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1.
Zhonghua Yu Fang Yi Xue Za Zhi ; 55(2): 171-176, 2021 Feb 06.
Artigo em Chinês | MEDLINE | ID: mdl-34645175

RESUMO

Antibody-dependent enhancement (ADE) refers to the process in which some virus-specific antibodies (generally non-neutralizing antibodies) bind to the virus and bind to some cells expressing FcR on the surface through their Fc segment, thereby mediating the endocytosis and replication of the virus and enhancing the infection of the virus. This review summarized experience of ADE in respiratory syncytial virus, dengue virus, influenza virus infection and explored the possible mechanism of COVID-19 high incidence and severity of the disease, which implied challenges in the process of vaccine development and provided some insights for COVID-19 pathogenesis.


Assuntos
COVID-19 , Vírus da Dengue , Dengue , Anticorpos Neutralizantes , Anticorpos Antivirais , Anticorpos Facilitadores , Humanos , SARS-CoV-2
2.
Int J Immunopathol Pharmacol ; 35: 20587384211050199, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34632844

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents an unprecedented global public health emergency with economic and social consequences. One of the main concerns in the development of vaccines is the antibody-dependent enhancement phenomenon, better known as ADE. In this review, we provide an overview of SARS-CoV-2 infection as well as the immune response generated by the host. On the bases of this principle, we also describe what is known about the ADE phenomenon in various viral infections and its possible role as a limiting factor in the development of new vaccines and therapeutic strategies.


Assuntos
Anticorpos Antivirais/imunologia , Anticorpos Facilitadores , COVID-19/imunologia , SARS-CoV-2/imunologia , Imunidade Adaptativa , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/uso terapêutico , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , SARS-CoV-2/patogenicidade , Vacinação
3.
BMC Infect Dis ; 21(1): 749, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34348665

RESUMO

BACKGROUND: Dengue virus (DENV) is endemic in many parts of the world. Antibody dependent enhancement (ADE) in DENV infections occurs when a person with primary immunity is infected by a second, different DENV strain. Antibodies to Zika virus (ZIKV), which emerged in the Western Hemisphere in 2015, are cross reactive with DENV and theoretically could provoke ADE in a DENV naïve individual. CASE PRESENTATION: DENV infection was suspected in a child who had recently returned from a one-month stay in the Dominican Republic. The child presented with fever, vomiting, abdominal pain, and in hypovolemic shock. Volume and pressor resuscitation were unsuccessful, and the child died less than 24 h after hospitalization. Laboratory results suggested an early acute first DENV infection since serum, plasma, and spinal fluid had DENV1 detected by polymerase chain reaction (PCR), yet the serum lacked IgG antibodies to DENV nonstructural protein 1 (NS1) of all four DENV serotypes. This acute DENV infection occurred in the presence of a remote ZIKV infection as determined by antibodies to ZIKV NS1 envelope by multiplex microsphere immunoassay and an exceptionally high plaque reduction neutralization titer to ZIKV. ZIKV IgG avidity index was high, confirming a past infection. DENV1 RNA was detected in all ten organs and tissues examined by PCR. The severe and fatal complications reported here suggest that a remote ZIKV infection may provoke an exaggerated immune response leading to hypovolemic shock when primarily infected by DENV1. CONCLUSION: We report the first known patient in the United States with a rapidly progressive and fatal case of travel-associated DENV in which prior exposure to ZIKV likely played a role in triggering an ADE phenomenon. This association of prior ZIKV immunity and subsequent new dengue infection is a worrisome phenomenon and an important contribution to the body of knowledge on immunity to flaviviruses.


Assuntos
Vírus da Dengue , Dengue , Infecção por Zika virus , Zika virus , Anticorpos Antivirais , Anticorpos Facilitadores , Criança , Reações Cruzadas , Humanos , Viagem , Infecção por Zika virus/diagnóstico
4.
Front Immunol ; 12: 690976, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335596

RESUMO

Different emerging viral infections may emerge in different regions of the world and pose a global pandemic threat with high fatality. Clarification of the immunopathogenesis of different emerging viral infections can provide a plan for the crisis management and prevention of emerging infections. This perspective article describes how an emerging viral infection evolves from microbial mutation, zoonotic and/or vector-borne transmission that progresses to a fatal infection due to overt viremia, tissue-specific cytotropic damage or/and immunopathology. We classified immunopathogenesis of common emerging viral infections into 4 categories: 1) deficient immunity with disseminated viremia (e.g., Ebola); 2) pneumocytotropism with/without later hyperinflammation (e.g., COVID-19); 3) augmented immunopathology (e.g., Hanta); and 4) antibody-dependent enhancement of infection with altered immunity (e.g., Dengue). A practical guide to early blocking of viral evasion, limiting viral load and identifying the fatal mechanism of an emerging viral infection is provided to prevent and reduce the transmission, and to do rapid diagnoses followed by the early treatment of virus neutralization for reduction of morbidity and mortality of an emerging viral infection such as COVID-19.


