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1.
Front Immunol ; 12: 641447, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34108961

RESUMO

The newly emerged novel coronavirus, SARS-CoV-2, the causative agent of COVID-19 has proven to be a threat to the human race globally, thus, vaccine development against SARS-CoV-2 is an unmet need driving mass vaccination efforts. The receptor binding domain of the spike protein of this coronavirus has multiple neutralizing epitopes and is associated with viral entry. Here we have designed and characterized the SARS-CoV-2 spike protein fragment 330-526 as receptor binding domain 330-526 (RBD330-526) with two native glycosylation sites (N331 and N343); as a potential subunit vaccine candidate. We initially characterized RBD330-526 biochemically and investigated its thermal stability, humoral and T cell immune response of various RBD protein formulations (with or without adjuvant) to evaluate the inherent immunogenicity and immunomodulatory effect. Our result showed that the purified RBD immunogen is stable up to 72 h, without any apparent loss in affinity or specificity of interaction with the ACE2 receptor. Upon immunization in mice, RBD generates a high titer humoral response, elevated IFN-γ producing CD4+ cells, cytotoxic T cells, and robust neutralizing antibodies against live SARS-CoV-2 virus. Our results collectively support the potential of RBD330-526 as a promising vaccine candidate against SARS-CoV-2.


Assuntos
Anticorpos Antivirais/sangue , Vacinas contra COVID-19/administração & dosagem , Imunidade Humoral/efeitos dos fármacos , Imunogenicidade da Vacina , Fragmentos de Peptídeos/administração & dosagem , Glicoproteína da Espícula de Coronavírus/administração & dosagem , Células Th1/efeitos dos fármacos , Adjuvantes Imunológicos/administração & dosagem , Animais , Biomarcadores/sangue , Vacinas contra COVID-19/imunologia , Chlorocebus aethiops , Estabilidade de Medicamentos , Glicosilação , Células HEK293 , Humanos , Imunização , Interferon gama/sangue , Masculino , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/imunologia , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Glicoproteína da Espícula de Coronavírus/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Células Vero
2.
Nat Commun ; 12(1): 3587, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: covidwho-1265955

RESUMO

There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1µg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Ácidos Esteáricos/administração & dosagem , Compostos de Alúmen/administração & dosagem , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Vacinas contra COVID-19/administração & dosagem , Modelos Animais de Doenças , Compostos Heterocíclicos com 3 Anéis/imunologia , Humanos , Macaca mulatta , Camundongos , Ligação Proteica , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/imunologia , Ácidos Esteáricos/imunologia
3.
Front Immunol ; 12: 641447, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1264330

RESUMO

The newly emerged novel coronavirus, SARS-CoV-2, the causative agent of COVID-19 has proven to be a threat to the human race globally, thus, vaccine development against SARS-CoV-2 is an unmet need driving mass vaccination efforts. The receptor binding domain of the spike protein of this coronavirus has multiple neutralizing epitopes and is associated with viral entry. Here we have designed and characterized the SARS-CoV-2 spike protein fragment 330-526 as receptor binding domain 330-526 (RBD330-526) with two native glycosylation sites (N331 and N343); as a potential subunit vaccine candidate. We initially characterized RBD330-526 biochemically and investigated its thermal stability, humoral and T cell immune response of various RBD protein formulations (with or without adjuvant) to evaluate the inherent immunogenicity and immunomodulatory effect. Our result showed that the purified RBD immunogen is stable up to 72 h, without any apparent loss in affinity or specificity of interaction with the ACE2 receptor. Upon immunization in mice, RBD generates a high titer humoral response, elevated IFN-γ producing CD4+ cells, cytotoxic T cells, and robust neutralizing antibodies against live SARS-CoV-2 virus. Our results collectively support the potential of RBD330-526 as a promising vaccine candidate against SARS-CoV-2.


Assuntos
Anticorpos Antivirais/sangue , Vacinas contra COVID-19/administração & dosagem , Imunidade Humoral/efeitos dos fármacos , Imunogenicidade da Vacina , Fragmentos de Peptídeos/administração & dosagem , Glicoproteína da Espícula de Coronavírus/administração & dosagem , Células Th1/efeitos dos fármacos , Adjuvantes Imunológicos/administração & dosagem , Animais , Biomarcadores/sangue , Vacinas contra COVID-19/imunologia , Chlorocebus aethiops , Estabilidade de Medicamentos , Glicosilação , Células HEK293 , Humanos , Imunização , Interferon gama/sangue , Masculino , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/imunologia , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Glicoproteína da Espícula de Coronavírus/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Células Vero
4.
Nat Commun ; 12(1): 3587, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117252

