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1.
Cancer Sci ; 110(10): 3049-3060, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31390678

RESUMO

Heat shock protein 105 (HSP105) is overexpressed in many cancers, including colorectal cancer (CRC) and esophageal cancer (EC). We carried out a phase I clinical trial of HLA-A24- and HLA-A2-restricted HSP105 peptide vaccines in patients with CRC or EC. In this additional study of the trial, we examined the immunological efficacy of the novel vaccine. Thirty patients with advanced CRC or EC underwent HSP105 peptide vaccination. Immunological responses were evaluated by ex vivo and in vitro γ-interferon enzyme-linked immunospot assays and their correlation with patients' prognosis was analyzed. The HSP105 peptide vaccines induced peptide-specific CTLs in 15 of 30 patients. Among HLA-A24 patients (n = 15), 7 showed induction of CTLs only ex vivo, whereas among HLA-A2 patients (n = 15), 4 showed the induction ex vivo and 6 in vitro. Heat shock protein 105-specific CTL induction correlated with suppression of cancer progression and was revealed as a potential predictive biomarker for progression-free survival (P = .008; hazard ratio = 3.03; 95% confidence interval, 1.34-6.85) and overall survival (P = .025; hazard ratio = 2.72; 95% confidence interval, 1.13-6.52). Production of cytokines by HSP105 peptide-specific CTLs was observed at the injection sites (skin) and tumor tissues, suggesting that HSP105-specific CTLs not only accumulated at vaccination sites but also infiltrated tumors. Furthermore, we established 2 HSP105 peptide-specific CTL clones, which showed HSP105-specific cytokine secretion and cytotoxicity. Our results suggest that the HSP105 peptide vaccine could induce immunological effects in cancer patients and improve their prognosis.


Assuntos
Vacinas Anticâncer/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Proteínas de Choque Térmico HSP110/química , Proteínas de Choque Térmico HSP110/metabolismo , Adulto , Idoso , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Citocinas/metabolismo , Intervalo Livre de Doença , Neoplasias Esofágicas/imunologia , Feminino , Antígeno HLA-A2/metabolismo , Antígeno HLA-A24/metabolismo , Células Hep G2 , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia
2.
MBio ; 10(2)2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940710

RESUMO

Zika virus is a mosquito-borne flavivirus which can cause severe disease in humans, including microcephaly and other congenital malformations in newborns and Guillain-Barré syndrome in adults. There are currently no approved prophylactics or therapeutics for Zika virus; the development of a safe and effective vaccine is an urgent priority. Preclinical studies suggest that the envelope glycoprotein can elicit potently neutralizing antibodies. However, such antibodies are implicated in the phenomenon of antibody-dependent enhancement of disease. We have previously shown that monoclonal antibodies targeting the Zika virus nonstructural NS1 protein are protective without inducing antibody-dependent enhancement of disease. Here, we investigated whether the NS1 protein itself is a viable vaccine target. Wild-type mice were vaccinated with an NS1-expressing DNA plasmid followed by two adjuvanted protein boosters, which elicited high antibody titers. Passive transfer of the immune sera was able to significantly protect STAT2 knockout mice against lethal challenge by Zika virus. In addition, long-lasting NS1-specific IgG responses were detected in serum samples from patients in either the acute or the convalescent phase of Zika virus infection. These NS1-specific antibodies were able to functionally engage Fcγ receptors. In contrast, envelope-specific antibodies did not activate Fc-mediated effector functions on infected cells. Our data suggest that the Zika virus NS1 protein, which is expressed on infected cells, is critical for Fc-dependent cell-mediated immunity. The present study demonstrates that the Zika virus NS1 protein is highly immunogenic and can elicit protective antibodies, underscoring its potential for an effective Zika virus vaccine.IMPORTANCE Zika virus is a global public health threat that causes microcephaly and congenital malformations in newborns and Guillain-Barré syndrome in adults. Currently, no vaccines or treatments are available. While antibodies targeting the envelope glycoprotein can neutralize virus, they carry the risk of antibody-dependent enhancement of disease (ADE). In contrast, antibodies generated against the NS1 protein can be protective without eliciting ADE. The present study demonstrates the effectiveness of an NS1-based vaccine in eliciting high titers of protective antibodies against Zika virus disease in a mouse model. Sera generated by this vaccine can elicit Fc-mediated effector functions against Zika virus-infected cells. Lastly, we provide human data suggesting that the antibody response against the Zika virus NS1 protein is long-lasting and functionally active. Overall, our work will inform the development of a safe and effective Zika virus vaccine.


