Malone wrote: changes in the receptor binding domain (RBD) of Spike will not only influence how well it can evade vaccine-induced antibodies, but also how it interacts with ACE 2: I agree, but....

by Paul Alexander

We must also consider that with so many mutations on the spike in omicron (RBD), that it has selected to use other cell surface receptors to gain access to the host cell; is this the reason?

Is it really the location and type of receptor being used to gain entry to host cells e.g. a natural selection away from ACE 2? It is difficult to fathom Dr. Malone’s depth and breadth and we are at a loss. Brilliance. I met him in a conference we gave together (and work with him now) and spoke to him and his wonderful wife in person. What a paid of beautiful human beings and brilliance and his partner is actually more adept than he is;-). This is an incredible mountain to even consider climbing and one must just stand from the plains and look on at him in awe. His recent substack (I embed the link below) was brilliant and I know of no one who can treat the complexities like him, and make it so palatable. I cannot even stand in his shadow.

I wanted to wade in to add to this giant of a piece, and just my small tidbit for it is fascinating for it may be that the S protein may exploit additional receptors for infection. This piece of Dr. Malone’s treatise is intriguing for it may explain at least in part, the heightened infectiousness and less lethality. This may explain what we are seeing here now with omicron as to how non-benign it is…this deserves urgent investigation.

Malone is arguing that changes in the receptor binding domain (RBD) of Spike will not only impact and guide and dictate how well it can evade vaccine-induced antibodies, but in addition, how it interacts with ACE 2. Thus with the 30 or so mutations reported on spike RBD on omicron, could it be it is not interacting readily with ACE 2 to enter cells and as such using an alternative receptor and could that entry route and receptor (s) be part reason for the very mild variant and yes indeed a much need gift from Santa this Christmas? Could those receptors be more readily expressed in the upper respiratory tract cells and not deep in the lungs and as such where this will more often result in more symptoms and illness? Could this be natural selection in full flight that has shifted the selection of ACE 2 and toward alternative receptors given the infectious pressure from the circulating virus intersecting with the sub-optimal vaccinal antibody pressure and pressure directed to the infectiousness of the S protein ??? Immense pressure on the S protein by the vaccinal antibodies???

It also brings lots of what Geert has been saying which is that we have grossly underestimated the evolutionary capacity of this virus to respond to the infectious pressure of the virus itself when confronted with sub-optimal ‘leaky’ imperfect vaccinal antibody pressure…and this intersection drives the natural selection of variants that could overcome the immune pressure and select for variants that are more infectious and potentially more lethal…the grave problem is we are vaccinating during a pandemic when there is circulating pathogen and this can only drive natural selection of the fittest variants e.g. CD-147 is another cell surface protein that mediates virus entering host cells by endocytosis. Studies are revealing a novel virus entry route, CD147-spike protein.

I provide some references of other alternative cell-surface receptors that S spike protein can potentially use to help broaden this discussion and allow us to think and reflect: