RESUMO
The present industry update covers the period 1-31 May 2020, with information sourced from company press releases, regulatory and patent agencies as well as scientific literature.
Assuntos
Sistemas de Liberação de Medicamentos/tendências , Vacinas Virais , Vacinas contra COVID-19 , Ensaios Clínicos como Assunto , Infecções por Coronavirus/prevenção & controle , Aprovação de Equipamentos , Indústria Farmacêutica , Humanos , Nanoestruturas , Vacinas Virais/administração & dosagem , Vacinas Virais/farmacocinética , Vacinas Virais/provisão & distribuiçãoRESUMO
Infectious bronchitis (IB) is a highly contagious respiratory disease of poultry, caused by the avian coronavirus infectious bronchitis virus (IBV). Currently, one of the most relevant genotypes circulating worldwide is IBV-QX (GI-19), for which vaccines have been developed by passaging virulent QX strains in embryonated chicken eggs. Here we explored the attenuated phenotype of a commercially available QX live vaccine, IB Primo QX, in specific pathogens free broilers. At hatch, birds were inoculated with QX vaccine or its virulent progenitor IBV-D388, and postmortem swabs and tissues were collected each day up to eight days post infection to assess viral replication and morphological changes. In the trachea, viral RNA replication and protein expression were comparable in both groups. Both viruses induced morphologically comparable lesions in the trachea, albeit with a short delay in the vaccinated birds. In contrast, in the kidney, QX vaccine viral RNA was nearly absent, which coincided with the lack of any morphological changes in this organ. This was in contrast to high viral RNA titers and abundant lesions in the kidney after IBV D388 infection. Furthermore, QX vaccine showed reduced ability to reach and replicate in conjunctivae and intestines including cloaca, resulting in significantly lower titers and delayed protein expression, respectively. Nephropathogenic IBVs might reach the kidney also via an ascending route from the cloaca, based on our observation that viral RNA was detected in the cloaca one day before detection in the kidney. In the kidney distal tubular segments, collecting ducts and ureter were positive for viral antigen. Taken together, the attenuated phenotype of QX vaccine seems to rely on slower dissemination and lower replication in target tissues other than the site of inoculation.
Assuntos
Vírus da Bronquite Infecciosa , Vacinas Virais/farmacocinética , Animais , Galinhas , Cloaca/virologia , Infecções por Coronavirus/prevenção & controle , Feminino , Vírus da Bronquite Infecciosa/imunologia , Vírus da Bronquite Infecciosa/patogenicidade , Vírus da Bronquite Infecciosa/fisiologia , Rim/patologia , Rim/virologia , Masculino , Distribuição Tecidual , Traqueia/patologia , Traqueia/virologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/farmacocinética , Vacinas Virais/administração & dosagem , Replicação ViralRESUMO
Recombinant viral vaccines expressing antigens of pathogenic microbes (e.g., HIV, Ebola virus, and malaria) have been designed to overcome the insufficient immune responses induced by the conventional vaccines. Our knowledge of and clinical experience with the new recombinant viral vaccines are insufficient, and a clear regulatory pathway is needed for the further development and evaluation of recombinant viral vaccines. In 2018, the research group supported by the Ministry of Health, Labour and Welfare, Japan (MHLW) published a concept paper to address the development of recombinant viral vaccines against infectious diseases. Herein we summarize the concept paper-which explains the Japanese regulatory concerns about recombinant viral vaccines-and provide a focus of discussion about the development of recombinant viral vaccines.
