SARS-CoV-2 Is Only A Few Mutations Away From Being Pan-Resistant To All Known Current Antibodies

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A new study by researchers from Columbia University has shown that the Omicron variant manifest striking antibody evasion properties.

The omicron variant which is to become globally dominant due to enhanced transmissibility possess a striking feature of the large number of spike mutations that pose a threat to the efficacy of current COVID-19 (coronavirus disease 2019) vaccines and antibody therapies.
 
This concern is amplified by the findings from this new study.
 
The study team found B.1.1.529 to be markedly resistant to neutralization by serum not only from convalescent patients, but also from individuals vaccinated with one of the four widely used COVID-19 vaccines. Even serum from persons vaccinated and boosted with mRNA-based vaccines exhibited substantially diminished neutralizing activity against B.1.1.529.
 
By evaluating a panel of monoclonal antibodies to all known epitope clusters on the spike protein, the study team noted that the activity of 17 of the 19 antibodies tested were either abolished or impaired, including ones currently authorized or approved for use in patients.
 
Alarmingly the study team also identified four new spike mutations (S371L, N440K, G446S, and Q493R) that confer greater antibody resistance to B.1.1.529. The Omicron variant presents a serious threat to many existing COVID-19 vaccines and antibody therapies, compelling the development of new interventions that anticipate the evolutionary trajectory of SARS-CoV-2.

The study findings were published in the peer review journal: Research Briefings by Nature. 

https://www.nature.com/articles/d41586-021-03826-3

Mutations conferring antibody resistance

To understand the specific B.1.1.529 mutations that confer antibody resistance, we next tested individually the same panel of 19 mAbs against pseudoviruses for each of the 34 mutations (excluding D614G) found in B.1.1.529 or B.1.1.529+R346K. Our findings not only confirmed the role of known mutations at spike residues 142-145, 417, 484, and 501 in conferring resistance to NTD or RBD (class 1 or class 2) antibodies4 but also revealed several mutations that were

previously not known to have functional importance to neutralization (Fig. 3a and Extended Data Fig. 4). Q493R, previously shown to affect binding of CB6 and LY-CoV55528 as well as polyclonal sera29, mediated resistance to CB6 (class 1) as well as to LY-CoV555 and 2-15 (class 2), findings that could be explained by the abolishment of hydrogen bonds due to the long side chain of arginine and induced steric clashes with CDRH3 in these antibodies (Fig. 3b, left panels).

Both N440K and G446S mediated resistance to REGN10987 and 2-7 (class 3), observations that could also be explained by steric hindrance (Fig. 3b, middle panels). The most striking and perhaps unexpected finding was that S371L broadly affected neutralization by mAbs in all 4 RBD classes (Fig. 3a and Extended Data Fig. 4). While the precise mechanism of this resistance is unknown, in silico modeling suggested two possibilities (Fig. 3b, right panels).

First, in the RBD- down state, mutating Ser to Leu results in an interference with the N343 glycan, thereby possibly altering its conformation and affecting class 3 antibodies that typically bind this region. Second, in the RBD-up state, S371L may alter the local conformation of the loop consisting of S371-S373- S375, thereby affecting the binding of class 4 antibodies that generally target a portion of this loop24. It is not clear how class 1 and class 2 RBD mAbs are affected by this mutation.

Evolution of SARS-CoV-2 to antibodies

To gain insight into the antibody resistance of B.1.1.529 relative to previous SARS-CoV-2 variants, we evaluated the neutralizing activity of the same panel of neutralizing mAbs against pseudoviruses for B.1.1.78, B.1.52630, B.1.42931, B.1.617.29, P.132, and B.1.35133.

It is evident from these results (Fig. 4 and Extended Data Fig. 5) that previous variants developed resistance only to NTD antibodies and class 1 and class 2 RBD antibodies. Here B.1.1.529, with or without R346K, has made a big mutational leap by becoming not only nearly completely resistant to class 1 and class 2 RBD antibodies, but also substantial resistance to both class 3 and class 4 RBD antibodies. B.1.1.529 is now the most complete “escapee” from neutralization by currently available antibodies.

Discussion

The Omicron variant struck fear almost as soon as it was detected to be spreading in South Africa. That this new variant would transmit more readily has come true in the ensuing weeks2. The extensive mutations found in its spike protein raised concerns that the efficacy of current COVID-

19 vaccines and antibody therapies might be compromised. Indeed, in this study, sera from convalescent patients (Fig. 1c) and vaccinees (Figs. 1d and 1e) showed markedly reduced neutralizing activity against B.1.1.529. Other studies have found similar losses34-38. These findings are in line with emerging clinical data on the Omicron variant demonstrating higher rates of reinfection11 and vaccine breakthroughs.

In fact, recent reports showed that the efficacy of two doses of BNT162b2 vaccine has dropped from over 90% against the original SARS-CoV-2 strain to approximately 40% and 33% against B.1.1.529 in the United Kingdom39 and South Africa40, respectively. Even a third booster shot may not adequately protect against Omicron infection39,41, although the protection against disease still makes it advisable to administer booster vaccinations. Vaccines that elicited lower neutralizing titers35,42 are expected to fare worse against B.1.1.529.

The nature of the loss in serum neutralizing activity against B.1.1.529 could be discerned from our findings on a panel of mAbs directed to the viral spike. The neutralizing activities of all four major classes of RBD mAbs and two distinct classes of NTD mAbs are either abolished or impaired (Figs. 2c and 2d).

In addition to previously identified mutations that confer antibody resistance4, we have uncovered four new spike mutations with functional consequences. Q493R confers resistance to some class 1 and class 2 RBD mAbs; N440K and G446S confer resistance to some class 3 RBD mAbs; and S371L confers global resistance to many RBD mAbs via mechanisms that are not yet apparent.

While performing these mAb studies, we also observed that nearly all the currently authorized or approved mAb drugs are rendered weak or inactive by B.1.1.529 (Figs. 2c and 3a). In fact, the Omicron variant that contains R346K almost flattens the antibody therapy landscape for COVID-19 (Fig. 2d and 3a).

The scientific community has chased after SARS-CoV-2 variants for a year. As more and more of them appeared, our interventions directed to the spike became increasingly ineffective. The Omicron variant has now put an exclamation mark on this point.

It is not too far-fetched to think that this SARS-CoV-2 is now only a mutation or two away from being pan-resistant to current antibodies, either monoclonal or polyclonal. We must devise strategies that anticipate the evolutional direction of the virus and develop agents that target better conserved viral elements.

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