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MAJOR ISSUES WITH SPIKE PROTEIN VACCINES AND ANTIBODY GENERATION.

"[M]ost initial efforts to generate subunit vaccines against SARS-2 have also focused on the... S protein and its receptor-binding domain. This effort may prove to be more difficult for SARS-2 than for SARS-1..."
"The affinity of SARS-2 S protein for its receptor ACE2 is approximately 15 nM—over 20 times tighter binding than that observed by SARS-1 S protein (Wrapp et al. 2020; Yan et al. 2020)."

ncbi.nlm.nih.gov/pmc/articles/P…
In actuality, SARS-CoV-2 has approximately 700 pM binding to ACE2. Some studies estimate that it's closer to 5 pM. The problem is even worse.
"[N]eutralizing antibodies cross-react between SARS-1 and SARS-2 and appear to bind the S protein core rather than the receptor-binding domain (ter Meulen et al. 2006; Tian et al. 2020; Wang et al. 2020a)."
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Andre Watson 🧬💊💉
@nanogenomic
Here is the virus in "closed" (teal) and "open" (green) form. In "open" form, it binds to ACE2. ACE2 also blocks the ideal neutralizing antibody sites, and binds with extremely high, picomolar affinity (similar binding strength to many strongly binding antibodies).
The "closed" variant is the Veesler Lab cryo-EM structure (biorxiv.org/content/10.110…). The "open" variant is the SWISS-MODEL simulated spike protein structure (swissmodel.expasy.org/repository/spe…). I did the ACE2 docking myself, before we had binding data of pocket.
Ligandal peptide nanoscaffolds are designed to interfere with ACE2-spike binding, while also promoting a strong immune response against the correct receptor-binding domain component for antibody generation. This means that you can give the nano-scaffold before or after infection.
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Andre Watson 🧬💊💉
@nanogenomic
This is really not good. SARS-infected cells are becoming MHC-negative. This means that chewed up pieces of the virus are not appearing on the cell surface for T cells to be able to recognize.
While innate immune cells (NK cells) actively clear cells that are MHC-, this is a big blow to adaptive immunity, especially when coupled with antibody avoidance techniques the virus has.
“[T]he killer T cells used in the study were not effective at eliminating the virus in infected cells. When the scientists took a closer look they found that a molecule known as major histocompatibility complex, or MHC, was missing.”
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Andre Watson 🧬💊💉
@nanogenomic
Ligandal nano-scaffolds will block the virus from binding to ACE2, act as adjuvants to other vaccines, present epitopes for correct B cell receptor and antibody formation, and exhibit T cell receptor epitopes for key immunogenic responses. This is just the start of what we do.
You could even give these scaffolds to people receiving Moderna’s vaccine, and other vaccines, and the tech is engineered so you would start preferentially generating the correct antibodies for forming a neutralizing response to the virus.
This will also be a therapeutic, which can be given after infection to 1) prevent viral entry, 2) prevent ACE2 coating of the virus, and 3) accentuate antibody responses to the receptor-binding domain of the virus.
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