Assuntos
Anticorpos Antivirais/sangue , Proteínas não Estruturais Virais/imunologia , Vacinas Virais/imunologia , Infecção por Zika virus/prevenção & controle , Animais , Linhagem Celular , Modelos Animais de Doenças , Humanos , Imunidade Celular , Esquemas de Imunização , Imunização Passiva , Imunoglobulina G/sangue , Camundongos , Camundongos Knockout , Receptores Fc/metabolismo , Análise de Sobrevida , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Vacinas Virais/administração & dosagem
3.
Vet Microbiol ; 230: 7-13, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30827407

RESUMO

Necrotic enteritis (NE) is an economically important disease of broiler chickens that is caused primarily by Clostridium perfringens strains that produce the NetB toxin. It is controlled in North America principally through the application of in-feed antimicrobials, but alternative control methods, such as vaccination, are urgently needed. We previously identified a cluster of C. perfringens genes prevalent in disease-causing strains, denominated VR-10B, that is predicted to encode a pilus. The current study evaluated the ability of three predicted pilin structural subunits (CnaA, FimA, FimB) to protect against NE in two immunization studies. In the first study, young broiler chickens were immunized twice intramuscularly (i.m.) with CnaA or FimA, which resulted in only a weak serum antibody response, and no reduction in the severity of intestinal lesions following experimental challenge with C. perfringens strain CP1. In the second study, chickens were injected subcutaneously (s.c.) with CnaA, FimB, or a combination of all three proteins, on days 7, 14 and 19, which resulted in a marked antibody response specific to each antigen. Chickens immunized with either CnaA or FimB had significantly reduced NE lesion severity, whereas immunization with all three proteins in combination did not provide protection. Western blot experiments using serum from immunized birds were also performed, providing the first experimental evidence to suggest that this locus may in fact encode a functional pilus structure.


Assuntos
Vacinas Bacterianas/imunologia , Infecções por Clostridium/veterinária , Clostridium perfringens/imunologia , Enterite/veterinária , Proteínas de Fímbrias/imunologia , Doenças das Aves Domésticas/prevenção & controle , Animais , Anticorpos Antibacterianos/sangue , Vacinas Bacterianas/administração & dosagem , Galinhas/imunologia , Infecções por Clostridium/prevenção & controle , Enterite/microbiologia , Enterite/prevenção & controle , Proteínas de Fímbrias/administração & dosagem , Fímbrias Bacterianas/genética , Fímbrias Bacterianas/imunologia , Injeções Intramusculares , Intestinos/patologia , Doenças das Aves Domésticas/microbiologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia
4.
Microb Pathog ; 129: 206-212, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30772476

RESUMO

Streptococcus pneumoniae infection is associated with very high morbidity and mortality throughout the world. Vaccines are an effective measure for the reduction of S. pneumoniae infection. In particular, protein vaccines are attracting increasing attention because of their good immunogenicity and wide coverage of serotypes. Therefore, identifying effective protein vaccine targets is important for protein vaccine development. SP0148 is a promising protein vaccine target for S. pneumoniae and is capable of reducing S. pneumoniae colonization in the nasopharynx of mice through the IL-17A pathway. However, the protective effects of SP0148 in fatal pneumococcal infection have not been evaluated. This study used subcutaneous and nasal immunization routes to systematically evaluate the protective effects of the SP0148 protein in fatal pneumococcal infection. Subcutaneous and nasal mucosal immunization with recombinant SP0148 protein produced effective immune protection against infection with a lethal dose of S. pneumoniae and significantly prolonged survival time and increased the survival rate of mice. Furthermore, nasal immunization with SP0148 induced mouse splenocytes to secrete high levels of the cytokines IFN-γ and IL-17A. Both recombinant SP0148 protein and its antiserum inhibited the adhesion of S.pneumoniae D39 to A549 human lung epithelial cells in a dose-dependent manner. In summary, SP0148 induced mice to produce protective immune responses to fatal S. pneumoniae infection, and our results could contribute to the accumulating data on the use of SP0148 protein vaccines.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Vacinas Pneumocócicas/imunologia , Pneumonia Pneumocócica/prevenção & controle , Streptococcus pneumoniae/imunologia , Células A549 , Administração Intranasal , Animais , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/genética , Aderência Bacteriana , Proteínas de Bactérias/genética , Modelos Animais de Doenças , Células Epiteliais/microbiologia , Feminino , Humanos , Injeções Subcutâneas , Interferon gama/metabolismo , Interleucina-17/metabolismo , Leucócitos Mononucleares/imunologia , Camundongos Endogâmicos C57BL , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/genética , Streptococcus pneumoniae/fisiologia , Análise de Sobrevida , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
5.
Drug Dev Ind Pharm ; 45(6): 882-894, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30767591

