatory, usually monophasic, immune mediate, demyelinating disease of the central nervous system which involves the white matter. ADEM is more frequent in children and usually occurs after viral infections, but may follow vaccinations, bacterial infections, or may occur without previous events. Only 5% of cases of ADEM are preceded by vaccination within one month prior to symptoms onset. The diagnosis of ADEM requires both multifocal involvement and encephalopathy and specific demyelinating lesions of white matter. Overall prognosis of ADEM patients is often favorable, with full recovery reported in 23% to 100% of patients from pediatric cohorts, and more severe outcome in adult patients. We describe the first case of ADEM occurred few days after administration of virosomal seasonal influenza vaccine. The patient, a 59-year-old caucasic man with unremarkable past medical history presented at admission decreased alertness, 10 days after flu vaccination. During the 2 days following hospitalization, his clinical conditions deteriorated with drowsiness and fever until coma. The magnetic resonance imaging of the brain showed multiple and symmetrical white matter lesions in both cerebellar and cerebral hemispheres, suggesting demyelinating disease with inflammatory activity, compatible with ADEM. The patient was treated with high dose of steroids and intravenous immunoglobulin with relevant sequelae and severe neurological outcomes.
Assuntos
Encefalomielite Aguda Disseminada/complicações , Encefalomielite Aguda Disseminada/diagnóstico , Vacinas contra Influenza/efeitos adversos , Doenças do Sistema Nervoso/diagnóstico , Anti-Inflamatórios/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encefalomielite Aguda Disseminada/tratamento farmacológico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Vacinas contra Influenza/administração & dosagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Radiografia , Esteroides/uso terapêutico , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/efeitos adversosRESUMO
As India is transitioning from high to intermediate hepatitis A endemicity, the need for hepatitis A vaccination programs increases. This study investigated the immunogenicity and safety of a virosomal hepatitis A vaccine (HAVpur Junior) compared with an aluminum-adsorbed hepatitis A vaccine (Havrix 720 Junior) in Indian children. Healthy children aged 18-47 months, stratified by age, were randomized to either HAVpur Junior or Havrix 720 Junior. The first dose of vaccine was administered on Day 1 and the second (booster) dose 6 months later. Antibodies against hepatitis A virus (HAV) were measured using a microparticle enzyme immunoassay. The primary objective assessed non-inferiority of HAVpur Junior to Havrix 720 Junior in terms of seroprotection rates (≥ 10 mIU/mL anti-HAV antibodies) at 1 month after the first vaccination. Non-inferiority was demonstrated if the lower limit of the 90% confidence interval of the group difference was greater than -10%. Local and systemic adverse events were recorded. The seroprotection rate at 1 month was 95.9% in the HAVpur Junior group and 96.6% in the Havrix 720 Junior group. As the lower limit of the 90% confidence interval of the group difference was greater than -10% (-4.7), non-inferiority of HAVpur Junior to Havrix 720 Junior was established. The overall incidence of adverse events (solicited and unsolicited) after each vaccination was similar in both groups. In conclusion, the aluminum-free virosomal vaccine HAVpur Junior induced a similar immune response to Havrix 720 Junior in healthy Indian children aged 18 to 47 months. Both vaccines were well tolerated. The study shows that the low-dose virosomal HAV vaccine is consistently efficacious and well tolerated in children of all age groups and is suitable for inclusion into Indian childhood vaccination schedules.