RESUMO

There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1µg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Ácidos Esteáricos/administração & dosagem , Compostos de Alúmen/administração & dosagem , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Vacinas contra COVID-19/administração & dosagem , Modelos Animais de Doenças , Compostos Heterocíclicos com 3 Anéis/imunologia , Humanos , Macaca mulatta , Camundongos , Ligação Proteica , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/imunologia , Ácidos Esteáricos/imunologia
5.
Food Funct ; 12(9): 4046-4059, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977945

RESUMO

Previous studies have reported that Portulaca oleracea L. polysaccharides (POL-P3b) is an immunoregulatory agent. However, few studies exist on POL-P3b as a novel immune adjuvant in combination with the DC vaccine for breast cancer treatment. In this work, a DC vaccine loaded with mouse 4T1 tumor cell antigen was prepared to evaluate the properties of POL-P3b in inducing the maturation and function of DC derived from mouse bone marrow, and then to investigate the effect of the DC vaccine combined with POL-P3b on breast cancer in vivo and in vitro. Morphological changes of DC were observed using scanning electron microscopy. Phenotypic and functional analyses of DC were detected by flow cytometry and allogeneic lymphocyte reaction. Cytokine levels in the DC culture supernatant were detected by ELISA. Western blotting analysis was used for the protein expression of TLR4, MyD88 and NF-κB. Apoptosis detection and protein expression of the tumor tissue were analyzed by TUNEL staining and immunohistochemistry, respectively. The security of POL-P3b was evaluated by the detection of hematological and blood biochemical indicators and pathological analysis for tissues. POL-P3b can induce DC activation and maturation, which is attributed to increasing the specific anti-tumor immune response, and the mechanism of action involved in the TLR4/MyD88/NF-κB signaling pathway. Experimental results in vivo further suggested that the administration of POL-P3b-treated antigen-primed DC achieved remarkable tumor growth inhibition through inducing apoptosis and enhancing immune responses. Moreover, the POL-P3b-treated DC vaccine was able to inhibit lung metastases. The results proved the feasibility of POL-P3b as an edible adjuvant of the DC vaccine for anti-breast cancer therapy.


Assuntos
Adjuvantes Imunológicos , Neoplasias da Mama/terapia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Polissacarídeos/imunologia , Portulaca/química , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/toxicidade , Animais , Antígenos de Neoplasias/imunologia , Apoptose , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Imunogenicidade da Vacina , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Polissacarídeos/toxicidade
6.
Lancet ; 397(10287): 1809-1818, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33964223

RESUMO

BACKGROUND: Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy. METHODS: In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5-17 months in Nanoro, Burkina Faso-a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 µg R21 plus 25 µg MM, group 2 received 5 µg R21 plus 50 µg MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1-3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months. Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint. This trial is registered with ClinicalTrials.gov, NCT03896724. FINDINGS: From May 7 to June 13, 2019, 498 children aged 5-17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the seven serious adverse events were attributed to the vaccine. At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria. Vaccine efficacy was 74% (95% CI 63-82) in group 1 and 77% (67-84) in group 2 at 6 months. At 1 year, vaccine efficacy remained high, at 77% (67-84) in group 1. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered 1 year later. INTERPRETATION: R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy. FUNDING: The European & Developing Countries Clinical Trials Partnership, Wellcome Trust, and National Institute for Health Research Oxford Biomedical Research Centre.


Assuntos
Anticorpos Antiprotozoários/imunologia , Imunogenicidade da Vacina , Vacinas Antimaláricas/uso terapêutico , Malária/prevenção & controle , Proteínas de Protozoários/imunologia , Vacinas de Partículas Semelhantes a Vírus/uso terapêutico , Adjuvantes Imunológicos/administração & dosagem , Burkina Faso , Método Duplo-Cego , Feminino , Antígenos de Superfície da Hepatite B , Humanos , Lactente , Malária Falciparum/prevenção & controle , Masculino , Nanopartículas/administração & dosagem , Modelos de Riscos Proporcionais , Saponinas/administração & dosagem , Resultado do Tratamento
7.
Nat Commun ; 12(1): 2626, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976179

RESUMO

By conferring systemic protection and durable benefits, cancer immunotherapies are emerging as long-term solutions for cancer treatment. One such approach that is currently undergoing clinical testing is a therapeutic anti-cancer vaccine that uses two different viruses expressing the same tumor antigen to prime and boost anti-tumor immunity. By providing the additional advantage of directly killing cancer cells, oncolytic viruses (OVs) constitute ideal platforms for such treatment strategy. However, given that the targeted tumor antigen is encoded into the viral genomes, its production requires robust infection and therefore, the vaccination efficiency partially depends on the unpredictable and highly variable intrinsic sensitivity of each tumor to OV infection. In this study, we demonstrate that anti-cancer vaccination using OVs (Adenovirus (Ad), Maraba virus (MRB), Vesicular stomatitis virus (VSV) and Vaccinia virus (VV)) co-administered with antigenic peptides is as efficient as antigen-engineered OVs and does not depend on viral replication. Our strategy is particularly attractive for personalized anti-cancer vaccines targeting patient-specific mutations. We suggest that the use of OVs as adjuvant platforms for therapeutic anti-cancer vaccination warrants testing for cancer treatment.


