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Role of antibody-dependent enhancement (ADE) in the virulence of SARS-CoV-2 and its mitigation strategies for the development of vaccines and immunotherapies to counter COVID-19.

ABSTRACT: Coronavirus disease-2019 (COVID-19) pandemic has become a global threat and death tolls are increasing worldwide. The SARS-CoV-2 though shares similarities with SARS-CoV and MERS-CoV, immunopathology of the novel virus is not understood properly. Previous reports from SARS and MERS-CoV documents that preexisting, non-neutralizing or poorly neutralizing antibodies developed as a result of vaccine or infection enhance subsequent infection, a phenomenon called as antibody-dependent enhancement (ADE). Since immunotherapy has been implicated for COVID-19 treatment and vaccine is under development, due consideration has to be provided on ADE to prevent untoward reactions. ADE mitigation strategies like the development of vaccine or immunotherapeutics targeting receptor binding motif can be designed to minimize ADE of SARS-CoV-2 since full-length protein-based approach can lead to ADE as reported in MERS-CoV. The present mini-review aims to address the phenomenon of ADE of SARS-CoV-2 through the lessons learned from SARS-CoV and MERS-CoV and ways to mitigate them so as to develop better vaccines and immunotherapeutics against SARS-CoV-2.

SUBMITTER: Karthik K

PROVIDER: S-EPMC7484565 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Role of antibody-dependent enhancement (ADE) in the virulence of SARS-CoV-2 and its mitigation strategies for the development of vaccines and immunotherapies to counter COVID-19.

Karthik Kumaragurubaran K Senthilkumar Tuticorin Maragatham Alagesan TMA Udhayavel Shanmugasundaram S Raj Gopal Dhinakar GD

Human vaccines & immunotherapeutics 20200826 12

Coronavirus disease-2019 (COVID-19) pandemic has become a global threat and death tolls are increasing worldwide. The SARS-CoV-2 though shares similarities with SARS-CoV and MERS-CoV, immunopathology of the novel virus is not understood properly. Previous reports from SARS and MERS-CoV documents that preexisting, non-neutralizing or poorly neutralizing antibodies developed as a result of vaccine or infection enhance subsequent infection, a phenomenon called as antibody-dependent enhancement (ADE ...[more]

PMID: 32845733

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Project description: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.

Project description:Limiting infection transmission is central to the safety of all in dentistry, particularly during the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Aerosol-generating procedures (AGPs) are crucial to the practice of dentistry; it is imperative to understand the inherent risks of viral dispersion associated with AGPs and the efficacy of available mitigation strategies. In a dental surgery setting, crown preparation and root canal access procedures were performed with an air turbine or high-speed contra-angle handpiece (HSCAH), with mitigation via rubber dam or high-volume aspiration and a no-mitigation control. A phantom head was used with a 1.5-mL min-1 flow of artificial saliva infected with Φ6-bacteriophage (a surrogate virus for SARS-CoV-2) at ~108 plaque-forming units mL-1, reflecting the upper limits of reported salivary SARS-CoV-2 levels. Bioaerosol dispersal was measured using agar settle plates lawned with the Φ6-bacteriophage host, Pseudomonas syringae. Viral air concentrations were assessed using MicroBio MB2 air sampling and particle quantities using Kanomax 3889 GEOα counters. Compared to an air turbine, the HSCAH reduced settled bioaerosols by 99.72%, 100.00%, and 100.00% for no mitigation, aspiration, and rubber dam, respectively. Bacteriophage concentrations in the air were reduced by 99.98%, 100.00%, and 100.00% with the same mitigations. Use of the HSCAH with high-volume aspiration resulted in no detectable bacteriophage, both on nonsplatter settle plates and in air samples taken 6 to 10 min postprocedure. To our knowledge, this study is the first to report the aerosolization in a dental clinic of active virus as a marker for risk determination. While this model represents a worst-case scenario for possible SARS-CoV-2 dispersal, these data showed that the use of HSCAHs can vastly reduce the risk of viral aerosolization and therefore remove the need for clinic fallow time. Furthermore, our findings indicate that the use of particle analysis alone cannot provide sufficient insight to understand bioaerosol infection risk.

Project description:Antibody therapeutics and vaccines are among our last resort to end the raging COVID-19 pandemic. They, however, are prone to over 5000 mutations on the spike (S) protein uncovered by a Mutation Tracker based on over 200 000 genome isolates. It is imperative to understand how mutations will impact vaccines and antibodies in development. In this work, we first study the mechanism, frequency, and ratio of mutations on the S protein which is the common target of most COVID-19 vaccines and antibody therapies. Additionally, we build a library of 56 antibody structures and analyze their 2D and 3D characteristics. Moreover, we predict the mutation-induced binding free energy (BFE) changes for the complexes of S protein and antibodies or ACE2. By integrating genetics, biophysics, deep learning, and algebraic topology, we reveal that most of the 462 mutations on the receptor-binding domain (RBD) will weaken the binding of S protein and antibodies and disrupt the efficacy and reliability of antibody therapies and vaccines. A list of 31 antibody disrupting mutants is identified, while many other disruptive mutations are detailed as well. We also unveil that about 65% of the existing RBD mutations, including those variants recently found in the United Kingdom (UK) and South Africa, will strengthen the binding between the S protein and human angiotensin-converting enzyme 2 (ACE2), resulting in more infectious COVID-19 variants. We discover the disparity between the extreme values of RBD mutation-induced BFE strengthening and weakening of the bindings with antibodies and angiotensin-converting enzyme 2 (ACE2), suggesting that SARS-CoV-2 is at an advanced stage of evolution for human infection, while the human immune system is able to produce optimized antibodies. This discovery, unfortunately, implies the vulnerability of current vaccines and antibody drugs to new mutations. Our predictions were validated by comparison with more than 1400 deep mutations on the S protein RBD. Our results show the urgent need to develop new mutation-resistant vaccines and antibodies and to prepare for seasonal vaccinations.

Dataset Information

Role of antibody-dependent enhancement (ADE) in the virulence of SARS-CoV-2 and its mitigation strategies for the development of vaccines and immunotherapies to counter COVID-19.

Publications

Role of antibody-dependent enhancement (ADE) in the virulence of SARS-CoV-2 and its mitigation strategies for the development of vaccines and immunotherapies to counter COVID-19.

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