Assuntos
Anticorpos Antivirais , Síndrome de COVID-19 Pós-Aguda , Humanos , Anticorpos Antivirais/efeitos adversos , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Síndrome de COVID-19 Pós-Aguda/sangue , Síndrome de COVID-19 Pós-Aguda/etiologia , Síndrome de COVID-19 Pós-Aguda/imunologia , Síndrome de COVID-19 Pós-Aguda/fisiopatologia , SARS-CoV-2/imunologia , Animais , CamundongosRESUMO
The FDA strongly encourages rigorous safety and efficacy studies in all age groups for which vaccines and treatments for pervasive and severe diseases are intended. Until recently, there had been no safety and efficacy studies conducted in children for human rabies immune globulins. The publication," Safety, and efficacy of rabies immunoglobulin in pediatric patients with suspected exposure", Human Vaccines & Immunotherapeutics, 17:7, 2090-2096, was the first study that prospectively reviewed the use of KEDRAB® 150 IU/ml in 30 pediatric patients ages 0.5-14.9 years old. The results showed that 93.3% achieved RVNA titer >/ = 5 IU/ml, on day 14. Also, no participants reported a serious adverse event (SAE), or an adverse event (AE) leading to study discontinuation, and there were no deaths. The most common treatment emergent adverse events (TEAE) were injection-site pain. Currently there are 3 HRIG products on the US market, KEDRAB®, HyperRab® and Imogam® Rabies HT, but only KEDRAB® has published safety and efficacy data in a pediatric population. While it is common practice to prescribe medications for pediatric patients "off-label" there now exists one product with safety data in children. It is worth considering if this creates a higher medical liability for the prescriber and institution.
Assuntos
Anticorpos Antivirais , Vacina Antirrábica , Raiva , Adolescente , Anticorpos Antivirais/efeitos adversos , Anticorpos Antivirais/uso terapêutico , Criança , Pré-Escolar , Humanos , Fatores Imunológicos , Lactente , Raiva/prevenção & controle , Vacina Antirrábica/efeitos adversos , Vacina Antirrábica/uso terapêutico , Vírus da RaivaRESUMO
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has required the urgent development of new therapies, among which passive immunotherapy is contemplated. CoviFab (INM005) is a RBD-specific F(ab')2 fragment derived from equine polyclonal antibodies. We investigate their preclinical security and biodistribution by in vivo and ex vivo NIR imaging after intravenous administration of a dose of 4 mg/kg at time 0 and 48 h. Images were taken at 1, 12, 24, 36, 48, 49, 60, 72, 84, 96, 108, 120, 132 and 144 h after the first intravenous injection. At 96 and 144 h, mice were sacrificed for haematology, serum chemistry, clinical pathology, histopathology and ex vivo imaging. The biodistribution profile was similar in all organs studied, with the highest fluorescence at 1 h after each injection, gradually decreasing after that each one and until the end of the study (144 h). The toxicology study revealed no significant changes in the haematology and serum chemistry parameters. Further, there were no changes in the gross and histological examination of organs. Nonclinical data of the current study confirm that CoviFab is safe, without observable adverse effects in mice. Furthermore, we confirm that bioimaging studies are a useful approach in preclinical trials to determine biodistribution.