Assuntos
Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias/imunologia , Vírus Oncolíticos/genética , Poli I-C/administração & dosagem , Poli I-C/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Vírus Vaccinia , Vírus da Estomatite Vesicular Indiana , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J Nanomedicine ; 16: 3125-3139, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981142

RESUMO

Background: Hepatocellular carcinoma-associated antigen 59 (HCA59) from excretory/secretory products of Haemonchus contortus is known to have the ability to modulate the functions of host cells. However, its immunogenicities using different nanoparticles adjuvants remain poorly understood. Purpose: The study aimed to select an efficient nanoparticle antigen delivery system, which could enhance the immune responses of Haemonchus contortus HCA59 in mice. Methods: Here, the immune responses induced by the recombinant protein of HCA59 (rHCA59) with poly-D,L-lactide-co-glycolide (PLGA) nanoparticles, Chitosan nanoparticles, mixture of PLGA and Chitosan nanoparticles (rHCA59-Chitosan-PLGA), and Freund's complete adjuvant were observed, respectively, in mice. Cytokine and antibody levels induced by different groups were detected by ELISA assay. The effects of lymphocyte proliferations on different groups were examined using CCK-8 kit. Phenotypes of T cells and dendritic cells were analyzed by flow cytometry. Results: On day 14 post vaccination, levels of IgM, IgG1, IgG2a, IFN-γ, IL-4, and IL-17 were significantly increased in the groups immunized with rHCA59 encapsulated with nanoparticles. After mice were vaccinated with rHCA59 loaded with Chitosan/PLGA nanoparticles, lymphocytes proliferated significantly. Additionally, the percentages of CD4+ T cells (CD3+ CD4+), CD8+ T cells (CD3+ CD8+), and dendritic cells (CD11c+ CD83+, CD11c+ CD86+) were obviously up-regulated in the mice immunized with nanoparticles, especially in the rHCA59-Chitosan-PLGA antigen delivery system group. Conclusion: The findings of this research demonstrated that rHCA59-Chitosan-PLGA antigen delivery system could induce higher immune responses in mice model and indicated that rHCA59 might be a good candidate molecule to develop nanovaccines against Haemonchus contortus in future study.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antígenos Glicosídicos Associados a Tumores/imunologia , Quitosana/química , Proteínas de Helminto/imunologia , Nanopartículas/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Linfócitos T/imunologia , Animais , Proliferação de Células , Citocinas/metabolismo , Feminino , Haemonchus/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos ICR , Nanopartículas/química , Linfócitos T/efeitos dos fármacos , Vacinação
9.
Sci Rep ; 11(1): 8761, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888840

RESUMO

The COVID-19 pandemic presents an unprecedented challenge to global public health. Rapid development and deployment of safe and effective vaccines are imperative to control the pandemic. In the current study, we applied our adjuvanted stable prefusion SARS-CoV-2 spike (S-2P)-based vaccine, MVC-COV1901, to hamster models to demonstrate immunogenicity and protection from virus challenge. Golden Syrian hamsters immunized intramuscularly with two injections of 1 µg or 5 µg of S-2P adjuvanted with CpG 1018 and aluminum hydroxide (alum) were challenged intranasally with SARS-CoV-2. Prior to virus challenge, the vaccine induced high levels of neutralizing antibodies with 10,000-fold higher IgG level and an average of 50-fold higher pseudovirus neutralizing titers in either dose groups than vehicle or adjuvant control groups. Six days after infection, vaccinated hamsters did not display any weight loss associated with infection and had significantly reduced lung pathology and most importantly, lung viral load levels were reduced to lower than detection limit compared to unvaccinated animals. Vaccination with either 1 µg or 5 µg of adjuvanted S-2P produced comparable immunogenicity and protection from infection. This study builds upon our previous results to support the clinical development of MVC-COV1901 as a safe, highly immunogenic, and protective COVID-19 vaccine.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , COVID-19/prevenção & controle , Oligodesoxirribonucleotídeos/administração & dosagem , Glicoproteína da Espícula de Coronavírus/imunologia , Hidróxido de Alumínio/imunologia , Animais , Anticorpos Neutralizantes/metabolismo , COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Linhagem Celular , Cricetinae , Feminino , Humanos , Imunização , Injeções Intramusculares , Oligodesoxirribonucleotídeos/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Carga Viral/efeitos dos fármacos
10.
Int J Mol Sci ; 22(7)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801683

