ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they are unable to prevent infection. Instead, these antibodies act as a “Trojan horse,” allowing the pathogen to get into cells and exacerbate the immune response. https://www.chop.edu/centers-programs/vaccine-education-center/vaccine-safety/antibody-dependent-enhancement-and-vaccines
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ADE was suspected in infections with influenza A virus subtype H7N9, but knowledge is limited. It is estimated that as many as 390 million individuals contract dengue annually.[33]
ADE may follow when a person who has previously been infected with one serotype becomes infected months or years later with a different serotype, producing higher viremia than in first-time infections. Accordingly, while primary (first) infections cause mostly minor disease (dengue fever) in children, re-infection is more likely to be associated with dengue hemorrhagic fever and/or dengue shock syndrome in both children and adults.[34] …ADE of infection has also been reported in HIV. Like dengue virus, non-neutralizing level of antibodies have been found to enhance the viral infection through interactions of the complement system and receptors.[48] The increase in infection has been reported to be over 350 fold which is comparable to ADE in other viruses like dengue virus.[48]
https://en.wikipedia.org/wiki/Antibody-dependent_enhancement#cite_ref-Willey2001_48-1
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9-9-20 One potential hurdle for antibody-based vaccines and therapeutics is the risk of exacerbating COVID-19 severity via antibody-dependent enhancement (ADE). ADE can increase the severity of multiple viral infections, including other respiratory viruses such as respiratory syncytial virus (RSV)9,10 and measles11,12. ADE in respiratory infections is included in a broader category named enhanced respiratory disease (ERD), which also includes non-antibody-based mechanisms such as cytokine cascades and cell-mediated immunopathology (Box 1). ADE caused by enhanced viral replication has been observed for other viruses that infect macrophages, including dengue virus13,14 and feline infectious peritonitis virus (FIPV)15. Furthermore, ADE and ERD has been reported for SARS-CoV and MERS-CoV both in vitro and in vivo. The extent to which ADE contributes to COVID-19 immunopathology is being actively investigated….
Evidence of ADE in coronavirus infections in vitro
While ADE has been well documented in vitro for a number of viruses, including human immunodeficiency virus (HIV)33,34, Ebola35,36, influenza37 and flaviviruses38, the relevance of in vitro ADE for human coronaviruses remains less clear. Several studies have shown increased uptake of SARS-CoV and MERS-CoV virions into FcR-expressing monocytes or macrophages in vitro32,39,40,41,42. Yip et al. found enhanced uptake of SARS-CoV and S-expressing pseudoviruses into monocyte-derived macrophages mediated by FcγRIIa and anti-S serum antibodies32. Similarly, Wan et al. showed that a neutralizing monoclonal antibody (mAb) against the RBD of MERS-CoV increased the uptake of virions into macrophages and various cell lines transfected with FcγRIIa39. However, the fact that antigen-specific antibodies drive phagocytic uptake is unsurprising, as monocytes and macrophages can mediate antibody-dependent phagocytosis via FcγRIIa for viral clearance, including for influenza43. Importantly, macrophages in infected mice contributed to antibody-mediated clearance of SARS-CoV44. While MERS-CoV has been found to productively infect macrophages45, SARS-CoV infection of macrophages is abortive and does not alter the pro-inflammatory cytokine gene expression profile after antibody-dependent uptake41,42. Findings to date argue against macrophages as productive hosts of SARS-CoV-2 infection31,32.
ADE in human coronavirus infections
No definitive role for ADE in human coronavirus diseases has been established. Concerns were first raised for ADE in patients with SARS when seroconversion and neutralizing antibody responses were found to correlate with clinical severity and mortality46. A similar finding in patients with COVID-19 was reported, with higher antibody titres against SARS-CoV-2 being associated with more severe disease47. One simple hypothesis is that greater antibody titres in severe COVID-19 cases result from higher and more prolonged antigen exposure due to higher viral loads48,49. However, a recent study showed that viral shedding in the upper respiratory tract was indistinguishable between patients with asymptomatic and symptomatic COVID-19 (ref. 50). Symptomatic patients showed higher anti-SARS-CoV-2 antibody titres and cleared the virus from the upper respiratory tract more quickly, contradicting a simpler hypothesis that antibody titres are simply caused by higher viral loads. Other studies showed that anti-SARS-CoV-2 T-cell responses could be found at high levels in mild and asymptomatic infections51,52. Taken together, the data suggest that strong T-cell responses can be found in patients with a broad range of clinical presentations, whereas strong antibody titres are more closely linked to severe COVID-19. One important caveat is that viral shedding was measured in the upper respiratory tract rather than in the lower respiratory tract50. The lower respiratory tract is likely more important for severe COVID-19 lung pathology, and it is unclear how closely SARS-CoV-2 viral shedding in the upper and lower respiratory tracts correlate throughout the disease course.
Beyond the host response to new SARS-CoV-2 infections, the potential of pre-existing antibodies against other human coronavirus strains to mediate ADE in patients with COVID-19 is another possible concern53. Antibodies elicited by coronavirus strains endemic in human populations (such as HKU1, OC43, NL63 and 229E) could theoretically mediate ADE by facilitating cross-reactive recognition of SARS-CoV-2 in the absence of viral neutralization. Preliminary data show that antibodies from SARS-CoV-2-naïve donors who had high reactivity to seasonal human coronavirus strains were found to have low levels of cross-reactivity against the nucleocapsid and S2 subunit of SARS-CoV-2 (ref. 54). Whether such cross-reactive antibodies can contribute to clinical ADE of SARS-COV-2 remains to be addressed….