RESUMO

Pulmonary infections are the most common cause of death globally. However, the development of mucosal vaccines that provide protective immunity against respiratory pathogens are limited. In contrast to needle-based vaccines, efficient vaccines that are delivered via noninvasive mucosal routes (such as via the lungs and nasal passage) produce both antigen-specific local mucosal IgA and systemic IgG protective antibodies. One major challenge in the development of pulmonary vaccines using subunit antigens however, is the production of optimal immune responses. Subunit vaccines therefore rely upon use of adjuvants to potentiate immune responses. While the lack of suitable mucosal adjuvants has hindered progress in the development of efficient pulmonary vaccines, particle-based systems can provide an alternative approach for the safe and efficient delivery of subunit vaccines. In particular, the rational engineering of particulate vaccines with optimal physicochemical characteristics can produce long-term protective immunity. These protect antigens against enzymatic degradation, target antigen presenting cells and initiate optimal humoral and cellular immunity. This review will discuss our current understanding of pulmonary immunology and developments in fabricating particle characteristics that may evoke potent and durable pulmonary immunity.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Pulmão/metabolismo , Mucosa Respiratória/metabolismo , Infecções Respiratórias/prevenção & controle , Vacinas/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacocinética , Administração por Inalação , Administração Intranasal/instrumentação , Animais , Inaladores de Pó Seco , Estudos de Viabilidade , Humanos , Imunogenicidade da Vacina , Pulmão/imunologia , Nanopartículas/química , Tamanho da Partícula , Permeabilidade , Mucosa Respiratória/imunologia , Infecções Respiratórias/microbiologia , Vacinas/imunologia , Vacinas/farmacocinética , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Vacinas de Subunidades/farmacocinética
6.
Cancer Immunol Immunother ; 68(3): 455-466, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30604041

RESUMO

Vaccines consisting of synthetic peptides representing cytotoxic T-lymphocyte (CTL) epitopes have long been considered as a simple and cost-effective approach to treat cancer. However, the efficacy of these vaccines in the clinic in patients with measurable disease remains questionable. We believe that the poor performance of peptide vaccines is due to their inability to generate sufficiently large CTL responses that are required to have a positive impact against established tumors. Peptide vaccines to elicit CTLs in the clinic have routinely been administered in the same manner as vaccines designed to induce antibody responses: injected subcutaneously and in many instances using Freund's adjuvant. We report here that peptide vaccines and poly-ICLC adjuvant administered via the unconventional intravenous route of immunization generate substantially higher CTL responses as compared to conventional subcutaneous injections, resulting in more successful antitumor effects in mice. Furthermore, amphiphilic antigen constructs such as palmitoylated peptides were shown to be better immunogens than long peptide constructs, which now are in vogue in the clinic. The present findings if translated into the clinical setting could help dissipate the wide-spread skepticism of whether peptide vaccines will ever work to treat cancer.


Assuntos
Vacinas Anticâncer/imunologia , Administração Intravenosa , Animais , Vacinas Anticâncer/administração & dosagem , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos/imunologia , Vacinação , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia
7.
J Microbiol Biotechnol ; 29(3): 489-499, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30691253

RESUMO

Subunit vaccines are safer and more stable than live vaccines although they have the disadvantage of eliciting poor immune response. To develop a subunit vaccine, an effective delivery system targeting the key elements of the protective immune response is a prerequisite. In this study, oxidized carbon nanospheres (OCNs) were used as a subunit vaccine delivery system and tuberculosis (TB) was chosen as a model disease. TB is among the deadliest infectious diseases worldwide and an effective vaccine is urgently needed. The ability of OCNs to deliver recombinant Mycobacterium tuberculosis (Mtb) proteins, Ag85B and HspX, into bone marrow derived macrophages (BMDMs) and dendritic cells (BMDCs) was investigated. For immunization, OCNs were mixed with the two TB antigens as well as the adjuvant monophosphoryl lipid A (MPL). The protective efficacy was analyzed in vaccinated mice by aerosol Mtb challenge with a virulent strain of Mtb and the bacterial burdens were measured. The results showed that OCNs are highly effective in delivering Mtb proteins into the cytosol of BMDMs and BMDCs. Upon immunization, this vaccine formula induced robust Th1 immune response characterized by cytokine profiles from restimulated splenocytes and specific antibody titer. More importantly, enhanced cytotoxic CD8⁺ T cell activation was observed. However, it did not reduce the bacteria burden in the lung and spleen from the aerosol Mtb challenge. Taken together, OCNs are highly effective in delivering subunit protein vaccine and induce robust Th1 and CD8⁺ T cell response. This vaccine delivery system is suitable for application in settings where cell-mediated immune response is needed.


Assuntos
Carbono/química , Sistemas de Liberação de Medicamentos/métodos , Nanosferas/química , Linfócitos T Citotóxicos/imunologia , Vacinas contra a Tuberculose , Tuberculose/prevenção & controle , Vacinas de Subunidades/química , Vacinas de Subunidades/imunologia , Aciltransferases/genética , Adjuvantes Imunológicos , Administração através da Mucosa , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Medula Óssea , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Imunidade Celular , Imunização , Pulmão/microbiologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/patogenicidade , Baço/microbiologia , Células Th1/efeitos dos fármacos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas Sintéticas
8.
FEMS Yeast Res ; 19(2)2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668686

RESUMO

In presently licensed vaccines, killed or attenuated organisms act as a source of immunogens except for peptide-based vaccines. These conventional vaccines required a mass culture of associated or related organisms and long incubation periods. Special requirements during storage and transportation further adds to the cost of vaccine preparations. Availability of complete genome sequence, well-established genetic, inherent natural adjuvant and non-pathogenic nature of yeast species viz. Saccharomyces cerevisiae, Pichia pastoris makes them an ideal model system for the development of vaccines both for public health and for on-farm consumption. In this review, we compile the work in this emerging field during last two decades with major emphases on S. cerevisiae and P. pastoris which are routinely used worldwide for expression of heterologous proteins with therapeutic value against infectious diseases along with possible use in cancer therapy. We also pointed towards the developments in use of whole recombinant yeast, yeast surface display and virus-like particles as a novel strategy in the fight against infectious diseases and cancer along with other aspects including suitability of yeast in vaccines preparations, yeast cell wall component as an immune stimulator or modulator and present status of yeast-based vaccines in clinical trials.


