Thread by @veeslerlab

We analyzed human plasma, mucosal and memory antibody responses against #SARSCoV2 and found a pan-variant neutralizing antibody!

Led by @YoungjunPark11 Dora Pinto @coronalexington @JZhuoming

Collab. with @DavideCorti6

@HHMINEWS
@Vir_Biotech

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biorxiv.org/content/10.110…

We assessed plasma neutralizing activity from humans previously infected in 2020 (WA-1-like) and then vaxed 2x or 3x, or vaxed before Delta or #Omicron BA.1 breakthrough infection or vaxed-'only' 3x

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#Omicron breakthrough cases had highest neutralizing activity against #SARSCoV2 variants, possibly due to exposure to BA.1 spike whereas neutralization of SARS-CoV-1 was low for all cohorts, due to genetic and antigenic divergence of the latter spike

3/24

We found that ≥80% of IgGs secreted by memory B cells (Bmem) from #Omicron breakthrough cases bound the Wuhan-Hu-1, BA.1, BA.2 and Delta RDBs & ≥90% of them blocked binding to ACE2 (a correlate of neutralization). No BA.1- or BA.2 RBD-specific antibodies were found!

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This illustrates how immunological imprinting from prior exposure can strongly affect responses to antigenically novel antigens: #Omicron infection preferentially expanded existing B cell pools primed by vaccination and elicited cross-reactive plasma cells and antibodies

5/24

Conversely, Bmem-derived RBD-specific secreted IgGs obtained from Omicron primary infections were present at low frequency and were mostly specific for BA.1 and BA.2!

6/24

We found a lower frequency of Bmem secreting IgGs recognizing antigenic site Ia/Ib (ACE2-binding site) and II for #Omicron breakthrough vs infected-vaxed cases, consistent with the presence of several immune escape mutations in the Omicron RBD.

7/24

For a definition of #SARSCoV2 RBD antigenic sites, please see

sciencedirect.com/science/articl…

8/24

We detected mucosal neutralizing activity against Wuhan-Hu-1/G614 and BA.1 in nasal swabs (ie the site of viral entry) for #Omicron breakthrough samples up to a month post symptom onset but not in vaccinated-only individuals

9/24

These findings motivate the development and evaluation of a next generation of vaccines administered intranasally, an idea shared by @VirusesImmunity and others

washingtonpost.com/health/2022/04…

10/24

Evaluation of the monoclonal antibodies (mAbs) currently used in the clinic revealed that they all experience reductions of neutralizing activity (to various extent) against BA.1, BA.2, BA.2.12.1, BA.3, BA.4 and BA.5.

11/24

The S2X324 mAb stood out as it neutralized all SARS-CoV-2 variants tested ultrapotently, including BA.1, BA.2.12.1, BA.2, BA.3, BA.4 and BA.5 and cross-reacted with the sarbecovirus clade 1b Pangolin-GD RBD, but did not recognize more divergent sarbecovirus RBDs

12/24

To understand the pan-variant S2X324 inhibitory activity, we determined a #cryoEM structure of the Omicron BA.1 spike trimer bound to the S2X324 Fab which binds to an RBD epitope partially overlapping with antigenic sites Ia/Ib and IV and accommodates #Omicron mutations

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S2X324 overlaps partially with the ACE2-binding site on the RBD and hinders receptor engagement sterically, thereby inhibiting viral attachment to the host surface

14/24

Prophylactic (pre-exposure) or therapeutic (post-exposure) administration of S2X324 protects hamsters challenged with the SARS-CoV-2 Delta and BA.2 variants, making it an ideal candidate for clinical development

15/24

Although S2X324 was isolated before the emergence of #Omicron, it illustrates the type of antibodies that can be recalled upon #Omicron breakthrough infection of convalescent or vaxed individuals

16/24

In summary, exposure to #Omicron primarily leads to a recall of existing Bmem specific for epitopes shared by multiple SARS-CoV-2 variants rather than by priming naïve B cells recognizing Omicron-specific epitopes (at least up to 100 days post breakthrough infection)

17/24

Although immune imprinting may be beneficial in stimulating responses to cross-reactive SARS-CoV-2 epitopes, antibody responses to some #Omicron-specific epitopes were markedly diminished by prior antigenic exposure

18/24

Our data concur with boosting pre-immune macaques with Beta or #Omicron mRNA spike or Beta RBD nanoparticle eliciting ≈high titers of antibodies broadly neutralizing variants relative to Wuhan-Hu-1-based vaccines

19/24

sciencedirect.com/science/articl…

biorxiv.org/content/10.110…

The limited cross-variant neutralization elicited by #Omicron primary infection in humans along with our data on the specificity of Bmem indicate that an #Omicron vaccine might elicit narrow(er) antibody responses

20/24

researchsquare.com/article/rs-153…

This suggests that a heterologous prime-boost or a multivalent approach might be be suited.

21/24

Our data show that Omicron breakthrough infections did not elicit high titers of pan-sarbecovirus neutralizing antibodies (e.g., directed against SARS-CoV-1), as opposed to SARS survivors who received #SARSCoV2 vaccines

nejm.org/doi/full/10.10…

22/24

These data underscore the need to develop vaccines eliciting broad sarbecovirus immunity

23/24

sciencedirect.com/science/articl…

Thank you so much @sprouse_kaitlin @AminAddetia @johnbowenbio Cameron Stewart & our wonderful collaborators including @HelenChuMD @LanzavecchiaB @vsv512 @DrLisaPurcell @neyts_johan @AnnaDeMarco83 @FLempp @HaVanDang2712 @SkiClimbSciNick & many others

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