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1.
Nat Immunol ; 12(8): 786-95, 2011 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-21743478

RESUMO

Here we have used a systems biology approach to study innate and adaptive responses to vaccination against influenza in humans during three consecutive influenza seasons. We studied healthy adults vaccinated with trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV). TIV induced higher antibody titers and more plasmablasts than LAIV did. In subjects vaccinated with TIV, early molecular signatures correlated with and could be used to accurately predict later antibody titers in two independent trials. Notably, expression of the kinase CaMKIV at day 3 was inversely correlated with later antibody titers. Vaccination of CaMKIV-deficient mice with TIV induced enhanced antigen-specific antibody titers, which demonstrated an unappreciated role for CaMKIV in the regulation of antibody responses. Thus, systems approaches can be used to predict immunogenicity and provide new mechanistic insights about vaccines.


Assuntos
Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Orthomyxoviridae/imunologia , Imunidade Adaptativa/imunologia , Adolescente , Adulto , Animais , Anticorpos Antivirais/sangue , Perfilação da Expressão Gênica , Testes de Inibição da Hemaglutinação , Humanos , Imunidade Inata/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Estações do Ano , Biologia de Sistemas/métodos , Vacinação/métodos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Adulto Jovem
2.
Vaccine ; 39(32): 4450-4457, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34218960

RESUMO

BACKGROUND: The World Health Organization (WHO) recommends the use of oral cholera vaccines (OCVs) as part of an integrated control program, both in highly endemic settings and during cholera epidemics. The available and internationally recommended WHO-prequalified OCVs (Dukoral, Shanchol, Euvichol) contain multiple heat and formalin-killed V. cholerae strains of Inaba and Ogawa serotypes. MSD Wellcome Trust Hilleman Laboratories Pvt. Ltd. in technical collaboration with University of Gothenburg, Sweden has developed a new single strain OCV, Hillchol. This vaccine consists of formaldehyde-inactivated whole cell El Tor V. cholerae O1 bacteria engineered into the Hikojima serotype for stable expression of both the Ogawa (AB) and Inaba (AC) LPS antigens on the bacterial surface. We evaluated the safety and immunogenicity of this novel and potentially much less expensive OCV in comparison with Shanchol. METHODS: We conducted a randomized, non-inferiority, age-descending clinical trial of OCV (Hillchol vs. Shanchol) in the Mirpur area of Dhaka city from July 2016 to May 2017. This study was carried out in three different age cohorts (1-<5, 5-17 and ≥18 years old). Two doses of vaccine were given at 14 days intervals to 560 healthy participants. FINDINGS: No serious adverse events were reported. There were no significant differences in the rates of adverse events between the test vaccine (Hillchol) and the comparator (Shanchol) group. Serum vibriocidal antibody responses in all age groups combined were comparable for all the O1 Ogawa (59% vs. 67%; 90% CI of difference: -14.55, -0.84) and Inaba (70% vs. 71%; 90% CI of difference: -7.24, 5.77) serotypes, showing that the Hillchol vaccine was non-inferior to Shanchol. This new vaccine was also non-inferior to Shanchol in the different age strata. CONCLUSION: The safety and immunogenicity profile of the new OCV Hillchol is comparable to Shanchol in persons residing in a cholera-endemic setting. ClinicalTrials.gov number: NCT02823899.


Assuntos
Vacinas contra Cólera , Cólera , Vibrio cholerae O1 , Administração Oral , Adolescente , Anticorpos Antibacterianos , Bangladesh , Cólera/prevenção & controle , Humanos , Suécia , Vacinas de Produtos Inativados/efeitos adversos
3.
J Microencapsul ; 27(6): 552-60, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20690791

RESUMO

Controlled release formulation of recombinant human growth hormone (r-hGH) was achieved using poly lactide-co-glycolide (PLGA) polymer. Denaturation of r-hGH by dichloromethane during primary emulsification step of particle preparation was minimized by using human serum albumin whereas inclusion of sucrose and sodium bicarbonate helped in reducing protein denaturation during lyophilization and polymer particle degradation. Encapsulation efficiency of r-hGH entrapped in PLGA particles (size approximately 30 microm) was around 45% with protein load 20 microg of r-hGH/mg of polymer particles. Porous particles showed quick release of r-hGH in comparison to non-porous particles in vitro. More than 10 ng/mL of bioactive r-hGH was found in the serum of the experimental animals observed for a 30-day period after a single intramuscular injection of the polymeric formulation. Incorporation of optimal stabilizers is thus essential for the development of a stable, month long controlled release of polymer particle based r-hGH formulation.