Assuntos
Portadores de Fármacos , Desenvolvimento de Medicamentos/tendências , Pichia/genética , Pichia/imunologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/imunologia , Vacinas Sintéticas/imunologia , Técnicas de Visualização da Superfície Celular , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/genética , Vacinas de Produtos Inativados/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/genética , Vacinas de Partículas Semelhantes a Vírus/imunologia
9.
Vet Microbiol ; 228: 112-118, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30593355

RESUMO

The present study was aimed to develop a safe and effective anti-Brucella subunit vaccine for mucosal protection against the respiratory exposure of Brucella infection. A chitosan-based Brucella nasal vaccine (BNV) was formulated using well-known Brucella immunogens, sodC, omp19, BLS and PrpA and tested against nasal Brucella challenge in BALB/c mice. The mice were intra-nasally vaccinated with sterile phosphate buffer saline (PBS), BNV or BNV plus Brucella LPS, and humoral (systemic IgG and mucosal IgA) and cell-mediated immune responses were analyzed. Results showed that mice vaccinated with either BNV or BNV plus LPS elicited significantly (p < 0.05) high IgG and IgA responses compared to the PBS control. The IgG responses were significantly (p < 0.05) higher than IgA levels, which showed almost comparable levels observed in either intestines or in lungs. Furthermore, the IgG and IgA responses against each individual component of the BNV formulation indicated that omp19 induced highest levels of both IgG and IgA levels than the other constituents of BNV formulation. Upon re-stimulation of the splenocytes with Brucella whole cell lysate, significantly (p < 0.05) high IFN-γ levels, lymphocyte proliferation, and CD4+ T cell responses were observed in mice vaccinated with BNV or BNV plus LPS. Upon sub-lethal nasal challenge with wild-type Brucella strain, vaccinated mice showed significant reduction of Brucella recovery in lungs and spleen compared to the PBS control. This study indicates that BNV formulation with or without Brucella LPS efficiently induced humoral and cell-mediated immune responses and conferred significant protection against the sub-lethal Brucella challenge.


Assuntos
Antígenos de Bactérias/imunologia , Vacina contra Brucelose/administração & dosagem , Brucella/imunologia , Brucelose/prevenção & controle , Administração Intranasal , Animais , Brucelose/microbiologia , Proliferação de Células , Feminino , Imunidade Celular , Imunidade Humoral , Imunização , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Baço/microbiologia , Linfócitos T/imunologia , Vacinas de Subunidades/administração & dosagem
10.
Appl Microbiol Biotechnol ; 102(17): 7499-7507, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29961099

RESUMO

Devastating outbreaks of porcine epidemic diarrhea (PED) started in China in late 2010 and rapidly spread to North America and Asia causing severe diarrhea and high mortality in neonatal piglets, indicating that a new generation of vaccine against porcine epidemic diarrhea virus (PEDV) is urgently needed. In the present study, to mimic the native spike (S) glycoprotein, a stable cell line producing the trimeric ectodomain of S glycoprotein of the PEDV Pintung-52 (PEDV-PT) strain was successfully established by incorporating T4 bacteriophage foldon sequence of fibritin trimerization domains at the C-terminal end and replacing the signal peptide of S protein with the tissue plasminogen activator signal peptide sequence at the N terminal end. The trimeric structure, bio-reactivity to PEDV-specific antibodies, and the N-glycosylation level of the recombinant S protein were characterized. To induce systemic and mucosal immunity, conventional 5-week-old piglets were immunized with the trimeric S glycoprotein combined with the B subunit of Escherichia coli heat-labile enterotoxin (LTB) by the intramuscular (IM) route. As compared with the control group, all piglets in the S protein-LTB immunized (IM PEDV S-LTB) group generated systemic PEDV S-specific IgG and neutralizing antibody in blood but a low level of fecal PEDV-specific IgA and limited protection against challenge of PEDV-PT strain. Our results suggest that the recombinant PEDV trimeric S glycoprotein could be a potential subunit vaccine candidate against PEDV, but IM immunization with LTB as the adjuvant provided insufficient protection. The development of a vaccine regimen for inducing mucosal immunity is an important task for generating a successful subunit vaccine against PEDVs.