Assuntos
COVID-19/imunologia , Doenças Transmissíveis Emergentes/imunologia , Evasão da Resposta Imune/imunologia , SARS-CoV-2/fisiologia , Viroses/imunologia , Animais , Anticorpos Facilitadores , COVID-19/mortalidade , COVID-19/prevenção & controle , Humanos , Pandemias , Análise de Sobrevida , Viroses/mortalidade , Viroses/prevenção & controle
5.
Nat Immunol ; 22(8): 958-968, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34267374

RESUMO

Antibody-dependent enhancement (ADE) is an important safety concern for vaccine development against dengue virus (DENV) and its antigenically related Zika virus (ZIKV) because vaccine may prime deleterious antibodies to enhance natural infections. Cross-reactive antibodies targeting the conserved fusion loop epitope (FLE) are known as the main sources of ADE. We design ZIKV immunogens engineered to change the FLE conformation but preserve neutralizing epitopes. Single vaccination conferred sterilizing immunity against ZIKV without ADE of DENV-serotype 1-4 infections and abrogated maternal-neonatal transmission in mice. Unlike the wild-type-based vaccine inducing predominately cross-reactive ADE-prone antibodies, B cell profiling revealed that the engineered vaccines switched immunodominance to dispersed patterns without DENV enhancement. The crystal structure of the engineered immunogen showed the dimeric conformation of the envelope protein with FLE disruption. We provide vaccine candidates that will prevent both ZIKV infection and infection-/vaccination-induced DENV ADE.


Assuntos
Anticorpos Facilitadores/imunologia , Antígenos Virais/imunologia , Reações Cruzadas/imunologia , Vacinas contra Dengue/imunologia , Dengue/prevenção & controle , Zika virus/imunologia , Aedes , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Chlorocebus aethiops , Cricetinae , Vírus da Dengue/imunologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptor de Interferon alfa e beta/genética , Vacinação , Células Vero , Infecção por Zika virus/imunologia , Infecção por Zika virus/prevenção & controle
6.
J Virol ; 95(19): e0068521, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34287040

RESUMO

The human angiotensin-converting enzyme 2 acts as the host cell receptor for SARS-CoV-2 and the other members of the Coronaviridae family SARS-CoV-1 and HCoV-NL63. Here, we report the biophysical properties of the SARS-CoV-2 spike variants D614G, B.1.1.7, B.1.351, and P.1 with affinities to the ACE2 receptor and infectivity capacity, revealing weaknesses in the developed neutralizing antibody approaches. Furthermore, we report a preclinical characterization package for a soluble receptor decoy engineered to be catalytically inactive and immunologically inert, with broad neutralization capacity, that represents an attractive therapeutic alternative in light of the mutational landscape of COVID-19. This construct efficiently neutralized four SARS-CoV-2 variants of concern. The decoy also displays antibody-like biophysical properties and manufacturability, strengthening its suitability as a first-line treatment option in prophylaxis or therapeutic regimens for COVID-19 and related viral infections. IMPORTANCE Mutational drift of SARS-CoV-2 risks rendering both therapeutics and vaccines less effective. Receptor decoy strategies utilizing soluble human ACE2 may overcome the risk of viral mutational escape since mutations disrupting viral interaction with the ACE2 decoy will by necessity decrease virulence, thereby preventing meaningful escape. The solution described here of a soluble ACE2 receptor decoy is significant for the following reasons: while previous ACE2-based therapeutics have been described, ours has novel features, including (i) mutations within ACE2 to remove catalytical activity and systemic interference with the renin/angiotensin system, (ii) abrogated FcγR engagement, reduced risk of antibody-dependent enhancement of infection, and reduced risk of hyperinflammation, and (iii) streamlined antibody-like purification process and scale-up manufacturability indicating that this receptor decoy could be produced quickly and easily at scale. Finally, we demonstrate that ACE2-based therapeutics confer a broad-spectrum neutralization potency for ACE2-tropic viruses, including SARS-CoV-2 variants of concern in contrast to therapeutic MAb.