Assuntos
Anticorpos Antivirais/metabolismo , Tratamento Farmacológico da COVID-19 , Receptores Imunológicos/metabolismo , Proteínas Recombinantes/metabolismo , SARS-CoV-2/metabolismo , Administração Intravenosa , Animais , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/efeitos adversos , COVID-19/metabolismo , COVID-19/prevenção & controle , Células HEK293 , Cavalos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Receptores Imunológicos/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , SARS-CoV-2/efeitos dos fármacos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologiaAssuntos
Encéfalo/fisiopatologia , Encéfalo/virologia , COVID-19/fisiopatologia , COVID-19/virologia , SARS-CoV-2/patogenicidade , Animais , Anticorpos Antivirais/efeitos adversos , Anticorpos Antivirais/imunologia , Astrócitos/virologia , Autoanticorpos/imunologia , Autopsia , Encéfalo/irrigação sanguínea , Encéfalo/imunologia , COVID-19/imunologia , COVID-19/patologia , Capilares/virologia , Cricetinae , Fadiga/complicações , Fadiga/virologia , Substância Cinzenta/patologia , Humanos , Imunoglobulinas Intravenosas/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Losartan/uso terapêutico , Transtornos da Memória/complicações , Transtornos da Memória/virologia , Neurônios/imunologia , Organoides/virologia , Pericitos/virologia , Pré-Publicações como Assunto , SARS-CoV-2/imunologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/virologia , VasoconstriçãoRESUMO
BACKGROUND: SYN023, a mixture of two anti-rabies humanized monoclonal antibodies (mAbs), namely, CTB011 and CTB012, has been developed as a safe and cost-effective alternative to RIG in the use of postexposure prophylaxis (PEP) after rabies exposure. METHODS: This phase I bridging study was designed to compare the pharmacokinetics (PK) of SYN023 (0.3 mg/kg) alone (cohort A, n = 8) or in combination with a rabies vaccine (cohort B, n = 24) in healthy Chinese subjects with those in American subjects to guide the design of further clinical trials. Their safety was assessed for the development of adverse events (AEs) by laboratory examinations. The levels of serum CTB011, CTB012 and anti-drug antibodies (ADAs) were measured longitudinally for 85 days. Serum rabies virus neutralizing antibody (RVNA) levels were measured as a pharmacodynamic (PD) surrogate. RESULTS: Some subjects with injectable SYN023 at 0.3 mg/kg developed temporary AEs and adverse drug reactions (ADRs) of Grade 1 or 2, particularly in cohort B, probably due to vaccine coadministration. SYN023 injection displayed a typical and reliable PK, similar to that of human IgGs. Following injection with SYN023, Chinese subjects had slower absorption with higher exposures for CTB011 but lower exposures for CTB012 than American subjects. The SYN023 recipients achieved protective levels of RVNA (≥0.5 IU/mL) on day 3 post injection. A few subjects developed temporary ADA, which did not affect the safety and PK/PD of SYN023 in Chinese subjects. CONCLUSION: SYN023 at 0.3 mg/kg is relatively saf e and effective and can be selected for further clinical trials in Chinese subjects. The clinical trial registration number is CTR20190281. http://www.chinadrugtrials.org.cn/eap/clinicaltrials.searchlist?a=a®_no=CTR20190281.
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Antivirais/farmacocinética , Vacina Antirrábica/farmacocinética , Raiva/prevenção & controle , Adulto , Animais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/efeitos adversos , Anticorpos Antivirais/farmacologia , Antivirais/efeitos adversos , Povo Asiático , Chlorocebus aethiops , Feminino , Humanos , Imunoglobulina G/efeitos adversos , Imunoglobulina G/farmacologia , Masculino , Pessoa de Meia-Idade , Raiva/imunologia , Vacina Antirrábica/efeitos adversos , Vírus da Raiva , Células VeroRESUMO
Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies. In vitro modelling of ADE has attributed enhanced pathogenesis to Fcγ receptor (FcγR)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative FcγR-dependent mechanisms of ADE overlap with the role of these receptors in mediating antiviral protection in various viral infections, necessitating a detailed understanding of how this diverse family of receptors functions in protection and pathogenesis. Here, we discuss the diversity of immune responses mediated upon FcγR engagement and review the available experimental evidence supporting the role of FcγRs in antiviral protection and pathogenesis through ADE. We explore FcγR engagement in the context of a range of different viral infections, including dengue virus and SARS-CoV, and consider ADE in the context of the ongoing SARS-CoV-2 pandemic.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Antivirais/administração & dosagem , Anticorpos Facilitadores/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Receptores de IgG/imunologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/biossíntese , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/efeitos adversos , Anticorpos Antivirais/biossíntese , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Dengue/tratamento farmacológico , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/imunologia , Vírus da Dengue/patogenicidade , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Leucócitos/imunologia , Leucócitos/virologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Receptores de IgG/antagonistas & inibidores , Receptores de IgG/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/efeitos dos fármacos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/imunologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/patogenicidade , SARS-CoV-2 , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Transdução de Sinais , Internalização do Vírus/efeitos dos fármacosRESUMO
Antibody-dependent enhancement (ADE) of disease is a general concern for the development of vaccines and antibody therapies because the mechanisms that underlie antibody protection against any virus have a theoretical potential to amplify the infection or trigger harmful immunopathology. This possibility requires careful consideration at this critical point in the pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we review observations relevant to the risks of ADE of disease, and their potential implications for SARS-CoV-2 infection. At present, there are no known clinical findings, immunological assays or biomarkers that can differentiate any severe viral infection from immune-enhanced disease, whether by measuring antibodies, T cells or intrinsic host responses. In vitro systems and animal models do not predict the risk of ADE of disease, in part because protective and potentially detrimental antibody-mediated mechanisms are the same and designing animal models depends on understanding how antiviral host responses may become harmful in humans. The implications of our lack of knowledge are twofold. First, comprehensive studies are urgently needed to define clinical correlates of protective immunity against SARS-CoV-2. Second, because ADE of disease cannot be reliably predicted after either vaccination or treatment with antibodies-regardless of what virus is the causative agent-it will be essential to depend on careful analysis of safety in humans as immune interventions for COVID-19 move forward.
