Antibody-dependent enhancement (ADE) immunological basis

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Antibody-dependent enhancement (ADE) immunological basis and tips for antibody vaccine development

Antibody-dependent enhancement (ADE) immunological basis.  Recently ADE has become a hot topic again, let’s review an important article about ADE.

Antibody-dependent enhancement (ADE) is that after a virus infection (similar to vaccination), the antibodies produced are non-neutralizing or weakly neutralizing. This type of antibody promotes the virus to enter and infect host cells, leading to infectivity And the virulence is enhanced.

In 1973, Halstead and other scientists described ADE in dengue fever infection. They believed that the main mechanism is the antibody that binds to the virus. Its IgG Fc segment is cross-linked with the cell surface FcγRs to form a polymer, and through endocytosis, the virus takes the opportunity to enter the cell. Inside, replicate, multiply, and produce infection.

FcγR and its functions

FcγR classification and immune cell expression

Among them, FcγRIIb and intracellular segment are ITIM (immunoreceptor tyrosine inhibitory motif), and FcγRIIIb does not contain intracellular segment. The remaining FcγRs are ITAM (immunoreceptor tyrosine activating motif).

B cells only express FcγRIIb (involved in the production of high-affinity antibodies in the germinal center), and T cells do not express FcγR.

FcγR signaling pathway

① FcγR is cross-linked by IgG immune complex
②ITAM phosphorylation, kinase SYKSRCPKC activation
③Calcium ion inflow
④ Actin rearrangement, phagocytosis of IgG immune complex
⑤Transcription activation
⑥Release of cytokines and chemokines

Features

Degranulation

After activation, granular cells (neutrophils, basic granulocytes, and acidic granulocytes) produce reactive oxygen species (ROS) and reactive nitrogen species (RNS), which produce cytotoxicity and resist microbial infections. In addition, the influx of calcium ions will also start degranulation (serine proteases, leukotrienes, antibacterial active proteins, such as lysozyme and lactoferrin, and antibacterial peptides, such as alpha defensins, etc.).
NK cells are similar. After activation, they release perforin and granzyme to produce antiviral activity.

Phagocytosis and antigen presentation

After FcγR is activated by cross-linking, DC cells, monocytes, and macrophages induce IgG opsonization to phagocytose viruses and infected cells (where the virus replicates), which is called antibody-dependent cellular endocytosis (antibody- dependent cellular phagocytosis. ADCP).

ADE

Some studies have shown that non-neutralizing antibodies in the body may cause ADE.

Dengue Fever ADE

The earliest report of ADE came from dengue fever. After pre-infection with dengue fever, the non-neutralizing antibodies produced will not only fail to protect against dengue fever again, but also cause ADE and promote viral infection (Reference 4).

In fact, ADE is also relying on antibody-mediated endocytosis (ADCP), in which FcγRIIa and FcγRIIIa have a promoting effect, and FcγRIIb has an inhibitory effect.

When the virus enters the cell through endocytosis, the structure of the envelope protein changes under the low pH environment of the phagosome, which promotes virus fusion and infection. In this way, the virus can enter cells without virus receptors, such as myeloid cells, epithelial cells, and endothelial cells.

ADE has since been reported on HIV, Ebola, and influenza.

Coronavirus ADE

Both SARS-CoV and MERS-CoV have reported ADE, which is mainly mediated by FcγRIIb. Anti-Spike protein antibodies, inactivated vaccines, and infected patient sera, in vitro models, mice, and non-human primates have reported ADEs, but based on this, it is impossible to predict the situation in the patient’s body.

SARS-CoV-2

In the SARS-CoV-2 (COVID-19 pathogenic virus) inactivated vaccine and neutralizing antibody, preclinical research data (from mice, rats, non-human primates, etc.) showed protective effects, and no ADE was found (References 12, 13, 14).

However, human FcγR is still very different from model animals, so preclinical data cannot fully predict human conditions. Although humanized FcγR mice have been used, the results cannot completely mimic the human body.

Serum therapy for COVID-19 patients, clinical studies have not shown an increase in disease, suggesting that there is no ADE. This is the difference between SARS-CoV-2 and SARS-CoV (Reference 16).

Future antibody and vaccine development tips

• Antibody technology: antibody subtype selection and Fc glycosylation modification, selective binding of different FcγR subtypes
• Preclinical model: construction of new humanized FcγR subtype model animals and cell lines
• Companion diagnosis: patient FcγRgenotype detection

(source:internet, reference only)

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