Assuntos
Vírus da Diarreia Epidêmica Suína/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Virais/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Antivirais/sangue , Linhagem Celular , Enterotoxinas/imunologia , Temperatura Alta , Suínos , Ativador de Plasminogênio Tecidual/genética , Ativador de Plasminogênio Tecidual/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Vacinas Virais/administração & dosagem
11.
Vaccine ; 36(31): 4621-4632, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-29961605

RESUMO

HIV-1 diversity and latent reservoir are the major challenges for the development of an effective AIDS vaccine. It is well indicated that Gag-specific CD8+ T cells serve as the dominant host immune surveillance for HIV-1 control, but it still remains a challenge for vaccine design to induce broader and stronger cytotoxic T cell immunity against the virus. Genetic variation of the HIV-1 gag gene across different clades is one of the reasons for the reduction of antigenic epitope coverage. Here, we report an immunization strategy with heterologous vaccines expressing a mosaic Gag antigen aimed to increase antigenic breadth against a wider spectrum of HIV-1 strains. Priming using a DNA vaccine via in vivo electroporation, followed by boosting with a live replication-competent modified vaccinia TianTan (MVTT) vectored vaccine, elicited greater and broader protective Gag-specific immune responses in mice. Compared to DNA or MVTT homologous immunization, the heterologous DNA/MVTT vaccination resulted in higher frequencies of broadly reactive, Gag-specific, polyfunctional, long-lived cytotoxic CD8+ T cells, as well as increased anti-Gag antibody titer. Importantly, the DNA/MVTT heterologous vaccination induced protection against EcoHIV and mesothelioma AB1-Gag challenges. In summary, the stronger protective Gag-specific immunity induced by the heterologous regimen using two safe vectors shows promise for further development to enhance anti-HIV-1 immunity. Our study has important implications for immunogen design and the development of an effective HIV-1 heterologous vaccination strategy.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Vacinas de DNA/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Animais , Portadores de Fármacos , Feminino , Anticorpos Anti-HIV/sangue , Camundongos Endogâmicos BALB C , Resultado do Tratamento , Vacinas de DNA/administração & dosagem , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Vírus Vaccinia/genética , Vírus Vaccinia/crescimento & desenvolvimento , Produtos do Gene gag do Vírus da Imunodeficiência Humana/administração & dosagem
12.
Vaccine ; 36(31): 4610-4620, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-29958739

RESUMO

BACKGROUND: Adjuvanted herpes zoster (HZ) subunit vaccine is recommended for adults aged ≥50 years. This study aimed to investigate cost-effectiveness of HZ subunit vaccine for older adults at different age in Hong Kong. METHODS: A life-long Markov model was designed to simulate outcomes of four alternatives: Vaccination at model entry (age 50 years); deferring vaccination to 60 years; deferring vaccination to 70 years; and no vaccination. Outcome measures included direct cost, indirect cost, HZ and post-herpetic neuralgia incidences, quality-adjusted life years (QALYs) loss, and incremental cost per QALY saved (ICER). Model clinical inputs were derived from literature. HZ treatment costs were collected from a cohort of HZ patients (n = 218). One-way and probabilistic sensitivity analyses were performed. RESULTS: In base-case analysis, vaccination at 50 years showed highest QALYs saved and increment cost (0.00258; USD166), followed by deferring to 60 years (0.00215 QALYs saved; USD102) and deferring to 70 years (0.00134 QALYs; USD62) when comparing to no vaccination. ICERs of vaccination arms versus no vaccine (46,267-64,341 USD/QALY) were between 1-3 × gross domestic product (GPD) per capita in Hong Kong (USD43,530-USD130,590). One-way sensitivity analyses found vaccine cost to be the common and most influential parameter for ICER of each vaccination strategy to become <1 × GDP per capita. In probabilistic sensitivity analysis, vaccination at 50 years, deferring to 60 years and 70 years were accepted as cost-effective in 90% of time at willingness-to-pay (WTP) of 78,400 USD/QALY, 57,680 USD/QALY and 53,760 USD/QALY, respectively. CONCLUSIONS: Cost-effectiveness of each strategy is highly subject to the vaccine cost and WTP threshold per QALY saved.


Assuntos
Análise Custo-Benefício , Vacina contra Herpes Zoster/administração & dosagem , Vacina contra Herpes Zoster/economia , Herpes Zoster/economia , Herpes Zoster/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Herpes Zoster/epidemiologia , Hong Kong/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Qualidade de Vida , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/economia
13.
Vaccine ; 36(29): 4228-4235, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29891346

