...publication that discusses ADE in previous MERS and SARS trials. The article I originally read may have incorrectly stated that the animals died of ADE (or I may have misquoted it), and it may not have all been related to mRNA vaccines - I haven't been able to confirm that - but the paper linked below discusses multiple issues with ADE in previous animal trials. Hopefully this won't be an issue with the COVID vaccines, but the fact that there is still so much we don't know about their long-term effects is the reason for my concern.


Vaccine Risks for Antibody-Dependent Enhancement (ADE)

Virus vaccines can use live-attenuated virus strains, inactivated (killed) virus, protein subunit, messenger ribonucleic acid (mRNA), or deoxyribonucleic acid (DNA) vaccine. Antibodies induced by vaccines can be neutralizing or non-neutralizing. Non-neutralizing antibodies can contribute to anti-viral activities with mechanisms including antibody-medicated complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) [reviewed (73)]. The yearly influenza vaccine induces both neutralizing and non-neutralizing antibodies that provide projection against the strains in the vaccine and closely related strains. Vaccine-associated enhanced disease (VAED) can result when there are multiple circularizing serotypes of virus [e.g., Dengue fever (55–57)] or when the virus uses antibodies for expanded host cell trophism of phagocytic immune cells.

Many of the viruses associated with ADE have cell membrane fusion mechanisms (38). For influenza A H1N1, vaccine-induced cross-reactive anti-HA2 antibodies in a swine model promote virus fusion causing vaccine-associated enhanced respiratory disease (VAERD) (74). ADE was observed for the respiratory syncytial virus (RSV) in the Bonnet monkey model (37). Van Erp et al. (37) recommends avoidance of induction of respiratory syncytial virus (RSV) non-neutralizing antibodies or subneutralizing antibodies to avoid ADE. ADE has been observed in multiple SARS-CoV-1 animal models. In a mouse model, attempts to create vaccines for SARS-CoV-1 lead to pulmonary immunopathology upon challenge with SARS-CoV-1 (75, 76); these vaccines included inactivated whole viruses, inactivated viruses with adjuvant, and a recombinant DNA spike (S) protein vaccine in a virus-like particle (VLP) vaccine. Severe pneumonia was observed in mice vaccinated with nucleocapsid protein after challenge with SARS-CoV-1 (77). Enhanced hepatitis was observed in a ferret model with a vaccine with recombinant modified vaccinia virus Ankara (rMVA) expressing the SARS-CoV-1 Spike protein (78). ADE was observed for rhesus macaques with SARS-CoV-1 vaccine (79). SARS-CoV-1 ADE is mediated by spike protein antibodies (80). Antibodies to the SARS-CoV-1 spike protein can mediate viral entry via Fc receptor-expressing cells in a dose-dependent manner (54). Jaume et al. (34) point out the potential pitfalls associated with immunizations against SARS-CoV-1 Spike protein due to Fc mediate infection of immune cells. This leads to the prediction that new attempts to create either SARS-CoV-1 vaccines, MERS-CoV vaccines (81), or SARS-CoV-2 vaccines have potentially higher risks for inducing ADE in humans facilitated by antibody infection of phagocytic immune cells. This potential ADE risk is independent of the vaccine technology (82) or targeting strategy selected due to predicted phagocytic immune cell infections upon antibody uptake. For MERS patients, the seroconversion rate increased with disease severity (83). Severe clinical worsening for SARS patients occurs concurrently with timing of IgG seroconversion (84). Clinical evidence of early high IgG responses in SARS patients is correlated with disease progression (85) and severity (62–67). Antibody treatments for critically ill COVID-19 patients have been halted due to a potential safety signal and unfavorable risk-benefit profile (86). Current SARS-CoV-2 vaccines appear to be providing protection with high antibody titers; the possibility of ADE risks associated with waning titers of antibodies over time remains unknown.