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2.
Comput Math Methods Med ; 2020: 1352982, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32908574

RESUMO

The current emergence of coronavirus (SARS-CoV-2) puts the world in threat. The structural research on the receptor recognition by SARS-CoV-2 has identified the key interactions between SARS-CoV-2 spike protein and its host (epithelial cell) receptor, also known as angiotensin-converting enzyme 2 (ACE2). It controls both the cross-species and human-to-human transmissions of SARS-CoV-2. In view of this, we propose and analyze a mathematical model for investigating the effect of CTL responses over the viral mutation to control the viral infection when a postinfection immunostimulant drug (pidotimod) is administered at regular intervals. Dynamics of the system with and without impulses have been analyzed using the basic reproduction number. This study shows that the proper dosing interval and drug dose both are important to eradicate the viral infection.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Modelos Biológicos , Pneumonia Viral/tratamento farmacológico , Ácido Pirrolidonocarboxílico/análogos & derivados , Tiazolidinas/administração & dosagem , Número Básico de Reprodução , Betacoronavirus/genética , Betacoronavirus/imunologia , Simulação por Computador , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Relação Dose-Resposta a Droga , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Conceitos Matemáticos , Mutação , Pandemias , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Ácido Pirrolidonocarboxílico/administração & dosagem , Receptores Virais/fisiologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T Citotóxicos/imunologia
3.
APMIS ; 128(11): 593-602, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32870528

RESUMO

Induction of broad Th1 cellular immune responses and cytokines is crucial characteristics for vaccines against intracellular infections such as hepatitis C virus (HCV). Plants (especially oilseed tissues) and plant-immunomodulators (like oil bodies) offer cost-effective and scalable possibilities for the production of immunologically relevant and safe vaccine antigens and adjuvants, respectively. Herein, we provide data of the murine immunization by transgenic canola oilseed-derived HCV core protein (HCVcp) soluble extract (TSE) and Escherichia coli- derived rHCVcp in combination with Canola oil bodies (oil) compared to that of the Freund's (FA) adjuvant. Mice immunized by TSE+ oil developed both strong humeral (IgG) and Th1-biased cellular responses, manifested by high levels of IFN-γ and lower IgG1/IgG2a ratio and IL-4 secretion. Results of the intracellular cytokine staining indicated that TSE+ oil immunization in mice triggered both CD4+ and CD8+ T cells to release IFN-γ, while CD4+ cells were mostly triggered when FA was used. Analyses by qRT-PCR indicated that a combination of rHCVcp/TSE with oil body induced high levels of IL-10 cytokines compared to that of the FA adjuvant. These characteristics are important properties for the design of an HCV vaccine candidate and indicate the potential of Canola-derived antigen and oil bodies in addressing these concerns.


Assuntos
Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Células Th1/efeitos dos fármacos , Proteínas do Core Viral/administração & dosagem , Vacinas contra Hepatite Viral/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Hepacivirus/imunologia , Hepacivirus/patogenicidade , Hepatite C Crônica/imunologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Imunidade Celular/efeitos dos fármacos , Imunoglobulina G/biossíntese , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-10/biossíntese , Interleucina-10/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Óleo de Brassica napus/administração & dosagem , Óleo de Brassica napus/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Células Th1/imunologia , Células Th1/virologia , Proteínas do Core Viral/biossíntese , Proteínas do Core Viral/imunologia , Vacinas contra Hepatite Viral/biossíntese
4.
PLoS One ; 15(9): e0238476, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32877451