RESUMO

PEDV variants, causing severe diarrhea in neonatal suckling piglets with a mortality rate up to 100%, have being epidemic since late 2010 in china. To meet the pressing need of safe and cost-efficient PED maternal vaccines against PEDV variant, we vaccinated growing piglets with a flagellin-adjuvanted PED vaccine rSF-COE-3D by injection at Houhai acupoint. The vaccination not only enhanced the antibody responses of serum IgG/IgA, mucosal IgA and serum neutralizing antibody, but also improved the production of IFN-γ and IL-4. Moreover, rSF-COE-3D could provide a better protection against the challenge of a high pathogenic PEDV variant, with less diarrhea pigs, less pigs with detectable PEDV shed, lower rank values of feces and less apparent lesions and inflammation in duodenum of the PEDV infected pigs. The improved protective efficiency of rSF-COE-3D compared with COE was mostly benefited from the enhanced production of serum IgA, mucosal IgA in feces and serum neutralizing antibody titers. Taken together, our data suggest that rSF-COE-3D would be a novel efficient PED vaccine.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Infecções por Coronavirus/veterinária , Flagelina/administração & dosagem , Vírus da Diarreia Epidêmica Suína/imunologia , Doenças dos Suínos/prevenção & controle , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , China , Infecções por Coronavirus/patologia , Infecções por Coronavirus/prevenção & controle , Imunidade nas Mucosas , Imunoglobulina A/análise , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Interferon gama/metabolismo , Interleucina-4/metabolismo , Leucócitos Mononucleares/imunologia , Suínos , Doenças dos Suínos/patologia , Resultado do Tratamento , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Vacinas Virais/administração & dosagem
14.
Adv Exp Med Biol ; 1045: 271-296, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29896672

RESUMO

The development of a cytomegalovirus (CMV) vaccine has become a top priority due to its potential cost-effectiveness and associated public health benefits. However, there are a number of challenges facing vaccine development including the following: (1) CMV has many mechanisms for evading immune responses , and natural immunity is not perfect, (2) the immune correlates for protection are unclear, (3) a narrow range of CMV hosts limits the value of animal models, and (4) the placenta is a specialized organ formed transiently and its immunological status changes with time. In spite of these limitations, several types of CMV vaccine candidate, including live-attenuated, DISC , subunit, DNA, vectored, and peptide vaccines, have been developed or are currently under development. The recognition of the pentameric complex as the major neutralization target and identification of various strategies to block viral immune response evasion mechanisms have opened new avenues to CMV vaccine development. Here, we discuss the immune correlates for protection, the characteristics of the various vaccine candidates and their clinical trials, and the relevant animal models.


Assuntos
Infecções por Citomegalovirus/prevenção & controle , Vacinas contra Citomegalovirus/imunologia , Citomegalovirus/imunologia , Animais , Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Vacinas contra Citomegalovirus/administração & dosagem , Vacinas contra Citomegalovirus/genética , Humanos , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia
15.
J Virol ; 92(16)2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29899087

RESUMO

Herpes simplex virus 1 (HSV-1) is a prevalent human pathogen that infects the cornea, causing potentially blinding herpetic disease. A clinical herpes vaccine is still lacking. In the present study, a novel prime/pull vaccine was tested in a human leukocyte antigen (HLA) transgenic rabbit model of ocular herpes (HLA Tg rabbits). Three peptide epitopes were selected, from the HSV-1 membrane glycoprotein C (UL44400-408), the DNA replication binding helicase (UL9196-204), and the tegument protein (UL25572-580), all preferentially recognized by CD8+ T cells from "naturally protected" HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who never had recurrent corneal herpetic disease). HLA Tg rabbits were immunized with a mixture of these three ASYMP CD8+ T cell peptide epitopes (UL44400-408, UL9196-204, and UL25572-580), which were delivered subcutaneously with CpG2007 adjuvant (prime). Fifteen days later, half of the rabbits received a topical ocular treatment with a recombinant neurotropic adeno-associated virus type 8 (AAV8) vector expressing the T cell-attracting CXCL10 chemokine (pull). The frequency and function of HSV-specific CD8+ T cells induced by the prime/pull vaccine were assessed in the peripheral blood, cornea, and trigeminal ganglion (TG). Compared to the cells generated in response to peptide immunization alone, the peptide/CXCL10 prime/pull vaccine generated frequent polyfunctional gamma interferon-positive (IFN-γ+) CD107+ CD8+ T cells that infiltrated both the cornea and TG. CD8+ T cell mobilization into the cornea and TG of prime/pull-vaccinated rabbits was associated with a significant reduction in corneal herpesvirus infection and disease following an ocular HSV-1 (strain McKrae) challenge. These findings draw attention to the novel prime/pull vaccine strategy for mobilizing antiviral CD8+ T cells into tissues to protect against herpesvirus infection and disease.IMPORTANCE There is an urgent need for a vaccine against widespread herpes simplex virus infections. The present study demonstrates that immunization of HLA transgenic rabbits with a peptide/CXCL10 prime/pull vaccine triggered mobilization of HSV-specific CD8+ T cells locally into the cornea and TG, the sites of acute and latent herpesvirus infections, respectively. Mobilization of antiviral CD8+ T cells into the cornea and TG of rabbits that received the prime/pull vaccine was associated with protection against ocular herpesvirus infection and disease following an ocular HSV-1 challenge. These results highlight the importance of the prime/pull vaccine strategy to bolster the number and function of protective CD8+ T cells within infected tissues.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Quimiocina CXCL10/metabolismo , Córnea/imunologia , Vacinas contra o Vírus do Herpes Simples/imunologia , Ceratite Herpética/prevenção & controle , Subpopulações de Linfócitos T/imunologia , Gânglio Trigeminal/imunologia , Animais , Animais Geneticamente Modificados , Quimiocina CXCL10/administração & dosagem , Modelos Animais de Doenças , Epitopos/imunologia , Antígenos HLA/genética , Antígenos HLA/metabolismo , Vacinas contra o Vírus do Herpes Simples/administração & dosagem , Humanos , Interferon gama/análise , Ceratite Herpética/patologia , Ceratite Herpética/virologia , Proteína 1 de Membrana Associada ao Lisossomo/análise , Coelhos , Simplexvirus/imunologia , Simplexvirus/isolamento & purificação , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Carga Viral
16.
Drug Deliv ; 25(1): 1319-1327, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29869539