Assuntos
Anticorpos Antivirais/efeitos adversos , Anticorpos Antivirais/imunologia , Anticorpos Facilitadores/imunologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Animais , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , COVID-19 , Vacinas contra COVID-19 , Infecções por Coronavirus/prevenção & controle , Vírus da Dengue/imunologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/imunologia , Macaca mulatta , Camundongos , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Orthomyxoviridae/imunologia , Pandemias , Ratos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/imunologia , SARS-CoV-2 , Vacinas Virais/efeitos adversos , Vacinas Virais/imunologiaRESUMO
COVID-19 has rapidly spread all over the world, progressing into a pandemic. This situation has urgently impelled many companies and public research institutes to concentrate their efforts on research for effective therapeutics. Here, we outline the strategies and targets currently adopted in developing a vaccine against SARS-CoV-2. Based on previous evidence and experience with SARS and MERS, the primary focus has been the Spike protein, considered as the ideal target for COVID-19 immunotherapies.
Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/efeitos adversos , Anticorpos Antivirais/biossíntese , Anticorpos Facilitadores/imunologia , Betacoronavirus/genética , Betacoronavirus/patogenicidade , COVID-19 , Vacinas contra COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Pesquisa Translacional Biomédica , Vacinas Virais/efeitos adversos , Vacinas Virais/genéticaRESUMO
A novel coronavirus (CoV), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 in Wuhan, China and has since spread as a global pandemic. Safe and effective vaccines are thus urgently needed to reduce the significant morbidity and mortality of Coronavirus Disease 2019 (COVID-19) disease and ease the major economic impact. There has been an unprecedented rapid response by vaccine developers with now over one hundred vaccine candidates in development and at least six having reached clinical trials. However, a major challenge during rapid development is to avoid safety issues both by thoughtful vaccine design and by thorough evaluation in a timely manner. A syndrome of "disease enhancement" has been reported in the past for a few viral vaccines where those immunized suffered increased severity or death when they later encountered the virus or were found to have an increased frequency of infection. Animal models allowed scientists to determine the underlying mechanism for the former in the case of Respiratory syncytial virus (RSV) vaccine and have been utilized to design and screen new RSV vaccine candidates. Because some Middle East respiratory syndrome (MERS) and SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a particular concern for SARS-CoV-2 vaccines. To address this challenge, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a scientific working meeting on March 12 and 13, 2020 of experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns and how animal models and immunological assessments in early clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for safety assessment of COVID-19 vaccine candidates in accelerated vaccine development.
Assuntos
Anticorpos Antivirais/efeitos adversos , Anticorpos Antivirais/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Vacinas Virais/efeitos adversos , Vacinas Virais/imunologia , Animais , Betacoronavirus/patogenicidade , COVID-19 , Vacinas contra COVID-19 , Ensaios Clínicos como Assunto , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Humanos , Pandemias , Pneumonia Viral/virologia , Medição de Risco , SARS-CoV-2 , Síndrome Respiratória Aguda Grave/imunologiaRESUMO
Passive immunotherapy with plasma derived from convalescent patients recovering from SARS-CoV-2 infection can be a promising approach in the treatment of COVID-19 patients. It is important that blood establishments are ready to satisfy requests for immune plasma by defining the requirements applicable to plasma donors and the standards for preparation, qualification, storage, distribution, and control of product use. This Position paper aims to give recommendations on the biological characteristics of a plasma preparation from convalescent donors and to support the evaluation of this therapeutic approach in more rigorous investigations.