Assuntos
Anticorpos Anti-Hepatite A/sangue , Vacinas contra Hepatite A/efeitos adversos , Vacinas contra Hepatite A/imunologia , Hepatite A/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Voluntários Saudáveis , Vacinas contra Hepatite A/administração & dosagem , Humanos , Técnicas Imunoenzimáticas , Índia , Lactente , Masculino , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/efeitos adversos , Vacinas Virossomais/imunologiaRESUMO
T cellular responses play a significant role in mediating protective immune responses against influenza in humans. In the current study, we evaluated the ability of a candidate virosomal H5N1 vaccine adjuvanted with Matrix M(TM) to induce CD4(+) and CD8(+) T cell responses in a phase 1 clinical trial. We vaccinated 60 healthy adult volunteers (at days 0 and 21) with 30 µg haemagglutinin (HA) alone or 1.5, 7.5, or 30 µg HA formulated with Matrix M(TM). To evaluate the T cellular responses, lymphocytes were stimulated in vitro with homologous (A/Vietnam/1194/2004 [H5N1]) and heterologous H5N1 (A/Anhui/1/05 or A/Bar-headed Goose/Qinghai/1A/05) antigens. The antigen-specific cytokine responses were measured by intracellular cytokine staining and by multiplex (Luminex) assays. An increase in CD4(+) Th1 and Th2 cytokines was detected 21 days after the first vaccine dose. No increase in Th cytokine responses was observed after the second dose, although it is possible that the cytokine levels peaked earlier than sampling point at day 42. Formulation with the Matrix M(TM) adjuvant augmented both the homologous and cross-reactive cytokine response. Antigen-specific CD8(+) T cell responses were detected only in a few vaccinated individuals. The concentrations of Th1 and to a lesser extent, Th2 cytokines at 21 days post-vaccination correlated moderately with subsequent days 35 and 180 serological responses as measured by the microneutralisation, haemagglutination inhibition, and single radial hemolysis assays. Results presented here show that the virosomal H5N1 vaccine induced balanced Th1/Th2 cytokine responses and that Matrix M(TM) is a promising adjuvant for future development of candidate pandemic influenza vaccines.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Linfócitos T CD4-Positivos/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , Células Th1/imunologia , Células Th2/imunologia , Adulto , Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Vacinas contra Influenza/administração & dosagem , Masculino , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/imunologiaRESUMO
The skin provides the largest immune barrier to infection and is a readily accessible site for vaccination, although intradermal (ID) injection can be challenging. The MicronJet™ microneedle is a novel device that consistently injects antigens very close to the skin's dendritic cells. A dose-sparing ID injection study was conducted in 280 healthy adult volunteers using trivalent virosomal adjuvanted influenza vaccine. ID injection of 3 µg using the MicronJet™ was well tolerated and showed a statistically higher geometric mean fold rise than the same dose ID using a conventional needle (Mantoux technique) for the H1N1 and B strains or a 15 µg intramuscular (IM) injection for the H3N2 strain. Thus, the immune response appears to partially depend on the delivery device and route of injection. The MicronJet™ may allow dose-sparing, yet give a superior response in influenza vaccination and warrants further clinical evaluation.
Assuntos
Vacinas contra Influenza/administração & dosagem , Injeções Intradérmicas/instrumentação , Agulhas , Adulto , Anticorpos Antivirais/sangue , Relação Dose-Resposta Imunológica , Humanos , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza B , Vacinas Virossomais/administração & dosagemRESUMO
AIM: To clarify the immunogenicity and safety of influenza vaccine in patients with end-stage kidney disease (ESKD) on dialysis or who have received a kidney transplant. METHODS: Sixty adolescents and young adults with ESKD (25 on hemodialysis and 35 kidney transplant recipients) were randomized 1:1 to receive a traditional trivalent split virion vaccine (TIIV) or a virosome-adjuvanted trivalent inactivated influenza vaccine (VATIIV). The immunogenicity and safety of the two vaccines was evaluated and compared with the findings observed in 30 healthy subjects of similar age and gender distribution who received TIIV. RESULTS: The results indicate that the immune response of the patients to TIIV and VATIIV were similar. The administered vaccines were safe and well tolerated, and no advantage was found with the use of VATIIV. CONCLUSION: Given the potential clinical relevance of influenza in patients with ESKD, these findings support the official recommendation that they should receive annual influenza vaccinations.
Assuntos
Imunização/métodos , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Transplante de Rim , Diálise Renal , Insuficiência Renal , Adolescente , Anticorpos Antivirais/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Imunização/efeitos adversos , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/imunologia , Masculino , Estudos Prospectivos , Método Simples-Cego , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/imunologia , Adulto JovemRESUMO
Effective and low-cost vaccines are essential to control severe group A streptococcus (GAS) infections prevalent in low-income nations and the Australian aboriginal communities. Highly diverse and endemic circulating GAS strains mandate broad-coverage and customized vaccines. This study describes an approach to deliver cross-reactive antigens from endemic GAS strains using modular virus-like particle (VLP) and capsomere systems. The antigens studied were three heterologous N-terminal peptides (GAS1, GAS2, and GAS3) from the GAS surface M-protein that are specific to endemic strains in Australia Northern Territory Aboriginal communities. In vivo data presented here demonstrated salient characteristics of the modular delivery systems in the context of GAS vaccine design. First, the antigenic peptides, when delivered by unadjuvanted modular VLPs or adjuvanted capsomeres, induced high titers of peptide-specific IgG antibodies (over 1 × 10(4) ). Second, delivery by capsomere was superior to VLP for one of the peptides investigated (GAS3), demonstrating that the delivery system relative effectiveness was antigen-dependant. Third, significant cross-reactivity of GAS2-induced IgG with GAS1 was observed using either VLP or capsomere, showing the possibility of broad-coverage vaccine design using these delivery systems and cross-reactive antigens. Fourth, a formulation containing three pre-mixed modular VLPs, each at a low dose of 5 µg (corresponding to <600 ng of each GAS peptide), induced significant titers of IgGs specific to each peptide, demonstrating that a multivalent, broad-coverage VLP vaccine formulation was possible. In summary, the modular VLPs and capsomeres reported here demonstrate, with promising preliminary data, innovative ways to design GAS vaccines using VLP and capsomere delivery systems amenable to microbial synthesis, potentially adoptable by developing countries.
