SARS-CoV-2 Spike Protein Induces Paracrine Senescence and Leukocyte Adhesion in Endothelial Cells
https://journals.asm.org/doi/10.1128/JVI.00794-21
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If the spike created by the vaccine is not able to bind ACE2, then other mechanisms being mentioned are the culprit for pathology.
New research on phagocytosis and SARS-CoV-2's spike protein
https://www.news-medical.net/news/20211020/New-research-on-phagocytosis-and-SARS-CoV-2s-spike-protein.aspx
Study findings
The results indicated that at a high plasma concentration, there was a reduction in the binding of TPH1 monocytes and the spike protein. This reduction was found to be independent of the age, gender, and disease severity of the patient. Experiments with monoclonal antibodies detected ten spike-reactive antibodies, out of which nine were found to bind to spike beads as detected by flow cytometry.
The results of the epitope analysis indicated that antibodies could bind the spike protein but they did not compete with the binding site of human ACE2. These antibodies included Ab11, 57, 59, 66, 77, 81, 94.
Ab94 could bind to both the receptor-binding domain (RBD) and N-terminal domain (NTD). Ab59 was a neutralizing antibody, while the others were non-neutralizing antibodies. Overall, Ab59 was found to be most effective in SARS-CoV-2 neutralization.
The results also indicated that the spike-specific monoclonal antibodies that were obtained from COVID-19 patients had a dose-dependent effect on the spike-THP-1 cell interactions. This effect was independent of the spike-ACE2 neutralization capability of the monoclonal antibodies.
Although the results indicated that the monoclonal antibodies were effective in the mediation of phagocytosis, a threshold that led to a reduction in interaction efficiency was identified.
Determination of the antibodies’ function in a physiological context took place with the help of mice models. The results from the in vivo study indicated that too high doses of neutralizing antibodies were not beneficial for treatment. Additionally, non-neutralizing antibodies were also found to provide protection against SARS-CoV-2.
Therefore, the current study represents a concentration-dependent modulation of phagocytosis that was brought about by anti-spike antibodies. It may also help to indicate the unclear clinical benefit of COVID-19 treatment with monoclonal antibodies.
Two monoclonal antibody cocktails, of which included both casirivimab and imdevim, as well as bamlanivimab and etesevim, were found to target the SARS-CoV-2 spike protein. As a result of their success during Phase III clinical trials, these two antibody treatments quickly received emergency use authorization (EUA) by the United States Food and Drug Administration (FDA).
Further, the trials indicated that the use of these antibody cocktails led to a reduction in symptoms, hospitalization, and mortality that was associated with early-stage COVID-19. However, the antibiotic cocktails did not show any benefit in case of severe COVID-19 infections.
The aforementioned therapeutic antibodies have been categorized as neutralizing antibodies. Neutralizing antibodies comprise only a fraction of the total antibodies that are generated by B-cells against the SARS-CoV-2 spike protein.
Comparatively, non-neutralizing antibodies comprise a majority of the humoral response against a pathogen. These antibodies are also known to have other immunological functions such as complement-dependent immune activation and viral phagocytosis. By carrying out either virus or cellular phagocytosis, phagocytic cells help to reduce the viral load.
In the case of certain viral infections such as Respiratory Syncytial Virus (RSV), SARS-CoV-2, and Dengue, the level of neutralizing antibodies is found to be insufficient. This allows non-neutralizing antibodies to mediate entry of the virions into the host immune cells resulting in an Antibody-Dependent-Enhancement (ADE). This further results in increased infection, along with worsened patient outcomes. To date, no study has shown evidence of ADE in the case of COVID-19 infections.
A new study published in the preprint server bioRxiv* showed evidence that convalescent patient plasma and monoclonal anti-spike antibodies were able to induce phagocytosis at high antibody concentrations. This study also demonstrated that neutralization potential did not have any effect on the activation and inhibition of phagocytosis. This study also utilized an experimental animal infection model to determine the role of non-neutralizing antibodies in providing protection against SARS-CoV-2.
How viruses evade neutralizing antibodies
Some viruses can evade the effects of neutralizing antibodies, such as the dengue virus and the Zika virus. The influenza virus is also able to evade neutralizing antibodies because it regularly mutates so that it is no longer recognized by antibodies, even though these antibodies may have recognized a previous strain of the influenza virus.
A process known as antibody-dependent enhancement (ADE), which leads to more severe infections, can take place when a virus binds to antibodies that help the virus infect cells. The virus is better able to enter into cells in the body and is sometimes more able to replicate once it has entered a host cell.
There are several ways by which antibody-dependent enhancement could take place.
In Dengue virus, neutralizing antibodies have been found to bind to a type of white blood cell known as a macrophage that helps the virus enter those white blood cells and replicate.
Additionally, proteins on the surface of a virus can be covered with antibodies that fight one serotype of a virus and can bind to a separate, similar virus with a different serotype.
The combination of the virus and antibodies then bind to the Fc-region antibody receptors (proteins that play a part in the protective role of the immune system) found on the cell membrane.
As a result, the cell is then able to internalize the virus and go on to replicate it, leading to enhanced infection.
Antibody-dependent enhancement has been seen in the following viruses:
Dengue virus
Yellow fever virus
Zika virus
Human immunodeficiency virus (HIV)
Coronaviruses affecting both humans and animals
ADE is a cause for concern in the development of vaccines. This is because vaccines often trigger the production of antibodies that could then facilitate ADE and cause more severe illness.
For instance, vaccinations against Dengue virus and a coronavirus affecting cats were deemed unsuccessful because they resulted in antibody-dependent enhancement that made the infection worse in those that had been vaccinated when compared to those that had not been vaccinated.
@Breaking911
JUST IN: Pfizer says COVID-19 vaccine more than 90% effective at protecting kids from infection, ahead of public review - AP
8:16 AM · Oct 22, 2021·
https://twitter.com/Breaking911/status/1451522731921580076