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Today's world is characterized by increasing population density, human mobility, urbanization, and climate and ecological change. This global dynamic has various effects, including the increased appearance of emerging infectious diseases (EIDs), which pose a growing threat to global health security.Outbreaks of EIDs, like the 2013-2016 Ebola outbreak in West Africa or the current Ebola outbreak in Democratic Republic of the Congo (DRC), have not only put populations in low- and middle-income countries (LMIC) at risk in terms of morbidity and mortality, but they also have had a significant impact on economic growth in affected regions and beyond.The Coalition for Epidemic Preparedness Innovation (CEPI) is an innovative global partnership between public, private, philanthropic, and civil society organizations that was launched as the result of a consensus that a coordinated, international, and intergovernmental plan was needed to develop and deploy new vaccines to prevent future epidemics.CEPI is focusing on supporting candidate vaccines against the World Health Organization (WHO) Blueprint priority pathogens MERS-CoV, Nipah virus, Lassa fever virus, and Rift Valley fever virus, as well as Chikungunya virus, which is on the WHO watch list. The current vaccine portfolio contains a wide variety of technologies, ranging across recombinant viral vectors, nucleic acids, and recombinant proteins. To support and accelerate vaccine development, CEPI will also support science projects related to the development of biological standards and assays, animal models, epidemiological studies, and diagnostics, as well as build capacities for future clinical trials in risk-prone contexts.
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Doenças Transmissíveis Emergentes , Epidemias , Vacinas , África Ocidental , Animais , Surtos de Doenças , Alemanha , HumanosRESUMO
In the original publication of this article, the author name Richard Hatchett was incorrectly published.
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Macromolecular complexes are responsible for many key biological processes. However, in most cases details of the assembly/disassembly of such complexes are unknown at the molecular level, as the low abundance and transient nature of assembly intermediates make analysis challenging. The assembly of virus capsids is an example of such a process. The hepatitis B virus capsid (core) can be composed of either 90 or 120 dimers of coat protein. Previous studies have proposed a trimer of dimers as an important intermediate species in assembly, acting to nucleate further assembly by dimer addition. Using novel genetically-fused coat protein dimers, we have been able to trap higher-order assembly intermediates and to demonstrate for the first time that both dimeric and trimeric complexes are on pathway to virus-like particle (capsid) formation.
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Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Vírus da Hepatite B/metabolismo , Vírion/metabolismo , Capsídeo/química , Capsídeo/metabolismo , Proteínas do Capsídeo/genética , Dimerização , Vírus da Hepatite B/química , Vírus da Hepatite B/genética , Vírus da Hepatite B/ultraestrutura , Modelos Moleculares , Vírion/química , Vírion/genética , Vírion/ultraestrutura , Montagem de VírusRESUMO
Several protein vaccine candidates are among the COVID-19 vaccines in development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of protein vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of such a vaccine platform. The structured and standardized assessment provided by the template would also help contribute to improved public acceptance and communication of licensed protein vaccines.
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Vacinas Virais/efeitos adversos , Vacinas Virais/imunologia , Antígenos Virais/administração & dosagem , Antígenos Virais/efeitos adversos , Antígenos Virais/imunologia , Vacinas contra COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Humanos , Segurança do Paciente , Medição de Risco , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia , Proteínas Virais/administração & dosagem , Proteínas Virais/efeitos adversos , Proteínas Virais/imunologia , Vacinas Virais/administração & dosagemRESUMO
Several live-attenuated viral vaccine candidates are among the COVID-19 vaccines in development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of live-attenuated viral vaccines. This will help key stakeholders assess potential safety issues and understand the benefit-risk of such vaccines. The standardized and structured assessment provided by the template would also help to contribute to improved communication and support public acceptance of licensed live-attenuated viral vaccines.
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Avaliação Pré-Clínica de Medicamentos/normas , Vacinas Atenuadas/efeitos adversos , Vacinas Virais/efeitos adversos , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Medição de Risco , Sociedades Científicas , Vacinas Atenuadas/farmacologia , Vacinas Virais/farmacologiaRESUMO
Inactivated viral vaccines have long been used in humans for diseases of global health threat and are now among the vaccines for COVID-19 under development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of inactivated viral vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of the vaccine platform. The standardized and structured assessment provided by the template would also help to contribute to improved communication and support public acceptance of licensed inactivated viral vaccines.