Assuntos
Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Antivirais/imunologia , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Anticorpos Neutralizantes/imunologia , Anticorpos Facilitadores , COVID-19/imunologia , Células HEK293 , Humanos , Cinética , Mutação , Ligação Proteica , Domínios Proteicos , Domínios e Motivos de Interação entre Proteínas , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo
7.
MAbs ; 13(1): 1953683, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34313527

RESUMO

The global pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in widespread social and economic disruption. Effective interventions are urgently needed for the prevention and treatment of COVID-19. Neutralizing monoclonal antibodies (mAbs) have demonstrated their prophylactic and therapeutic efficacy against SARS-CoV-2, and several have been granted authorization for emergency use. Here, we discover and characterize a fully human cross-reactive mAb, MW06, which binds to both SARS-CoV-2 and SARS-CoV spike receptor-binding domain (RBD) and disrupts their interaction with angiotensin-converting enzyme 2 (ACE2) receptors. Potential neutralization activity of MW06 was observed against both SARS-CoV-2 and SARS-CoV in different assays. The complex structure determination and epitope alignment of SARS-CoV-2 RBD/MW06 revealed that the epitope recognized by MW06 is highly conserved among SARS-related coronavirus strains, indicating the potential broad neutralization activity of MW06. In in vitro assays, no antibody-dependent enhancement (ADE) of SARS-CoV-2 infection was observed for MW06. In addition, MW06 recognizes a different epitope from MW05, which shows high neutralization activity and has been in a Phase 2 clinical trial, supporting the development of the cocktail of MW05 and MW06 to prevent against future escaping variants. MW06 alone and the cocktail show good effects in preventing escape mutations, including a series of variants of concern, B.1.1.7, P.1, B.1.351, and B.1.617.1. These findings suggest that MW06 recognizes a conserved epitope on SARS-CoV-2, which provides insights for the development of a universal antibody-based therapy against SARS-related coronavirus and emerging variant strains, and may be an effective anti-SARS-CoV-2 agent.


Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/virologia , Vírus da SARS/imunologia , SARS-CoV-2/imunologia , Sequência de Aminoácidos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/química , Anticorpos Antivirais/uso terapêutico , Anticorpos Facilitadores , COVID-19/tratamento farmacológico , COVID-19/terapia , Sequência Conservada , Reações Cruzadas , Epitopos/química , Epitopos/genética , Epitopos/imunologia , Humanos , Modelos Moleculares , Testes de Neutralização , Pandemias , Domínios Proteicos , Domínios e Motivos de Interação entre Proteínas , Vírus da SARS/química , Vírus da SARS/genética , SARS-CoV-2/química , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
8.
Front Immunol ; 12: 574411, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211454

RESUMO

Dengue virus (DENV) poses a serious threat to global health as the causative agent of dengue fever. The virus is endemic in more than 128 countries resulting in approximately 390 million infection cases each year. Currently, there is no approved therapeutic for treatment nor a fully efficacious vaccine. The development of therapeutics is confounded and hampered by the complexity of the immune response to DENV, in particular to sequential infection with different DENV serotypes (DENV1-5). Researchers have shown that the DENV envelope (E) antigen is primarily responsible for the interaction and subsequent invasion of host cells for all serotypes and can elicit neutralizing antibodies in humans. The advent of high-throughput sequencing and the rapid advancements in computational analysis of complex data, has provided tools for the deconvolution of the DENV immune response. Several types of complex statistical analyses, machine learning models and complex visualizations can be applied to begin answering questions about the B- and T-cell immune responses to multiple infections, antibody-dependent enhancement, identification of novel therapeutics and advance vaccine research.


Assuntos
Linfócitos B/imunologia , Vacinas contra Dengue/imunologia , Vírus da Dengue/fisiologia , Dengue/imunologia , Linfócitos T/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/metabolismo , Anticorpos Facilitadores , Antivirais/uso terapêutico , Inteligência Artificial , Simulação por Computador , Dengue/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Aprendizado de Máquina , Proteínas do Envelope Viral/imunologia
9.
Infez Med ; 29(2): 167-180, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34061781