RESUMO

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMM) is a chronic, progressive, inflammatory and immune-mediated disease that affects the central nervous system and is characterized by episodes of neurological dysfunction followed by a period of remission. The pharmacological strategy aims to delay the progression of the disease and prevent relapse. Interferon beta and glatiramer are commonly used in the Brazilian public health system and are available to patients who meet the guideline criteria. The scenario of multiple treatments available and in development brings the need for discussion and evaluation of the technologies already available before the incorporation of new drugs. This study analyses the effectiveness of first-line treatment of RRMS measured by real-world evidence data, from the Brazilian National Health System (SUS). METHODS AND FINDINGS: We conducted a non-concurrent national cohort between 2000 and 2015. The study population consisted of 22,722 patients with RRMS using one of the following first-line drugs of interest: glatiramer or one of three presentations of interferon beta. Kaplan-Meier analysis was used to estimate the time to treatment failure. A univariate and multivariate Cox proportional hazard model was used to evaluate factors associated with treatment failure. In addition, patients were propensity score-matched (1:1) in six groups of comparative first-line treatments to evaluate the effectiveness among them. The analysis indicated a higher risk of treatment failure in female patients (HR = 1.08; P = 0,01), those with comorbidities at baseline (HR = 1.20; P<0,0001), in patients who developed comorbidities after starting treatment (i.e., rheumatoid arthritis-HR = 1.65; P<0,0001), those exclusive SUS patients (HR = 1.31; P<0,0001) and among patients using intramuscular interferon beta (IM ßINF-1a) (28% to 60% compared to the other three treatments; P<0,0001). Lower risk of treatment failure was found among patients treated with glatiramer. CONCLUSIONS: This retrospective cohort suggests that glatiramer is associated with greater effectiveness compared to the three presentations of interferon beta. When evaluating beta interferons, the results suggest that the intramuscular presentation is not effective in the treatment of multiple sclerosis.


Assuntos
Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Resultado do Tratamento , Adjuvantes Imunológicos/uso terapêutico , Adulto , Brasil/epidemiologia , Estudos de Coortes , Análise Custo-Benefício , Feminino , Acetato de Glatiramer/uso terapêutico , Humanos , Interferon beta/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Esclerose Múltipla/tratamento farmacológico , Modelos de Riscos Proporcionais , Estudos Retrospectivos
5.
PLoS Pathog ; 16(9): e1008764, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32881968

RESUMO

To augment HIV-1 pox-protein vaccine immunogenicity using a next generation adjuvant, a prime-boost strategy of recombinant modified vaccinia virus Ankara and multimeric Env gp145 was evaluated in macaques with either aluminum (alum) or a novel liposomal monophosphoryl lipid A (MPLA) formulation adsorbed to alum, ALFA. Binding antibody responses were robust and comparable between arms, while antibody-dependent neutrophil and monocyte phagocytotic responses were greatly enhanced by ALFA. Per-exposure vaccine efficacy against heterologous tier 2 SHIV mucosal challenge was 90% in ALFA-adjuvanted males (P = 0.002), while alum conferred no protection. Half of the ALFA-adjuvanted males remained uninfected after the full challenge series, which spanned seven months after the last vaccination. Antibody-dependent monocyte and neutrophil phagocytic responses both strongly correlated with protection. Significant sex differences in infection risk were observed, with much lower infection rates in females than males. In humans, MPLA-liposome-alum adjuvanted gp120 also increased HIV-1-specific phagocytic responses relative to alum. Thus, next-generation liposome-based adjuvants can drive vaccine elicited antibody effector activity towards potent phagocytic responses in both macaques and humans and these responses correlate with protection. Future protein vaccination strategies aiming to improve functional humoral responses may benefit from such adjuvants.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/prevenção & controle , Vacinas contra a SAIDS/uso terapêutico , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Adolescente , Adulto , Animais , Anticorpos Neutralizantes/imunologia , Método Duplo-Cego , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , Humanos , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Vacinas contra a SAIDS/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/imunologia , Adulto Jovem
6.
Adv Mater ; 32(40): e2004210, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32864794