Assuntos
Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Vacinas Sintéticas/normas , Vacinas Virais/normas , Animais , Anticoncepcionais Masculinos/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Hospedeiro Imunocomprometido , Japão , Microrganismos Geneticamente Modificados , Controle de Qualidade , Distribuição Tecidual , Vacinas Sintéticas/farmacologia , Vacinas Virais/farmacocinética , Replicação Viral/fisiologia , Eliminação de Partículas ViraisRESUMO
Infectious laryngotracheitis (ILT) is an upper respiratory tract disease of chickens that is caused by infectious laryngotracheitis virus (ILTV), an alphaherpesvirus. This disease causes significant economic loses in poultry industries worldwide. Despite widespread use of commercial live attenuated vaccines, many poultry industries continue to experience outbreaks of disease caused by ILTV. Efforts to improve the control of this disease have resulted in the generation of new vaccine candidates, including ILTV mutants deficient in virulence factors. A glycoprotein G deletion mutant vaccine strain of ILTV (ΔgG ILTV), recently licenced as Vaxsafe ILT (Bioproperties Pty Ltd), has been extensively characterised in vitro and in vivo, but the minimum effective dose required to protect inoculated animals has not been determined. This study performed a vaccination and challenge experiment to determine the minimum dose of ΔgG ILTV that, when delivered by eye-drop to seven-day-old specific pathogen-free chickens, would protect the birds from a robust challenge with a virulent field strain of virus (class 9 ILTV). A dose of 10(3.8) plaque forming units was the lowest dose capable of providing a high level of protection against challenge, as measured by clinical signs of disease, tracheal pathology and virus replication after challenge. This study has shown that the ΔgG ILTV vaccine strain is capable of inducing a high level of protection against a virulent field virus at a commercially feasible dose. These results lay the foundations upon which a commercial vaccine can be developed, thereby offering the potential to provide producers with another important tool to help control ILTV.
Assuntos
Herpesvirus Galináceo 1/patogenicidade , Vacinação/métodos , Vacinas Atenuadas/farmacologia , Vacinas Atenuadas/farmacocinética , Animais , Galinhas/imunologia , Glicoproteínas/farmacologia , Soluções Oftálmicas/administração & dosagem , Doenças das Aves Domésticas/prevenção & controle , Vacinas/administração & dosagem , Proteínas do Envelope Viral/imunologia , Vacinas Virais/farmacocinética , Vacinas Virais/farmacologia , Fatores de Virulência , Replicação ViralRESUMO
UNLABELLED: : Mesenchymal stromal cells (MSCs) are being exploited as gene delivery vectors for various disease and injury therapies. We provide proof-of-concept that engineered MSCs can provide a useful, effective platform for protection against infectious disease. Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne pathogen affecting humans and equines and can be used in bio-warfare. No licensed vaccine or antiviral agent currently exists to combat VEEV infection in humans. Direct antibody administration (passive immunity) is an effective, but short-lived, method of providing immediate protection against a pathogen. We compared the protective efficacy of human umbilical cord perivascular cells (HUCPVCs; a rich source of MSCs), engineered with a transgene encoding a humanized VEEV-neutralizing antibody (anti-VEEV), to the purified antibody. In athymic mice, the anti-VEEV antibody had a half-life of 3.7 days, limiting protection to 2 or 3 days after administration. In contrast, engineered HUCPVCs generated protective anti-VEEV serum titers for 21-38 days after a single intramuscular injection. At 109 days after transplantation, 10% of the mice still had circulating anti-VEEV antibody. The mice were protected against exposure to a lethal dose of VEEV by an intramuscular pretreatment injection with engineered HUCPVCs 24 hours or 10 days before exposure, demonstrating both rapid and prolonged immune protection. The present study is the first to describe engineered MSCs as gene delivery vehicles for passive immunity and supports their utility as antibody delivery vehicles for improved, single-dose prophylaxis against endemic and intentionally disseminated pathogens. SIGNIFICANCE: Direct injection of monoclonal antibodies (mAbs) is an important strategy to immediately protect the recipient from a pathogen. This strategy is critical during natural outbreaks or after the intentional release of bio-weapons. Vaccines require weeks to become effective, which is not practical for first responders immediately deployed to an infected region. However, mAb recipients often require booster shots to maintain protection, which is expensive and impractical once the first responders have been deployed. The present study has shown, for the first time, that mesenchymal stromal cells are effective gene delivery vehicles that can significantly improve mAb-mediated immune protection in a single, intramuscular dose of engineered cells. Such a cell-based delivery system can provide extended life-saving protection in the event of exposure to biological threats using a more practical, single-dose regimen.
Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Neutralizantes/imunologia , Vírus da Encefalite Equina Venezuelana/patogenicidade , Encefalomielite Equina Venezuelana/prevenção & controle , Terapia Genética/métodos , Células-Tronco Mesenquimais/imunologia , Cordão Umbilical/citologia , Vacinas Virais/imunologia , Animais , Anticorpos Monoclonais Humanizados/biossíntese , Anticorpos Monoclonais Humanizados/genética , Anticorpos Neutralizantes/biossíntese , Anticorpos Neutralizantes/genética , Células Cultivadas , Vírus da Encefalite Equina Venezuelana/imunologia , Encefalomielite Equina Venezuelana/imunologia , Encefalomielite Equina Venezuelana/virologia , Feminino , Genótipo , Meia-Vida , Interações Hospedeiro-Patógeno , Humanos , Injeções Intramusculares , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/virologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Fenótipo , Estabilidade Proteica , Transfecção , Vacinas Virais/administração & dosagem , Vacinas Virais/genética , Vacinas Virais/farmacocinéticaRESUMO
Middle East respiratory syndrome (MERS), an emerging infectious disease caused by MERS coronavirus (MERS-CoV), has garnered worldwide attention as a consequence of its continuous spread and pandemic potential, making the development of effective vaccines a high priority. We previously demonstrated that residues 377-588 of MERS-CoV spike (S) protein receptor-binding domain (RBD) is a very promising MERS subunit vaccine candidate, capable of inducing potent neutralization antibody responses. In this study, we sought to identify an adjuvant that optimally enhanced the immunogenicity of S377-588 protein fused with Fc of human IgG (S377-588-Fc). Specifically, we compared several commercially available adjuvants, including Freund's adjuvant, aluminum, Monophosphoryl lipid A, Montanide ISA51 and MF59 with regard to their capacity to enhance the immunogenicity of this subunit vaccine. In the absence of adjuvant, S377-588-Fc alone induced readily detectable neutralizing antibody and T-cell responses in immunized mice. However, incorporating an adjuvant improved its immunogenicity. Particularly, among the aforementioned adjuvants evaluated, MF59 is the most potent as judged by its superior ability to induce the highest titers of IgG, IgG1 and IgG2a subtypes, and neutralizing antibodies. The addition of MF59 significantly augmented the immunogenicity of S377-588-Fc to induce strong IgG and neutralizing antibody responses as well as protection against MERS-CoV infection in mice, suggesting that MF59 is an optimal adjuvant for MERS-CoV RBD-based subunit vaccines.
Assuntos
Adjuvantes Imunológicos/farmacologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Glicoproteína da Espícula de Coronavírus/farmacologia , Vacinas Virais/farmacocinética , Adjuvantes Imunológicos/química , Animais , Anticorpos Antivirais/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Feminino , Humanos , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/farmacologia , Vacinas Virais/imunologiaRESUMO
One impediment to the successful oral vaccination in fish is the hostile stomach environment that antigens must cross. Furthermore, uptake of antigens from the gut to systemic distribution is required for induction of systemic immunity, the dynamics of which are poorly understood. In the present study, groups of Atlantic salmon parr were intubated with live or inactivated infectious pancreatic necrosis virus (IPNV), either orally or anally. At 1, 24 and 72 h post infection (p.i.), the fish were sacrificed. Serum was used for assessing IPNV by ELISA, while formalin-fixed head-kidney, spleen, liver and intestine tissues were used for the demonstration of antigens by immunohistochemistry. Both live and inactivated IPNV antigens were observed in enterocytes of the intestines and in immune cells of the head-kidneys and spleens of all groups. In the liver, no antigens were observed in any of the groups. Significantly higher serum antigen OD values (p < 0.04) were observed in orally- compared to anally-intubated fish. By contrast, no difference (p = 0.05) was observed in tissue antigens between these groups by immunohistochemistry. No significant difference (p = 0.05) in serum antigens was observed between groups intubated with live and inactivated IPNV, while in tissues, significantly more antigens (p < 0.03) were observe in the latter compared to the former. These findings demonstrate that both live and inactivated IPNV are taken up by enterocytes in the intestines of Atlantic salmon, likely by receptor-mediated mechanisms. Higher IPNV uptake by the oral compared to anal route suggests that both the anterior and posterior intestines are important for the uptake of the virus and that IPNV is resistant to gastric degradation of the Atlantic salmon stomach.
Assuntos
Antígenos Virais/imunologia , Vírus da Necrose Pancreática Infecciosa/fisiologia , Salmo salar/virologia , Vacinas Virais/imunologia , Vacinas Virais/farmacocinética , Administração Oral , Administração Retal , Estruturas Animais/química , Estruturas Animais/virologia , Animais , Antígenos Virais/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Vacinas Virais/administração & dosagemRESUMO
Mucosal application is the most common route of vaccination to prevent outbreaks of infectious diseases like Newcastle disease virus (NDV). To gain more knowledge about distribution and uptake of a vaccine after mucosal vaccination, we studied the distribution pattern of antigens after different mucosal routes of administration. Chickens were intranasally (i.n.), intratracheally (i.t.) or intraocularly (i.o.) inoculated with fluorescent beads and presence of beads in nasal-associated lymphoid tissue (NALT), Harderian gland (HG), conjunctiva-associated lymphoid tissue (CALT), trachea, lungs, air sacs, oesophagus and blood was characterized. The distribution patterns differed significantly between the three inoculation routes. After i.t. inoculation, the beads were mainly retrieved from trachea, NALT and lung. I.n. inoculation resulted in beads found mainly in NALT but detectable in all organs sampled. Finally, after i.o. inoculation, the beads were detected in NALT, CALT, HG and trachea. The highest number of beads was retrieved after i.n. inoculation. Development of novel vaccines requires a comprehensive knowledge of the mucosal immune system in birds in order to target vaccines appropriately and to provide efficient adjuvants. The NALT is likely important for the induction of mucosal immune responses. We therefore studied the phenotype of antigen-presenting cells isolated from NALT after i.n. inoculation with uncoated beads or with NDV-coated beads. Both types of beads were efficiently taken up and low numbers of bead+ cells were detected in all organs sampled. Inoculation with NDV-coated beads resulted in a preferential uptake by NALT antigen-presenting cells as indicated by high percentages of KUL01+-, MHC II+ and CD40+ bead+ cells.
Assuntos
Células Apresentadoras de Antígenos/metabolismo , Galinhas/imunologia , Imunidade nas Mucosas/fisiologia , Tecido Linfoide/metabolismo , Doença de Newcastle/prevenção & controle , Vírus da Doença de Newcastle/genética , Vacinas Virais/farmacocinética , Sacos Aéreos/metabolismo , Animais , Túnica Conjuntiva/metabolismo , Esôfago/metabolismo , Citometria de Fluxo , Fluorescência , Glândula de Harder/metabolismo , Pulmão/metabolismo , Microesferas , Estatísticas não Paramétricas , Traqueia/metabolismoAssuntos
Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Microinjeções/instrumentação , Agulhas , Absorção Cutânea/fisiologia , Vacinas Virais/administração & dosagem , Vacinas Virais/farmacocinética , Administração Cutânea , Animais , Desenho de Equipamento , Análise de Falha de Equipamento , Humanos , MacacaRESUMO
Both rectal and vaginal mucosal surfaces serve as transmission routes for pathogenic microorganisms. Vaccination through large intestinal mucosa, previously proven protective for both of these mucosal sites in animal studies, can be achieved successfully by direct intracolorectal (i.c.r.) administration, but this route is clinically impractical. Oral vaccine delivery seems preferable but runs the risk of the vaccine's destruction in the upper gastrointestinal tract. Therefore, we designed a large intestine-targeted oral delivery with pH-dependent microparticles containing vaccine nanoparticles, which induced colorectal immunity in mice comparably to colorectal vaccination and protected against rectal and vaginal viral challenge. Conversely, vaccine targeted to the small intestine induced only small intestinal immunity and provided no rectal or vaginal protection, demonstrating functional compartmentalization within the gut mucosal immune system. Therefore, using this oral vaccine delivery system to target the large intestine, but not the small intestine, may represent a feasible new strategy for immune protection of rectal and vaginal mucosa.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Intestino Grosso , Reto/imunologia , Vaccinia virus/imunologia , Vacínia/prevenção & controle , Vagina/imunologia , Vacinas Virais/administração & dosagem , Adjuvantes Imunológicos , Administração Oral , Sequência de Aminoácidos , Animais , Linfócitos T CD8-Positivos/imunologia , Feminino , Imunidade nas Mucosas , Intestino Grosso/virologia , Ácido Láctico , Lipopeptídeos , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Nanopartículas , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/imunologia , Especificidade de Órgãos , Ovário/virologia , Poli I-C , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ácidos Polimetacrílicos , Organismos Livres de Patógenos Específicos , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/farmacocinética , Vacínia/imunologia , Vaccinia virus/isolamento & purificação , Carga Viral , Vacinas Virais/imunologia , Vacinas Virais/farmacocinéticaRESUMO
To study the kinetics in vivo of a Hantaan virus DNA vaccine, we constructed a fusion DNA vaccine, pEGFP/S, by cloning the S segment of Hantavirus into the vector, pEGFP-C1, which encodes Green fluorescent protein EGFP. In this report, we provide evidence that pEGFP/S was distributed and persistently expressed for more than 60 days in several organs after inoculation. Our findings suggest that the persistent immune responses induced by a Hantaan virus DNA vaccine are likely due to the plasmid pEGFP/S deposited in vivo, which acts as a booster immunization.
Assuntos
Vírus Hantaan/genética , Vacinas de DNA/administração & dosagem , Vacinas de DNA/farmacocinética , Vacinas Virais/administração & dosagem , Vacinas Virais/farmacocinética , Animais , Feminino , Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Injeções Intramusculares , Camundongos , Camundongos Endogâmicos BALB C , Plasmídeos/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Coloração e Rotulagem/métodos , Fatores de TempoRESUMO
Nasal administration has emerged as a promising and attractive route for vaccination, especially for the prophylaxis of respiratory diseases. Our previous studies have shown that severe acute respiratory syndrome coronavirus (SARS-CoV) virus-like particles (VLPs) can be assembled using a recombinant baculovirus (rBV) expression system and such VLPs induce specific humoral and cellular immune responses in mice after subcutaneous injection. Here, we investigated mucosal immune responses to SARS-CoV VLPs in a mouse model. Mice were immunized in parallel, intraperitoneally or intranasally, with VLPs alone or with VLPs plus cytosine-phosphate-guanosine (CpG). Immune responses, including the production of SARS-CoV-specific serum immunoglobulin G (IgG) and secretory immunoglobulin A (sIgA), were determined in mucosal secretions and tissues. Both immunizations induced SARS-CoV-specific IgG, although the levels of IgG in groups immunized via the intraperitoneal (i.p.) route were higher. sIgA was detected in saliva in groups immunized intranasally but not in groups immunized intraperitoneally. CpG had an adjuvant effect on IgA production in genital tract washes when administered intranasally but only affected IgA production in faeces samples when administered intraperitoneally. In addition, IgA was also detected in mucosal tissues from the lung and intestine, while CpG induced an increased level of IgA in the intestine. Most importantly, neutralization antibodies were detected in sera after i.p. and intranasal (i.n.) immunizations. Secretions in genital tract washes from the i.n. group also showed neutralization activity. Furthermore, VLPs that were administered intraperitoneally elicited cellular immune responses as demonstrated by enzyme-linked immunospot (ELISPOT) assay analyses. In summary, our study indicates that mucosal immunization with rBV SARS-CoV VLPs represent an effective means for eliciting protective systemic and mucosal immune responses against SARS-CoV, providing important information for vaccine design.
Assuntos
Adjuvantes Imunológicos/farmacologia , Imunidade nas Mucosas/imunologia , Oligodesoxirribonucleotídeos/farmacocinética , Síndrome Respiratória Aguda Grave/imunologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/imunologia , Vacinas Virais/farmacocinética , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Baculoviridae , Modelos Animais de Doenças , Feminino , Imunidade nas Mucosas/efeitos dos fármacos , Imunização/métodos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/sangue , Síndrome Respiratória Aguda Grave/prevenção & controle , Vacinas Virais/genética , Vacinas Virais/imunologiaRESUMO
The HCV nonstructural protein 3 (NS3) and core protein are highly conserved among various HCV genotypes, and several B- and T-cell epitopes have been characterized with these antigens. The immunotherapeutic vaccine GI-5005, being developed by GlobeImmune Inc, is a Tarmogen (targeted molecular immunogen) consisting of recombinant Saccharomyces cerevisiae yeast expressing an HCV NS3-core fusion protein designed to elicit antigen-specific host CD4+ and CD8+ T-cell responses for the treatment of chronic HCV infection. GI-5005 has demonstrated robust immunogenicity in preclinical in vitro and in vivo models. In a phase Ib clinical trial, GI-5005 monotherapy was well tolerated and displayed efficacy in patients with chronic HCV infection. At the time of publication, interim data were available from a completed phase II trial that evaluated a triple therapy of GI-5005 in combination with the standard-of-care (SOC; PEGylated-IFNalpha and ribavirin) regimen, compared with the SOC regimen alone. Triple therapy resulted in improved early virological responses in all treatment-naïve patients. End-of-trial results, including data of sustained virological responses, are required to better evaluate the efficacy of GI-5005 for the improvement of viral clearance and to compare the efficacy of the agent with other approaches such as NS3 protease inhibitors.
Assuntos
Antivirais/uso terapêutico , Vetores Genéticos/genética , Hepatite C Crônica/tratamento farmacológico , Saccharomyces cerevisiae/genética , Vacinas Sintéticas/uso terapêutico , Proteínas Virais de Fusão/metabolismo , Proteínas não Estruturais Virais/metabolismo , Vacinas Virais/uso terapêutico , Antivirais/efeitos adversos , Ensaios Clínicos como Assunto , Contraindicações , Avaliação Pré-Clínica de Medicamentos , Hepatite C Crônica/imunologia , Humanos , Patentes como Assunto , Relação Estrutura-Atividade , Vacinas Sintéticas/efeitos adversos , Vacinas Virais/efeitos adversos , Vacinas Virais/farmacocinéticaRESUMO
A chicken embryo-adapted duck enteritis virus (DEV) strain is the most widely used vaccine against duck virus enteritis (DVE) infection. The kinetics of attenuated DEV vaccine was examined in tissues of ducklings vaccinated by the mucosal or systemic route at 20 days of age and sampled regularly up to 60 days post-vaccination (p.v.). Significant numbers of virus genomes in the lymphoid and other parenchymatous organs were first detected at 60 min p.v., and subsequently rose to peak levels during 90 min to 1 day p.v. independent of the route of vaccine administration. The peak level of vaccine virus in the individual parenchymatous organs of subcutaneously immunized ducklings was significantly higher than that of orally or nasally immunized ducklings. The route of vaccine administration had significant effect on the initial tissue distribution of vaccine virus in respiratory and digestive tracts. Vaccine viruses spread to digestive tract and trachea tissues by mucosal route, i.e. oral and nasal administration, early than that by subcutaneous route. The rapid early increase of vaccine virus levels in all samples examined followed by a steady decline from 90 min to 6 days p.v. The real-time PCR analysis of a variety of tissues is significant for further investigation of the mechanism of vaccinal protection, and the optimization of vaccination regimes.
Assuntos
Alphaherpesvirinae/fisiologia , Patos , Infecções por Herpesviridae/veterinária , Doenças das Aves Domésticas/virologia , Vacinas Virais/farmacocinética , Administração Intranasal , Administração Oral , Alphaherpesvirinae/imunologia , Animais , DNA Viral/biossíntese , DNA Viral/genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/prevenção & controle , Infecções por Herpesviridae/virologia , Injeções Subcutâneas , Reação em Cadeia da Polimerase/veterinária , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/prevenção & controle , Distribuição Aleatória , Distribuição Tecidual , Vacinação/métodos , Vacinação/veterinária , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/farmacocinética , Vacinas Virais/administração & dosagem , Replicação ViralRESUMO
The Vaccine Research Center has developed vaccine candidates for different diseases/infectious agents (including HIV-1, Ebola, and Marburg viruses) built on an adenovirus vector platform, based on adenovirus type 5 or 35. To support clinical development of each vaccine candidate, pre-clinical studies were performed in rabbits to determine where in the body they biodistribute and how rapidly they clear, and to screen for potential toxicities (intrinsic and immunotoxicities). The vaccines biodistribute only to spleen, liver (Ad5 only), and/or iliac lymph node (Ad35 only) and otherwise remain in the site of injection muscle and overlying subcutis. Though approximately 10(11) viral particles were inoculated, already by Day 9, all but 10(3) to 10(5) genome copies per mu g of DNA had cleared from the injection site muscle. By three months, the adenovector was cleared with, at most, a few animals retaining a small number of copies in the injection site, spleen (Ad5), or iliac lymph node (Ad35). This pattern of limited biodistribution and extensive clearance is consistent regardless of differences in adenovector type (Ad5 or 35), manufacturer's construct and production methods, or gene-insert. Repeated dose toxicology studies identified treatment-related toxicities confined primarily to the sites of injection, in certain clinical pathology parameters, and in body temperatures (Ad5 vectors) and food consumption immediately post-inoculation. Systemic reactogenicity and reactogenicity at the sites of injection demonstrated reversibility. These data demonstrate the safety and suitability for investigational human use of Ad5 or Ad35 adenovector-based vaccine candidates at doses of up to 2 x 10(11) given intramuscularly to prevent various infectious diseases.
Assuntos
Vacinas contra a AIDS/farmacocinética , Vacinas contra Ebola/farmacocinética , Ebolavirus/imunologia , HIV-1/imunologia , Marburgvirus/imunologia , Vacinas Virais/farmacocinética , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/imunologia , Vacinas contra a AIDS/toxicidade , Adenoviridae/classificação , Adenoviridae/genética , Adenoviridae/imunologia , Animais , Anticorpos Antivirais/sangue , DNA Viral/análise , Avaliação Pré-Clínica de Medicamentos , Vacinas contra Ebola/administração & dosagem , Vacinas contra Ebola/imunologia , Vacinas contra Ebola/toxicidade , Feminino , Vetores Genéticos/classificação , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Vetores Genéticos/farmacocinética , Infecções por HIV/prevenção & controle , Doença pelo Vírus Ebola/prevenção & controle , Humanos , Injeções Intramusculares , Masculino , Doença do Vírus de Marburg/prevenção & controle , Reação em Cadeia da Polimerase , Coelhos , Sorotipagem , Fatores de Tempo , Distribuição Tecidual , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Vacinas de DNA/farmacocinética , Vacinas de DNA/toxicidade , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia , Vacinas Virais/toxicidadeRESUMO
While a new generation of vaccine vectors has been developed for eliciting cellular immune responses, little is known about the optimal routes for their administration or about the ramifications of the kinetics of in vivo vaccine antigen expression for immunogenicity. We evaluated the kinetics of vaccine antigen expression by real-time in vivo photon imaging and showed dramatic differences in these kinetics using different vectors and different routes of administration. Further, using a gamma interferon enzyme-linked immunospot assay to measure T-lymphocyte immune responses, we observed an association between the kinetics of vaccine antigen expression in vivo and the magnitude of vaccine-elicited memory T-lymphocyte responses. These results highlight the utility of the real-time in vivo photon-imaging technology in evaluating novel immunization strategies and suggest an association between the kinetics of vaccine antigen clearance and the magnitude of vaccine-elicited T-lymphocyte memory immune responses.
Assuntos
Adenoviridae/imunologia , Linfócitos T/imunologia , Vaccinia virus/imunologia , Vacinas Virais/farmacocinética , Adenoviridae/genética , Animais , Antígenos Virais/biossíntese , Antígenos Virais/imunologia , Vias de Administração de Medicamentos , Feminino , Memória Imunológica , Luciferases/biossíntese , Luciferases/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacocinética , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Vacinas de DNA/farmacocinética , Vaccinia virus/genética , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologiaRESUMO
Vaccination is a proven public health initiative, however it is imperative in the context of increasing concerns about vaccine induced adverse reactions and a decreasing incidence of diseases they prevent that the optimal route for their administration is defined. Traditionally all vaccines were given by subcutaneous injection until it was recognized that adjuvanted vaccines given via this route induced an unacceptable rate of injection site reaction. Evidence-based medicine has been championed as a way of improving the quality of patient care. Application of this methodology to the route of administration of vaccines demonstrates that vaccines should be given by intramuscular injection in preference to subcutaneous injection as the intramuscular route is associated with better immune response and a lower rate of injection site reaction. The basis of this superiority is discussed.
Assuntos
Vias de Administração de Medicamentos , Vacinação/métodos , Vacinas/administração & dosagem , Administração Cutânea , Administração Intranasal , Administração Oral , Administração Retal , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/farmacocinética , Medicina Baseada em Evidências , Humanos , Injeções Subcutâneas , Vacinas/farmacocinética , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia , Vacinas Virais/farmacocinéticaRESUMO
The aim of this study was to investigate the subcutaneous tissue response to administration of a single dose of multi-component vaccine in the cat. Three groups of 15 cats were injected with one of three vaccine products with saline as a negative control. Cats in group A received non-adjuvanted vaccine; cats in group B received vaccine with a lipid-based adjuvant; whilst those in group C were vaccinated with a product adjuvanted with an alum-Quil A mixture. The vaccine and saline injection sites were sampled on days 7, 21 and 62 post-vaccination. Biopsies of these vaccine sites were examined qualitatively and scored semi-quantitatively for a series of parameters related to aspects of the inflammatory and tissue repair responses. These data were analysed statistically, including by principal component analysis. At all three time points of the experiment, there was significantly less inflammation associated with administration of non-adjuvanted vaccine (p=0.000). Although there was evidence of tissue repair by day 62 in all groups, those cats receiving adjuvanted vaccines had evidence of residual adjuvant material accumulated within macrophages at this late time point. The severity of tissue reactions may vary significantly in response to vaccines which include adjuvants or are non-adjuvanted.
Assuntos
Adjuvantes Imunológicos/farmacocinética , Tela Subcutânea/imunologia , Vacinas Virais/imunologia , Vacinas Virais/farmacocinética , Adjuvantes Imunológicos/farmacologia , Compostos de Alúmen/farmacocinética , Compostos de Alúmen/farmacologia , Animais , Calicivirus Felino/imunologia , Gatos , Vírus da Panleucopenia Felina/imunologia , Herpesviridae/imunologia , Inflamação/etiologia , Inflamação/imunologia , Saponinas de Quilaia , Saponinas/farmacocinética , Saponinas/farmacologia , Tela Subcutânea/patologia , Vacinas Combinadas/imunologia , Vacinas Combinadas/farmacocinética , Vacinas Combinadas/farmacologia , Vacinas Virais/farmacologiaRESUMO
A successful vaccine triggers the interaction of various cells of the immune system as does a regular immune response. It is thus necessary to introduce the vaccine antigens into an anatomic site where they will contact immune cells. The route of administration is thus critical for the outcome of vaccination. Intramuscular or subcutaneous injections are the most popular. Antigens injected intramuscularly can form persistent precipitates that are dissolved and re-absorbed relatively slowly. If injecting antigens is a quick, easy and reproducible way to vaccination, it requires trained personnel. Alternatives exist, through non-invasive formulations which allow administration by the patient or a third party with no particular expertise. The skin, especially its epidermal layer, is an accessible and competent immune environment and an attractive target for vaccine delivery, through transcutaneous delivery or immunostimulant patches. Mucosal immunization is another strategy: its major rationale is that organisms invade the body via mucosal surfaces. Therefore, local protection at mucosal surface as well as systemic defense is beneficial. Various formulations of mucosal vaccines have been developed, such as the Sabin oral polio vaccine (OPV), rotavirus vaccines, cold-adapted influenza vaccines or vaccine against typhoid fever. Thus we are entering in an era where mucosal and transcutaneous immunisation will play an important role in disease management. However, it has not been so easy to obtain regulatory approval for mucosal or transcutaneous formulations and needle-based vaccines continue to dominate the market.
Assuntos
Vacinação/métodos , Vacinas/administração & dosagem , Administração Cutânea , Administração Intranasal , Administração Oral , Administração Retal , Adulto , Aerossóis , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/farmacocinética , Criança , Vias de Administração de Medicamentos , Humanos , Imunidade nas Mucosas , Injeções Subcutâneas , Vacinas/farmacocinética , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia , Vacinas Virais/farmacocinéticaRESUMO
West Nile (WN) virus is an important cause of febrile exanthem and encephalitis. Since it invaded the U.S. in 1999, >19,000 human cases have been reported. The threat of continued epidemics has spurred efforts to develop vaccines. ChimeriVax-WN02 is a live, attenuated recombinant vaccine constructed from an infectious clone of yellow fever (YF) 17D virus in which the premembrane and envelope genes of 17D have been replaced by the corresponding genes of WN virus. Preclinical tests in monkeys defined sites of vaccine virus replication in vivo. ChimeriVax-WN02 and YF 17D had similar biodistribution but different multiplication kinetics. Prominent sites of replication were skin and lymphoid tissues, generally sparing vital organs. Viruses were cleared from blood by day 7 and from tissues around day 14. In a clinical study, healthy adults were inoculated with 5.0 log(10) plaque-forming units (PFU) (n = 30) or 3.0 log10 PFU (n = 15) of ChimeriVax-WN02, commercial YF vaccine (YF-VAX, n = 5), or placebo (n = 30). The incidence of adverse events in subjects receiving the vaccine was similar to that in the placebo group. Transient viremia was detected in 42 of 45 (93%) of ChimeriVax-WN02 subjects, and four of five (80%) of YF-VAX subjects. All subjects developed neutralizing antibodies to WN or YF, respectively, and the majority developed specific T cell responses. ChimeriVax-WN02 rapidly elicits strong immune responses after a single dose, and is a promising candidate warranting further evaluation for prevention of WN disease.