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Fri May 14, 2021, 12:08 AM

Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera

Before citing this paper, let me start with the "Do not panic button, by excerpting the study's limitations from the end of the paper.

To wit:

Limitations of the study

The correlates of protection from SARS-CoV-2 infection are yet to be established. The in vitro neutralization assays reported here do not convey the contributions to in vivo protection provided by T cells nor the contributions of Fcγ receptor interactions and complement activation. Convalescent plasma and vaccine serum were taken relatively soon after acute illness or following vaccination; it is possible that titers will drop over time to a point where they are no longer high enough to provide protection. It will be interesting to understand the antibody response made by people infected by B.1.1.7, particularly how antibodies adapt to the N501Y change, but also the deletions occurring in the NTD. It will also be instructive to look at how well convalescent or vaccine serum can neutralize the other recently described variants B.1.351 and P.1 and, conversely, how well serum from patients infected with these variants can neutralize B.1.1.7 and the original Wuhan strains.

I have added the bold.

The paper under discussion is this one: Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera (Mongkolsapaya, Stuart, Screaton et al., Cell VOLUME 184, ISSUE 8, P2201-2211.E7, APRIL 15, 2021)

This article is open sourced, and anyone can read it, so I'll just excerpt a few things, and show, for convenience, a few graphics.

From the introduction:

Since its first appearance in Wuhan in December 2019, SARS-CoV-2 rapidly spread around the world leading the WHO to declare a pandemic on March 11, 2020. Since then, drastic public health measures, including draconian lockdowns with severe economic cost, have been enacted to contain virus spread. Although initially successful at containing disease, many countries are now experiencing further waves of infection, coinciding with winter in the northern hemisphere, with infections in some countries outpacing those seen during the first wave (Kröger and Schlickeiser, 2021).
Huge strides have been made in the understanding of SARS-CoV-2 over the last year, which are exemplified by the licensing of several vaccines (in the UK those made by Pfizer-BioNtech, Moderna, and Oxford-AstraZeneca), which are being rolled out in massive global vaccination programs, with the aim to reach billions of individuals in 2021. Furthermore, Janssen and Novavax have recently reported results showing good efficacy and also report efficacy against the UK B.1.1.7 strain (https://blogs.sciencemag.org/pipeline/archives/2021/01/29/jj-and-novavax-data). In parallel, a number of potently neutralizing monoclonal antibodies (mAbs) have been developed that are in late-stage trials to be used prophylactically or therapeutically (Baum et al., 2020, Yang et al., 2020).

SARS-CoV-2 is a large positive-stranded RNA virus; the major virion surface glycoprotein is the trimeric spike that attaches the virus to host cells via the ACE2 receptor and, through a series of conformational changes, allows fusion of host and virion membranes releasing the virus RNA into the cell to start the infection cycle (Hoffmann et al., 2020; Ou et al., 2020). Spike is the target of RNA (Polack et al., 2020; Baden et al., 2021), viral vectored (Voysey et al., 2021), and inactivated virus and recombinant protein-based vaccines (Yadav et al., 2020).

Because of the huge number of genome replications that occur in infected populations and error-prone replication, viral mutations do and will continue to occur (Robson et al., 2020). Although the vast majority will be inconsequential or detrimental to viral fitness, a few may give the virus a competitive advantage and be the subject of rapid natural selection relating to transmission advantage, including enhanced replication and immune evasion. This leads to the emergence of dominant new variant viruses. Coronaviruses, as we are seeing with COVID-19, have the potential to alter their proteins with dramatic effect (Denison et al., 2011).

In recent months, a number of mutations in the spike protein have been exemplified by viruses that have grown in alternative hosts such as mink and transmitted back to humans or in immunocompromised chronically infected individuals (Kemp et al., 2020; Oude Munnink et al., 2021; Hayashi et al., 2020). While most of these mutations currently show little evidence of a selective advantage in humans, variants have been identified with multiple mutations in spike, which appear to have distinct selective advantages and have rapidly expanded in prevalence, notably that first identified in Kent in the UK (lineage B.1.1.7) and unrelated variants detected in South Africa (501Y.V2 also known as B.1.351) and Manaus in Brazil (P.1). All of these contain mutations in the ACE2 receptor binding footprint of the receptor binding domain (RBD), one in B.1.1.7, three in 501Y.V2, and three in P.1, with the N501Y mutation being common to all.

"N501Y" refers to the 501st amino acid residue in the spike protein. The "N" refers to the asparagine that was in that position in the original virus first sequenced in Wuhan patients which has been replaced by a tyrosine ("Y" in the mutant "B.1" series. I have read elsewhere that it has been recently discovered that this mutant is slightly more lethal than the original, and also that it is more infectious.

The tests described herein are in vitro, sometimes called, someone niavely as being "test tube." There is very little evidence that this variant has reduced the protective effects of the existent vaccines by a large amount, and the vaccines are still helping us in a very big way.