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Infecções por Coronavirus/prevenção & controle , Aprovação de Drogas/legislação & jurisprudência , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Medição de Risco , Vacinas Virais/normas , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , COVID-19 , Vacinas contra COVID-19 , Defesa Civil , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Regulamentação Governamental , Humanos , Imunogenicidade da Vacina , Cooperação Internacional , Segurança do Paciente , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , SARS-CoV-2 , Vacinas de Produtos Inativados , Vacinas Virais/administração & dosagem , Vacinas Virais/biossínteseRESUMO
Due to influenza viruses continuously displaying antigenic variation, current seasonal influenza vaccines must be updated annually to include the latest predicted strains. Despite all the efforts put into vaccine strain selection, vaccine production, testing, and administration, the protective efficacy of seasonal influenza vaccines is greatly reduced when predicted vaccine strains antigenically mismatch with the actual circulating strains. Moreover, preparing for a pandemic outbreak is a challenge, because it is unpredictable which strain will cause the next pandemic. The European Commission has funded five consortia on influenza vaccine development under the Seventh Framework Programme for Research and Technological Development (FP7) in 2013. The call of the EU aimed at developing broadly protective influenza vaccines. Here we review the scientific strategies used by the different consortia with respect to antigen selection, vaccine delivery system, and formulation. The issues related to the development of novel influenza vaccines are discussed.
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Pesquisa Biomédica , Vacinas contra Influenza , Influenza Humana/prevenção & controle , Pesquisa Biomédica/economia , União Europeia , Humanos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/química , Influenza Humana/imunologia , Pandemias/prevenção & controle , Apoio à Pesquisa como AssuntoRESUMO
Immunotherapy offers new and exciting therapeutic options for patients with late-stage prostate cancer. While the concept of using the immune system to combat cancer is not new, it is only in this post-genomics era that the realistic possibility exists of effectively harnessing the immune system against disease. Immunotherapies can be loosely divided into three major categories: non-specific immune stimulation, specific target antigens and whole-cell approaches. All three systems have merits and drawbacks, although the goal of overcoming 'self' tolerance is common to all of them. This review highlights some of the more recent experiments in each of these three fields, focusing particularly on prostate cancer. We suggest that it is unlikely that one single cancer antigen exists and that recent data support this by showing that strong immune responses to prostate antigens can be elicited in a variety of ways. Therefore, a multivalent approach is likely to be most clinically efficacious. Data gathered from the past three years are discussed in this review and lead to the inescapable conclusion that immunotherapy is now a reality.
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Imunoterapia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Antígenos/imunologia , Antígenos/uso terapêutico , Humanos , Masculino , Células Tumorais Cultivadas/transplanteRESUMO
The core protein of the hepatitis B virus, HBcAg, assembles into highly immunogenic virus-like particles (HBc VLPs) when expressed in a variety of heterologous systems. Specifically, the major insertion region (MIR) on the HBcAg protein allows the insertion of foreign sequences, which are then exposed on the tips of surface spike structures on the outside of the assembled particle. Here, we present a novel strategy which aids the display of whole proteins on the surface of HBc particles. This strategy, named tandem core, is based on the production of the HBcAg dimer as a single polypeptide chain by tandem fusion of two HBcAg open reading frames. This allows the insertion of large heterologous sequences in only one of the two MIRs in each spike, without compromising VLP formation. We present the use of tandem core technology in both plant and bacterial expression systems. The results show that tandem core particles can be produced with unmodified MIRs, or with one MIR in each tandem dimer modified to contain the entire sequence of GFP or of a camelid nanobody. Both inserted proteins are correctly folded and the nanobody fused to the surface of the tandem core particle (which we name tandibody) retains the ability to bind to its cognate antigen. This technology paves the way for the display of natively folded proteins on the surface of HBc particles either through direct fusion or through non-covalent attachment via a nanobody.
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Fusão Gênica Artificial/métodos , Escherichia coli/genética , Antígenos do Núcleo do Vírus da Hepatite B/química , Antígenos do Núcleo do Vírus da Hepatite B/genética , Nicotiana/genética , Multimerização Proteica , Vírus , Proteínas de Fluorescência Verde/genética , Modelos Moleculares , Estrutura Quaternária de Proteína , Anticorpos de Domínio Único/genéticaRESUMO
There is clear evidence that certain forms of immunotherapy can be successful against certain cancers. However, it would appear that cancerous cells of various origin are exceptionally adept at subverting the immune response. Consequently, it is probable that the most efficacious therapy will be one in which multiple responses of the immune system are activated. There is currently an embarrassment of riches with regard to multiple vaccine strategies in the clinic, although no single method seems to hold the solution. Here, we draw together several of the humoral- and cellular-activating strategies currently under clinical investigation.