Assuntos
Anticorpos Antivirais/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/terapia , Imunização Passiva/métodos , Plasma/imunologia , Pneumonia Viral/terapia , Anticorpos Antivirais/efeitos adversos , Bancos de Sangue/organização & administração , Bancos de Sangue/normas , Doadores de Sangue/legislação & jurisprudência , COVID-19 , Europa (Continente) , Humanos , Esquemas de Imunização , Imunização Passiva/efeitos adversos , Imunização Passiva/normas , Consentimento Livre e Esclarecido , Itália , Pandemias , SARS-CoV-2 , Soroterapia para COVID-19Assuntos
Anticorpos Antivirais/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/terapia , Imunoglobulinas Intravenosas/administração & dosagem , Pneumonia Viral/terapia , Anticorpos Antivirais/efeitos adversos , Anticorpos Antivirais/imunologia , COVID-19 , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Imunização Passiva/efeitos adversos , Imunização Passiva/métodos , Imunoglobulinas Intravenosas/efeitos adversos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/imunologia , Resultado do Tratamento , Soroterapia para COVID-19RESUMO
The pandemic spread of a novel coronavirus - SARS coronavirus-2 (SARS-CoV-2) as a cause of acute respiratory illness, named Covid-19, is placing the healthcare systems of many countries under unprecedented stress. Global economies are also spiraling towards a recession in fear of this new life-threatening disease. Vaccines that prevent SARS-CoV-2 infection and therapeutics that reduces the risk of severe Covid-19 are thus urgently needed. A rapid method to derive antiviral treatment for Covid-19 is the use of convalescent plasma derived hyperimmune globulin. However, both hyperimmune globulin and vaccine development face a common hurdle - the risk of antibody-mediated disease enhancement. The goal of this review is to examine the body of evidence supporting the hypothesis of immune enhancement that could be pertinent to Covid-19. We also discuss how this risk could be mitigated so that both hyperimmune globulin and vaccines could be rapidly translated to overcome the current global health crisis.
Assuntos
Anticorpos Antivirais/efeitos adversos , Infecções por Coronavirus/imunologia , Pandemias , Pneumonia Viral/imunologia , Vacinas Virais/imunologia , Internalização do Vírus , Animais , Anticorpos Antivirais/imunologia , COVID-19 , Vacinas contra COVID-19 , Ensaios Clínicos Fase I como Assunto , Convalescença , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Células Dendríticas/virologia , Saúde Global , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunização Passiva , Macrófagos/virologia , Modelos Animais , Monócitos/virologia , Pandemias/prevenção & controle , Plasma , Plasmaferese , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/terapia , Receptores Fc/imunologia , Pesquisa Translacional Biomédica , Soroterapia para COVID-19RESUMO
Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients, and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled trial, we evaluated the safety and efficacy of CSJ148 for prophylaxis of HCMV in patients undergoing allogeneic hematopoietic stem cell transplantation. As would be expected in the study population, all the patients (100%) reported at least one treatment-emergent adverse event. There were 22 deaths during this study, and over 80% of the patients receiving placebo or CSJ148 developed at least one adverse event of grade 3 or higher severity. No subject who received antibody developed a hypersensitivity- or infusion-related reaction. CSJ148-treated patients showed trends toward decreased viral load, shorter median duration of preemptive therapy, and fewer courses of preemptive therapy. However, the estimated probability that CSJ148 decreases the need for preemptive therapy compared to placebo was 69%, with a risk ratio of 0.89 and a 90% credible interval of 0.61 to 1.31. The primary efficacy endpoint was therefore not met, indicating that CSJ148 did not prevent clinically significant HCMV reactivation in recipients of allogeneic hematopoietic cell transplants. (This study has been registered at ClinicalTrials.gov under identifier NCT02268526 and at EudraCT under number 2017-002047-15.).