RESUMO

BACKGROUND: In recent years, there has been great interest in developing molecular adjuvants based on antisense oligonucleotides (ASOs) targeting immunosuppressor pathways with inhibitory effects on regulatory T cells (Tregs) to improve immunogenicity and vaccine efficacy. We aim to evaluate the immunostimulating effect of 2'OMe phosphorothioated Foxp3-targeted ASO in an antifungal adjuvanted recombinant vaccine. METHODS: The uptake kinetics of Foxp3 ASO, its cytotoxicity and its ability to deplete Tregs were evaluated in murine splenocytes in vitro. Groups of mice were vaccinated with recombinant enolase (Eno) of Sporothix schenckii in Montanide Gel 01 adjuvant alone or in combination with either 1 µg or 8 µg of Foxp3 ASO. The titers of antigen-specific antibody in serum samples from vaccinated mice (male C57BL/6) were determined by ELISA (enzyme-linked immunosorbent assay). Cultured splenocytes from each group were activated in vitro with Eno and the levels of IFN-γ and IL-12 were also measured by ELISA. The results showed that the anti-Eno antibody titer was significantly higher upon addition of 8 µM Foxp3 ASO in the vaccine formulation compared to the standard vaccine without ASO. In vitro and in vivo experiments suggest that Foxp3 ASO enhances specific immune responses by means of Treg depletion during vaccination. CONCLUSION: Foxp3 ASO significantly enhances immune responses against co-delivered adjuvanted recombinant Eno vaccine and it has the potential to improve vaccine immunogenicity.


Assuntos
Fatores de Transcrição Forkhead/genética , Inativação Gênica , Imunogenicidade da Vacina , Oligonucleotídeos Antissenso/química , Sporothrix/imunologia , Vacinas Sintéticas/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Farmacêuticos , Animais , Sistema Imunitário , Interferon gama/metabolismo , Subunidade p35 da Interleucina-12/metabolismo , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Baço/citologia , Linfócitos T Reguladores/metabolismo
11.
Sci Rep ; 11(1): 8761, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: covidwho-1199318

RESUMO

The COVID-19 pandemic presents an unprecedented challenge to global public health. Rapid development and deployment of safe and effective vaccines are imperative to control the pandemic. In the current study, we applied our adjuvanted stable prefusion SARS-CoV-2 spike (S-2P)-based vaccine, MVC-COV1901, to hamster models to demonstrate immunogenicity and protection from virus challenge. Golden Syrian hamsters immunized intramuscularly with two injections of 1 µg or 5 µg of S-2P adjuvanted with CpG 1018 and aluminum hydroxide (alum) were challenged intranasally with SARS-CoV-2. Prior to virus challenge, the vaccine induced high levels of neutralizing antibodies with 10,000-fold higher IgG level and an average of 50-fold higher pseudovirus neutralizing titers in either dose groups than vehicle or adjuvant control groups. Six days after infection, vaccinated hamsters did not display any weight loss associated with infection and had significantly reduced lung pathology and most importantly, lung viral load levels were reduced to lower than detection limit compared to unvaccinated animals. Vaccination with either 1 µg or 5 µg of adjuvanted S-2P produced comparable immunogenicity and protection from infection. This study builds upon our previous results to support the clinical development of MVC-COV1901 as a safe, highly immunogenic, and protective COVID-19 vaccine.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , COVID-19/prevenção & controle , Oligodesoxirribonucleotídeos/administração & dosagem , Glicoproteína da Espícula de Coronavírus/imunologia , Hidróxido de Alumínio/imunologia , Animais , Anticorpos Neutralizantes/metabolismo , COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Linhagem Celular , Cricetinae , Feminino , Humanos , Imunização , Injeções Intramusculares , Oligodesoxirribonucleotídeos/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Carga Viral/efeitos dos fármacos
12.
Arch Virol ; 166(7): 1977-1984, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33871696

