RESUMO
PURPOSE OF REVIEW: Advancements in antiretroviral therapy (ART) have positively impacted the life expectancy and possibility of living a normal life for people with HIV-1. However, lifelong daily medication is necessary to prevent disease progression. To this end, immunotherapeutic strategies are being tested with the aim of developing a functional cure in which the immune system effectively controls HIV-1 in the absence of ART. RECENT FINDINGS: The most promising advances in achieving sustained HIV-1 remission or cure include broadly neutralizing antibodies (bNAbs) that are administered alone or in combination with other agents. Newer and more innovative approaches redirecting T cells or natural killer cells to kill HIV-1 infected cells have also shown promising results. Finally, multiple ongoing trials focus on combining bNAbs with other immune-directed therapies to enhance both innate and adaptive immunity. SUMMARY: While immunotherapies as an alternative to conventional ART have generally proven to be well tolerated, these therapeutic approaches have largely been unsuccessful in inducing ART-free control of HIV-1. However, promising results from recent trials involving bNAbs that have reported durable HIV-1 control among a subset of participants, provide reason for cautious optimism that we with further optimization of these treatment strategies may be able to achieve functional cure for HIV-1.
Assuntos
Infecções por HIV , HIV-1 , Imunoterapia , Humanos , Infecções por HIV/imunologia , Infecções por HIV/terapia , HIV-1/imunologia , Imunoterapia/métodos , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/uso terapêutico , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêuticoRESUMO
Venezuelan equine encephalitis virus (VEEV) is a mosquito borne alphavirus which leads to high viremia in equines followed by lethal encephalitis and lateral spread to humans. In addition to naturally occurring outbreaks, VEEV is a potential biothreat agent with no approved human vaccine or therapeutic currently available. Single domain antibodies (sdAb), also known as nanobodies, have the potential to be effective therapeutic agents. Using an immune phage display library derived from a llama immunized with an equine vaccine that included inactivated VEEV, five sdAb sequence families were identified that showed varying ability to neutralize VEEV. One of the sequence families had been identified previously in selections against chikungunya virus, a related alphavirus of public health concern. A key advantage of sdAb is the ability to optimize properties such as neutralization capacity through protein engineering. Neutralization of VEEV was improved by two orders of magnitude by genetically linking sdAb. One of the bivalent constructs showed effective neutralization of both VEEV and chikungunya virus. Several of the bivalent constructs neutralized VEEV in cell-based assays with reductions in the number of plaques by 50% at protein concentrations of 1 ng/mL or lower, making future evaluation of their therapeutic potential compelling.
Assuntos
Anticorpos Neutralizantes/uso terapêutico , Vírus da Encefalite Equina Venezuelana/imunologia , Encefalomielite Equina Venezuelana/prevenção & controle , Encefalomielite Equina Venezuelana/virologia , Doenças dos Cavalos/prevenção & controle , Doenças dos Cavalos/virologia , Anticorpos de Domínio Único/uso terapêutico , Animais , Anticorpos Neutralizantes/farmacologia , Cavalos , Humanos , Engenharia de Proteínas , Anticorpos de Domínio Único/farmacologiaRESUMO
CONTEXTE: Le présent document ainsi que les constats qu'il énonce ont été rédigés en réponse à une interpellation du ministère de la Santé et des Services sociaux dans le contexte de la crise sanitaire liée à la maladie à coronavirus (COVID-19) au Québec. L'objectif est de réaliser une recension des données publiées et de mobiliser les savoirs clés afin d'informer les décideurs publics et les professionnels de la santé et des services sociaux. Bien que les constats reposent sur un repérage exhaustif des données scientifiques publiées, sur l'évaluation de la qualité méthodologique des études et sur une appréciation du niveau de preuve scientifique par paramètre clinique d'intérêt ainsi que sur la consultation de cliniciens avec différentes spécialités et expertises, le processus ne repose pas entièrement sur les normes habituelles à l'INESSS. Dans les circonstances d'une telle crise de santé publique, l'INESSS reste à l'affût de tout