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome virus 2 (SARS-CoV-2), in a very short span of thirteen months has taken a considerable toll on humanity, resulting in over 3 million deaths with more than 150 million confirmed cases as on May 1, 2021. In the scarcity of a potential antiviral and protective vaccine, COVID-19 has posed high public health concerns, panic, and challenges to limit the spread of this pandemic virus. Only recently have a few vaccine candidates been developed, and vaccination programs have started in some countries. Multiple clinical presentations of COVID-19, animal spillover, cross-species jumping, zoonotic concerns, and emergence of virus variants have altogether created havoc during this ongoing pandemic. Several bodies of research are continuously working to elucidate the exact molecular mechanisms of the pathogenesis. To develop a prospective antiviral therapy/vaccine for SARSCoV-2, it is quite essential to gain insight into the immunobiology and molecular virology of SARS-CoV-2. A thorough literature search was conducted up to 28th February 2021 in the PubMed and other databases for the articles describing the immunopathology and immune response of SARS-CoV-2 infection, which were critically evaluated and used to compile this article to present an overall update. Some of the information was drawn from studies on previous MERS and SARS viruses. Innate as well as adaptive immunity responses are elicited by exposure to SARS-CoV-2. SARS-CoV-2 establishes a successful infection by escaping the host immunity as well as over activating the innate immune mechanisms that result in severe disease outcomes, including cytokine storm. This review summarizes the immunopathology and molecular immune mechanisms elicited during SARS-CoV-2 infection, and their similarities with MERS-CoV and SARS-CoV.


Assuntos
Imunidade Adaptativa , COVID-19/imunologia , Imunidade Inata , SARS-CoV-2/imunologia , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Facilitadores/imunologia , Linfócitos B/imunologia , COVID-19/virologia , Humanos , Imunidade Celular , Pulmão/enzimologia , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Linfócitos T/imunologia , Ligação Viral
10.
Mol Cells ; 44(6): 392-400, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34059562

RESUMO

It has been more than a year since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged. Many studies have provided insights into the various aspects of the immune response in coronavirus disease 2019 (COVID-19). Especially for antibody treatment and vaccine development, humoral immunity to SARS-CoV-2 has been studied extensively, though there is still much that is unknown and controversial. Here, we introduce key discoveries on the humoral immune responses in COVID-19, including the immune dynamics of antibody responses and correlations with disease severity, neutralizing antibodies and their cross-reactivity, how long the antibody and memory B-cell responses last, aberrant autoreactive antibodies generated in COVID-19 patients, and the efficacy of currently available therapeutic antibodies and vaccines against circulating SARS-CoV-2 variants, and highlight gaps in the current knowledge.


Assuntos
Anticorpos Neutralizantes/biossíntese , Linfócitos B/imunologia , COVID-19/imunologia , Switching de Imunoglobulina , Imunoglobulina G/biossíntese , SARS-CoV-2/patogenicidade , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/biossíntese , Anticorpos Facilitadores , Autoanticorpos/biossíntese , Linfócitos B/virologia , COVID-19/tratamento farmacológico , COVID-19/mortalidade , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina A/biossíntese , Imunoglobulina M/biossíntese , Memória Imunológica , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Análise de Sobrevida
11.
Science ; 372(6546): 1102-1105, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34083490

RESUMO

Although antiviral antibodies generally confer protective functions, antibodies against dengue virus (DENV) are associated with enhanced disease susceptibility. Antibodies can mediate DENV infection of leukocytes via Fcγ receptors, likely contributing to dengue disease pathogenesis. To determine if this mechanism accounts for variable disease severity, we examined Fab and Fc structures of anti-DENV antibodies from patients before and after infection and with variable disease outcomes. Neither antibody titers nor neutralizing activity correlated with disease severity in DENV-infected populations. Rather, DENV infection induced a specific increase in immunoglobulin G1 (IgG1) afucosylation, and the levels of afucosylated IgG1 were predictive of dengue disease severity. Thus, the IgG1 fucosylation status represents a robust prognostic tool for dengue disease, highlighting the key role of the Fc glycan structure in dengue pathogenesis.


Assuntos
Anticorpos Antivirais/sangue , Anticorpos Antivirais/química , Vírus da Dengue/imunologia , Dengue/imunologia , Fucose/análise , Dengue Grave/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Facilitadores , Criança , Coinfecção/imunologia , Dengue/fisiopatologia , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/química , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/química , Imunoglobulina G/imunologia , Masculino , Receptores de IgG/química , Receptores de IgG/imunologia , Dengue Grave/fisiopatologia , Índice de Gravidade de Doença , Infecção por Zika virus/imunologia
12.
Virus Res ; 301: 198454, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34015363

