Our guest today is Dr. Ariel Fernandez, the former Karl F. Hasselmann Chair in Bioengineering at Rice University, now director of the Daruma Institute for Artificial Intelligence in Pharmaceutical Research. Ariel Fernandez authored nearly 500 peer-reviewed professional papers, four books and several biotech patents. He recently turned his attention to COVID-19 for obvious reasons, and has published eight papers listed below on different aspects of the problem. He looks at the disease mostly from a biophysical/structural perspective, an angle hardly adopted by anyone else.
WM: Dr. Fernandez, I glanced at your Covid-19 publications [listed below]. In the last one titled “SARS-CoV-2 glycosylation suggests that vaccines should have adopted the S1 subunit as antigen” you claim that the current vaccines have picked the wrong antigen?
AF: No, no, that’s a harsh statement. What I meant to say is that the antigen that the pharmas picked was suboptimal, not optimal.
WM: The antigen currently used is basically the spike protein, right? What is wrong with that?
AF: The key operational word here is “basically”. When you say that the vaccines adopted “basically” the spike protein as antigen what do you mean? The spike in the virus is a trimer, that is a complex made up of three identical units, and it is presented by the virus to the immune system in a highly glycosylated form.
WM: And what does that mean in terms of picking the right antigen for vaccination?
AF: Well, glycosylation is an extensive chemical modification consisting of attachment of a string of saccharides at many different sites on the surface of the protein during translation or right after. As the virus infects, it hijacks the translational machinery of the host cell, and also the tributary machinery that enzymatically performs glycosylation. This glycosylation, because it uses the same glycans as the host cell proteins, serves as camouflage vis-à-vis the immune system of the infected human. It is like a thief disguised with plants taken from your garden. Before going to bed, you turn on the lights outside to check that everything is OK, and spot some bushes that seem overgrown and maybe misplaced (?!), but you don’t worry enough to go outside and check closely …
WM: Now, THAT is such a good image! I picture the situation perfectly well. I would go out and check, though… [laughs] So, you are saying that the vaccine presents an antigen to the immune system which is camouflaged in the virus?
AF: Pretty much, yeah. The extent of glycosylation was NOT known at the time when the vaccines were developed. Then, around September/October , the extent of glycosylation camouflage became known, and I imagine this became the 800-pound gorilla in the room…
AF: Meaning no one wanted to talk about it but everyone saw it and could not ignore it… Glycosylation is extensive and modulates the immune surveillance induced by the vaccine. The good news is that not every antigenic epitope [site] is glycosylated. The key one, the one that the virus uses to anchor to the host cell for entry, the antigenic region of the virus that interfaces with the host-cell receptor ACE2, does not get glycosylated. It is obvious why, when you think about it. If that region were glycosylated it would not be able to recognize – bind – the receptor ACE2, and the virus would fail to infect, a fitness cost much too high to pay…
WM: So, the vaccine antibodies go there?
AF: Yes, but many other vaccine-induced antibodies will recognize other antigenic regions (epitopes) that are camouflaged by the virus. So, to a considerable degree, the vaccine sidetracks the immune system.
WM: Hmm, let me think: so a current vaccine is like an inefficient state-sponsored retirement plan. Most people get covered but because of the high administrative costs, you receive little money… [LOL]
AF: [LOL] Brilliant. The vaccines are reported to be highly effective in the sense that everyone gets immunity, but maybe we get 1/3 of the immunity we should be getting!
WM: OK, got it. And what about immune evasion crafted by the virus?
AF: Precisely. Bear in mind that the selection pressure is now circumscribed to the ACE2-binding region, the ACE2 interface, a part of the so-called receptor binding domain, or RBD. We are already seeing evolutionary routes to avoid vaccine-induced surveillance, especially in the South African strain, which presents mutations precisely in that RBD subregion. This may cause the virus to evolutionarily engineer an immune evasion route. But it becomes tricky for the virus, because those mutations may also abrogate or partially impair its recognition of the ACE2 receptor, a fitness cost the virus is never ready to afford, unless the virus changes receptor.
WM: Or changes host?
AF: That would be a great scenario! If the vaccines push the virus to select another host, that would be great, if it selects another human receptor, that would be nightmarish, though…
WM: So if the antigen that the current vaccines adopted is not optimal given what we now know, what other antigen should we use from now on? Because the immunity conferred by the current vaccines is short lived, from what you and others are telling.
AF: In my paper, I propose to use as antigen a subunit of the spike protein named S1. It forms a complex with another subunit, S2, and this complex is one of the three identical monomers that come together to form the spike protein.