Assuntos
Preparações de Ação Retardada/química , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/farmacologia , Ácido Láctico/química , Ácido Poliglicólico/química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Liofilização , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/química , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Desnaturação Proteica , Estabilidade Proteica , Ratos , Ratos Wistar , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/sangue , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologia
4.
Vaccine ; 38(50): 7998-8009, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33139137

RESUMO

Cholera remains an important global health problem with up to 4 million cases and 140,000 deaths annually. Oral cholera vaccines (OCVs) are now a cornerstone of the WHOs "Ending Cholera - A Global Roadmap to 2030" global program for the eventual elimination of cholera. There are currently three WHO prequalified OCVs available, Dukoral®, Shanchol® and Euvichol-Plus®. These vaccines are effective but due to a multiple strain composition and two different methods of inactivation, are complex and costly to manufacture. We describe here the characterization and industrial scale development of Hillchol®; a novel, likely affordable single-component OCV for low and middle-income countries. Hillchol® consists of formalin-inactivated bacteria of a stable recombinant Vibrio cholerae O1 El Tor Hikojima serotype strain expressing approximately 50% each of Ogawa and Inaba O1 LPS antigens. The novel OCV can be manufactured on an industrial scale at a low cost. Hillchol® was well tolerated in animal toxicology studies and shown to have non-inferior oral immunogenicity in mice for both intestinal-mucosal and serological immune responses when compared with a WHO-prequalified OCV. The optimized production of this single component OCV will reduce cost of OCV production and thus substantially increase vaccine availability. Based on these results, Hillchol® has been produced at a GMP facility and used successfully for clinical phase I/II studies.


Assuntos
Vacinas contra Cólera , Cólera , Vibrio cholerae O1 , Administração Oral , Animais , Anticorpos Antibacterianos , Cólera/prevenção & controle , Camundongos , Sorogrupo , Vacinas de Produtos Inativados , Vibrio cholerae O1/genética
5.
Hum Vaccin Immunother ; 16(3): 693-702, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-31526218

RESUMO

Objectives: To assess the safety and reactogenicity of single oral dose of heat-stable rotavirus vaccine (HSRV) in healthy adults aged 18-45 years followed by assessment of safety, reactogenicity, and immunogenicity of three doses of HSRV in healthy infants aged 6-8 weeks at enrollment.Trial Design: Single-center randomized controlled, sequential, blinded (adults) and open-label (infants).Setting: Single site at International Center for Diarrheal Disease Research, Bangladesh (icddr,b).Participants: Fifty eligible adults randomized in 1:1 ratio (HSRV: Placebo) followed by 50 eligible infants randomized in 1:1 ratio (HSRV: Comparator (RotaTeq®, pentavalent human-bovine (WC3) reassortant live-attenuated, rotavirus vaccine)).Intervention: Adults received either a single dose of HSRV or placebo and followed for 14 days. Infants received three doses of either HSRV or comparator with a follow-up for 28 days after each dose.Main Outcome Measures: Solicited and unsolicited adverse events (AEs) along with any serious adverse events (SAEs) were part of the safety and reactogenicity assessment in adults and infants whereas serum anti-rotavirus IgA response rates were part of immunogenicity assessment in infants only. Post-vaccination fecal shedding of vaccine-virus rotavirus strains was also determined in adults and infants.Results: In this study, HSRV, when compared with placebo, did not result in increase in solicited adverse events (solicited AEs) in adults. In infants, HSRV had a safety profile similar to comparator vis-à-vis solicited AEs. In infants, fecal shedding of vaccine-virus strains was not detected in HSRV recipients but was observed in two comparator recipients. Percentage of infants exhibiting threefold rise in serum anti-rotavirus IgA titers from baseline to 1-month post-dose 3 in HSRV group was 88% (22/25) and 84% (21/25) in comparator group.Conclusion: HSRV was found to be generally well-tolerated in both adults and infants and immunogenic in infants.


Assuntos
Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Adulto , Animais , Anticorpos Antivirais , Bangladesh , Bovinos , Método Duplo-Cego , Temperatura Alta , Humanos , Imunogenicidade da Vacina , Lactente , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/efeitos adversos , Vacinas Atenuadas/efeitos adversos
6.
Biomaterials ; 28(35): 5344-57, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17825905

RESUMO

Size of the polymeric particulate antigen delivery system and its interactions with antigen-presenting cells (APCs) influence the immune response both qualitatively and quantitatively. In this paper, we report that antigen-loaded polymeric microparticles elicit antibody titers without being phagocytosed by macrophages; and size of the antigen-loaded particles modulates immune response from single-point immunization. Antibody titers varied significantly from single-point immunization with different sized polylactide (PLA) particles entrapping hepatitis B surface antigen. Nanoparticles (200-600 nm) were efficiently taken up by macrophages and elicited lower antibody titers in comparison to microparticles (2-8 microm). PLA microparticles that elicited highest and long-lasting antibody titers from single-point immunization were not taken up by the macrophages and found attached to the surface of the macrophages. Immunization with nanoparticles (200-600 nm) was associated with higher levels of IFN-gamma production, upregulation of MHC class I molecules along with antibody isotypes favoring Th1-type immune response. Immunization with microparticles (2-8 microm size) promoted IL-4 secretion, upregulated MHC class II molecules and favored Th2-type immune response. Western blot analysis showed that release of HBsAg from surface-attached microparticles into macrophages increased with time, but was more or less constant in case of nanoparticles. Our results suggest that continuous release of high concentration of antigen from cell surface-attached PLA microparticles into APCs results in improved antibody response from single-point immunization. It also offers an exciting possibility of designing size-based polymer particle delivery system to modulate immune response.


Assuntos
Antígenos de Superfície da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Poliésteres/metabolismo , Animais , Sistemas de Liberação de Medicamentos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Ratos , Ratos Wistar , Vacinas contra Hepatite Viral
8.
Biomaterials ; 33(28): 6843-57, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22748669

RESUMO

Polysaccharides in their great majority are thymus-independent (TI) antigens. Anti-polysaccharide antibody responses are generally weak and characterized by lack of memory, isotype restriction and delayed ontogeny. We report here the generation of protective memory antibody response by multivalent display of polysaccharide antigens on biodegradable polymeric particles. Single dose immunization using polylactide (PLA) polymer particles entrapping Vi capsular polysaccharide antigen from Salmonella typhi promoted isotype switching and induced polysaccharide-specific memory antibody response in experimental animals. PLA nanoparticles as well as microparticles entrapping Vi polysaccharides elicited high IgG titer in comparison to soluble Vi immunization. Immunizations with particles co-entrapping both Vi polysaccharide and tetanus toxoid did not improve the anti-polysaccharide antibody responses. Lower antibody response from co-entrapped formulation was mostly due to inhibition of particle phagocytosis by the macrophages. Immunization using polylactide particles entrapping only Vi polysaccharide with higher density on surface elicited highest secondary antibody response as well as promoted isotype switching. The vaccination potential of particle based immunizations was further confirmed by the generation of quick memory antibody responses while challenging the immunized animals with live S. typhi. This approach provides a multivalent display of polysaccharide antigen using polymer particles and elicits protective memory antibody response without conjugation to a carrier protein.


Assuntos
Formação de Anticorpos/imunologia , Antígenos/administração & dosagem , Antígenos/imunologia , Memória Imunológica/imunologia , Polissacarídeos Bacterianos/administração & dosagem , Polissacarídeos Bacterianos/imunologia , Vacinação/métodos , Análise de Variância , Animais , Anticorpos/imunologia , Feminino , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Tamanho da Partícula , Poliésteres/metabolismo , Propriedades de Superfície , Toxoide Tetânico/imunologia
9.
Eur J Pharm Sci ; 38(1): 18-28, 2009 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-19467323