Still, the need to not panic does not preclude an understanding, as mentioned in the introductory text, that this virus can, and does mutate, and given the situation. Therefore it is a good idea to hold on to supplies you may have, such as masks and sanitizers.

Some pictures from the text:

In the caption, "RBD" refers to the "receptor binding domain," the part of the spike protein that attaches to the ACE2 protein on the surface of cells.

The caption:

Figure 1The B.1.1.7 variant spike protein and effect on ACE binding of the N501Y mutation

(A) The SARS-CoV-2 spike trimer is depicted as a gray surface with mutations highlighted in yellow-green or with symbols. The RBD N501Y and the NTD 144 and 69–70 deletions are highlighted with green stars and red triangles, respectively. On the right, a protomer is highlighted as a colored ribbon within the transparent gray spike surface, illustrating its topology and marking key domains.

(B) The RBD “torso” analogy. The RBD is represented as a gray surface with the ACE2 receptor binding site in dark green. Binding sites for the panel of antibodies (Dejnirattisai et al., 2021) on which this study draws are represented by spheres. The spheres represent the point at which placing spherical antibodies would optimally predict the BLI competition data and are colored according to their neutralization, from red (potent) to blue (non-neutralizing). The position of the B.1.1.7 N501Y mutation in the RBD is highlighted in light green toward the right shoulder.

(C) Proximity of ACE2 to N501Y. The RBD is depicted as in (B) with ACE2 bound (in yellow cartoon format) with glycosylation drawn as sticks.

(D) Left panel: interactions of N501 of WT RBD with residues Y41 and K353. The structure shown is the complex of N501 RBD with ACE2 determined by X-ray crystallography (PDB ID 6M0J, Lan et al., 2020). When the 501 is mutated to a tyrosine with the conformation seen in the N501Y RBD-269 Fab complex (right panel), Y501 makes T-shaped ring stacking interactions with Y41 and more hydrophobic contacts with K353 of ACE2 (note there are minor clashes of the side chain of Y501 to the end of the K353 side chain, which has ample room to adjust to optimize interactions).

(E) BLI plots for WT (left) and N501Y (right) RBDs binding to ACE2. A titration series is shown for each (see STAR Methods). Note the much slower off rate for the mutant.

Some text:

Characterizing the N501Y mutation in the RBD

The RBD may be likened to a classic human torso; in this analogy, the shoulders and neck are involved in interactions with the ACE2 receptor (Figures 1B and 1C) (Dejnirattisai et al., 2021). In this context, residue 501 lies within the footprint of the receptor on the right shoulder and is involved in hydrophobic interactions, especially with the side chains of residues Y41 and K353 of ACE2 with the 501 mutation from N to Y offering the opportunity for enhanced interactions (Figures 1C and 1D).
Effect on ACE2 affinity

It has been reported that mutations at 501 can increase affinity for ACE2 (Starr et al., 2020; Gu et al., 2020), although these data are not for the mutation to Y. In contrast, Zahradník et al., 2021 report direct selection of N501Y when evolving the RBD to enhance affinity. We therefore investigated the effect of this mutation on ACE2 binding by RBD using biolayer interferometry (BLI) (Figure 1E). The results indicate a marked (7-fold) increase in binding affinity due to a slower off rate: WT RBD(501N)-ACE2: KD 75.1 nM (Kon 3.88E4 /Ms, Koff 2.92E-3 /s), RBD(501Y)-ACE2: KD 10.7 nM (Kon 6.38E4 /Ms, Koff 6.85E-4/s). This is in-line with enhanced interactions of the tyrosine side chain with the side chains of residues Y41 and K353 of ACE2 (Figure 1D). In the context of a multivalent interaction at the cell surface, this effect would be amplified. This alone might account for the selection of the N501Y mutation and an increase in transmission.

The authors utilized a set of 377 antibodies isolated from patients either who had been infected in the first wave. 80 of these have been fully mapped to elucidate the binding sites of the antibodies. In many cases, they found reduced binding.

However, as noted in the first excerpt from the last part of the paper's main text, the reduced binding does not preclude vaccine protection. Notably, the infection can be managed by T-cells as opposed to B-cell antibodies.

The full paper is available for reading for free. It may take some sophistication to understand all that is being said in there, but I think it readable and it's worth mucking around in it. If there are any questions that I may be able to answer, let me know and I'll do my best.

For now, we seem safe, if we've been vaccinated. If we're dumb assed anti-vax Republicans, the Darwin award awaits; this strain is definitely more lethal, although still susceptible to being managed by the vaccines.

Still the situation in India, affording many opportunities to generate new strains suggests that new vaccines may be required at some point. Some that have modified to reflect the new strains have already been prepared and are being tested in patients. We have considerable infrastructure for the manufacture of these, and considerable knowledge capital as well, so we're in relatively good shape. It is important that we do our best to provide other nations with access to these vaccines, since all of humanity shares this risk.

Be safe. Be well.

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