RESUMO

COVID-19 pandemic has resulted in millions of deaths and a social-economic crisis. A worldwide effort was made to develop efficient vaccines for this disease. A vaccine should produce immune responses with specific and neutralizing antibodies, and without harmful effects such as the antibody-dependent enhancement that may be associated with severe acute respiratory syndrome. Vaccine design involves the selection of platforms that includes viral, viral-vector, protein, nucleic acid, or trained immunity-based strategies. Its development initiates at a pre-clinical stage, followed by clinical trials when successful. Only if clinical trials show no significant evidence of safety concerns, vaccines can be manufactured, stored, and distributed to immunize the population. So far, regulatory authorities from many countries have approved nine vaccines with phase 3 results. In the current pandemic, a paradigm for the COVID-19 vaccine development has arisen, as many challenges must be overcome. Mass-production and cold-chain storage to immunize large human populations should be feasible and fast, and a combination of different vaccines may boost logistics and immunization. In silico trials is an emerging and innovative field that can be applied to predict and simulate immune, molecular, clinical, and epidemiological outcomes of vaccines to refine, reduce, and partially replace steps in vaccine development. Vaccine-resistant variants of SARS-CoV-2 might emerge, leading to the necessity of updates. A globally fair vaccine distribution system must prevail over vaccine nationalism for the world to return to its pre-pandemic status.


Assuntos
Vacinas contra COVID-19 , COVID-19/prevenção & controle , Pandemias/prevenção & controle , SARS-CoV-2/imunologia , Anticorpos Neutralizantes , Anticorpos Antivirais , Anticorpos Facilitadores , COVID-19/virologia , Humanos
13.
PLoS One ; 16(4): e0245417, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33886573

RESUMO

BACKGROUND: COVID-19 vaccines are approved, vaccination campaigns are launched, and worldwide return to normality seems within close reach. Nevertheless, concerns about the safety of COVID-19 vaccines arose, due to their fast emergency approval. In fact, the problem of antibody-dependent enhancement was raised in the context of COVID-19 vaccines. METHODS AND FINDINGS: We introduce a complex extension of the model underlying the pandemic preparedness tool CovidSim 1.1 (http://covidsim.eu/) to optimize vaccination strategies with regard to the onset of campaigns, vaccination coverage, vaccination schedules, vaccination rates, and efficiency of vaccines. Vaccines are not assumed to immunize perfectly. Some individuals fail to immunize, some reach only partial immunity, and-importantly-some develop antibody-dependent enhancement, which increases the likelihood of developing symptomatic and severe episodes (associated with higher case fatality) upon infection. Only a fraction of the population will be vaccinated, reflecting vaccination hesitancy or contraindications. The model is intended to facilitate decision making by exploring ranges of parameters rather than to be fitted by empirical data. We parameterized the model to reflect the situation in Germany and predict increasing incidence (and prevalence) in early 2021 followed by a decline by summer. Assuming contact reductions (curfews, social distancing, etc.) to be lifted in summer, disease incidence will peak again. Fast vaccine deployment contributes to reduce disease incidence in the first quarter of 2021, and delay the epidemic outbreak after the summer season. Higher vaccination coverage results in a delayed and reduced epidemic peak. A coverage of 75%-80% is necessary to prevent an epidemic peak without further drastic contact reductions. CONCLUSIONS: With the vaccine becoming available, compliance with contact reductions is likely to fade. To prevent further economic damage from COVID-19, high levels of immunization need to be reached before next year's flu season, and vaccination strategies and disease management need to be flexibly adjusted. The predictive model can serve as a refined decision support tool for COVID-19 management.


Assuntos
Anticorpos Facilitadores , Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , Programas de Imunização , COVID-19/epidemiologia , Alemanha/epidemiologia , Humanos , Esquemas de Imunização , SARS-CoV-2/fisiologia , Software
14.
Nat Rev Immunol ; 21(6): 382-393, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33875867

RESUMO

Several neutralizing monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and are now under evaluation in clinical trials. With the US Food and Drug Administration recently granting emergency use authorizations for neutralizing mAbs in non-hospitalized patients with mild-to-moderate COVID-19, there is an urgent need to discuss the broader potential of these novel therapies and to develop strategies to deploy them effectively in clinical practice, given limited initial availability. Here, we review the precedent for passive immunization and lessons learned from using antibody therapies for viral infections such as respiratory syncytial virus, Ebola virus and SARS-CoV infections. We then focus on the deployment of convalescent plasma and neutralizing mAbs for treatment of SARS-CoV-2. We review specific clinical questions, including the rationale for stratification of patients, potential biomarkers, known risk factors and temporal considerations for optimal clinical use. To answer these questions, there is a need to understand factors such as the kinetics of viral load and its correlation with clinical outcomes, endogenous antibody responses, pharmacokinetic properties of neutralizing mAbs and the potential benefit of combining antibodies to defend against emerging viral variants.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , COVID-19/terapia , SARS-CoV-2 , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Facilitadores , COVID-19/imunologia , COVID-19/virologia , Desenvolvimento de Medicamentos , Farmacorresistência Viral/genética , Farmacorresistência Viral/imunologia , Humanos , Imunização Passiva/efeitos adversos , Imunização Passiva/métodos , Modelos Imunológicos , Pandemias , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , SARS-CoV-2/imunologia
15.
Front Immunol ; 12: 640093, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717193