RESUMO

To enhance the potency of a foot-and-mouth disease (FMD) vaccine, saponin was included in the vaccine formula. In this study, the combined effect of Montanide ISA 50 and saponin was evaluated. Two experiments were performed in guinea pigs and one in cattle to determine the optimal antigen and saponin doses. Only serotype O of foot-and-mouth disease virus (O/PanAsia-2 of ME-SA topotype) was employed in preparation of the monovalent vaccine. All animals were immunized twice with a four-week interval, except for the negative controls. Blood was collected 10 days after the second booster, and the immune response was evaluated using a serum neutralization test. Oil-based FMD vaccines containing saponin induced higher neutralizing antibody levels than formulations lacking saponin. The addition of saponin to formulations with low antigen payload (2.5 µg of inactivated whole virus particles [146S particles] per dose) gave significantly higher neutralizing antibody levels (p < 0.005) than 5 µg of 146S without saponin, suggesting that it can be used to improve FMD vaccine potency in susceptible animals. No adverse effects were observed in vaccinated cattle or guinea pigs.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Vírus da Febre Aftosa/imunologia , Febre Aftosa/imunologia , Saponinas/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Bovinos , Doenças dos Bovinos/imunologia , Doenças dos Bovinos/virologia , Febre Aftosa/virologia , Cobaias , Testes de Neutralização/métodos , Sorogrupo , Vacinação/métodos
13.
Fish Shellfish Immunol ; 113: 69-78, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33798719

RESUMO

The shrimp aquaculture industry has experienced serious economic losses due to diseases caused by Vibrio species. The application of antibiotics to combat diseases has led to environmental hazards, antibiotic-resistance in pathogens and accumulation of antibiotics in tissues. This study explores the use of probiotics as an alternative to antibiotics. A probiotic consortium SFSK4 (comprising salt pan bacteria Bacillus licheniformis TSK71, Bacillus amyloliquefaciens SK27, Bacillus subtilis SK07, Pseudomonas sp. ABSK55) was used as a water additive during shrimp culture. It significantly increased shrimp (Litopenaeus vannamei) immunity i.e. total hemocyte count, phagocytosis, total plasma protein, respiratory burst and bactericidal activity as compared to the control. It also stimulated the phenoloxidase activity by two-fold. Proteomic analysis revealed the differential expression of 50 immune proteins (39 up-regulated and 11 down-regulated) in SFSK4 treated shrimps. Four major immune modulation proteins viz. Caspase2, GTPase activating protein, Hemocyanin and Glucan pattern-recognition lipoprotein involved in cell mediated immune response were identified in SFSK4 treated shrimp hemolymph. SFSK4 decreased shrimp mortality by more than 50% against pathogens. Toxicology studies revealed that administration of the highest dose of probiotic (1012 CFU/mL) showed no adverse effect on shrimp survival (LC50 analysis) and neither exhibited cytotoxicity. Genotoxicity study confirmed that the probiotic did not cause DNA damage in shrimps. The findings suggest that the probiotic SFSK4 is an eco-friendly water additive to enhance shrimp immunity against diseases in aquaculture, which could help curtail environmental hazards as an effective alternative to antibiotics.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Bacillus/química , Imunidade Inata , Penaeidae/imunologia , Probióticos/administração & dosagem , Probióticos/efeitos adversos , Vibrio/efeitos dos fármacos , Animais , Aquicultura , Imunidade Inata/efeitos dos fármacos , Probióticos/química
14.
BMC Cancer ; 21(1): 266, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33706705

RESUMO

BACKGROUND: To explore possible solutions to overcome chronic Bacillus Calmette-Guérin (BCG) shortage affecting seriously the management of non-muscle invasive bladder cancer (NMIBC) in Europe and throughout the world, we investigated whether non-maintenance eight-dose induction BCG (iBCG) was comparable to six-dose iBCG plus maintenance BCG (mBCG). METHODS: This observational study evaluated 2669 patients with high- or highest-risk NMIBC who treated with iBCG with or without mBCG during 2000-2019. The patients were classified into five groups according to treatment pattern: 874 (33%) received non-maintenance six-dose iBCG (Group A), 405 (15%) received six-dose iBCG plus mBCG (Group B), 1189 (44%) received non-maintenance seven-/eight-dose iBCG (Group C), 60 (2.2%) received seven-/eight-dose iBCG plus mBCG, and 141 (5.3%) received only ≤5-dose iBCG. Recurrence-free survival (RFS), progression-free survival, and cancer-specific survival were estimated and compared using Kaplan-Meier analysis and the log-rank test, respectively. Propensity score-based one-to-one matching was performed using a multivariable logistic regression model based on covariates to obtain balanced groups. To eliminate possible immortal bias, 6-, 12-, 18-, and 24-month conditional landmark analyses of RFS were performed. RESULTS: RFS comparison confirmed that mBCG yielded significant benefit following six-dose iBCG (Group B) in recurrence risk reduction compared to iBCG alone (groups A and C) before (P < 0.001 and P = 0.0016, respectively) and after propensity score matching (P = 0.001 and P = 0.0074, respectively). Propensity score-matched sequential landmark analyses revealed no significant differences between groups B and C at 12, 18, and 24 months, whereas landmark analyses at 6 and 12 months showed a benefit of mBCG following six-dose iBCG compared to non-maintenance six-dose iBCG (P = 0.0055 and P = 0.032, respectively). There were no significant differences in the risks of progression and cancer-specific death in all comparisons of the matched cohorts. CONCLUSIONS: Although non-maintenance eight-dose iBCG was inferior to six-dose iBCG plus mBCG, the former might be an alternative remedy in the BCG shortage era. To overcome this challenge, further investigation is warranted to confirm the real clinical value of non-maintenance eight-dose iBCG.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacina BCG/administração & dosagem , Quimioterapia de Indução/métodos , Recidiva Local de Neoplasia/epidemiologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Seguimentos , Humanos , Quimioterapia de Indução/estatística & dados numéricos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Quimioterapia de Manutenção/estatística & dados numéricos , Masculino , Recidiva Local de Neoplasia/prevenção & controle , Intervalo Livre de Progressão , Estudos Retrospectivos , Bexiga Urinária/imunologia , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
15.
BMC Urol ; 21(1): 50, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: covidwho-1159540

