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; Senthilkumar, Tuticorin Maragatham Alagesan; Udhayavel, Shanmugasundaram; Raj, Gopal Dhinakar

doi:10.1080/21645515.2020.1796425

Cited by 73 publications

(90 citation statements)

References 56 publications

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“…Antibody enhancement of virus infection in vitro has been reported for MERS-CoV and SARS-CoV (Gu et al, 2005; Liu et al, 2020a; Wan et al, 2020; Wang et al, 2016) and is a critical question facing the safe administration of antibody prophylaxis, antibody therapy, and antibody-based COVID-19 vaccines (Halstead and Katzelnick, 2020; Karthik et al, 2020; Lee et al, 2020; Ulrich et al, 2020). The effects of SARS-CoV-2 antibodies have been further questioned since individuals who seroconverted earlier tend to have more severe COVID-19 disease than later seroconverters (Ho et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

The functions of SARS-CoV-2 neutralizing and infection-enhancing antibodies in vitro and in mice and nonhuman primates

Li¹,

Edwards²,

Manne³

et al. 2021

Preprint

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SummarySARS-CoV-2 neutralizing antibodies (NAbs) protect against COVID-19, making them a focus of vaccine design. A safety concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated potent NAbs against the receptor-binding domain (RBD) and the N-terminal domain (NTD) of SARS-CoV-2 spike protein from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV-1 infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of antibody binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both in vitro neutralizing and infection-enhancing RBD or infection-enhancing NTD antibodies protected from SARS-CoV-2 challenge in non-human primates and mice. One of 30 monkeys infused with enhancing antibodies had lung pathology and bronchoalveolar lavage cytokine evidence suggestive of enhanced disease. Thus, these in vitro assessments of enhanced antibody-mediated infection do not necessarily indicate biologically relevant in vivo infection enhancement.

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Section: Discussionmentioning

confidence: 99%

The functions of SARS-CoV-2 neutralizing and infection-enhancing antibodies in vitro and in mice and nonhuman primates

Li¹,

Edwards²,

Manne³

et al. 2021

Preprint

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show abstract

“…It should be noted that although vaccine candidates based on the full-length S protein of the closely related SARS-CoV could elicit neutralizing antibody responses against infection of SARS-CoV, they may also induce harmful immune responses, including liver damage of the vaccinated animals, infection of human immune cells by SARS-CoV, and antibody-dependent enhancement of SARS-CoV infection (85)(86)(87)(88)(89). Therefore, although the S proteins of both SARS-CoV and SARS-CoV-2 are thought to be promising vaccine immunogens for generating protective immunity, optimizing antigen design is critical to ensure an optimal immune response through exposing more neutralizing epitopes and displaying fewer potentially weakly or non-neutralizing epitopes (90).…”

Section: Insights Into the Design And Development Of S Protein-based mentioning

confidence: 99%

The SARS-CoV-2 Spike Glycoprotein Biosynthesis, Structure, Function, and Antigenicity: Implications for the Design of Spike-Based Vaccine Immunogens

et al. 2020

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The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a grave threat to global public health and imposes a severe burden on the entire human society. Like other coronaviruses, the SARS-CoV-2 genome encodes spike (S) glycoproteins, which protrude from the surface of mature virions. The S glycoprotein plays essential roles in virus attachment, fusion and entry into the host cell. Surface location of the S glycoprotein renders it a direct target for host immune responses, making it the main target of neutralizing antibodies. In the light of its crucial roles in viral infection and adaptive immunity, the S protein is the focus of most vaccine strategies as well as therapeutic interventions. In this review, we highlight and describe the recent progress that has been made in the biosynthesis, structure, function, and antigenicity of the SARS-CoV-2 S glycoprotein, aiming to provide valuable insights into the design and development of the S protein-based vaccines as well as therapeutics.

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“…Another possible mechanism for CoV entry may occur through antibodies. During the binding of the virus-antibody complex, simultaneous binding of viral proteins to antigenbinding fragment (Fab) regions of immunoglobulin G (IgG) and of the fragment crystallizable (Fc) portion of the antibody to Fc gamma receptors (FcgRs) that are expressed by immune cells occurs, promoting viral entry without the use of the ACE2 receptor (69,70). However, the presence of viral RNA in the endosomes signals via the Toll-like 3 (TLR3), TLR7, or TLR8 receptor, activating the host cell to release pro-inflammatory cytokines that lead to exacerbated tissue damage, a phenomenon called antibody-dependent enhancement (ADE) (71).…”

Section: Pathogenesis Of Sars-cov-2 Viral Entry and Replicationmentioning

confidence: 99%

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

et al. 2020

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Coronavirus Disease 2019 (COVID-19) has been classified as a global threat, affecting millions of people and killing thousands. It is caused by the SARS-CoV-2 virus, which emerged at the end of 2019 in Wuhan, China, quickly spreading worldwide. COVID-19 is a disease with symptoms that range from fever and breathing difficulty to acute respiratory distress and death, critically affecting older patients and people with previous comorbidities. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and mainly spreads through the respiratory tract, which it then uses to reach several organs. The immune system of infected patients has been demonstrated to suffer important alterations, such as lymphopenia, exhausted lymphocytes, excessive amounts of inflammatory monocytes and macrophages, especially in the lungs, and cytokine storms, which may contribute to its severity and difficulty of establishing an effective treatment. Even though no specific treatment is currently available, several studies have been investigating potential therapeutic strategies, including the use of previously approved drugs and immunotherapy. In this context, this review addresses the interaction between SARS-CoV-2 and the patient's host immune system during infection, in addition to discussing the main immunopathological mechanisms involved in the development of the disease and potential new therapeutic approaches.

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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

Cited by 73 publications

References 56 publications

The functions of SARS-CoV-2 neutralizing and infection-enhancing antibodies in vitro and in mice and nonhuman primates

The functions of SARS-CoV-2 neutralizing and infection-enhancing antibodies in vitro and in mice and nonhuman primates

The SARS-CoV-2 Spike Glycoprotein Biosynthesis, Structure, Function, and Antigenicity: Implications for the Design of Spike-Based Vaccine Immunogens

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

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