RESUMO

For rapid response against the prevailing COVID-19 (coronavirus disease 19), it is a global imperative to exploit the immunogenicity of existing formulations for safe and efficient vaccines. As the most accessible adjuvant, aluminum hydroxide (alum) is still the sole employed adjuvant in most countries. However, alum tends to attach on the membrane rather than entering the dendritic cells (DCs), leading to the absence of intracellular transfer and process of the antigens, and thus limits T-cell-mediated immunity. To address this, alum is packed on the squalene/water interphase is packed, forming an alum-stabilized Pickering emulsion (PAPE). "Inheriting" from alum and squalene, PAPE demonstrates a good biosafety profile. Intriguingly, with the dense array of alum on the oil/water interphase, PAPE not only adsorbs large quantities of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antigens, but also harbors a higher affinity for DC uptake, which provokes the uptake and cross-presentation of the delivered antigens. Compared with alum-treated groups, more than six times higher antigen-specific antibody titer and three-fold more IFN-γ-secreting T cells are induced, indicating the potent humoral and cellular immune activations. Collectively, the data suggest that PAPE may provide potential insights toward a safe and efficient adjuvant platform for the enhanced COVID-19 vaccinations.


Assuntos
Adjuvantes Imunológicos/química , Vacinas Virais/química , Compostos de Alúmen/química , Animais , Antígenos Virais/química , Antígenos Virais/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Emulsões , Células HEK293 , Humanos , Interferon gama/metabolismo , Camundongos Endogâmicos BALB C , Pandemias , Pneumonia Viral/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia
7.
N Engl J Med ; 383(12): 1139-1148, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32877599

RESUMO

BACKGROUND: In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with BRAF V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit, longer-term data were needed. METHODS: We randomly assigned 870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapse-free survival. Here, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached. RESULTS: The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period. CONCLUSIONS: In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.).


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imidazóis/uso terapêutico , Melanoma/tratamento farmacológico , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/genética , Análise de Sobrevida
8.
Sheng Wu Gong Cheng Xue Bao ; 36(7): 1378-1385, 2020 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-32748595

RESUMO

Listeria monocytogenes (Lm) is zoonotic pathogen that can cause listeriosis, and vaccine is one of the effective methods to prevent this pathogen infection. In this study, we developed a novel vaccine that is a mixture of inactivated bacteria and Montanide™ ISA 61 VG, a mineral oil adjuvant, and evaluated the safety and immune response characteristics of this vaccine. The mice immunized with the ISA 61 VG adjuvant had high safety, and it could induce significantly higher titer of anti-listeriolysin O (LLO) antibody and higher value of IgG2a/IgG1 ratio compared with the group without the adjuvant. In particular, it could provide 100% immune protection against lethal doses of Lm challenge in mice. In summary, ISA 61VG adjuvant significantly enhanced the ability of inactivated listeria vaccine to induce humoral and cellular immune responses, thereby enhanced the protective immune response in the host, and it is a potential vaccine candidate for the prevention of Lm infection in humans and animals.


Assuntos
Adjuvantes Imunológicos , Proteínas Hemolisinas , Imunidade Celular , Listeria monocytogenes , Listeriose , Adjuvantes Imunológicos/farmacologia , Animais , Proteínas Hemolisinas/imunologia , Proteínas Hemolisinas/farmacologia , Imunidade Celular/efeitos dos fármacos , Listeria monocytogenes/imunologia , Listeriose/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Vacinas de Produtos Inativados/imunologia
9.
PLoS One ; 15(8): e0237218, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760143

