Vaccinated persons get infected or re-infected with COVID/omicron, why? These eight (8) studies help explain this increased risk and why it is happening; key is binding of non-neutralizing antibodies

by Paul Alexander

Note, some say we should discard term 'COVID' & now use 'omicron' only as it is sufficiently different & one can argue this for BA.5 sub-variant/clade & this is why it is such an immune re-challenge

By the facilitating or enhancing or non-neutralizing antibodies binding to the target antigen (which is the spike protein, the receptor binding domain or N-terminal domain on the spike) yet not eliminating/sterilizing/neutralizing the virus, the binding increases infectiousness of the virus to the vaccinated person. It is not the virus, for it is no intrinsic properties of the virus, it is the non-neutralizing vaccinal antibodies binding to the spike protein yet not neutralizing the virus, that is causing increased infectiousness to the vaccinated person.

This first study by Liu et al. is particularly instructive.

1)Liu et al.: An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies

Key statement:

‘found that some of antibodies against the N-terminal domain (NTD) induced the open conformation of RBD and thus enhanced the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2. Mutational analysis revealed that all of the infectivity-enhancing antibodies recognized a specific site on the NTD. Structural analysis demonstrated that all infectivity-enhancing antibodies bound to NTD in a similar manner. The antibodies against this infectivity-enhancing site were detected at high levels in severe patients.’

2)Yahi et al.: Infection-enhancing anti-SARS-CoV-2 antibodies recognize both the original Wuhan/D614G strain and Delta variants. A potential risk for mass vaccination?

‘We show that enhancing antibodies have a higher affinity for Delta variants than for Wuhan/D614G NTDs. We show that enhancing antibodies reinforce the binding of the spike trimer to the host cell membrane by clamping the NTD to lipid raft microdomains. This stabilizing mechanism may facilitate the conformational change that induces the demasking of the receptor binding domain. As the NTD is also targeted by neutralizing antibodies, our data suggest that the balance between neutralizing and facilitating antibodies in vaccinated individuals is in favor of neutralization for the original Wuhan/D614G strain. However, in the case of the Delta variant, neutralizing antibodies have a decreased affinity for the spike protein, whereas facilitating antibodies display a strikingly increased affinity. Thus, ADE may be a concern for people receiving vaccines based on the original Wuhan strain spike sequence (either mRNA or viral vectors).’

3)Van Egeren et al.: “Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein

‘Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly -and repeatedly- under positive selection. Predicted resistance timelines are comparable to those of the decay kinetics of nAbs raised against vaccinal or natural antigens, raising a second potential mechanism for loss of immunity in the population.’

4)Lempp et al.: Lectins enhance SARS-CoV-2 infection and influence neutralizing antibodies

‘SARS-CoV-2 infection-which involves both cell attachment and membrane fusion-relies on the angiotensin-converting enzyme 2 (ACE2) receptor, which is paradoxically found at low levels in the respiratory tract1-3, suggesting that there may be additional mechanisms facilitating infection. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN and the sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) function as attachment receptors by enhancing ACE2-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies.’

5)Asarnow et al.: Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia

‘Strikingly, these neutralizing antibodies can inhibit or enhance Spike-mediated membrane fusion and formation of syncytia, which are associated with chronic tissue damage in individuals with COVID-19.’

6)Martin et al.: The emergence and ongoing convergent evolution of the SARS-CoV-2 N501Y lineages

‘The independent emergence late in 2020 of the B.1.1.7, B.1.351, and P.1 lineages of SARS-CoV-2 prompted renewed concerns about the evolutionary capacity of this virus to overcome public health interventions and rising population immunity. Here, by examining patterns of synonymous and non-synonymous mutations that have accumulated in SARS-CoV-2 genomes since the pandemic began, we find that the emergence of these three "501Y lineages" coincided with a major global shift in the selective forces acting on various SARS-CoV-2 genes.’

7)Hoffmann et al.: The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic

‘The Omicron spike was resistant against most therapeutic antibodies but remained susceptible to inhibition by sotrovimab. Similarly, the Omicron spike evaded neutralization by antibodies from convalescent patients or individuals vaccinated with the BioNTech-Pfizer vaccine (BNT162b2) with 12- to 44-fold higher efficiency than the spike of the Delta variant. Neutralization of the Omicron spike by antibodies induced upon heterologous ChAdOx1 (Astra Zeneca-Oxford)/BNT162b2 vaccination or vaccination with three doses of BNT162b2 was more efficient, but the Omicron spike still evaded neutralization more efficiently than the Delta spike. These findings indicate that most therapeutic antibodies will be ineffective against the Omicron variant and that double immunization with BNT162b2 might not adequately protect against severe disease induced by this variant.’

8)Kimura et al.: Virological characteristics of the novel SARS-CoV-2 Omicron variants including BA.2.12.1, BA.4 and BA.5