What happened to antibody-dependent enhancement?
A person who has antibodies against one virus (from infection or vaccination) may experience worse disease when infected by a second, closely related virus. This is a phenomenon known as antibody-dependent enhancement (ADE), and it occurs when the antibodies have a special and uncommon reaction with proteins on the surface of the second virus.
ADE is not an uncommon or new phenomenon. The enhancement of disease by antibody-dependent mechanisms has been described clinically in children given formalin-inactivated respiratory syncytial virus (RSV) or measles vaccines in the 1960s, in dengue haemorrhagic fever due to secondary infection with another dengue serotype, and in feline infectious peritonitis virus (FIPV) upon re-infection with an identical serotype of the virus.
There are two main ADE mechanisms in viral diseases and both of them rely on non-neutralizing or sub-neutralizing antibodies.
FcγRIIa-mediated endocytosis - For viruses that infect primary cultures of macrophages such as dengue virus and FIPV, non-neutralizing or sub-neutralizing antibodies cause increased viral infection of monocytes or macrophages via receptor-mediated cell ingestion (FcγRIIa-mediated endocytosis), resulting in more severe disease.
Immune complexes - Non-neutralizing antibodies can create immune complexes with viral antigens inside airway tissues for non-macrophage-tropic respiratory viruses like RSV and measles. These immune complexes cause the release of pro-inflammatory cytokines, the recruitment of immune cells, and the activation of the complement cascade within lung tissue. In severe circumstances, the following inflammation might result in airway blockage and acute respiratory distress syndrome.
These two processes are demonstrated in the diagram below.
The extent to which ADE plays a role in coronavirus infections is unclear. Reports confirming the existence of ADE in coronavirus infections are based on experiments using cell cultures or animal models.
Existing evidence suggests that immune complex formation, complement deposition and local immune activation present the most likely ADE mechanisms in COVID-19 immunopathology as SARS-CoV-2 has not been shown to productively infect macrophages.
Currently, though feared by many before these jabs were mass introduced, we have no evidence indicating that ADE is a relevant mechanism counteracting the role of anti-spike protein antibodies generated by vaccines in humans.
Yes, one study did note that ADE was more likely to develop in patients with high titers of SARS-CoV-2 RBD-and S1-specific antibodies, and more likely to develop in elderly patients with severe and critical conditions, longer hospital stays and disease duration. But this was an in vitro study.
ADE has also been theorised to likely cause more problems with the emergence of newer strains like Delta. But again we’ve got no real-life evidence so far.
Reassuringly one very large study of 20,000 people receiving blood from people who've recovered from COVID-19 reported no safety concerns.
The closest thing so far to ADE I have found is one autopsy study that did note that viral dissemination within organ systems was higher in vaccinated cases versus unvaccinated cases. The authors state that one reason for their finding could be ADE. But they also note that the other reason may be that those affected worse after vaccination were more likely to have underlying immunosuppressive conditions and tended to be older.
Currently, we lack real-life evidence of ADE caused by mRNA jabs, this may be down to a handful of reasons. Firstly there are currently no assays or biomarkers have been established to prove ADE in vivo. Secondly, many people may have already died via ADE mechanisms, but due to the lack of autopsies, we have no way of proving this. And thirdly, maybe ADE isn’t as much of a threat as once feared.
Only time will tell.
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