RESUMO

Influenza is an infectious respiratory illness caused by influenza viruses. Despite yearly updates, the efficacy of influenza vaccines is significantly curtailed by the virus antigenic drift and antigenic shift. These constant changes to the influenza virus make-up also challenge the development of a universal flu vaccine, which requires conserved antigenic regions shared by influenza viruses of different subtypes. We propose that it is possible to bypass these challenges by the development of an influenza vaccine based on conserved proteins delivered in an adjuvanted nanoparticle system. In this study, we generated influenza nanoparticle constructs using trimethyl chitosan nanoparticles (TMC nPs) as the carrier of recombinant influenza hemagglutinin subunit 2 (HA2) and nucleoprotein (NP). The purified HA2 and NP recombinant proteins were encapsulated into TMC nPs to form HA2-TMC nPs and NP-TMC nPs, respectively. Primary human intranasal epithelium cells (HNEpCs) were used as an in vitro model to measure immunity responses. HA2-TMC nPs, NP-TMC nPs, and HA2-NP-TMC nPs (influenza nanoparticle constructs) showed no toxicity in HNEpCs. The loading efficiency of HA2 and NP into the TMC nPs was 97.9% and 98.5%, respectively. HA2-TMC nPs and NP-TMC nPs more efficiently delivered HA2 and NP proteins to HNEpCs than soluble HA2 and NP proteins alone. The induction of various cytokines and chemokines was more evident in influenza nanoparticle construct-treated HNEpCs than in soluble protein-treated HNEpCs. In addition, soluble factors secreted by influenza nanoparticle construct-treated HNEpCs significantly induced MoDCs maturation markers (CD80, CD83, CD86 and HLA-DR), as compared to soluble factors secreted by protein-treated HNEpCs. HNEpCs treated with the influenza nanoparticle constructs significantly reduced influenza virus replication in an in vitro challenge assay. The results indicate that TMC nPs can be used as influenza vaccine adjuvants and carriers capable of delivering HA2 and NP proteins to HNEpCs.


Assuntos
Adjuvantes Imunológicos/farmacologia , Quitosana/farmacologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/farmacologia , Influenza Humana/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Animais , Linhagem Celular , Células Cultivadas , Quitosana/administração & dosagem , Cães , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/administração & dosagem , Glicoproteínas de Hemaglutininação de Vírus da Influenza/farmacologia , Humanos , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Células Madin Darby de Rim Canino , Nanopartículas/administração & dosagem , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Proteínas de Ligação a RNA/administração & dosagem , Proteínas de Ligação a RNA/farmacologia , Proteínas do Core Viral/administração & dosagem , Proteínas do Core Viral/farmacologia
10.
Int J Nanomedicine ; 15: 5083-5095, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764938

RESUMO

Background: ß-glucans are chiral polysaccharides with well-defined immunological properties and supramolecular wrapping ability of its chiral feature. However, the exploitation of chiral properties of these nanoparticles in drug delivery systems was seldom conducted. Methods: ß-glucan molecules with different chain lengths were extracted from yeast Saccharomyces cerevisiae and thereafter modified. In a conformation transition process, these ß-glucan molecules were then self-assembled with anti-cancer drug doxorubicin into nanoparticles to construct drug delivery systems. The chiral interactions between the drug and carriers were revealed by circular dichroism spectra, ultraviolet and visible spectrum, fourier transform infrared spectroscopy, dynamic light scattering and transmission electron microscope. The immune-potentiation properties of modified ß-glucan nanoparticles were evaluated by analysis of the mRNA expression in RAW264.7 cell model. Further, the antitumor efficacy of the nanoparticles against the human breast cancer were studied in MCF-7 cell model by cellular uptake and cytotoxicity experiments. Results: ß-glucan nanoparticles can activate macrophages to produce immune enhancing cytokines (IL-1ß, IL-6, TNF-α, IFN-γ). A special chirality of the carriers in diameter of 50~160 nm can also associate with higher drug loading ability of 13.9% ~38.2% and pH-sensitive release with a change of pH from 7.4 to 5.0. Cellular uptake and cytotoxicity experiments also prove that the chiral-active ß-glucan nanoparticles can be used in anti-cancer nanomedicine. Conclusion: This work demonstrates that ß-glucans nanoparticles with special chiral feature which leading to strong immunopotentiation ability and high drug loading efficiency can be developed as a novel type of nanomedicine for anti-cancer treatment.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , beta-Glucanas/imunologia , Adjuvantes Imunológicos/química , Animais , Antineoplásicos/imunologia , Dicroísmo Circular , Portadores de Fármacos/química , Humanos , Células MCF-7 , Camundongos , Nanopartículas/química , Células RAW 264.7 , Saccharomyces cerevisiae/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo , beta-Glucanas/química
11.
Sr Care Pharm ; 35(9): 398-402, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32807264