RESUMO

COVID-19 (SARS-CoV-2) disease severity and stages varies from asymptomatic, mild flu-like symptoms, moderate, severe, critical, and chronic disease. COVID-19 disease progression include lymphopenia, elevated proinflammatory cytokines and chemokines, accumulation of macrophages and neutrophils in lungs, immune dysregulation, cytokine storms, acute respiratory distress syndrome (ARDS), etc. Development of vaccines to severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome coronavirus (MERS-CoV), and other coronavirus has been difficult to create due to vaccine induced enhanced disease responses in animal models. Multiple betacoronaviruses including SARS-CoV-2 and SARS-CoV-1 expand cellular tropism by infecting some phagocytic cells (immature macrophages and dendritic cells) via antibody bound Fc receptor uptake of virus. Antibody-dependent enhancement (ADE) may be involved in the clinical observation of increased severity of symptoms associated with early high levels of SARS-CoV-2 antibodies in patients. Infants with multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 may also have ADE caused by maternally acquired SARS-CoV-2 antibodies bound to mast cells. ADE risks associated with SARS-CoV-2 has implications for COVID-19 and MIS-C treatments, B-cell vaccines, SARS-CoV-2 antibody therapy, and convalescent plasma therapy for patients. SARS-CoV-2 antibodies bound to mast cells may be involved in MIS-C and multisystem inflammatory syndrome in adults (MIS-A) following initial COVID-19 infection. SARS-CoV-2 antibodies bound to Fc receptors on macrophages and mast cells may represent two different mechanisms for ADE in patients. These two different ADE risks have possible implications for SARS-CoV-2 B-cell vaccines for subsets of populations based on age, cross-reactive antibodies, variabilities in antibody levels over time, and pregnancy. These models place increased emphasis on the importance of developing safe SARS-CoV-2 T cell vaccines that are not dependent upon antibodies.


Assuntos
Anticorpos Facilitadores , COVID-19/imunologia , Mastócitos/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Fagócitos/imunologia , SARS-CoV-2/fisiologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Animais , Anticorpos Antivirais/metabolismo , COVID-19/transmissão , Criança , Reações Cruzadas , Feminino , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Modelos Imunológicos , Gravidez , Receptores Fc/metabolismo , Risco , Linfócitos T/imunologia
16.
J Virol ; 95(12)2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-33762420

RESUMO

Dengue virus (DENV) is the most common vector-borne viral disease, with nearly 400 million worldwide infections each year concentrated in the tropical and subtropical regions of the world. Severe dengue complications are often associated with a secondary heterotypic infection of one of the four circulating serotypes. In this scenario, humoral immune responses targeting cross-reactive, poorly neutralizing epitopes can lead to increased infectivity of susceptible cells via antibody-dependent enhancement (ADE). In this way, antibodies produced in response to infection or vaccination are capable of contributing to enhanced disease in subsequent infections. Currently, there are no available therapeutics to combat DENV disease, and there is an urgent need for a safe and efficacious vaccine. Here, we developed a nucleotide-modified mRNA vaccine encoding the membrane and envelope structural proteins from DENV serotype 1 encapsulated in lipid nanoparticles (prM/E mRNA-LNP). Vaccination of mice elicited robust antiviral immune responses comparable to viral infection, with high levels of neutralizing antibody titers and antiviral CD4+ and CD8+ T cells. Immunocompromised AG129 mice vaccinated with the prM/E mRNA-LNP vaccine were protected from a lethal DENV challenge. Vaccination with either a wild-type vaccine or a vaccine with mutations in the immunodominant fusion loop epitope elicited equivalent humoral and cell-mediated immune responses. Neutralizing antibodies elicited by the vaccine were sufficient to protect against a lethal challenge. Both vaccine constructs demonstrated serotype-specific immunity with minimal serum cross-reactivity and reduced ADE in comparison to a live DENV1 viral infection.IMPORTANCE With 400 million worldwide infections each year, dengue is the most common vector-borne viral disease. Forty percent of the world's population is at risk, with dengue experiencing consistent geographic spread over the years. With no therapeutics available and vaccines performing suboptimally, the need for an effective dengue vaccine is urgent. Here, we develop and characterize a novel mRNA vaccine encoding the dengue serotype 1 envelope and premembrane structural proteins that is delivered via a lipid nanoparticle. Our DENV1 prM/E mRNA-LNP vaccine induces neutralizing antibody and cellular immune responses in immunocompetent mice and protects an immunocompromised mouse from a lethal DENV challenge. Existing antibodies against dengue can enhance subsequent infections via antibody-dependent enhancement (ADE). Importantly our vaccine induced only serotype-specific immune responses and did not induce ADE.