RESUMO

This study was aimed at understanding the role of alum in improving the immunogenicity of biodegradable polymer particle entrapped antigens. Presence of alum formed a fine network around PLA particles holding them together and promoted attachment of higher number of particles on macrophage surface for a considerable period of time. Use of alum lowered the burst release of the entrapped antigen from particles and thereafter also reduced the cumulative release of antigen from particles. Apart from this, PLA microparticles alone induced macrophages to release TNF-alpha similar to that induced by alum. However admixture of PLA particles and alum enhanced the secretion of TNF-alpha from 876pg/ml at 6h to 3500pg/ml at 24h which was higher than that induced by alum adsorbed TT. Immunization with admixture of antigen loaded polylactide (PLA) microparticles (2-8microm) and alum improved the antibody titers almost twice than that achieved from particle alone in experimental animals. Single point immunization with particle entrapped antigens and alum also elicited antibody titers comparable to two doses of alum adsorbed tetanus toxoid (TT) or diphtheria toxoid (DT). Our results suggest that presence of alum acts in multiple ways to improve the antibody titers of polymer particles entrapped antigens. Such co-operative adjuvant action of alum and polymer particles can be exploited to improve the immunogenicity of other antigens.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/imunologia , Antígenos/administração & dosagem , Antígenos/imunologia , Portadores de Fármacos/metabolismo , Poliésteres/química , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Hidróxido de Alumínio/química , Hidróxido de Alumínio/farmacologia , Animais , Formação de Anticorpos/imunologia , Disponibilidade Biológica , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Feminino , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Ratos , Ratos Wistar , Toxoide Tetânico/administração & dosagem , Toxoide Tetânico/imunologia , Toxoide Tetânico/farmacocinética , Vacinação/métodos , Vacinas/administração & dosagem , Vacinas/química , Vacinas/imunologia
10.
Biomaterials ; 30(27): 4763-76, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19540583

RESUMO

Memory antibody response is the hallmark of long lasting immunity. In this study, we report the generation of memory antibody response while immunizing with single dose of polymer particle entrapped antigens. Immunization with admixture of alum and polylactide (PLA) polymer particles (2-8 microm) entrapping antigens not only elicited long lasting primary antibody response but also very high levels of memory antibody titer upon re-exposure to very small amount of soluble antigen. In the case of tetanus toxoid (TT), the memory antibody titers from PLA particle based immunization were almost four times higher than that achieved from two doses of alum adsorbed antigen and sustained at a higher level for a longer period of time. Memory antibody response was detected even after challenging the animals after 18 months of primary immunization. Similar enhanced memory antibody response was also observed in the case of immunization with PLA particle entrapping diphtheria toxoid (DT). Memory antibody response generated from polymeric formulations was highly antigen specific. Polymer particles with different release profile of antigen were used as a model system to evaluate the role of antigen on immunological memory. The results suggest that slow and continuous release of antigen from polymer particles plays a critical role in eliciting improved memory antibody response from single point immunization.


Assuntos
Formação de Anticorpos/imunologia , Antígenos/administração & dosagem , Antígenos/imunologia , Memória Imunológica/imunologia , Poliésteres/metabolismo , Animais , Especificidade de Anticorpos/imunologia , Linfócitos B/imunologia , Toxoide Diftérico/imunologia , Epitopos/imunologia , Feminino , Imunização , Cinética , Modelos Imunológicos , Nanopartículas/ultraestrutura , Porosidade , Ratos , Ratos Wistar , Propriedades de Superfície , Toxoide Tetânico/imunologia , Fatores de Tempo
11.
J Biomater Appl ; 24(4): 309-25, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18987018

RESUMO

PLGA and PLA microparticles entrapping insulin are prepared by solvent evaporation method and are evaluated in diabetes-induced rat for its efficacy in maintaining blood sugar level from a single intramuscular dose. In vitro release of insulin from PLGA and PLA microparticles are 75.35 +/- 1.73% and 67.536 +/- 2.23%, respectively in 168 h (7 days). Released insulin from polymer particles are mostly in monomeric form without aggregation. Optimal use of stabilizers during particle formulation helps in reducing protein denaturation and thus results in stabilized insulin-loaded polymer particles. Intramuscular administration of insulin-loaded PLGA (50 : 50) and PLA microparticles (equivalent to 25 IU insulin/kg of animal weight) in alloxaninduced diabetic rats result in 53.86 +/- 4.2% and 39.52 +/- 6.7% reduction in blood glucose level, respectively in 96 h. This effect continued up to 7 days in case of PLGA and PLA microparticles.


Assuntos
Sistemas de Liberação de Medicamentos , Infusões Parenterais , Insulina/análogos & derivados , Insulina/administração & dosagem , Insulina/metabolismo , Ácido Láctico/química , Ácido Poliglicólico/química , Polímeros/química , Animais , Diabetes Mellitus Experimental , Portadores de Fármacos/uso terapêutico , Feminino , Humanos , Hipoglicemia , Injeções Intramusculares , Insulina/uso terapêutico , Microesferas , Tamanho da Partícula , Poliésteres , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Ratos Wistar , Fatores de Tempo
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