We characterized the structural basis of #SARSCoV2 #OmicronVariant binding to the host ACE2 receptor and neutralization by the S309/sotrovimab clinical antibody therapeutic!

Led by @Dr_MattMcCallum & Nadine Czudnochowski Collab w Gyorgy Snell


We show that the #OmicronVariant spike NTD antigenic supersite is structurally rearranged, relative to the Wuhan-Hu-1 NTD, explaining the loss of binding and neutralization by a panel of NTD-targeted monoclonal antibodies we recently evaluated (nature.com/articles/d4158…).

The #OmicronVariant spike S2 subunit (fusion machinery) harbors mutations introducing additional electrostatic contacts with the S1 subunit, which might explain the reduced S1 shedding described in this preprint (biorxiv.org/content/10.110…)

Reduced S1/S2 cleavage shown in this preprint (biorxiv.org/content/10.110…) from @GuptaR_lab likely also participates in limiting S1 shedding which might enhance the Fc-mediated effector functions of some antibodies

We provide a blueprint of the #OmicronVariant spike RBD mutations explaining the marked dampening of binding of all therapeutic mAbs, leading to reduced neutralizing activity, except for S309/sotrovimab that has 2-3x reduced binding/neutralization

Finally, we reveal a remodeling of (electrostatic) interactions with human ACE2 due to K417N, S477N, Q493R, Q498R & N501Y explaining enhanced receptor binding relative to Wuhan-Hu-1.

This work provides a structural framework to understand broad evasion of humoral immunity and underscores the #SARSCoV2 spike mutational plasticity and the importance of targeting conserved epitopes for vaccine and therapeutics design.

Thank you so much to @SamK_Zepeda @johnbowenbio and our fantastic collaborators including @DavideCorti6


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More from @veeslerlab

21 Dec 21
Can we correlate #SARSCoV2 spike (S) biochemical properties with the specificity, magnitude & quality of antibody responses? Put another way, how to make a good #CovidVaccine ?

@johnbowenbio led the charge to answer these questions



We compared antibody responses elicited by 6 #CovidVaccine distributed globally: Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, AstraZeneca AZD1222, Gamaleya Sputnik V and Sinopharm BBIBP-CorV, after 2 doses, Janssen Ad26.COV2.S after 1 dose, and human convalescent plasma

Prefusion S/S2, RBD & NTD antibody binding titers were highest after 2 doses of mRNA-1273 or BNT162b2 and lowest for 1 dose of Ad26.COV2.S. The other 2 dose vaccines and #SARSCoV2 infection resulted in intermediate binding titers.

Read 22 tweets
14 Dec 21
Here is our assessment of #SARSCoV2 #Omicron receptor usage and immune evasion in collaboration with the team of @DavideCorti6 @Vir_Biotech

Led by Elisabetta Cameroni, Christian Saliba, @johnbowenbio & Laura E. Rosen

@HHMINEWS @UWBiochemistry


#SARSCoV2 #Omicron harbors a staggering 37 amino acid mutations in the spike with 15 of them in the receptor-binding domain (RBD), which is the main target of neutralizing antibodies. The number and positions of these mutations is concerning for tropism & immune evasion.

We found that the #SARSCoV2 #Omicron RBD has ~2.5-fold enhanced ACE2 binding affinity, relative to the Wuhan-Hu-1 RBD, similar to what we previously showed for the Beta variant of concern.


Read 8 tweets
10 Dec 21
Are you wondering what antibody responses are like in #SARSCoV2 Delta breakthrough patients?

We answer this question and many others in this study led by @coronalexington

@HHMINEWS @UWBiochemistry


We followed 4 cohorts longitudinally for up to 6 months:
-Delta breakthrough (vaccinated then infected)
-subjects infected and then vaccinated (2x and 3x)
-vaccinated-only (2x and 3x)

in collaboration with @HelenChuMD and her HAARVI team.

Serum IgG binding titers correlated with the number of SARS-CoV-2 spike 'exposures' through vaccination and/or infection and were therefore highest for 3x vaccinated subjects (infected or not) and Delta breakthrough cases.

Read 15 tweets
26 Oct 21
Have you heard of the recently discovered 8th human-infecting #coronavirus designated CCoV-HuPn-2018?
We reveal the architecture of its spike (ie infection machinery), receptor usage and antigenic properties!

Led by @aletortorici


CCoV-HuPn-2018 is a canine-feline recombinant alpha-#coronavirus isolated from the respiratory swab of a child hospitalized with pneumonia, indicating that more coronaviruses are spilling over to humans than previously appreciated.


We determined #cryoEM structures of the CCoV-HuPn-2018 spike in two markedly different conformational states which we propose to correspond to two snapshots of viral entry.

Read 12 tweets
11 Aug 21
Sharing our latest preprint on #SARSCoV2 B.1.617.2 (delta), B.1.617.2+ (delta+) and B.1.617.1 (kappa) variants led by @Dr_MattMcCallum


We show that vaccine-elicited neutralizing activity is reduced against delta and kappa and even more against delta+ relative to the vaccine-matched pseudovirus. Delta+ reduces neutralization ~ to B.1.351 (beta) which has the greatest magnitude of immune evasion thus far.

Half of the J&J-vaccinated individuals in our panel had no residual variant neutralization. Although we only analyzed neutralizing antibodies (T cells are also key players for in vivo protection), this supports offering second vaccine dose


Read 9 tweets
1 Apr 21
The #SARSCoV2 CAL20.C (B.1.427/B.1.429) variant is skyrocketing in California. We describe how it evades the host immune response with @DavideCorti6 @LucaPiccoli9

Led by @Dr_MattMcCallum, Jessica Bassi, Anna De Marco, Alex Chen & @coronalexington


The #SARSCoV2 CAL20.C (B.1.427/B.1.429) variant comprises 3 spike mutations: S13I, W152C & L452R reducing plasma neutralizing activity by ~3x and ~5x for vaccine- and infection-elicited antibodies (Abs), compared to the 'ancestral' virus.

The neutralization potency of 1/3 of RBD Abs is reduced or abrogated by the L452R spike mutation present in #SARSCoV2 CAL20.C (B.1.427/B.1.429), including clinical-stage antibodies such as Eli Lilly LY-CoV555 (bamlanivimab) & Celltrion CT-P59 (regdanvimab)

Read 7 tweets

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