Assuntos
Anticorpos Antivirais/farmacologia , Infecções por Citomegalovirus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Administração Intravenosa , Adulto , Idoso , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacocinética , Antivirais/farmacologia , Infecções por Citomegalovirus/etiologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
In recent years, there has been a renewed interest in utilizing antibody fragment crystallizable (Fc) functions to prevent and control viral infections. The protective and therapeutic potential of Fc-mediated antibody functions have been assessed for some clinically important human viruses, including HIV, hemorrhagic fever viruses and influenza virus. There is mounting evidence that influenza-specific antibodies with Fc-mediated functions, such as antibody-dependent cellular cytotoxicity and antibody-dependent phagocytosis, can aid in the clearance of influenza virus infection. Recent influenza challenge studies and intravenous immunoglobulin G therapy studies in humans suggest a protective role for Fc effector functions in vivo. Broadly reactive influenza antibodies with Fc-mediated functions are prevalent in the human population and could inform the development of a universally protective influenza vaccine or therapy. In this review, we explore the utility of antibodies with Fc-mediated effector functions against viral infections with a focus on influenza virus.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Fragmentos Fc das Imunoglobulinas/fisiologia , Influenza Humana/imunologia , Orthomyxoviridae/imunologia , Fagocitose/imunologia , Receptores Fc/fisiologia , Animais , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Antivirais/efeitos adversos , Citotoxicidade Celular Dependente de Anticorpos , Proteínas do Sistema Complemento/imunologia , Humanos , Vacinas contra Influenza/imunologia , Influenza Humana/virologia , Viroses/imunologiaRESUMO
Adeno-associated virus (AAV)-based liver gene therapy has been shown to be clinically successful. However, the presence of circulating neutralizing antibodies (NABs) against AAV vector capsids remains a major challenge as it may prevent successful transduction of the target cells. Therefore, there is a need to develop strategies that would enable AAV-mediated gene delivery to patients with preexisting anti-AAV NABs. In the current study, the feasibility of using an immunoadsorption (IA) procedure for repeated, liver-targeted gene delivery in nonhuman primates was explored. The animals were administered IV with recombinant AAV5 (rAAV5) carrying the reporter gene human secreted embryonic alkaline phosphatase (hSEAP). Seven weeks after the first rAAV treatment, all of the animals were readministered with rAAV5 carrying the therapeutic hemophilia B gene human factor IX (hFIX). Half of the animals administered with rAAV5-hSEAP underwent IA prior to the second rAAV5 exposure. The transduction efficacies of rAAV5-hSEAP and rAAV5-hFIX were assessed by measuring the levels of hSEAP and hFIX proteins. Although no hFIX was detected after rAAV5-hFIX readministration without prior IA, all animals submitted to IA showed therapeutic levels of hFIX expression, and a threshold of anti-AAV5 NAB levels compatible with successful readministration was demonstrated. In summary, our data demonstrate that the use of a clinically applicable IA procedure enables successful readministration of an rAAV5-based gene transfer in a clinically relevant animal model. Finally, the analysis of anti-AAV NAB levels in human subjects submitted to IA confirmed the safety and efficacy of the procedure to reduce anti-AAV NABs. Furthermore, clinical translation was assessed using an immunoglobulin G assay as surrogate.