RESUMO

Advanced age is associated with an increase in morbidity and mortality from influenza. Immunization is the best option to protect individuals against influenza and its complications. Older people are less likely than their younger counterparts to mount an appropriate immune response to influenza vaccines. The adjuvanted inactivated influenza vaccine quadrivalent (aIIV4) is designed to elicit a more robust immune response in older people compared with traditional inactivated influenza vaccines. The aIIV4 is indicated for active immunization against influenza caused by influenza virus subtypes A and types B contained in the vaccine and is licensed by the Food and Drug Administration for use in persons 65 years of age and older. The aIIV4 should be administered by intramuscular injection. Like other influenza vaccines, aIIV4 carries a warning regarding the occurrence of Guillain-Barré syndrome. The most common adverse reactions associated with aIIV4 are injection site pain, fatigue, headache, arthralgia, and myalgia.


Assuntos
Vacinas contra Influenza , Influenza Humana , Adjuvantes Imunológicos , Adjuvantes Farmacêuticos , Idoso , Idoso de 80 Anos ou mais , Humanos , Vacinas de Produtos Inativados
12.
PLoS Pathog ; 16(7): e1008609, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32702057

RESUMO

Primary infection of human herpesvirus 6B (HHV-6B) occurs in infants after the decline of maternal immunity and causes exanthema subitum accompanied by a high fever, and it occasionally develops into encephalitis resulting in neurological sequelae. There is no effective prophylaxis for HHV-6B, and its development is urgently needed. The glycoprotein complex gH/gL/gQ1/gQ2 (called 'tetramer of HHV-6B') on the virion surface is a viral ligand for its cellular receptor human CD134, and their interaction is thus essential for virus entry into the cells. Herein we examined the potency of the tetramer as a vaccine candidate against HHV-6B. We designed a soluble form of the tetramer by replacing the transmembrane domain of gH with a cleavable tag, and the tetramer was expressed by a mammalian cell expression system. The expressed recombinant tetramer is capable of binding to hCD134. The tetramer was purified to homogeneity and then administered to mice with aluminum hydrogel adjuvant and/or CpG oligodeoxynucleotide adjuvant. After several immunizations, humoral and cellular immunity for HHV-6B was induced in the mice. These results suggest that the tetramer together with an adjuvant could be a promising candidate HHV-6B vaccine.


Assuntos
Exantema Súbito/imunologia , Vacinas contra Herpesvirus/imunologia , Proteínas do Envelope Viral/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Exantema Súbito/virologia , Herpesvirus Humano 6 , Humanos , Camundongos , Camundongos Endogâmicos BALB C
13.
Proc Natl Acad Sci U S A ; 117(30): 17957-17964, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32661157

RESUMO

There is a need for improved influenza vaccines. In this study we compared the antibody responses in humans after vaccination with an AS03-adjuvanted versus nonadjuvanted H5N1 avian influenza virus inactivated vaccine. Healthy young adults received two doses of either formulation 3 wk apart. We found that AS03 significantly enhanced H5 hemagglutinin (HA)-specific plasmablast and antibody responses compared to the nonadjuvanted vaccine. Plasmablast response after the first immunization was exclusively directed to the conserved HA stem region and came from memory B cells. Monoclonal antibodies (mAbs) derived from these plasmablasts had high levels of somatic hypermutation (SHM) and recognized the HA stem region of multiple influenza virus subtypes. Second immunization induced a plasmablast response to the highly variable HA head region. mAbs derived from these plasmablasts exhibited minimal SHM (naive B cell origin) and largely recognized the HA head region of the immunizing H5N1 strain. Interestingly, the antibody response to H5 HA stem region was much lower after the second immunization, and this suppression was most likely due to blocking of these epitopes by stem-specific antibodies induced by the first immunization. Taken together, these findings show that an adjuvanted influenza vaccine can substantially increase antibody responses in humans by effectively recruiting preexisting memory B cells as well as naive B cells into the response. In addition, we show that high levels of preexisting antibody can have a negative effect on boosting. These findings have implications toward the development of a universal influenza vaccine.