Assuntos
Humanos , Anticorpos Neutralizantes/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , COVID-19/tratamento farmacológico , Avaliação em Saúde , Análise Custo-BenefícioRESUMO
BACKGROUND: COVID-19 high-titer CCP selection is a concern, because neutralizing antibody (nAb) testing requires sophisticated labs and methods. Surrogate tests are an alternative for measuring nAb levels in plasma bags, including those that are pathogen-reduced. STUDY DESIGN/METHODS: We studied a panel consisting of 191 samples from convalescent donors tested by nAb (CPE-VNT), obtained from 180 CCP donations (collection: March 20-January 21) and 11 negative controls, with a total of 80 and 111 serum and plasma samples (71 amotosalen/UV treated), with nAb titers ranging from negative to 10,240. Samples were blindly tested for several surrogates: one anti-RBD, two anti-spike, and four anti-nucleocapsid tests, either isolated or combined to improve their positive predictive values as predictors of the presence of high-titer nAbs, defined as those with titers ≥160. RESULTS: Except for combined and anti-IgA/M tests, all isolated surrogate tests showed excellent performance for nAb detection: sensitivity (98.3%-100%), specificity (85.7%-100%), PPV (98.9%-100%), NPV (81.3%-100%), and AUC (0.93-0.96), with a variable decrease in sensitivity and considerably lower specificity when using FDA authorization and concomitant nAb titers ≥160. All surrogates had AUCs that were statistically different from CPE-VNT if nAb≥160, including when using combined, orthogonal approaches. CONCLUSIONS: Surrogate tests (isolated or in combination) have an indirect good performance in detecting the presence of nAb, with lower sensitivity and specificity when high nAb titer samples are used, possibly accepting a considerable number of donors whose nAb titers are actually low, which should be evaluated by each laboratory responsible for CCP collection.
Assuntos
Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , COVID-19/terapia , Doadores de Sangue , Humanos , Imunização Passiva , SARS-CoV-2 , Soroterapia para COVID-19RESUMO
INTRODUCIÓN: El presente informe es producto del trabajo colaborativo de la Comisión Nacional de Evaluación de Tecnologías de Salud (CONETEC), dependiente del Ministerio de Salud de la Nación y creada por RM N° 623/2018. La CONETEC realiza evaluaciones y emite recomendaciones a la autoridad sanitaria sobre la incorporación, forma de uso, financiamiento y políticas de cobertura de las tecnologías sanitarias desde una perspectiva global del sistema de salud argentino. En sus evaluaciones y recomendaciones, la CONETEC tiene en cuenta criterios de calidad, seguridad, efectividad, eficiencia y equidad, evaluados bajo dimensiones éticas, médicas, económicas y sociales. Sus resultados son consensuados mediante discusiones públicas y ponderados a través de un marco de valor explícito, con la participación de todos los actores involucrados en el proceso de toma de decisiones en salud. Los informes y recomendaciones de esta comisión surgen de este proceso público, transparente y colaborativo, siendo de libre consulta y acceso para toda la sociedad. El objetivo del presente informe es evaluar parámetros de eficacia, seguridad y conveniencia de anticuerpos policlonales equinos (suero equino hiperinmune) para el tratamiento de pacientes con COVID-19. OBJETIVO El objetivo del presente informe es evaluar parámetros de eficacia, seguridad y conveniencia de anticuerpos policlonales equinos (suero equino hiperinmune) para el tratamiento de pacientes con COVID-19. METODOLOGÍA: Realizamos una evaluación "viva" (con un proceso de actualización continua) de una tecnología sanitaria, basada en evidencia proveniente de revisiones sistemáticas "vivas" de referencia y guías de práctica clínica de alta calidad metodológica para brindar parámetros actualizados y balanceados que sean de utilidad para la toma de decisiones en los diferentes niveles de gestión. RESULTADOS: Se identificó una revisión sistemática que cumple con los criterios de inclusión del presente informe. Adicionalmente se identificaron otras dos revisiones sistemáticas con adecuado proceso de desarrollo pero ninguna contestó la pregunta pertinente al presente informe. La revisión sistemática identificada incluyó un estudio aleatorizado con un total de 243 pacientes aleatorizados a suero equino