WM: So instead of the spike, the vaccines should use a piece of it? What advantage would that bring in terms of improving immunogenicity?
AF: A big advantage. As the virus gets activated to enter the host cell, the S1/S2 linkage gets cleaved, and the S1 and S2 subunits adopt different roles, S1 contains the entire RBD, so it anchors to the host cell, while S2 becomes some sort of harpoon, and orchestrates the cell penetration. So, the new S1-based vaccine-induced immune response may defuse the virus at two stages, a) the virion stage, by recognizing the ACE2 interface in the RBD and, b) as the virus gets activated for cell entry, the antigenic region of S1 that was interacting with S2 before cleavage. This last antigenic region is not glycosylated because as such it couldn’t have interacted with S2. We know it is not glycosylated because we have the crystal structures of the complete spike as trimer.
WM: So the antigen you propose retains the same active epitope we already have with the current vaccines and adds new epitopes that are not glycosylated in the virus.
AF: Yes, precisely! And the new ones are presented by the virus at a different stage of its infection cycle. So if the “new S1 vaccines” do not neutralize the virion at one phase, they do it at the next phase, when it gets activated for cell penetration.
WM: Can something go wrong?
AF: Hell if I knew. Perhaps the structure of S1 within the spike trimer is different in the RBD region than what it is in the free form, as it will be administered in the new vaccines. Then the vaccine-induced antibodies will not be able to attack the virus during the virion phase. But I doubt that is the case, because recent experiments show that the ACE2 binding is as strong in the virion phase as it is in the preactivation stage, when the free S1 subunit binds to ACE2.
WM: I hope and trust your article will get the attention of the authorities for the benefit of humanity. Have you written to Dr. Anthony Fauci already?
AF: Don’t get me started. Tony Fauci should have anticipated most of what I said today. His predictions have always been wrong, consistently wrong. Fauci is NOT the voice of science, he is the voice of science bureaucracy at its worse. He did not see the big gorilla in the room at the time when it was already visible. And if he was so adamantly opposed to everything he saw was happening during the previous administration, why didn’t he resign or firmly voiced his opposition and paid the consequences? His moral and intellectual stature is truly appalling. That is my opinion.
WM: Thanks much, Dr. Fernandez. That was most illuminating, in every regard.
Ariel Fernandez’s COVID-19 bibliography:
- Ariel Fernández: “Structural impact of mutation D614G in SARS-CoV-2 spike protein: enhanced infectivity and therapeutic opportunity”. ACS Medicinal Chemistry Letters 11, 1667-1670 (2020). https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00410
- Ariel Fernández: “Therapeutically targeted destabilization of the quaternary structure of the spike protein in the dominant G614 strain of SARS-CoV-2.” ACS Pharmacology and Translational Science 3, 1027-1029 (2020). https://pubs.acs.org/doi/10.1021/acsptsci.0c00114
- Ariel Fernández: “Achilles’ heel of SARS-CoV-2 structure.” ACS Pharmacology and Translational Science 3, 1030-1031 (2020). https://pubs.acs.org/doi/10.1021/acsptsci.0c00128
- Ariel Fernández: “Defusing Sars-CoV-2: Emergency brakes in a vaccine failure scenario.” ACS Pharmacology and Translational Science 3, 1425-1426 (2020). https://dx.doi.org/10.1021/acsptsci.0c00152
- Ariel Fernández: “Targeted Disassembling of SARS-CoV-2 as It Gets Ready for Cell Penetration.” ACS Medicinal Chemistry Letters 11, 2055–2057 (2020)
- Ariel Fernández: “COVID-19 Evolution in the Post-Vaccination Phase: Endemic or Extinct?” ACS Pharmacology and Translational Science, published online December 31, 2020. DOI: https://pubs.acs.org/doi/10.1021/acsptsci.0c00220
- Ariel Fernández: “Glycosylation of SARS-CoV-2 Steers Evolutionary Outcomes in the Postvaccination Phase”. ACS Pharmacology and Translational Science, published online January 21, 2021. DOI: https://pubs.acs.org/doi/10.1021/acsptsci.1c00015
- Ariel Fernández: “SARS-CoV-2 Glycosylation Suggests That Vaccines Should Have Adopted the S1 Subunit as Antigen”. ACS Pharmacology and Translational Science, published online February 2, 2021. DOI: https://pubs.acs.org/doi/full/10.1021/acsptsci.1c00036