Assuntos
Antígenos de Bactérias/metabolismo , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Transporte/imunologia , Vacinas Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Vacinas Sintéticas/imunologia , Vacinas Virossomais/imunologia , Virossomos/metabolismo , Animais , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/genética , Proteínas de Transporte/genética , Reações Cruzadas , Humanos , Imunoglobulina G/sangue , Camundongos , Havaiano Nativo ou Outro Ilhéu do Pacífico , Northern Territory/epidemiologia , Infecções Estreptocócicas/epidemiologia , Infecções Estreptocócicas/prevenção & controle , Vacinas Estreptocócicas/administração & dosagem , Vacinas Estreptocócicas/genética , Vacinas Estreptocócicas/isolamento & purificação , Streptococcus pyogenes/genética , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/genética , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/isolamento & purificação , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/isolamento & purificação , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/genética , Vacinas Virossomais/isolamento & purificação , Virossomos/genéticaRESUMO
Despite its impact on global health, there is no vaccine available for the prevention of respiratory syncytial virus (RSV) infection. Failure to develop a licensed vaccine is not due to lack of effort, as numerous vaccine candidates have been characterized in preclinical and clinical studies spanning five decades. The vaccine candidates thus far explored can be generally divided into four categories: (1) whole inactivated virus, (2) replication competent, attenuated virus including recombinant viruses, (3) gene-based vectors, and (4) subunit and particulate forms of RSV antigens. The first clinically tested RSV vaccine candidate was a formalin-inactivated purified virus preparation administered to infants and children in the late 1960s. Due to the disastrous outcome of these trials and results of animal models investigating the mechanisms involved, there have been no further studies with inactivated RSV vaccines. Rather, efforts have focused on development of other approaches. In this chapter, we review the history and status of purified proteins, peptides, virus-like particles, virosomes, and nanoparticles and discuss their future potential.
Assuntos
Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Vacinas Virossomais/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Pré-Escolar , Especificidade de Hospedeiro , Humanos , Lactente , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/virologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vírus Sincicial Respiratório Humano/patogenicidade , Vacinas de Subunidades Antigênicas , Vacinas Virossomais/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Virossomos/genética , Virossomos/imunologiaRESUMO
BACKGROUND: Non-replicating respiratory syncytial virus (RSV) vaccine candidates could potentially prime for enhanced respiratory disease (ERD) due to a T-cell-mediated immunopathology, following RSV infection. Vaccines with built-in immune response modifiers, such as Toll-like receptor (TLR) ligands, may avoid such aberrant imprinting of the immune system. METHODS: We developed reconstituted RSV envelopes (virosomes) with incorporated TLR4 ligand, monophosphoryl lipid A (RSV-MPLA virosomes). Immune responses and lung pathology after vaccination and challenge were investigated in ERD-prone cotton rats and compared with responses induced by live virus and formaldehyde-inactivated vaccine (FI-RSV), a known cause of ERD upon RSV challenge. RESULTS: Vaccination with RSV-MPLA virosomes induced higher levels of virus-neutralizing antibodies than FI-RSV or live virus infection and provided protection against infection. FI-RSV, but not RSV-MPLA virosomes, primed for increases in expression of Th2 cytokines IL-4, IL-5, IL-13, and Th1 cytokine IL-1b, 6 hour-5 days after infection. By contrast, RSV-MPLA virosomes induced IFN-γ transcripts to similar levels as induced by live virus. Animals vaccinated with FI-RSV, but not RSV-MPLA virosomes showed alveolitis, with prominent neutrophil influx and peribronchiolar and perivascular infiltrates. CONCLUSION: These results show that RSV-MPLA virosomes represent a safe and immunogenic vaccine candidate that warrants evaluation in a clinical setting.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Lipídeo A/análogos & derivados , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sinciciais Respiratórios/imunologia , Animais , Modelos Animais de Doenças , Feminino , Lipídeo A/administração & dosagem , Pulmão/patologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/patologia , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Sigmodontinae , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/efeitos adversos , Vacinas Virossomais/imunologiaRESUMO