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Imunoterapia , Neoplasias/terapia , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Humanos , Neoplasias/imunologia , Evasão TumoralRESUMO
Antigen-loaded dendritic cells (DC) are considered potent stimulators of protective immunity. In some studies, DC hybridized with tumor cells have shown promising antitumor responses in mice as well as in humans. A practical drawback of this approach is the limited availability of autologous tumor samples. We investigated the possibility of hybridizing allogeneic prostate cancer cells with human-monocyte-derived DC, and thereby combine the wide repertoire of antigens from the tumor cells with the costimulatory features of the autologous antigen-presenting cells. Three tumor cell lines were used for hybridization using polyethylene glycol (PEG). We show that all three cell lines formed hybrids with DC to the same extent and without significant loss of viability. Restimulation of autologous T cells with these hybrids resulted in generation of tumor-specific IFNgamma-producing T cells with all three tumor cell lines. Similar tumor specificity could not be obtained if T cells were stimulated using a mixture of non-PEG-fused tumor cells and DC. Moreover, these T cells were capable of specific recognition of other tumor cells of prostate cancer origin and autologous DC pulsed with lysate from these prostate cancer cell lines, while a panel of unrelated EBV-transformed B cell lines were not recognized. These results are strongly indicative of the true tumor specificity of these T cells. Our results suggest that DC hybridized with allogeneic prostate cancer cell lines are potent stimulators of a broad prostate-tumor-specific response.
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Antígenos de Neoplasias/imunologia , Vacinas Anticâncer , Fusão Celular , Células Dendríticas , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Linfócitos T/imunologia , Citometria de Fluxo , Humanos , Células Híbridas , Imunoterapia/métodos , Masculino , Monócitos , Células Tumorais CultivadasAssuntos
Imunoterapia/métodos , Neoplasias/terapia , Adjuvantes Imunológicos/uso terapêutico , Animais , Antígenos de Neoplasias/administração & dosagem , Antineoplásicos/uso terapêutico , Vacinas Anticâncer/imunologia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Terapia de Imunossupressão/métodos , Neoplasias/imunologiaRESUMO
UNLABELLED: Broad T cell and B cell responses to multiple HCV antigens are observed early in individuals who control or clear HCV infection. The prevailing hypothesis has been that similar immune responses induced by prophylactic immunization would reduce acute virus replication and protect exposed individuals from chronic infection. Here, we demonstrate that immunization of naïve chimpanzees with a multicomponent HCV vaccine induced robust HCV-specific immune responses, and that all vaccinees exposed to heterologous chimpanzee-adapted HCV 1b J4 significantly reduced viral RNA in serum by 84%, and in liver by 99% as compared to controls (P=0.024 and 0.028, respectively). However, despite control of HCV in plasma and liver in the acute period, in the chronic phase, 3 of 4 vaccinated animals developed persistent infection. Analysis of expression levels of proinflammatory cytokines in serial hepatic biopsies failed to reveal an association with vaccine outcome. However, expression of IDO, CTLA-4 [corrected] and PD-1 levels in liver correlated with clearance or chronicity. CONCLUSION: Despite early control of virus load, a virus-associated tolerogenic-like state can develop in certain individuals independent of vaccination history.
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Antígenos CD/metabolismo , Hepatite C/imunologia , Vacinas contra Hepatite Viral/uso terapêutico , Animais , Antígenos Virais/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Doença Crônica/prevenção & controle , Citocinas/metabolismo , DNA Viral/genética , Hepacivirus/genética , Hepacivirus/imunologia , Hepatite C/prevenção & controle , Pan troglodytes , Receptor de Morte Celular Programada 1 , Carga ViralRESUMO
Significant improvements in our knowledge of tumor immunology have resulted in more sophisticated vaccine approaches for the treatment of cancer. However, research into biomarkers that correlate with the clinical outcome of immunotherapy has lagged behind vaccine development. To this extent, very few immunological or other markers exist that can be used in clinical trials for immunotherapy. In this review, we discuss the current status of biomarker development specifically for the monitoring and development of cancer vaccines. This includes immunological biomarkers (measurement of T-cell and cytokine responses), autoimmunity as a correlate for treatment outcome, and the possible development of multiple biomarkers using high-throughput proteomics technologies. The generation of such biomarkers will allow us to make clinical decisions about patient treatment at an earlier stage and should aid in shortening the development time for vaccines.