Assuntos
Anticorpos Antivirais/isolamento & purificação , Dependovirus/imunologia , Técnicas de Transferência de Genes/normas , Técnicas de Imunoadsorção , Fígado/metabolismo , Fosfatase Alcalina/administração & dosagem , Fosfatase Alcalina/genética , Animais , Anticorpos Antivirais/efeitos adversos , Dependovirus/genética , Fator IX/administração & dosagem , Fator IX/genética , Humanos , PrimatasRESUMO
OBJECTIVE: To use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS). METHODS: This retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions. RESULTS: This study included 35,521 patients (primary analysis: 1,988 EID, 13,132 SID; secondary analysis: 3,331 EID, 15,424 SID; tertiary analysis: 815 EID, 23,168 SID). Mean average dosing intervals were 35.0 to 43.0 and 29.8 to 30.5 days for the EID and SID cohorts, respectively. Hazard ratios (95% confidence intervals) of PML risk for EID vs SID were 0.06 (0.01-0.22, p < 0.001) and 0.12 (0.05-0.29, p < 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID. CONCLUSION: Natalizumab EID is associated with clinically and statistically significantly lower PML risk than SID. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/etiologia , Esclerose Múltipla/tratamento farmacológico , Natalizumab/efeitos adversos , Adulto , Anticorpos Antivirais/efeitos adversos , Feminino , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Natalizumab/uso terapêutico , Estudos Retrospectivos , Fatores de RiscoRESUMO
Vaccination is one of the most important tools to protect pigs against infection with porcine reproductive and respiratory syndrome virus 1 (PRRSV-1). Although neutralizing antibodies are considered to represent an important mechanism of protective immunity, anti-PRRSV antibodies, in particular at subneutralizing concentrations, have also been reported to exacerbate PRRSV infection, probably through FcγR-mediated uptake of antibody-opsonized PRRSV, resulting in enhanced infection of, and replication in, target cells. Therefore, we investigated this pathway using sera from an animal experiment in which vaccine-mediated enhancement of clinical symptoms was observed. Three groups of six pigs were vaccinated with an inactivated PRRSV vaccine based on the PRRSV-1 subtype 3 strain Lena and challenged after a single or a prime-boost immunization protocol, or injected with PBS. We specifically tested if sera obtained from these animals can enhance macrophage infections, viral shedding, or cytokine release at different dilutions. Neither the presence of neutralizing antibodies nor general anti-PRRSV antibodies, mediated an enhanced infection, increased viral release or cytokine production by macrophages. Taken together, our data indicate that the exacerbated disease was not caused by antibodies.
Assuntos
Anticorpos Antivirais/imunologia , Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Animais , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/efeitos adversos , Citocinas/imunologia , Macrófagos/imunologia , Macrófagos/virologia , Síndrome Respiratória e Reprodutiva Suína/genética , Síndrome Respiratória e Reprodutiva Suína/prevenção & controle , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Sus scrofa , Suínos , Vacinação/efeitos adversos , Eliminação de Partículas ViraisRESUMO
Preexisting immunity against dengue virus or West Nile virus was previously reported to mediate antibody-dependent enhancement (ADE) of Zika virus (ZIKV) infection in a mouse model. We show here that ZIKV-immune plasma samples from both symptomatic and asymptomatic individuals mediated ZIKV ADE of infection in vitro and in mice. In a lethal infection model with a viral inoculum 10 times higher, both ADE and protection were observed, depending on the amount of infused immune plasma. In a vertical-transmission model, ZIKV-immune plasma infused to timed pregnant mice increased fetal demise and decreased the body weight of surviving fetuses. Depletion of IgG from an immune plasma abolished ADE of infection, and the presence of purified IgG alone mediated ADE of infection. Higher viral loads and proinflammatory cytokines were detected in mice treated with ZIKV-immune plasma samples compared to those receiving control plasma. Together, these data show that passive immunization with homotypic ZIKV antibodies, depending on the concentration, could either worsen or limit a subsequent ZIKV infection.IMPORTANCE Antibody-dependent enhancement (ADE) of virus infection is common to many viruses and is problematic when plasma antibody levels decline to subneutralizing concentrations. ADE of infection is especially important among flaviviruses, many of which are the cause of global health problems. Recently, human plasma samples immune to heterologous flaviviruses were shown to promote Zika virus (ZIKV) infection. Here we showed in immunocompromised mouse models that homologous immune plasma samples protect mice from subsequent infection at high antibody concentrations but that they mediate ADE of infection and increase ZIKV pathogenesis in adult mice and fetal demise during pregnancy at low concentrations.