RESUMO

OBJECTIVES: To establish the role of BCG instillations in the incidence and mortality of COVID-19. PATIENTS AND METHODS: NMIBC patients in instillations with BCG (induction or maintenance) during 2019/2020 were included, establishing a COVID-19 group (with a diagnosis according to the national registry) and a control group (NO-COVID). The cumulative incidence (cases/total patients) and the case fatality rate (deaths/cases) were established, and compared with the national statistics for the same age group. T-test was used for continuous variables and Fisher's exact test for categorical variables. RESULTS: 175 patients were included. Eleven patients presented CIS (11/175, 6.3%), 84/175 (48.0%) Ta and 68/175 (38.9%) T1. Average number of instillations = 13.25 ± 7.4. One hundred sixty-seven patients (95.4%) had complete induction. Forty-three patients (cumulative incidence 24.6%) were diagnosed with COVID-19. There is no difference between COVID-19 and NO-COVID group in age, gender or proportion of maintenance completed. COVID-19 group fatality rate = 1/43 (2.3%). Accumulated Chilean incidence 70-79 years = 6.3%. Chilean fatality rate 70-79 years = 14%. CONCLUSIONS: According to our results, patients with NMIBC submitted to instillations with BCG have a lower case-fatality rate than the national registry of patients between 70 and 79 years (2.3% vs. 14%, respectively). Intravesical BCG could decrease the mortality due to COVID-19, so instillation schemes should not be suspended in a pandemic.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacina BCG/administração & dosagem , COVID-19/epidemiologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Chile , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Índice de Gravidade de Doença , Neoplasias da Bexiga Urinária/patologia
16.
Res Vet Sci ; 136: 310-317, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33756379

RESUMO

Oral probiotics are used to induce immune responses in the intestines to protect against infection. However, oral probiotics may also affect immune responses in other mucosal tissues such as in the respiratory tract. To examine this possibility, we explored the potential of immunocytes to home to the respiratory system after oral administration of Bacillus subtilis. The results showed that B. subtilis could promote intestinal development and not cause pathological changes in the respiratory tract. Following the oral administration with B. subtilis, the number of IgA-secreting cells and CD3+ T cells not only significantly increased in the intestinal tracts but also in respiratory tracts (P < 0.01). Moreover, the levels of secretory IgA were significantly higher in the trachea, lungs, ileum, and jejunum after oral B. subtilis administration than in the control groups (P < 0.05). The mRNA expression of interleukin (IL)-1ß, IL-5, IL-6, tumor necrosis factor-α, B cell activating factor, and IgA-inducing protein increased following B. subtilis administration (P < 0.01) in the trachea, lungs, ileum, and jejunum. These data suggest that B. subtilis administration regulates the immune response not only in the intestine but also in the respiratory tract of piglets. Our work highlights a potentially new strategy for promoting respiratory mucosal immunity and may contribute to the design of vaccines with B. subtilis as a mucosal adjuvant.