Assuntos
Vacinas contra Dengue/imunologia , Vírus da Dengue/imunologia , Dengue/prevenção & controle , Vacinas Sintéticas/imunologia , Imunidade Adaptativa , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Anticorpos Facilitadores , Linhagem Celular , Reações Cruzadas , Dengue/imunologia , Vacinas contra Dengue/administração & dosagem , Vírus da Dengue/classificação , Vírus da Dengue/genética , Imunidade Humoral , Esquemas de Imunização , Lipossomos , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas , RNA Mensageiro/genética , RNA Viral/genética , Sorogrupo , Linfócitos T/imunologia , Vacinas Sintéticas/administração & dosagem , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Proteínas Virais/genética , Proteínas Virais/imunologia
17.
Curr Opin Chem Biol ; 62: 43-52, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33684633

RESUMO

Cytokines are key modulators of the immune responses and represent promising therapeutics for a variety of cancers. However, successful translation of cytokine-based therapy to the clinic is limited by, among others, severe toxicities and lack of efficacy due to cytokine pleiotropy and off-target activation of cells. Engineering cytokines with enhanced therapeutic properties has emerged as a promising strategy to overcome these challenges. Advances in protein engineering and protein-polymer conjugate technologies have fostered the generation of cytokines with enhanced target cell specificity and longer half-life than the native ones. These novel cytokines exhibit reduced systemic toxicities while focusing the activities at the tumor site, thus, enhancing antitumor immunity. The growing toolbox of cytokine engineering strategies will further stimulate the development of smart cytokine-based immunotherapies with enhanced efficacy and safety profiles.


Assuntos
Anticorpos Monoclonais/imunologia , Citocinas/imunologia , Imunoterapia/métodos , Neoplasias/imunologia , Engenharia de Proteínas/métodos , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Facilitadores , Citocinas/efeitos adversos , Citocinas/uso terapêutico , Matriz Extracelular/metabolismo , Humanos , Terapia de Alvo Molecular , Mutagênese , Neoplasias/terapia , Peptídeos/química , Polietilenoglicóis/química , Conformação Proteica
18.
Infect Immun ; 89(4)2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33558319

RESUMO

Antibody-dependent enhancement (ADE) of viral disease has been demonstrated for infections caused by flaviviruses and influenza viruses; however, antibodies that enhance bacterial disease are relatively unknown. In recent years, a few studies have directly linked antibodies with exacerbation of bacterial disease. This ADE of bacterial disease has been observed in mouse models and human patients with bacterial infections. This antibody-mediated enhancement of bacterial infection is driven by various mechanisms that are disparate from those found in viral ADE. This review aims to highlight and discuss historic evidence, potential molecular mechanisms, and current therapies for ADE of bacterial infection. Based on specific case studies, we report how plasmapheresis has been successfully used in patients to ameliorate infection-related symptomatology associated with bacterial ADE. A greater understanding and appreciation of bacterial ADE of infection and disease could lead to better management of infections and inform current vaccine development efforts.


Assuntos
Anticorpos Facilitadores/imunologia , Infecções Bacterianas/etiologia , Interações Hospedeiro-Patógeno/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Aderência Bacteriana , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/terapia , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Imunidade Humoral , Fagocitose/imunologia , Prevalência , Proteólise , Virulência
19.
mSphere ; 6(1)2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627511