Assuntos
Anticorpos Facilitadores , Soros Imunes/administração & dosagem , Soros Imunes/efeitos adversos , Infecção por Zika virus/imunologia , Infecção por Zika virus/fisiopatologia , Zika virus/imunologia , Adulto , Animais , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/efeitos adversos , Modelos Animais de Doenças , Humanos , Camundongos , Modelos Teóricos , Carga Viral , Infecção por Zika virus/prevenção & controleRESUMO
Several next-generation (universal) influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these mediate inhibitions of virus replication at the postentry stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of viral infection or disease. In the current study, two monoclonal antibodies (MAbs) 72/8 and 69/1, enhanced respiratory disease (ERD) in mice following H3N2 virus challenge by demonstrating increased lung pathology and changes in lung cytokine/chemokine levels. MAb 78/2 caused changes in the lung viral loads in a dose-dependent manner. Both MAbs increased HA sensitivity to trypsin cleavage at a higher pH range, suggesting MAb-induced conformational changes. pHrodo-labeled virus particles' entry and residence time in the endocytic compartment were tracked during infection of Madin-Darby canine kidney (MDCK) cells. Both MAbs reduced H3N2 virus residence time in the endocytic pathway, suggesting faster virus fusion kinetics. Structurally, 78/2 and 69/1 Fabs bound the globular head or base of the head domain of influenza hemagglutinin (HA), respectively, and induced destabilization of the HA stem domain. Together, this study describes Mab-induced destabilization of the influenza HA stem domain, faster kinetics of influenza virus fusion, and ERD in vivo. The in vivo animal model and in vitro assays described could augment preclinical safety evaluation of antibodies and next-generation influenza vaccines that generate antibodies which do not block influenza virus-receptor interaction.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Anticorpos Antivirais/efeitos adversos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Pulmão/virologia , Infecções por Orthomyxoviridae/virologia , Internalização do Vírus/efeitos dos fármacos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Anticorpos Antivirais/química , Anticorpos Antivirais/metabolismo , Sítios de Ligação , Cães , Endocitose/efeitos dos fármacos , Endocitose/imunologia , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/patogenicidade , Pulmão/imunologia , Pulmão/patologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Ligação Proteica , Proteólise , Carga Viral/efeitos dos fármacos , Vírion/efeitos dos fármacos , Vírion/imunologia , Vírion/patogenicidade , Replicação Viral/efeitos dos fármacosRESUMO
Dengue virus is the most globally prevalent mosquito-transmitted virus. Primary infection with one of four cocirculating serotypes (DENV-1 to -4) causes a febrile illness, but secondary infection with a heterologous serotype can result in severe disease, due in part to antibody-dependent enhancement of infection (ADE). In ADE, cross-reactive but nonneutralizing antibodies, or subprotective levels of neutralizing antibodies, promote uptake of antibody-opsonized virus in Fc-γ receptor-positive cells. Thus, elicitation of broadly neutralizing antibodies (bNAbs), but not nonneutralizing antibodies, is desirable for dengue vaccine development. Domain III of the envelope glycoprotein (EDIII) is targeted by bNAbs and thus is an attractive immunogen. However, immunization with EDIII results in sera with limited neutralization breadth. We developed "resurfaced" EDIII immunogens (rsDIIIs) in which the A/G strand epitope that is targeted by bNAb 4E11 is maintained but less desirable epitopes are masked. RsDIIIs bound 4E11, but not serotype-specific or nonneutralizing antibodies. One rsDIII and, unexpectedly, wild-type (WT) DENV-2 EDIII elicited cross-neutralizing antibody responses against DENV-1 to -3 in mice. While these sera were cross-neutralizing, they were not sufficiently potent to protect AG129 immunocompromised mice at a dose of 200 µl (50% focus reduction neutralization titer [FRNT50], â¼1:60 to 1:130) against mouse-adapted DENV-2. Our results provide insight into immunogen design strategies based on EDIII.IMPORTANCE Dengue virus causes approximately 390 million infections per year. Primary infection by one serotype causes a self-limiting febrile illness, but secondary infection by a heterologous serotype can result in severe dengue syndrome, which is characterized by hemorrhagic fever and shock syndrome. This severe disease is thought to arise because of cross-reactive, non- or poorly neutralizing antibodies from the primary infection that are present in serum at the time of secondary infection. These cross-reactive antibodies enhance the infection rather than controlling it. Therefore, induction of a broadly and potently neutralizing antibody response is desirable for dengue vaccine development. Here, we explore a novel strategy for developing immunogens based on domain III of the E glycoprotein, where undesirable epitopes (nonneutralizing or nonconserved) are masked by mutation. This work provides fundamental insight into the immune response to domain III that can be leveraged for future immunogen design.