In the present study we first compare immunogenicity against vaccine and heterologous circulating A(H1N1)pdm09 strains, tolerability and safety of intradermal Intanza 15 µg and of virosomal adjuvanted, intramuscularly delivered influenza vaccine, Inflexal V, in healthy elderly volunteers. Five-hundred participants were enrolled in the study and randomly assigned to the two vaccine groups to receive either one dose of Intanza 15 µg or Inflexal V vaccine. All subjects reported solicited local and systemic reactions occurred within 7 d after vaccination and unsolicited adverse events up to 21 d post-immunization and any serious adverse event appeared during the study. A subset of 55 participants was randomly selected for immunogenicity and cross-protection evaluations. Serum samples were collected before and 1 and 3 mo after immunization. Antibody responses were measured using hemagglutination inhibition (HI) against all viruses used in the study and neutralization (NT) assays against A(H1N1)pdm09 strains. At least one of the CHMP criteria for influenza vaccine approval in the elderly was met by virosomal vaccine against all the tested viruses; intradermal vaccine met all criteria against all strains. Several parameters of immune response against strains with a different antigenic pattern from that of vaccine A/California/04/09(H1N1)pdm09 were significantly higher in the intradermal vaccine group compared with the virosomal group. Safety and systemic tolerability of both vaccines were excellent, but injection site reactions occurred significantly more frequently in the intradermal vaccination group. Immunogenicity of Intanza 15 µg intradermal vaccine tended to be higher than that of Inflexal V against heterologous strains in healthy elderly.
Assuntos
Proteção Cruzada , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Injeções Intradérmicas , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/efeitos adversos , Vacinas Virossomais/imunologiaRESUMO
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.
Assuntos
Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/imunologia , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vacinas contra Vírus Sincicial Respiratório/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adolescente , Adulto , Compostos de Alumínio/administração & dosagem , Compostos de Alumínio/efeitos adversos , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Biotecnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nanopartículas/administração & dosagem , Nanopartículas/efeitos adversos , Fosfatos/administração & dosagem , Fosfatos/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/genética , Células Sf9 , Método Simples-Cego , Tecnologia Farmacêutica , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas Virossomais/administração & dosagem , Vacinas Virossomais/efeitos adversos , Vacinas Virossomais/genética , Vacinas Virossomais/imunologia , Adulto JovemRESUMO
Annual vaccination is the main mean of preventing influenza in the elderly. In order to evaluate the effectiveness of the adjuvanted seasonal influenza vaccines available in Italy in preventing hospitalization for influenza and pneumonia, a matched case-control study was performed in elderly subjects during the 2010-2011 season in Genoa (Italy). Cases and controls were matched in a 1:1 ratio according to gender, age, socio-economic status and type of influenza vaccine. Vaccine effectiveness was calculated as IVE = [(1-OR)x100] and crude odds ratios were estimated through conditional logistic regression models. Adjusted odds ratios were estimated through multivariable logistic models. In the study area, influenza activity was moderate in the 2010-2011 season, with optimal matching between circulating viruses and vaccine strains. We recruited 187 case-control pairs; 46.5% of cases and 79.1% of controls had been vaccinated. The adjuvanted influenza vaccines (Fluad (®) considered together with Inflexal V (®) ) were associated with a significant reduction in the risk of hospitalization, their effectiveness being 94.8% (CI 77.1-98.8). Adjusted vaccine effectiveness was 95.2% (CI 62.8-99.4) and 87.8 (CI 0.0-98.9) for Inflexal V (®) and Fluad (®) , respectively. Both adjuvanted vaccines proved effective, although the results displayed statistical significance only for Inflexal V (®) (p = 0.004), while for Fluad (®) statistical significance was not reached (p = 0.09). Our study is the first to provide information on the effectiveness of Inflexal V (®) in terms of reducing hospitalizations for influenza or pneumonia in the elderly, and demonstrates that this vaccine yields a high degree of protection and that its use would generate considerable saving for the National Health Service.