RESUMO

In the past 40 years, the nanoparticle drug delivery system for tumor peptide vaccines has been widely studied which also reached a splendid result. Nanomaterial can enhance the targeting of vaccines, help vaccines enter the cells and trigger immune response by themselves. They also help in increasing cellular uptake, improving permeability and efficacy. Currently, several categories of nanopreparation, such as liposome, polymeric micelle, polymeric nanoparticle, gold nanoparticle and so on, are proved that they are appropriate for peptide vaccines. This review we discussed the possible mechanisms of nanomaterial's action on the regulation of immunological functions and several major applications of this advanced drug delivery system for tumor peptide vaccine.


Assuntos
Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/química , Portadores de Fármacos/química , Nanopartículas/química , Peptídeos/química , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/química , Animais , Sistemas de Liberação de Medicamentos/métodos , Humanos , Peptídeos/administração & dosagem
17.
J Appl Microbiol ; 125(4): 997-1007, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29877008

RESUMO

AIMS: The aim of this study was to screen vaccine candidates from virulence factors of Streptococcus iniae in flounder model. METHODS AND RESULTS: The immunogenicity of recombinant phosphoglucomutase (rPGM) and rCAMP factor was confirmed by Western blot. The percentage of surface membrane immunoglobulin-positive (sIg+ ) lymphocytes in peripheral blood leucocytes, the specific and total serum IgM and the activity of acid phosphatase (ACP) and peroxidase (POD) in flounder were determined with flow cytometry, ELISA and commercial enzyme activity kits, respectively, after intraperitoneal immunization with rPGM and rCAMP factor. The results showed that rPGM and rCAMP factor could induce significant rise in sIg+ lymphocytes, specific serum IgM and activities of ACP and POD. Additionally, the relative percent survival rate of the vaccinated flounder was 64 and 54% in challenge experiment using S. iniae, respectively. These results indicated that rPGM and rCAMP factor could evoke humoural and innate immune response in flounder and provide high-efficiency immunoprotection against S. iniae infection. CONCLUSIONS: Phosphoglucomutase (PGM) and CAMP factor were promising vaccine candidates against S. iniae in flounder. SIGNIFICANCE AND IMPACT OF THE STUDY: Phosphoglucomutase and CAMP factor have the potential to be vaccine candidates, which provide important information for us to develop the effective subunit vaccines, especially the multivaccine, against S .iniae in aquaculture.


Assuntos
Proteínas de Bactérias/imunologia , Vacinas Bacterianas/imunologia , Doenças dos Peixes/prevenção & controle , Proteínas Hemolisinas/imunologia , Fosfoglucomutase/imunologia , Infecções Estreptocócicas/veterinária , Streptococcus iniae/imunologia , Vacinas de Subunidades/imunologia , Animais , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/genética , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/genética , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Linguado/microbiologia , Proteínas Hemolisinas/administração & dosagem , Proteínas Hemolisinas/genética , Imunidade Inata , Fosfoglucomutase/administração & dosagem , Fosfoglucomutase/genética , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/prevenção & controle , Streptococcus iniae/enzimologia , Streptococcus iniae/genética , Vacinação , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética
18.
Vaccine ; 36(29): 4287-4297, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29885770

RESUMO

Human adenoviruses (AdVs) have been extensively studied as vectors for gene therapy and vaccination. However, little attention has been paid to AdV vaccine development and treatment. Currently, there is a lack of information concerning the immunogenicity of AdV major capsid proteins. Here, using AdV7 as a model, we compared the immunogenicity and protection efficacy of its three major capsid proteins in DNA forms, pFiber, pHexon and pPenton, on a mouse model. Quantification of antigen-specific antibodies showed that pHexon induced highest IgG in sera while pPenton induced highest IgA in respiratory mucosae. A neutralization assay revealed that pPenton elicited the highest neutralizing activity against the homologous AdV7 in both sera and bronchoalveolar lavages (BALs). In addition, sera and BALs from mice immunized with either of the three constructs had cross-neutralizing activities against the heterologous AdV3. Furthermore, pHexon and pPenton induced Th1/2- and Th1/17-biased cellular responses, respectively, with pFiber being the weakest in the induction of cellular responses. Virus challenge assay showed that, pPenton group had the fastest virus clearance rate, followed by pFiber and pHexon groups. Likewise, the inflammation in the lung was well controlled in pPenton group against virus challenge. Taken together, our data demonstrate that penton base is better than fiber and hexon as a vaccine candidate against AdVs. Our findings provide important information for the development of subunit vaccines against AdVs.