Assuntos
Adjuvantes Imunológicos , Linfócitos B/imunologia , Reações Cruzadas/imunologia , Memória Imunológica , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Especificidade de Anticorpos/imunologia , Linfócitos B/metabolismo , Epitopos de Linfócito B/imunologia , Feminino , Humanos , Imunização Secundária , Masculino , Plasmócitos/imunologia , Plasmócitos/metabolismo
14.
Proc Natl Acad Sci U S A ; 117(30): 17543-17550, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32669433

RESUMO

Highly heterogenous cancers, such as triple-negative breast cancer (TNBC), remain challenging immunotherapeutic targets. Herein, we describe the synthesis and evaluation of immunotherapeutic liposomal spherical nucleic acids (SNAs) for TNBC therapy. The SNAs comprise immunostimulatory oligonucleotides (CpG-1826) as adjuvants and encapsulate lysates derived from TNBC cell lines as antigens. The resulting nanostructures (Lys-SNAs) enhance the codelivery of adjuvant and antigen to immune cells when compared to simple mixtures of lysates with linear oligonucleotides both in vitro and in vivo, and reduce tumor growth relative to simple mixtures of lysate and CpG-1826 (Lys-Mix) in both Py230 and Py8119 orthotopic syngeneic mouse models of TNBC. Furthermore, oxidizing TNBC cells prior to lysis and incorporation into SNAs (OxLys-SNAs) significantly increases the activation of dendritic cells relative to their nonoxidized counterparts. When administered peritumorally in vivo in the EMT6 mouse mammary carcinoma model, OxLys-SNAs significantly increase the population of cytotoxic CD8+ T cells and simultaneously decrease the population of myeloid derived suppressor cells (MDSCs) within the tumor microenvironment, when compared with Lys-SNAs and simple mixtures of oxidized lysates with CpG-1826. Importantly, animals administered OxLys-SNAs exhibit significant antitumor activity and prolonged survival relative to all other treatment groups, and resist tumor rechallenge. Together, these results show that the way lysates are processed and packaged has a profound impact on their immunogenicity and therapeutic efficacy. Moreover, this work points toward the potential of oxidized tumor cell lysate-loaded SNAs as a potent class of immunotherapeutics for cancers lacking common therapeutic targets.


Assuntos
Antígenos de Neoplasias/imunologia , Imunomodulação , Ácidos Nucleicos/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Adjuvantes Imunológicos , Animais , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Humanos , Imunoterapia , Camundongos , Oligodesoxirribonucleotídeos/imunologia , Oligonucleotídeos/imunologia , Oxirredução , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
16.
Bull Cancer ; 107(5S): S49-S55, 2020 Jun.
Artigo em Francês | MEDLINE | ID: mdl-32620207

RESUMO

Local and systemic immunotherapies are used for the management of bladder cancer in daily practice. BCG has been administered for almost 40 years in patients with non-muscle invasive bladder cancer (NMIBC). Despite its efficacy, disease progression is observed in nearly 30% of patients. Given the antitumor activity of immune checkpoint inhibitors in metastatic setting, these therapies are currently investigated in NMIBC. Pembrolizumab is now approved by the Food and Drug Administration (FDA) for the treatment of patients with BCG-unresponsive, high-risk, NMIBC with carcinoma in situ with or without papillary tumors who are ineligible for or have not elected to undergo cystectomy. Several phase 3 trials are ongoing to investigate the efficacy of PD(L)1 inhibitors combined with BCG such as ALBAN study in France.


