Neutralizing Antibodies and Antibody-Dependent Enhancement in COVID-19: A Perspective

Abstract

Antibody-dependent enhancement (ADE) is an alternative route of viral entry in the susceptible host cell. In this process, antiviral antibodies enhance the entry access of virus in the cells via interaction with the complement or Fc receptors leading to the worsening of infection. SARS-CoV-2 variants pose a general concern for the efficacy of neutralizing antibodies that may fail to neutralize infection, raising the possibility of a more severe form of COVID-19. Data from various studies on respiratory viruses raise the speculation that antibodies elicited against SARS-CoV-2 and during COVID-19 recovery could potentially exacerbate the infection through ADE at sub-neutralizing concentrations; this may contribute to disease pathogenesis. It is, therefore, of utmost importance to study the effectiveness of the anti-SARS-CoV-2 antibodies in COVID-19-infected subjects. Theoretically, ADE remains a general concern for the efficacy of antibodies elicited during infection, most notably in convalescent plasma therapy and in response to vaccines where it could be counterproductive.

Keywords: ADE; ARDS; ERD; Enhancement; Neutralizing antibodies; SARS-CoV-2.

Figure 1:

Antibody-dependent enhancement in DENV. a Primary infection of DENV induces neutralizing antibodies at sufficient concentration that potentially neutralizes and destroys DENV providing protective immunity. b In secondary infection, neutralizing antibodies that are elicited successfully neutralize the virus when the DENV serotype is similar to the primary DENV infection. c Antibody-dependent enhancement of infection in DENV infection occurs when non-neutralizing antibodies formed from primary infection bind with different DENV serotypes during secondary infection, these Ab from a primary infection are unable to neutralize the different DENV serotype that enhances the virus entry and replicate into cells leading to a heightened risk of dengue viral infection severity. Image credit smart.servier.com.

Figure 2:

Fc-dependent mechanism of ADE. a Non-neutralizing antibodies enhancing viral infection through Fc-dependent pathway as a result of failure to block binding of virus-specific receptors to host cell receptor. As the Fc region of non-neutralizing antibodies bind with viral spike protein epitope at sites other than the receptor binding with the FcγR on myeloid cells such as macrophage, phagocytosis occurs, resulting in an increased number of virus particles. b Entry of virus occurs through clathrin-coated vesicles through FcγRII receptors. Created with BioRender.com.

Figure 3:

Complement-mediated pathway of ADE. a Binding of non-neutralizing antibodies to the viral spike protein forming an antigen–antibody complex formed by either IgG or IgM. b The formation of the Immune complex activates the classical pathway of the complement system. The Ag–Ab complex induces a conformational change in the Fc region of an antibody that exposes the binding site for complement proteins to bind to the Fc region. c Complement protein C1q/C3 attached to Ag–Ab complex binds with complement receptor on macrophage leading to the d internalization of Virus particles enhancing infection as a result of replication of the virus. Created with BioRender.com.

Figure 4:

Secretion of neutralizing antibodies and its mechanism of blocking of viral infection. a B cell with B-cell receptors (BCR). b Antigen binds with a B-cell receptor specific to this antigen. c Clonal selection of an antigen-activated B cell leads to a clone of effector B cells and memory B cells, these clone cells are specific to the attached antigen; plasma cells secrete antibody reactive with the activating antigen. d Neutralizing antibodies binding to the critical sites on viral spike proteins e. blocking sites of attachment to host cell receptor ACE2 preventing fusion between. Created with BioRender.com.