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Biomarcadores Tumorais/imunologia , Vacinas Anticâncer/imunologia , Neoplasias/diagnóstico , Linfócitos T/imunologia , Extratos de Tecidos/imunologia , Vacinas de DNA/uso terapêutico , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/química , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Feminino , Humanos , Imunoterapia Ativa , Masculino , Melanoma/imunologia , Melanoma/terapia , Neoplasias/genética , Neoplasias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Valor Preditivo dos Testes , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Proteômica , Extratos de Tecidos/efeitos adversos , Extratos de Tecidos/química , Extratos de Tecidos/uso terapêuticoRESUMO
The search for molecules that correlate with cancer progression is an evolving and exciting area of research. Such biomarkers have utility in a number of areas, most notably in a variety of clinical development programs. Modern technologies are revealing multiple potential biomarker candidates. However, the challenge remains in validating the correlation in levels of a particular molecule with clinical parameters. In this article, the area of biomarkers and cancer vaccines is briefly reviewed and the possibility of combining multiple molecules to generate a profile that correlates with outcome, rather than using more conventional single molecule biomarker systems, is explored.
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Allogeneic whole tumour cell vaccines are inherently practical compared with autologous vaccines. Cell lines are derived from allogeneic tumour, grown in bulk and then administered as a vaccine to the patient, following irradiation, which not only prevents any replication but also enhances antigen presentation. Protection is believed to occur through the presentation of antigens shared between the syngeneic and allogeneic tumours. Although cytokine-transfected tumour whole cell vaccines have been used clinically, little data is available comparing the effects of immunomodulatory cytokine-transfection directly on the same cells when used as both an allogeneic and autologous vaccine. To address this, weakly immunogenic B16-F10 (H-2b) murine melanoma was transfected to secrete either GM-CSF, IL-4 or IL-7. Prophylactic vaccination of both syngeneic C57/BL6 (H-2b) (B6) and allogeneic C3H/Hej (H-2k) (C3H) mice showed the effects of transfected cytokine varied between models. Both GM-CSF and IL-7 significantly (P<0.05) increased the levels of protection within syngeneic B6 mice, but had a diminished effect (P>0.05) within C3H allogeneic mice. Allogeneic B16-F10 cells and syngeneic K1735 cells generated CTL against K1735 suggesting cross-reactive immunity. Using cells labeled with fluorescent dye we demonstrate that irradiated vaccines, of either syngeneic or allogeneic origin, appear to generate potent immune responses and fragments of either vaccine remain at the injection site for up to 9 days. This study shows that protection can be enhanced in vivo by using transfected cytokine, but suggests that irradiated whole cell vaccines, of either tissue-type, are rapidly processed. This leads to the conclusion that the cytokine effects are transient and thus transfection with cytokine may be of limited long-term use in situ.
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Vacinas Anticâncer/efeitos da radiação , Citocinas/metabolismo , Melanoma Experimental/prevenção & controle , Transplante Homólogo/imunologia , Transplante Isogênico/imunologia , Animais , Transplante de Células , Citotoxicidade Imunológica , Feminino , Citometria de Fluxo , Camundongos , Transplante de Neoplasias , Transfecção , Células Tumorais CultivadasRESUMO
OBJECTIVE: To assess the feasibility, toxicity and immunogenicity of dendritic cell (DC)-based immunotherapy in patients with advanced urological cancers. PATIENTS AND METHODS: Patients with hormone-refractory prostate cancer (11) and metastatic renal cell carcinoma (five) received 1-3 x 10(6) intradermal allogeneic tumour lystate-pulsed DCs fortnightly for six vaccinations then monthly until disease progression. Intradermal keyhole limpet haemocyanin was injected near the DCs as the adjuvant. DC vaccine was prepared from buffy coats, then lysate-pulsed, cryopreserved in aliquots, and tested for phenotypic expression and activity in an allogeneic mixed lymphocyte reaction before clinical use. RESULTS: There was no evidence of significant toxicity from vaccine or adjuvant. Delayed-type hypersensitivity skin testing and biopsy revealed a cellular infiltrate to intradermal re-challenge to tumour lysate and adjuvant in almost all patients. In addition, there was increased expression of T helper type 1 cytokines, interferon-gamma-expressing T cell by ELISPOT analysis, but also interleukin-10 in a few patients. Vaccination resulted in a reduction in the level of prostate-specific antigen (PSA) in one patient, a reduction in PSA velocity in a further man and an increased PSA doubling time in six. Two of five patients with renal cell carcinoma had stabilization of disease. CONCLUSION: The cryopreservation and repeated administration of DC vaccine was feasible and not toxic. There was evidence of induction of both humoral and cellular immunity to vaccine and adjuvant in most patients. The use of sequential aliquots of identical cryopreserved vaccine will ensure quality control and greatly facilitate future clinical studies in terms of consistency of vaccine administered and the provision of primed DCs for in vitro assessment of response.