Assuntos
Bacillus subtilis/química , Vacinas Bacterianas/imunologia , Complexo CD3/imunologia , Imunidade nas Mucosas , Sistema Respiratório/imunologia , Linfócitos T/imunologia , Adjuvantes Imunológicos/administração & dosagem , Administração Oral , Animais , Animais Recém-Nascidos , Imunoglobulina A Secretora/imunologia , Masculino , Sus scrofa
17.
Fish Shellfish Immunol ; 113: 125-138, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33746060

RESUMO

Oral delivery is the most convenient way to vaccinate cultured fish, however it is still problematic, primarily due to a lack of a commercially valid vaccine vehicle to protect the antigen against gastric degradation and ensure its uptake from the intestine. With the goal of advancing the potential to vaccinate orally, this study evaluates a novel silicon nanoparticle-based vehicle (VacSaf carrier). Aeromonas salmonicida antigens were formulated with the VacSaf carrier using different preparation methods to generate dry powder and liquid formulations. Twelve formulations were first subjected to an in vitro evaluation where the A. salmonicida bacterin conjugated to VacSaf carriers were found superior at inducing pro-inflammatory cytokine expression in primary leucocyte cultures and the macrophage/monocyte cell line RTS-11 compared with A. salmonicida bacterin alone. This was especially apparent after exposure to acid conditions to mimic stomach processing. One formulation (FD1) was taken forward to oral delivery using two doses and two administration schedules (5 days vs 10 days, the latter 5 days on, 5 days off, 5 days on), and the transcript changes of immune genes in the intestine (pyloric caeca, midgut and hindgut) and spleen were evaluated by qPCR and serum IgM was measured by ELISA. The VacSaf carrier alone was shown to be safe for use in vivo, in that no side-effects were seen, but it did induce expression of some cytokines, and may have value as an oral adjuvant candidate. The FD1 bacterin formulation was effective at inducing a range of cytokines associated with innate and adaptive immunity, mainly in the pyloric caeca, compared to A. salmonicida bacterin alone (which had almost no effect), and confirms the immune competence of this gut region following appropriate oral vaccination. These results reveal that in vitro screening of formulations for oral delivery has value and can be used to assess the most promising formulations to test further.


Assuntos
Aeromonas salmonicida/imunologia , Vacinas Bacterianas/imunologia , Doenças dos Peixes/imunologia , Nanopartículas/administração & dosagem , Oncorhynchus mykiss/imunologia , Vacinação/veterinária , Imunidade Adaptativa , Adjuvantes Imunológicos/administração & dosagem , Administração Oral , Animais , Antígenos de Bactérias/imunologia , Vacinas Bacterianas/administração & dosagem , Linhagem Celular , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/veterinária , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Imunidade Inata , Macrófagos/imunologia , Monócitos/imunologia , Vacinação/instrumentação , Vacinação/métodos
18.
BMC Urol ; 21(1): 50, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785004

RESUMO

OBJECTIVES: To establish the role of BCG instillations in the incidence and mortality of COVID-19. PATIENTS AND METHODS: NMIBC patients in instillations with BCG (induction or maintenance) during 2019/2020 were included, establishing a COVID-19 group (with a diagnosis according to the national registry) and a control group (NO-COVID). The cumulative incidence (cases/total patients) and the case fatality rate (deaths/cases) were established, and compared with the national statistics for the same age group. T-test was used for continuous variables and Fisher's exact test for categorical variables. RESULTS: 175 patients were included. Eleven patients presented CIS (11/175, 6.3%), 84/175 (48.0%) Ta and 68/175 (38.9%) T1. Average number of instillations = 13.25 ± 7.4. One hundred sixty-seven patients (95.4%) had complete induction. Forty-three patients (cumulative incidence 24.6%) were diagnosed with COVID-19. There is no difference between COVID-19 and NO-COVID group in age, gender or proportion of maintenance completed. COVID-19 group fatality rate = 1/43 (2.3%). Accumulated Chilean incidence 70-79 years = 6.3%. Chilean fatality rate 70-79 years = 14%. CONCLUSIONS: According to our results, patients with NMIBC submitted to instillations with BCG have a lower case-fatality rate than the national registry of patients between 70 and 79 years (2.3% vs. 14%, respectively). Intravesical BCG could decrease the mortality due to COVID-19, so instillation schemes should not be suspended in a pandemic.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacina BCG/administração & dosagem , COVID-19/epidemiologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Chile , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Índice de Gravidade de Doença , Neoplasias da Bexiga Urinária/patologia
19.
Actas urol. esp ; 45(2): 93-102, mar. 2021. tab
Artigo em Espanhol | IBECS | ID: ibc-201614

