Antibody-dependent enhancement
[4] In ADE, antiviral antibodies promote viral infection of target immune cells by exploiting the phagocytic FcγR or complement pathway.
[5] After interaction with a virus, the antibodies bind Fc receptors (FcR) expressed on certain immune cells or complement proteins.
Essentially, the virus “deceives” the process of phagocytosis of immune cells and uses the host's antibodies as a Trojan horse.
ADE may occur because of the non-neutralizing characteristic of an antibody, which binds viral epitopes other than those involved in host-cell attachment and entry.
[1][9][10] It has been observed mainly with positive-strand RNA viruses, including flaviviruses such as dengue, yellow fever, and Zika;[11][12][13] alpha- and betacoronaviruses;[14] orthomyxoviruses such as influenza;[15] retroviruses such as HIV;[16][17][18] and orthopneumoviruses such as RSV.
Prior to the COVID-19 pandemic, ADE was observed in animal studies of laboratory rodents with vaccines for SARS-CoV, the virus that causes severe acute respiratory syndrome (SARS).
[26][27][28][29][30] Prior receipt of 2008–09 TIV (Trivalent Inactivated Influenza Vaccine) was associated with an increased risk of medically attended pH1N1 illness during the spring-summer 2009 in Canada.
[39] Neutralizing heterotypic (cross-reactive) IgG antibodies are responsible for this cross-protective immunity, which typically persists for a period of months to a few years.
[47] A study conducted by Modhiran et al.[48] attempted to explain how non-neutralizing antibodies down-regulate the immune response in the host cell through the Toll-like receptor signaling pathway.
In vitro experiments showed that the inflammatory cytokines and type 1 interferon production were reduced when the ADE-dengue virus complex bound to the Fc receptor of THP-1 cells.
On the other hand, many proteins (TRIF, TRAF6, TRAM, TIRAP, IKKα, TAB1, TAB2, NF-κB complex) involved in the Toll-like receptor signaling pathway are down-regulated, which led to a decrease in cytokine production.
[40] This scenario can be explained by the presence of sufficient neutralizing heterotypic IgG antibodies in 1981, whose titers had decreased by 1997 to the point where they no longer provided significant cross-protective immunity.
Like dengue virus, non-neutralizing level of antibodies have been found to enhance the viral infection through interactions of the complement system and receptors.
[53] The deposition of complement on the virus brings the gp120 protein close to CD4 molecules on the surface of the cells, thus leading to facilitated viral entry.
[53] Viruses pre-exposed to non-neutralizing complement system have also been found to enhance infections in interdigitating dendritic cells.
Opsonized viruses have not only shown enhanced entry but also favorable signaling cascades for HIV replication in interdigitating dendritic cells.
[57] Increase in viral protein synthesis and RNA production have been reported to occur during the complement-mediated enhancement of infection.
Cells that are challenged with non-neutralizing levels of complements have been found to have accelerated release of reverse transcriptase and viral progeny.
However, the virus might escape the antibody complex and start its replication cycle inside the immune cell, avoiding the degradation.
Upon phagocytosis by macrophages or other immune cells, the complex may release the virus due to poor binding with the antibody.
