Alphacoronaviruses Edit The feline infectious peritonitis virus (FIPV) is an alphacoronavirus that is a very common pathogen in both domestic and wild cats.[7] It is believed that FIPV can cause antibody-dependent enhancement (ADE). Thus, vaccination against FIPV surprisingly increases the disease seriousness.[8] Moreover, it was demonstrated that infection of macrophages by FIPV in vitro can be triggered by non-neutralising monoclonal antibodies targeting the Spike (S)-protein, and this phenomenon can also occur with diluted neutralising antibodies.[9] ADE explains why half of cats develop peritonitis after being passively immunized with antivirus antibodies and being challenged with the same FIPV serotype. [10] In several countries an attenuated virus vaccine is available in a form of nasal drops; however, its application is still considered controversial by many experts, both in terms of safety and efficacy.[11] The mechanism of antibody-dependent enhancement for FIPV is illustrated in the video. [1]

Betacoronaviruses Edit

Antibody-dependent enhancement during coronavirus infection The neutralization ability of an antibody on a virion is dependent on concentration and the strength of interaction between antibody and antigen. High-affinity antibodies can cause virus neutralization by recognizing specific viral epitopes. However, pathogen-specific antibodies can promote a phenomenon known as antibody-dependent enhancement (ADE), which can be induced when the strength of antibody-antigen interaction is below the certain threshold.[12][13]

There are multiple examples of ADE triggered by betacoronaviruses.[12][13] Non-human primates vaccinated with modified vaccinia Ankara virus encoding full-length SARS-CoV spike glycoprotein and challenged with the SARS-CoV virus had lower viral loads but suffered from acute lung injury due to ADE.[14] ADE has been observed in both severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) animal models allowing the respective viruses to enter cells expressing Fc𝛾R including myeloid lineage cells.[15] It was shown that the SARS-CoV-1 virus (SARS-CoV) can enter macrophages via a antibody-mediated pathway and it can replicate in these cells. [16]

S-protein and N-protein models of SARS-CoV-2 virus. Both models are reproduced with modifications from the https://www.preprints.org/manuscript/202003.0138/v1n. [13] . It is likely that the amino acids variability of the S-protein represents a result of antigenic drift. ADE of acute lung injury has been documented in animal models of both SARS and MERS. Rabbits intranasally infected with MERS-CoV developed a pulmonary infection characterized by viremia and perivascular inflammation of the lung, and an antibody response that lacked neutralizing antibodies.[17] The rabbits developed more severe lung disease on re-exposure to MERS-CoV, and developed neutralizing antibodies after reinfection.[17] In SARS, mice vaccinated with four types of vaccines against SARS-CoV, as well as those infected with SARS-CoV itself, developed neutralizing antibodies.[18] Mice were then challenged with live SARS-CoV, upon which all developed immunopathologic-type lung disease, although none had detectable virus two days after challenge and were protected compared to control.[18] The development of immunopathology upon exposure has been a major challenge for coronavirus vaccine development[18] and may similarly impact SARS-CoV-2 vaccine research.

ADE in coronavirus infection can be caused by high mutation rate of the gene that encodes spike (S) protein. A thorough analysis of amino acid variability in SARS-CoV-2 virus proteins, that included the S-protein, revealed that least conservative amino acids are in most exposed fragments of S-protein including receptor binding domain (RBD). Therefore, antigenic drift is a most likely cause of amino-acids variability in this protein [13][19] and ADE. This drift can occur in a form of changes of both types of antigenic epitopes, including conformational and linear.

The pathophysiology of SARS and COVID-19 diseases may be associated with ADE. The authors of the study[13] believe that ADE is a key step in the progression of disease from its mild to severe form. Onset of ADE, due to antigenic drift, can explain the observed sudden immune dysregulation, including apoptosis of immune cells, which promotes the development of T-cell lymphopenia and an inflammatory cascade with the lung accumulation of macrophages and neutrophils, as well as a cytokine storm. ADE goes along with reduction of Th1 cytokines IL2, TNF-α and IFN-γ and increase of Th2 cytokines IL-10, IL-6, PGE-2 and INF-α, as well as with inhibition of STAT pathway.[20]

Perhaps ADE is the reason why the course of SARS and COVID-19 is more severe for older people compared to younger people. It is likely that in older people the production of antibodies is slower and by the time the antibodies are developed in the titer that is sufficient to neutralize the virus, the virus changes its antigenic determinants. In this case, immuno-dominant neutralizing antibodies might start forming unstable complexes with the new form of the virus and start to infect monocytes/macrophages causing ADE. This process can trigger generalized infection of immune cells in multiple organs and cytokine storm.[21][22]

It is interesting that in mice similar phenomenon of developing more severe disease in old compared to young animals exists. In contrast to old mice, in young mice, despite detectable viral replication оf SARS-CoV-1 in the lungs upon infection, clinical signs of the disease do not develop.[23]

You guys removed this part ...for... some... odd...reason.... while it was for the article for over a year at least.

Add it back up.