RESUMO

INTRODUCCIÓN: El tratamiento de elección para el cáncer vesical no músculo infiltrante (CVNMI) de alto riesgo es el bacilo de Calmette-Guérin (BCG). Sin embargo, cuando éste falla, el tratamiento indicado es la cistectomía radical. En los últimos años se están desarrollando ensayos con diversos fármacos para evitar esta cirugía en pacientes con fracaso a BCG. El objetivo de este artículo es llevar a cabo una puesta al día de los tratamientos en estudio para la preservación vesical en esta población de pacientes. Material y MÉTODOS: Revisión no sistemática, realizando una búsqueda en PubMed con los términos "Bladder cancer", "Non-muscle invasive bladder cancer", "NMIBC", "BCG", "BCG-refractory", "Mitomycin C", "MMC", "Hyperthermia", "Electromotive Drug Administration", "EMDA" Empleamos los buscadores clinicaltrials.gov y clinicaltrialsregister.eu para localizar ensayos clínicos. RESULTADOS: El único fármaco intravesical aprobado por la Food and Drug Administration (FDA) para carcinoma in situ (CIS) tras fracaso a BCG es la valrubicina. Recientemente la FDA ha aprobado pembrolizumab intravenoso, tras la publicación de los datos preliminares del estudio KEYNOTE-057. Atezolizumab ha demostrado unos resultados preliminares similares de eficacia. En las guías europeas se reconoce como alternativa únicamente la quimiohipertermia inducida por microondas y EMDA-MMC (electromotive drug administration). Otras alternativas en investigación son los taxanos y la gemcitabina, solos o en combinación, los virus recombinantes y la quimiohipertermia intravesical asistida por dispositivos. CONCLUSIONES: Los resultados de los nuevos fármacos son prometedores, con gran número de ensayos en marcha. Conocer los mecanismos de resistencia a BCG es imprescindible para la exploración de nuevas alternativas terapéuticas


INTRODUCTION: The treatment of choice for high-risk non-muscle invasive bladder cancer (NMIBC) is bacillus Calmette-Guérin (BCG). However, when this fails, the indicated treatment is radical cystectomy. In recent years, trials are being developed with various drugs to avoid this surgery in patients with BCG failure. The aim of this article is to update the treatments under study for bladder preservation in this patient population. MATERIAL AND METHODS: Non-systematic review, searching PubMed with the terms "Bladder cancer", "Non-muscle invasive bladder cancer", "NMIBC", "BCG", "BCG-refractory", "Mitomycin C", "MMC", "Hyperthermia", "Electromotive Drug Administration", "EMDA" We used the search engines clinicaltrials.gov and clinicaltrialsregister.eu to find clinical trials. RESULTS: The only intravesical drug approved by the Food and Drug Administration (FDA) for carcinoma in situ (CIS) after failure to BCG is valrubicin. Recently, the FDA has approved intravenous pembrolizumab, following the publication of preliminary data from the KEYNOTE-057 study. Atezolizumab has demonstrated similar preliminary efficacy results. Only microwave-induced chemohyperthermia and EMDA-MMC (electromotive drug administration) are recognized as alternatives in European guidelines. Other options under investigation are taxanes and gemcitabine, alone or in combination, recombinant viruses and device-assisted intravesical chemohyperthermia. CONCLUSIONS: The results of new drugs are promising, with a large number of trials underway. Knowing the mechanisms of resistance to BCG is essential to explore new therapeutic options


Assuntos
Humanos , Vacina BCG/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Falha de Tratamento , Recidiva Local de Neoplasia , Intervalo Livre de Doença
20.
Sci Adv ; 7(6)2021 02.
Artigo em Inglês | MEDLINE | ID: covidwho-1066792

RESUMO

The profound consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mandate urgent development of effective vaccines. Here, we evaluated an Amphiphile (AMP) vaccine adjuvant, AMP-CpG, composed of diacyl lipid-modified CpG, admixed with the SARS-CoV-2 Spike-2 receptor binding domain protein as a candidate vaccine (ELI-005) in mice. AMP modification efficiently delivers CpG to lymph nodes, where innate and adaptive immune responses are generated. Compared to alum, immunization with AMP-CpG induced >25-fold higher antigen-specific T cells that produced multiple T helper 1 (TH1) cytokines and trafficked into lung parenchyma. Antibody responses favored TH1 isotypes (IgG2c and IgG3) and potently neutralized Spike-2-ACE2 receptor binding, with titers 265-fold higher than natural convalescent patient COVID-19 responses; T cell and antibody responses were maintained despite 10-fold dose reduction in Spike antigen. Both cellular and humoral immune responses were preserved in aged mice. These advantages merit clinical translation to SARS-CoV-2 and other protein subunit vaccines.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Imunidade Celular , Imunidade Humoral , Linfonodos/imunologia , SARS-CoV-2/imunologia , Tensoativos/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Feminino , Células HEK293 , Humanos , Imunogenicidade da Vacina , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Testes de Neutralização , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/imunologia , Domínios e Motivos de Interação entre Proteínas/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Resultado do Tratamento , Vacinação/métodos , Vacinas de Subunidades/imunologia
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