Assuntos
Infecções por Adenoviridae/prevenção & controle , Adenoviridae/imunologia , Vacinas contra Adenovirus/imunologia , Proteínas do Capsídeo/imunologia , Vacinas contra Adenovirus/administração & dosagem , Animais , Anticorpos Antivirais/sangue , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Feminino , Imunoglobulina A/análise , Imunoglobulina G/sangue , Camundongos Endogâmicos BALB C , Testes de Neutralização , Mucosa Respiratória/imunologia , Soro/imunologia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Viremia/prevenção & controle
19.
Vaccine ; 36(28): 4023-4031, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29861179

RESUMO

Vaccination can significantly reduce worldwide morbidity and mortality to infectious diseases, thereby reducing the health burden as a result of microbial infections. Effective vaccines contain three components: a delivery system, an antigenic component of the pathogen, and an adjuvant. With the growing use of purely recombinant or synthetic antigens, there is a need to develop novel adjuvants that enhance the protective efficacy of a vaccine against infection. Using a structure-activity relationship (SAR) model, we describe here the synthesis of a novel TLR4 ligand adjuvant compound, BECC438, by bacterial enzymatic combinatorial chemistry (BECC). This compound was identified using an in vitro screening pipeline consisting of (i) NFκB activation and cytokine production by immortalized cell lines, (ii) cytokine production by primary human PBMCs, and (iii) upregulation of surface costimulatory markers by primary human monocyte-derived dendritic cells. Using this SAR screening regimen, BECC438 was shown to produce an innate immune activation profile comparable to the well-characterized TLR4 agonist adjuvant compound, phosphorylated hexa-acyl disaccharide (PHAD). To evaluate the in vivo adjuvant activity of BECC438, we used the known protective Yersinia pestis (Yp) antigen, rF1-V, in a murine prime-boost vaccination schedule followed by lethal challenge. In addition to providing protection from lethal challenge, BECC438 stimulated production of higher levels of rF1-V-specific total IgG as compared to PHAD after both prime and boost vaccinations. Similar to PHAD, BECC438 elicited a balanced IgG1/IgG2c response, indicative of active TH2/TH1-driven immunity. These data demonstrate that the novel BECC-derived TLR4L adjuvant, BECC438, elicits cytokine profiles in vitro similar to PHAD, induces high antigen-specific immune titers and a TH1-associated IgG2c immune titer skew, and protects mice against a lethal Yp challenge.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Lipídeo A/química , Vacina contra a Peste/imunologia , Peste/prevenção & controle , Receptor 4 Toll-Like/agonistas , Adjuvantes Imunológicos/química , Animais , Anticorpos Antibacterianos/sangue , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Imunoglobulina G/sangue , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Camundongos Endogâmicos C57BL , Vacina contra a Peste/administração & dosagem , Relação Estrutura-Atividade , Análise de Sobrevida , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia
20.
Vet Microbiol ; 219: 40-48, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29778203

RESUMO

Bluetongue virus (BTV), a vector-borne pathogen, is the causative agent of bluetongue disease in ruminants. In view of the recent emergence of BTV in regions previously known to be free from the disease and/or specific serotypes or strains, optimization of the currently available vaccination strategies to control the spread of vector-borne bluetongue is crucial. The main objective of the current study was to develop a subunit vaccine candidate targeting BTV-16, a strain previously isolated in China from sheep with obvious clinical signs. To this end, five polyhistidine-tagged recombinant proteins (BTV-16 VP2, VP3, VP7, NS2 and a truncated version of VP5 (VP5-41amino acids) were expressed using the baculovirus or Escherichia coli expression system for characterization of protective activity. To determine ovine and murine immune responses to the five proteins, sheep and mice were immunized twice at 4- and 2-week intervals, respectively, with one of two different protein combinations in MontanideTM ISA201 VG adjuvant or placebo. Data from the competitive enzyme linked immunosorbent assay revealed significantly higher antibody titers in immunized than control animals. Expressed VP5 and NS2 induced a protein-specific humoral response. Interestingly, a serum neutralization test against the BTV-1 serotype showed promising cross-serotype immune response by the vaccine. Based on the collective data, we suggest that these recombinant purified proteins present promising candidates for the design of effective novel vaccines against BTV.


Assuntos
Anticorpos Antivirais/sangue , Vírus Bluetongue/imunologia , Bluetongue/prevenção & controle , Vacinas de Subunidades/imunologia , Proteínas Virais/imunologia , Vacinas Virais/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Baculoviridae/genética , Bluetongue/imunologia , Bluetongue/virologia , Proteínas do Capsídeo/administração & dosagem , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Ensaio de Imunoadsorção Enzimática , Escherichia coli/genética , Imunização/métodos , Camundongos , Sorogrupo , Ovinos/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Proteínas Virais/administração & dosagem , Proteínas Virais/genética , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
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