hiperinmune o placebo. Se realizaron múltiples análisis de subgrupo incluyendo uno que comparó pacientes según su severidad al comienzo del estudio. Ninguno de estos análisis mostró resultados que sugieran un efecto diferencial en los subgrupos comparados. CONCLUSIONES: El cuerpo de evidencia disponible hasta el momento muestra que existe incertidumbre en el efecto de los anticuerpos policlonales equinos (suero equino hiperinmune) sobre la mortalidad y el ingreso en ventilación mecánica. El uso de anticuerpos policlonales equinos (suero equino hiperinmune) podría impactar positivamente en el tiempo de mejoría clínica, pero podría no incrementar la proporción de pacientes que alcanzan la recuperación clínica que lleva al alta hospitalaria. Los anticuerpos policlonales equinos (suero equino hiperinmune) podrían no asociarse a afectos adversos severos. La incertidumbre sobre el efecto de la tecnología evaluada sobre los desenlaces críticos para pacientes hospitalizados con COVI-19 (mortalidad y requerimiento de ventilación invasiva) determina que la certeza en los efectos de suero equino sobre la salud de pacientes con COVID-19 sea muy baja. A pesar que la tecnología se produce en Argentina lo que facilitaría su acceso, encontramos barreras relacionadas con una amplia población objetivo y elevado costo comparativo de esta intervención que podrían acarrear problemas de producción y afectar la distribución equitativa en situaciones de alta demanda. No identificamos recomendaciones con el rigor metodológico apropiado para ser incluidas en el informe.
Assuntos
Humanos , Animais , Imunização Passiva/métodos , Anticorpos Neutralizantes/uso terapêutico , COVID-19/tratamento farmacológico , Índice de Gravidade de Doença , Imunização Passiva/economia , Análise Custo-Benefício , Anticorpos Neutralizantes/economia , Índice Terapêutico , CavalosRESUMO
The Spike protein is the target of both antibody-based therapeutics (convalescent plasma, polyclonal serum, monoclonal antibodies) and vaccines. Mutations in Spike could affect efficacy of those treatments. Hence, monitoring of mutations is necessary to forecast and readapt the inventory of therapeutics. Different phylogenetic nomenclatures have been used for the currently circulating SARS-CoV-2 clades. The Spike protein has different hotspots of mutation and deletion, the most dangerous for immune escape being the ones within the receptor binding domain (RBD), such as K417N/T, N439K, L452R, Y453F, S477N, E484K, and N501Y. Convergent evolution has led to different combinations of mutations among different clades. In this review we focus on the main variants of concern, that is, the so-called UK (B.1.1.7), South African (B.1.351) and Brazilian (P.1) strains.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , COVID-19/terapia , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/química , Anticorpos Antivirais/metabolismo , Anticorpos Antivirais/uso terapêutico , Brasil/epidemiologia , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Expressão Gênica , Humanos , Evasão da Resposta Imune , Imunização Passiva/métodos , Mutação , Filogenia , Ligação Proteica , Medição de Risco , SARS-CoV-2/classificação , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , África do Sul/epidemiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Reino Unido/epidemiologia , Soroterapia para COVID-19RESUMO
COVID-19 is a pandemic caused by SARS-CoV-2. In Chile, half a million people have been infected and more than 16,000 have died from COVID-19. As part of the clinical trial NCT04384588, we quantified IgG against S1-RBD of SARS-CoV-2 (anti-RBD) in recovered people in Santiago and evaluated their suitability as COVID-19 convalescent plasma donors. ELISA and a luminescent SARS-CoV-2 pseudotype were used for IgG and neutralizing antibody quantification. 72.9% of the convalescent population (468 of 639) showed seroconversion (5-55 µg/mL anti-RBD IgG) and were suitable candidates for plasma donation. Analysis by gender, age, and days after symptom offset did not show significant differences. Neutralizing activity correlated with an increased concentration of anti-RBD IgG (p < 0.0001) and showed a high variability between donors. We confirmed that the majority of the Chilean patients have developed anti-SARS-CoV-2 antibodies. The quantification of anti-RBD IgG in convalescent plasma donors is necessary to increase the detection of neutralizing antibodies.
