A review: Antibody-dependent enhancement in COVID-19: The not so friendly side of antibodies

Abstract

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.

Keywords: ADE; COVID-19; SARS-CoV-2; antibody-dependent enhancement; vaccine.

Figure 1.

The Immune Response and Immunopathology of COVID-19. (a) The entry of SARS-CoV-2 into cells is mediated by the binding of TMPRSS2 and S-glycoprotein with the ACE2 acting as a receptor that facilitates viral binding to the membrane of the host cells. The virus enters by endocytosis and releases its RNA, replicates and creates new virions that cause a rapid progression of the infection. (b) Bronchial epithelial cells, type I and type II alveolar pneumocytes, and capillary endothelial cells become infected and a response occurs that leads to recruitment of macrophages, monocytes, neutrophils, and cytokine production in response to virus entry. (c) Sub-epithelial dendritic cells recognize the virus antigen and present them to CD4 + T cells that induce the differentiation of B cells into plasma cells that promote the production of virus-specific antibodies. Neutralizing antibodies can interact with phagocytes and NK cells and enhance antibody-mediated clearance of SARS-CoV. (d) A dysfunctional immune response leads to excessive cell infiltration, cytokine storm, inflammation, apoptosis, and multi-organ damage. Ab, antibody; ACE2, angiotensin-converting enzyme 2; FcγR, Fcγ receptor; IL, interleukin; MHC, major histocompatibility complex; TCR, T-cell receptor; TMPRSS2, transmembrane protease serine 2; TNF-a, tumor necrosis factor.

Figure 2.

ADE phenomenon. (a) The conventional mechanism of infection by SARS-CoV 2 consists of the binding of its S-protein to the cellular receptor ACE2. After the union of the SARS-CoV-2 virus to the receptor, a conformational change occurs in the S-protein necessary for the fusion of the viral envelope with the cell membrane for subsequent endocytosis. Subsequently, SARS-CoV-2 releases its genetic material into the host cell. The RNA of the viral genome is then translated into proteins necessary for the subsequent assembly of viriomes in the ER and Golgi. These visions are then transported through vesicles outside the cell by exocytosis. The ADE phenomenon can be classified as two different mechanisms: ADE through enhanced infection and ADE through enhanced immune activation. (b) In ADE through increased infection, antibodies of a non-neutralizing or sub-neutralizing nature cause viral infection through FcγRIIa-mediated endocytosis, resulting in a more severe disease phenotype. (c) In ADE via enhanced immune activation, non-neutralizing antibodies can form immune complexes with viral antigens inside airway tissues, resulting in the secretion of pro-inflammatory cytokines, immune cell recruitment, and activation of the complement cascade within lung tissue. ADE, antibody-dependent enhancement; ACE2, angiotensin-converting enzyme 2; CR, compliment receptor; ER, endoplasmic reticulum; FcγRIIa, Fc γ receptor IIa; IFN-a, interferon a; IL, interleukin; IRF, interferon regulatory factors; iNOS, inducible nitric oxide synthase; PGE2, prostaglandin E2, RNA, ribonucleic acid; TNF-a, tumor necrosis factor.