Assuntos
Imunoterapia , Neoplasias da Bexiga Urinária/terapia , Adjuvantes Imunológicos/uso terapêutico , Administração Intravesical , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Vacina BCG/uso terapêutico , Humanos , Invasividade Neoplásica , Nivolumabe/uso terapêutico , Neoplasias da Bexiga Urinária/patologia
17.
Tohoku J Exp Med ; 251(3): 175-181, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32641644

RESUMO

The novel coronavirus disease 2019 (COVID-19) is now officially declared as a pandemic by the World Health Organization (WHO), and most parts of the world are taking drastic measures to restrict human movements to contain the infection. Millions around the world are wondering, if there is anything that could be done, other than maintaining high personal hygiene, and be vigilant of the symptoms, to reduce the spread of the disease and chances of getting infected, or at least to lessen the burden of the disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The National and International health agencies, including the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the WHO have provided clear guidelines for both preventive and treatment suggestions. In this article, I will briefly discuss, why keeping adequate zinc balance might enhance the host response and be protective of viral infections.


Assuntos
Betacoronavirus , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Zinco/fisiologia , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Fatores Etários , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Suplementos Nutricionais , Resistência à Doença/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Sistema Imunitário/efeitos dos fármacos , Micronutrientes/fisiologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Replicação Viral/efeitos dos fármacos , Zinco/administração & dosagem , Zinco/deficiência , Zinco/farmacologia
18.
Braz J Med Biol Res ; 53(8): e9886, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609262

RESUMO

The objective of this study was to compare the safety and efficacy of 0.2% hyaluronic acid (HA) topical gel and dexamethasone topical ointment in the treatment of recurrent aphthous ulcers (RAU) in children. This retrospective observational study included 104 patients who had more than two episodes of oral aphthous ulcers per year and were treated with HA (n=52) or dexamethasone (n=52) from August 15, 2014 to September 3, 2018. Therapy efficacy was evaluated based on the ulcer size and pain score before versus 7 days after either therapy. The paired t-test, chi-squared test, and independent t-test were utilized for statistical analyses. There was no significant difference in ulcer size or pain score between the HA and dexamethasone groups, on day 1 or day 7. Both treatments were tolerated well and no side effects were reported. No significant differences in body temperature, respiration rate, pulse, or systolic/diastolic blood pressure were observed between the start (day 1) and end of treatment (day 7), for either treatment. HA and dexamethasone showed similar efficacy in reducing ulcer size and pain scores, and were tolerated equally well in children with RAU. Future high-quality studies with larger numbers of patients are needed to confirm our findings.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Dexametasona/uso terapêutico , Ácido Hialurônico/uso terapêutico , Estomatite Aftosa/tratamento farmacológico , Criança , Feminino , Humanos , Masculino , Dor , Recidiva , Estudos Retrospectivos
19.
BMC Infect Dis ; 20(1): 493, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32650739

RESUMO

BACKGROUND: Toxoplasma gondii is an obligate intracellular parasite that can infect almost all warm-blooded animals, avian species and humans. Toxoplasmosis is asymptomatic in healthy individuals, whereas it may lead to death in immune suppressed or deficient patients. A vaccine against T. gondii is required to prevent consequences of the infection. The aim of this study is to generate a multivalent recombinant protein vaccine against T. gondii. METHODS: 49 previously discovered antigenic proteins of T gondii were evaluated by their expression level in E. coli and by comprehensive bioinformatics analyses to determine antigenic epitopes. Based on these analyses, six vaccine candidate proteins were selected to generate a hexavalent recombinant protein vaccine adjuvanted with Montanide ISA 50 V. Humoral and cellular immune responses were determined by flow cytometry and ELISA. Vaccinated mice were challenged with T. gondii Ankara strain tachyzoites. RESULTS: In mice vaccinated with hexavalent vaccine, strong total IgG (P < 0.0001) and IgG2a (P < 0.001) responses were induced compared to controls, the ratio of CD4+ and CD8+ T lymphocytes secreting IFN-γ increased, and significantly higher extracellular IFN-γ secretion was achieved compared to the controls (P < 0.001). The survival time of the vaccinated mice increased to 8.38 ± 2.13 days which was significantly higher than controls (P < 0.01). CONCLUSIONS: Altogether, these results show that the hexavalent vaccine which is developed for the first time against T. gondii induced strong and balanced Th1 and Th2 immune responses as well as conferred significant protection against challenge with lethal toxoplasmosis in murine model.