RESUMO

The majority of infections with SARS-CoV-2 are asymptomatic or mild without the necessity of hospitalization. It is of importance to reveal if these patients develop an antibody response against SARS-CoV-2 and to define which antibodies confer virus neutralization. We conducted a comprehensive serological survey of 49 patients with a mild course of disease and quantified neutralizing antibody responses against a clinical SARS-CoV-2 isolate employing human cells as targets. Four patients (8%), even though symptomatic, did not develop antibodies against SARS-CoV-2, and two other patients (4%) were positive in only one of the six serological assays employed. For the remaining 88%, antibody response against the S protein correlated with serum neutralization whereas antibodies against the nucleocapsid were poor predictors of virus neutralization. None of the sera enhanced infection of human cells with SARS-CoV-2 at any dilution, arguing against antibody-dependent enhancement of infection in our system. Regarding neutralization, only six patients (12%) could be classified as high neutralizers. Furthermore, sera from several individuals with fairly high antibody levels had only poor neutralizing activity. In addition, employing a novel serological Western blot system to characterize antibody responses against seasonal coronaviruses, we found that antibodies against the seasonal coronavirus 229E might contribute to SARS-CoV-2 neutralization. Altogether, we show that there is a wide breadth of antibody responses against SARS-CoV-2 in patients that differentially correlate with virus neutralization. This highlights the difficulty to define reliable surrogate markers for immunity against SARS-CoV-2.IMPORTANCE There is strong interest in the nature of the neutralizing antibody response against SARS-CoV-2 in infected individuals. For vaccine development, it is especially important which antibodies confer protection against SARS-CoV-2, if there is a phenomenon called antibody-dependent enhancement (ADE) of infection, and if there is cross-protection by antibodies directed against seasonal coronaviruses. We addressed these questions and found in accordance with other studies that neutralization is mediated mainly by antibodies directed against the spike protein of SARS-CoV-2 in general and the receptor binding site in particular. In our test system, utilizing human cells for infection experiments, we did not detect ADE. However, using a novel diagnostic test we found that antibodies against the coronavirus 229E might be involved in cross-protection to SARS-CoV-2.


Assuntos
Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , COVID-19/imunologia , Infecções por Coronavirus/imunologia , SARS-CoV-2/imunologia , Adulto , Anticorpos Neutralizantes/imunologia , Anticorpos Facilitadores/imunologia , Sítios de Ligação/imunologia , Feminino , Hospitalização , Humanos , Masculino , Testes de Neutralização/métodos , Nucleocapsídeo/imunologia , Estações do Ano , Testes Sorológicos/métodos , Glicoproteína da Espícula de Coronavírus/imunologia , Inquéritos e Questionários , Vacinas/imunologia
20.
mBio ; 12(1)2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531399

RESUMO

Human bocavirus 1 (HBoV1), a nonenveloped single-stranded DNA parvovirus, causes mild to life-threatening respiratory tract infections, acute otitis media, and encephalitis in young children. HBoV1 often persists in nasopharyngeal secretions for months, hampering diagnosis. It has also been shown to persist in pediatric palatine and adenoid tonsils, which suggests that lymphoid organs are reservoirs for virus spread; however, the tissue site and host cells remain unknown. Our aim was to determine, in healthy nonviremic children with preexisting HBoV1 immunity, the adenotonsillar persistence site(s), host cell types, and virus activity. We discovered that HBoV1 DNA persists in lymphoid germinal centers (GCs), but not in the corresponding tonsillar epithelium, and that the cell types harboring the virus are mainly naive, activated, and memory B cells and monocytes. Both viral DNA strands and both sides of the genome were detected, as well as infrequent mRNA. Moreover, we showed, in B-cell and monocyte cultures and ex vivo tonsillar B cells, that the cellular uptake of HBoV1 occurs via the Fc receptor (FcγRII) through antibody-dependent enhancement (ADE). This resulted in viral mRNA transcription, known to occur exclusively from double-stranded DNA in the nucleus, however, with no detectable productive replication. Confocal imaging with fluorescent virus-like particles moreover disclosed endocytosis. To which extent the active HBoV1 GC persistence has a role in chronic inflammation or B-cell maturation disturbances, and whether the virus can be reactivated, will be interesting topics for forthcoming studies.IMPORTANCE Human bocavirus 1 (HBoV1), a common pediatric respiratory pathogen, can persist in airway secretions for months hampering diagnosis. It also persists in tonsils, providing potential reservoirs for airway shedding, with the exact location, host cell types, and virus activity unknown. Our study provides new insights into tonsillar HBoV1 persistence. We observed HBoV1 persistence exclusively in germinal centers where immune maturation occurs, and the main host cells were B cells and monocytes. In cultured cell lines and primary tonsillar B cells, we showed the virus uptake to be significantly enhanced by HBoV1-specific antibodies, mediated by the cellular IgG receptor, leading to viral mRNA synthesis, but without detectable productive replication. Possible implications of such active viral persistence could be tonsillar inflammation, disturbances in immune maturation, reactivation, or cell death with release of virus DNA, explaining the long-lasting HBoV1 airway shedding.


Assuntos
Anticorpos Facilitadores , Centro Germinativo/virologia , Bocavirus Humano/imunologia , Tonsila Palatina/virologia , Infecções por Parvoviridae/virologia , Adolescente , Adulto , Idoso , Linfócitos B/virologia , Criança , Pré-Escolar , DNA Viral/análise , Endossomos/virologia , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Monócitos/virologia , Infecções por Parvoviridae/imunologia , Adulto Jovem
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