Vaccines with a high theoretical risk of inducing pathologic ADE or ERD include inactivated viral vaccines, which may contain non-neutralizing antigen targets and/or the S protein in non-neutralizing conformations, providing a multitude of non-protective targets for antibodies that could drive additional inflammation via the well-described mechanisms observed for other respiratory pathogens….
Ongoing animal and human clinical studies will provide important insights into the mechanisms of ADE in COVID-19. Such evidence is sorely needed to ensure product safety in the large-scale medical interventions that are likely required to reduce the global burden of COVID-19. https://www.nature.com/articles/s41564-020-00789-5
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9-15-20 Antibody-dependent enhancement has been discovered in both severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, but the mechanism is not completely clear; different studies have led to different opinions.
Many scientist have mentioned the potential existence of antibody-dependent enhancement in the 2019 novel coronavirus – severe acute respiratory syndrome coronavirus 2.
The most recent studies on both convalescent plasma transmission and the application of inactivated vaccine did not report any case of antibody-dependent enhancement….
However, in some viruses, the binding of specific antibodies to viral surface proteins can promote viral invasion into certain types of cell instead, and enhance viral infection. This effect is called antibody-dependent enhancement (ADE) (see Glossary) (Taylor et al., 2015). ADE happens in two main cases: (1) when viral-specific antibody promotes viral entry into host monocytes/macrophages and granulocytes, and (2) when it enhances viral infection in cells via interplay with the Fc receptor (FcR) and/or complement receptor. Enhancement of the attachment between viruses and target cells play important role in most cases. ADE has been identified in over 40 kinds of virus….
It has been sequentially confirmed in subsequent studies that ADE of SARS-CoV and MERS-CoV also occur, with different mechanisms. Whether ADE works in other kinds of coronavirus infections remains to be investigated. Unlike dengue virus, ADE in SARS and MERS is not triggered by a heterovirus strain, however it is clear that the effects of both have negative consequences for the human body and are probably an obstacle to the development of viral vaccines (Yong et al., 2019). …
Up until 2019, the mechanism of ADE in SARS-CoV remained unclear. Then Chen et al. studied the mechanism of the SARS-CoV viral spike induced effect in detail, using the Chinese rhesus monkey as an animal model. This team developed the first SARS vaccine in 2005, which encodes the complete SARS-CoV viral spike in the modified attenuated poxvirus vector. A study was performed in 2019 to investigate the vaccine. It was found to induce the production of large amounts of neutralizing antibodies (S-IgG) soon after injection. Although these antibodies can effectively reduce the viral load in the upper respiratory tract, they also enhance lung injury. A positive correlation has been found between the amount of neutralizing antibody in serum and the degree of pathological injury in the lung. Further studies found that the virus enters macrophages with the help of FcR during ADE (Liu et al., 2019). …
MERS: Receptor-binding domains on each S1 subunit induce the recognition of receptor, while the S2 subunit possesses an S2′ cleavage site, which allows its hydrophobic amino acid to insert into cells and mediates fusion of the viral envelope and the cell membrane. The viral receptor of MERS-CoV on cells is dipeptidyl peptidase 4 (DPP4). During MERS-CoV viral packaging, spike protein is cleaved. The S1 subunit on the spike protein binds with DPP4 and stabilizes the receptor-binding site, which promotes a conformational change in the spike protein. Successive cleavage of the S1/S2 and S2′ enzymatic cleavage sites by host protease will lead to the S1 subunit departing and a change in the conformation of the S2 subunit, which gradually induces membrane fusion of the virus and host cells. …
Not long after the outbreak of COVID-19 was declared, the heterogeneity of severe cases in Hubei Province, China and in other areas was noted and this was attributed to ADE. Before a vaccine or specific therapy is available, convalescent plasma therapy is considered to be a useful tool for research….Nevertheless, use of the vaccine in humans has not yet been reported in a research paper, so whether SARS-CoV-2 will induce ADE in patients still needs further verification. As stated by Jiang (who has contributed towards vaccines and treatments for coronaviruses), safety testing matters most during the counterattack against the new coronavirus (Jiang, 2020)….
The third approach is to take advantage of some inhibitors. For example, protease inhibitors and Fc inhibitors play roles in the inhibition of ADE in MERS-CoV and SARS-CoV, respectively (Liu et al., 2019; Wan et al., 2020). Previous studies on SARS-CoV showed that an adjuvant promoted Th2-type immunity and reduced the immunopathology, thereby suggesting the latent importance of adjuvant (Hotez et al., 2020). In addition, the case of dengue virus can also be of reference; for example, reduce the risk of ADE by modifying the FcγR binding site on the antibody Fc portion. Another difficulty in these cases is to guarantee the inhibition of classical viral entry via antibodies while solving ADE. A potential solution is to combine Cyclospora A and Chinese drugs pharmaceutics that have an immunodepression function with colloidal subparticles, which can enhance the targeting to macrophages and promote an immunosuppressive effect. This could act not only by inhibiting the immune-injury inflammation but also against the virus and bacteria.
https://www.sciencedirect.com/science/article/pii/S1201971220307311
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“It is the antibodies produced by the virus that enable an infection to become stronger,” Dr. Luc Montagnier said in an interview with Pierre Barnerias of Hold-Up Media earlier this month. “The new SARS2 variants are a production and result from the vaccination.” https://telanganatoday.com/mass-vaccination-during-pandemic-historical-blunder-nobel-laureate …………………..............................................................................
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