Assuntos
Adjuvantes Imunológicos/farmacologia , Vacinas Protozoárias/farmacologia , Toxoplasmose/prevenção & controle , Vacinas de DNA/farmacologia , Animais , Ensaio de Imunoadsorção Enzimática , Epitopos/genética , Epitopos/imunologia , Escherichia coli/genética , Feminino , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina G/sangue , Camundongos , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia , Vacinas Protozoárias/genética , Vacinas Protozoárias/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Toxoplasma/patogenicidade , Toxoplasmose/imunologia , Vacinas de DNA/imunologia
20.
Inflamm Res ; 69(9): 801-812, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32656668

RESUMO

During the current COVID-19 pandemic, the global ratio between the dead and the survivors is approximately 1 to 10, which has put humanity on high alert and provided strong motivation for the intensive search for vaccines and drugs. It is already clear that if we follow the most likely scenario, which is similar to that used to create seasonal influenza vaccines, then we will need to develop improved vaccine formulas every year to control the spread of the new, highly mutable coronavirus SARS-CoV-2. In this article, using well-known RNA viruses (HIV, influenza viruses, HCV) as examples, we consider the main successes and failures in creating primarily highly effective vaccines. The experience accumulated dealing with the biology of zoonotic RNA viruses suggests that the fight against COVID-19 will be difficult and lengthy. The most effective vaccines against SARS-CoV-2 will be those able to form highly effective memory cells for both humoral (memory B cells) and cellular (cross-reactive antiviral memory T cells) immunity. Unfortunately, RNA viruses constantly sweep their tracks and perhaps one of the most promising solutions in the fight against the COVID-19 pandemic is the creation of 'universal' vaccines based on conservative SARS-CoV-2 genome sequences (antigen-presenting) and unmethylated CpG dinucleotides (adjuvant) in the composition of the phosphorothioate backbone of single-stranded DNA oligonucleotides (ODN), which can be effective for long periods of use. Here, we propose a SARS-CoV-2 vaccine based on a lasso-like phosphorothioate oligonucleotide construction containing CpG motifs and the antigen-presenting unique ACG-containing genome sequence of SARS-CoV-2. We found that CpG dinucleotides are the most rare dinucleotides in the genomes of SARS-CoV-2 and other known human coronaviruses, and hypothesized that their higher frequency could be responsible for the unwanted increased lethality to the host, causing a 'cytokine storm' in people who overexpress cytokines through the activation of specific Toll-like receptors in a manner similar to TLR9-CpG ODN interactions. Interestingly, the virus strains sequenced in China (Wuhan) in February 2020 contained on average one CpG dinucleotide more in their genome than the later strains from the USA (New York) sequenced in May 2020. Obviously, during the first steps of the microevolution of SARS-CoV-2 in the human population, natural selection tends to select viral genomes containing fewer CpG motifs that do not trigger a strong innate immune response, so the infected person has moderate symptoms and spreads SARS-CoV-2 more readily. However, in our opinion, unmethylated CpG dinucleotides are also capable of preparing the host immune system for the coronavirus infection and should be present in SARS-CoV-2 vaccines as strong adjuvants.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/imunologia , Oligodesoxirribonucleotídeos/imunologia , Pneumonia Viral/imunologia , Vacinas Virais , Adjuvantes Imunológicos , Linfócitos B/virologia , Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Citocinas/imunologia , Genoma Viral , HIV/genética , Hepacivirus/genética , Humanos , Imunidade Humoral , Memória Imunológica , Inflamação , Mutação , Orthomyxoviridae/genética , Pandemias/prevenção & controle , Oligonucleotídeos Fosforotioatos/imunologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Linfócitos T/virologia
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