Assuntos
COVID-19/imunologia , COVID-19/terapia , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/sangue , Anticorpos Antivirais/uso terapêutico , Chile , Feminino , Humanos , Imunização Passiva/métodos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Soroconversão , Adulto Jovem , Soroterapia para COVID-19RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged during the last months of 2019, spreading throughout the world as a highly transmissible infectious illness designated as COVID-19. Vaccines have now appeared, but the challenges in producing sufficient material and distributing them around the world means that effective treatments to limit infection and improve recovery are still urgently needed. This review focuses on the relevance of different glycobiological molecules that could potentially serve as or inspire therapeutic tools during SARS-CoV-2 infection. As such, we highlight the glycobiology of the SARS-CoV-2 infection process, where glycans on viral proteins and on host glycosaminoglycans have critical roles in efficient infection. We also take notice of the glycan-binding proteins involved in the infective capacity of virus and in human defense. In addition, we critically evaluate the glycobiological contribution of candidate drugs for COVID-19 therapy such as glycans for vaccines, anti-glycan antibodies, recombinant lectins, lectin inhibitors, glycosidase inhibitors, polysaccharides, and numerous glycosides, emphasizing some opportunities to repurpose FDA-approved drugs. For the next-generation drugs suggested here, biotechnological engineering of new probes to block the SARS-CoV-2 infection might be based on the essential glycobiological insight on glycosyltransferases, glycans, glycan-binding proteins, and glycosidases related to this pathology.
Assuntos
Antivirais/uso terapêutico , COVID-19/prevenção & controle , Reposicionamento de Medicamentos , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Glicosiltransferases/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Anticorpos Neutralizantes/uso terapêutico , Antivirais/química , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Desenho de Fármacos , Descoberta de Drogas , Expressão Gênica , Glicômica/métodos , Glicosaminoglicanos/química , Glicosaminoglicanos/imunologia , Glicosaminoglicanos/metabolismo , Glicosiltransferases/química , Glicosiltransferases/genética , Glicosiltransferases/imunologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Lectinas/química , Lectinas/imunologia , Lectinas/metabolismo , Polissacarídeos/química , Polissacarídeos/imunologia , Polissacarídeos/metabolismo , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Transdução de Sinais , Proteínas Virais/química , Proteínas Virais/genética , Proteínas Virais/imunologiaRESUMO
Com referencial teórico do ano de 2020, foram condensadas as evidências sobre o uso de plasma convalescente no tratamento da Covid-19, abordando um estudo de uma série de casos de cinco pacientes com diagnóstico de COVID-19 e síndrome do desconforto respiratório; um estudo piloto, 10 pacientes com diagnostico de COVID-19 confirmado por RT-PCR; um estudo (preprint) envolvendo 5.000 pacientes; um ensaio clínico aberto, multicêntrico incluindo 103 pacientes com quadro grave de COVID-19; uma atualização de Revisão da Cochrane, que incluiu 20 estudos, 5443 participantes (5211 receberam tratamento com plasma). Resumem as Diretrizes de Food and Drug Administration (FDA), dos Estados Unidos para utilização da terapia. No Brasil, pontua as recomendações da ANVISA, as considerações do Ministério da Saúde e os esclarecimentos do Ofício Circular nº 40/2020. Os estudos analisados pontuam resultados positivos quanto à eficácia e segurança e apontam necessidade de maiores evidências
With the theoretical framework of the year 2020, the evidence on the use of convalescent plasma in the treatment of Covid-19 was condensed, addressing a study of a case series of five patients diagnosed with COVID-19 and respiratory distress syndrome; a pilot study, 10 patients with a diagnosis of COVID-19 confirmed by RT-PCR; a study (preprint) involving 5,000 patients; an open, multicenter clinical trial including 103 patients with severe COVID-19; a Cochrane Review update, which included 20 studies, 5443 participants (5211 received plasma treatment). They summarize the US Food and Drug Administration (FDA) Guidelines for using the therapy. In Brazil, the recommendations of ANVISA, the considerations of the Ministry of Health and the clarifications of Circular Letter nº 40/2020 are punctuated. The analyzed studies show positive results regarding efficacy and safety and point to the need for more evidence
Assuntos
Humanos , Plasma , Pneumonia Viral/terapia , Infecções por Coronavirus/terapia , Anticorpos Neutralizantes/uso terapêutico , Terapias Complementares/efeitos adversosRESUMO
O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 5 protocolos.