Nature: Dig deepinto the antibody-dependent enhancement of SARS-CoV-2.

http://photos.!--.s./29/--- During the 1918 influenza pandemic, the benefits of passive antibody therapy in improving infectious diseases were recognizedSince then, hyperimmune globulin has been widely used as a pre- and post-exposure prophylaxis for hepatitis A, hepatitis B, chickenpox, rabies and other indications, but no evidence of antibody dependence (antibody-dependent enhancement, ADE, hereinafter known as disease ADE) has been foundAntibody detection has also been a reliable indicator of the effectiveness of vaccines for many listed peopleThe antiviral activity of known antibodies is largely mediated by inhibiting the effect of infectious viral particles entering host cells (neutralizing) and antibodies in the recruitment of other components of the immune systemPhoto from Nature, 2020, doi: 10.1038/s41586-020-2538-8Neutralizing antibodies enter the protein by targeting the viral protein seiscombined or inhibiting fusion after the virus has attached to it, acting on the virus entering the protein that binds to the cell surface receptorWhen different viruses enter the protein with the same epitope, antibodies can cross in and related virusesAntibodies can also eliminate viruses by binding Fab fragments of immunoglobulin G (IgG) to viral proteins on the surface of viruses or infected cells and the effects of their Fc fragments binding to the Fc gamma receptors expressed by immune cellsAntibodies that mediate the function of Fcsieand R and complement-dependent effects may have or are not neutralized, can identify other viral proteins that do not participate in host cell entry, and can protect the body without relying on any Fab-mediated viral suppressionIn the latest advances in FcR biology, four active FcR--- Fc-RiRi, Fc-RiIc, Fc-RiIc, Fc-RiIa--- and an inhibitory Fc-RiIb, which have different Fc ligand specificity and cell signal transduction base sequencesNewborn FcRn has been described as supporting antibody recycling as well as B and T-cell immunity through dendritic intracellular swallowing of immune complexesNatural killer cells (NK) identify IgG on the surface of infected cells through FcsR: viral protein complexes to mediate antibody-dependent cytotoxicity (ADCC), and myelin cells use these interactions to remove conditioned viral particles and viral infection cells through antibody-dependent cell phagocytosis (ADCP)The complement pathway is also activated by the combination of Fc and C1q, which leads to conditioning of viruses or infected cells and recruitment of bone marrow cellsAntibody effect function also contributes to the immune response mediated by antiviral T cells in the bodyIt is worth noting that new knowledge about the function of the Fc effect has led to the improvement of passive antibody therapy through Fc modification, which reduces or enhances the interaction of Fc sorcery R, prolongs the half-life of the antibody, and may enhance the delivery of antigens to T cells, thus providing the so-called vaccine effectWhile their importance in fighting pathogen infection is unquestionable, the concern about ADE stems from the presence of antibodies at the time of infection that may increase the severity of the diseaseIn the 1960s, in children who received the inactivated RSV or measles virus vaccine in Formarin, scientists have clinically described the severity of the disease through antibody dependence mechanisms, as well as dengue haemorrhagic fever caused by different serotype infections of dengue virus For example, antibodies may allow the virus to enter cells that carry Fc-R, bypassing specific receptor-mediated cells, which are usually done after the virus degrades, but may increase viral infection if sub-viral particles are produced Although cytokine release caused by viral-antibody-Fc-R interaction seyly is also very beneficial due to direct antiviral action and immune cell recruitment, tissue damage caused by viral infection may be aggravated While recognizing that other mechanisms of immune enhancement may also occur, in a recent review of the type of commentary published in the journal Nature entitled "A perspective on antibody-dependency of SARS-CoV-2", researchers from Vir Biotechnology in the United States reviewed clinical experience, in vitro analysis and animal models related to understanding the potential risks of antibody dependence and its impact on vaccine and antibody development, which is critical to preventing the global catastrophe of the SARS-CoV-2 pandemic The goal of these authors is to evaluate the hypothesis that antibody mediated enhancement is caused by the assumption that low affinity antibodies bind to viral entry proteins, but have limited neutrality or no neutral activity, and ii) antibodies with ADE are caused by infection or vaccination of a closely related pathogen serotype, called cross-reactive antibodies, or iii) are not optimal in terms of efficacy of neutralizing antibodies that are otherwise effective We assessed whether there was an experimental method that reliably predicted ADE from human disease and concluded that this was not the case The principle of assessing potential disease ADE uses ADE to indicate that the increase in severity of the disease must be strictly distinguished from the ADE of infection, i.e replication, binding, ingestion, cytokine release or other activity of in vitro detected antibodies The first principle is that in vitro antibody dependence does not represent or predict a Disease ADE if there is no evidence that antibodies play a role in the pathogenesis of more severe clinical outcomes The second principle is that animal models used to evaluate human polyclonal antibodies or monoclonal antibodies (mAb) should be carefully judged, since the combination of IgG and FcR is species-specific, as should complement activation Antibodies in animals may have very different properties and cannot be used to predict antibody properties in human host bodies because the effects of antibodies are altered by species-specific interactions between antibodies and immune cells Animals may also produce antibodies against therapeutic antibodies, which can limit their effectiveness or cause immunopathological In addition, given that most viruses are highly species-specific, the pathogenesis of model strains in animals does not fully reflect human infection These differences may incorrectly support the protective or immunopathological effects of vaccines and antibodies The third principle is that the nature of the antibody response depends on the form of the viral protein identified by the immune system, which determines which epitopes are present Protective and non-protective antibodies may be caused by different forms of the same protein !--/ewebeditor:!--webeditor:page title"--The fourth principle is that the pathogenesis in the human host is very different between different viruses and even a particular strain Therefore, studies on the effects of passive antibodies or vaccine-induced immunity on clinical outcomes cannot be safely inferred from one viral pathogen to another It is clear that after years of effort and a great deal of attention, the knowledge of ADE, a disease after vaccination or the application of antiviral antibodies, is not enough to confidently predict the negative outcomes of specific immune interventions against viral infections Although this information is important in the COVID-19 pandemic, in vitro testing does not predict disease ADE, and most vaccine and antibody interventions show protective effects in animal models, but animal models that suggest the presence of potential disease ADE are uncertain and the exact mechanism has not yet been determined Conclusion While ADE is a concern, it is also clear that antibodies are an essential component of protective immunity to all pathogens discussed in this article, and their protective effect depends on both the binding of their Fab fragments to viral proteins and the effects they give to The Fc fragments Even though vaccine preparations such as Formarin's inactivated RSV or measles virus vaccine have an enhanced effect on disease, neutralizing antibodies with optimized properties have a protective effect In addition, the potential mechanisms of disease ADE may be viral-specific, and importantly, clinical markers do not distinguish between severe infections and immune enhancement More mechanism-focused research is needed to determine whether small animal and non-human primate models of viral infections, including SARS-CoV-2, can predict the potential benefits or risks of vaccine or passive antibody intervention in humans Optimizing these models requires understanding the factors associated with the protective effects of natural human infections and on SARS-CoV-2 in the evaluation of vaccines and antibodies in humans This research on the mechanisms of different viral pathogens is essential so that people are better prepared for future pandemics At the same time, it is necessary to directly test the safety of vaccines and antibodies for SARS-CoV-2 and other viral pathogens in human clinical trials and to determine the protective factors of these vaccines and antibodies (Bioon.com) Reference: Ann M Arvin et al A perspective on potential antibody-dependent enhancement of SARS-CoV-2 Nature, 2020, doi: 10.1038/s41586-020-2538-8.!--/ewebeditor.