A neutralizing epitope on the SD1 domain of SARS-CoV-2 spike targeted following infection and vaccination

Seow, Jeffrey; Khan, Hataf; Rosa, Annachiara; Calvaresi, Valeria; Graham, Carl; Pickering, Suzanne; Pye, V.E.; Cronin, Nora; Huettner, Isabella; Malim, Michael H.; Politis, Argyris; Cherepanov, Peter; Doores, Katie J.

doi:10.1016/j.celrep.2022.111276

Cited by 36 publications

(42 citation statements)

References 75 publications

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“…Next, plasma neutralization breadth and potency were determined using HIV-1 lentiviral particles pseudotyped with either the SARS-CoV-2 Spike of Wuhan-1 (vaccine strain), alpha, delta, beta or omicron/BA.1 VOCs and a HeLa cell line stably expressing ACE2 as the target cell [13]. We have previously shown that the ID 50 values generated using the pseudotype assay correlate well with ID 50 values obtained using a live virus neutralization assay [13,19]. Analysis of neutralizing responses after a single vaccine dose (post 1 st ) was only conducted on the extended-group due to sample availability (Fig 1A).…”

Section: Previous Sars-cov-2 Infection Leads To Higher Nab Titres Fol...mentioning

confidence: 96%

The effect of Omicron breakthrough infection and extended BNT162b2 booster dosing on neutralization breadth against SARS-CoV-2 variants of concern

et al. 2022

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COVID-19 vaccines are playing a vital role in controlling the COVID-19 pandemic. As SARS-CoV-2 variants encoding mutations in the surface glycoprotein, Spike, continue to emerge, there is increased need to identify immunogens and vaccination regimens that provide the broadest and most durable immune responses. We compared the magnitude and breadth of the neutralizing antibody response, as well as levels of Spike-reactive memory B cells, in individuals receiving a second dose of BNT126b2 at a short (3–4 week) or extended interval (8–12 weeks) and following a third vaccination approximately 6–8 months later. We show that whilst an extended interval between the first two vaccinations can greatly increase the breadth of the immune response and generate a higher proportion of Spike reactive memory B cells, a third vaccination leads to similar levels between the two groups. Furthermore, we show that the third vaccine dose enhances neutralization activity against omicron lineage members BA.1, BA.2 and BA.4/BA.5 and this is further increased following breakthrough infection during the UK omicron wave. These findings are relevant for vaccination strategies in populations where COVID-19 vaccine coverage remains low.

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Section: Previous Sars-cov-2 Infection Leads To Higher Nab Titres Fol...mentioning

confidence: 96%

The effect of Omicron breakthrough infection and extended BNT162b2 booster dosing on neutralization breadth against SARS-CoV-2 variants of concern

et al. 2022

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“…In the current report, we sought to generate a comprehensive human B cell epitope map of OspA using our available collection of unique OspA-specific MAbs. For the purpose of epitope mapping, we principally employed hydrogen exchange–mass spectrometry (HX-MS), an emerging methodology that provides insights into protein dynamics and protein–protein interactions that has proven especially useful in deciphering antibody–antigen interactions across an array of targets, including toxins like ricin, − botulinum neurotoxin, SEB, viruses like HIV-1 and SARS-CoV-2, , and bacteria like Neisseria meningitidis , to name just a few. The methodology affords considerably greater resolution than can be achieved through antigen truncation or site-directed mutagenesis, but notably less than afforded by X-ray crystallography or cryo-electron microscopy, due to the fact that HX-MS relies on peptidic analysis of antigen targets. , Nonetheless, the HX reaction is conducted in solution and capable of capturing antibody-induced changes in backbone flexibility, where strong reductions in HX are interpreted as points of protein–protein contact …”

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confidence: 99%

Human B Cell Epitope Map of the Lyme Disease Vaccine Antigen, OspA

Haque

Ejemel²,

Vance

et al. 2022

ACS Infect. Dis.

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The Lyme disease (LD) vaccine formerly approved for use in the United States consisted of recombinant outer surface protein A (OspA) from Borrelia burgdorferi sensu stricto (ss), the bacterial genospecies responsible for the vast majority of LD in North America. OspA is an ∼30 kDa lipoprotein made up of 21 antiparallel β-strands and a C-terminal α-helix. In clinical trials, protection against LD following vaccination correlated with serum antibody titers against a single epitope near the C-terminus of OspA, as defined by the mouse monoclonal antibody (MAb), LA-2. However, the breadth of the human antibody response to OspA following vaccination remains undefined even as next-generation multivalent OspA-based vaccines are under development. In this report, we employed hydrogen exchange–mass spectrometry (HX-MS) to localize the epitopes recognized by a unique panel of OspA human MAbs, including four shown to passively protect mice against experimental B. burgdorferi infection and one isolated from a patient with antibiotic refractory Lyme arthritis. The epitopes grouped into three spatially distinct bins that, together, encompass more than half the surface-exposed area of OspA. The bins corresponded to OspA β-strands 8–10 (bin 1), 11–13 (bin 2), and 16–20 plus the C-terminal α-helix (bin 3). Bin 3 was further divided into sub-bins relative to LA-2’s epitope. MAbs with complement-dependent borreliacidal activity, as well as B. burgdorferi transmission-blocking activity in the mouse model were found within each bin. Therefore, the resulting B cell epitope map encompasses functionally important targets on OspA that likely contribute to immunity to B. burgdorferi.

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“…S7 A to D, and table S4). Superposition of the cryo-EM sd1.040-S protomer complex on published prefusion S structures, indiscriminate of RBD conformation, revealed minor clashes with the N-terminal domain of the adjacent protomer similar to antibody P008_60 ( 23 ) which contrasts the recently described SD1-specific murine antibody S3H3 ( 24 ) (Fig. 4B, inset, and fig.…”

Section: Resultsmentioning

confidence: 66%

Human neutralizing antibodies to cold linear epitopes and to subdomain 1 of SARS-CoV-2

Bianchini

Crivelli

Abernathy

et al. 2022

Preprint

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Emergence of SARS-CoV-2 variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the fourgenera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2’ site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization and, like fp.006 and hr2.016, protects mice when present as bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive withOrthocoronavirinae, including SARS-CoV-2 variants.One sentence summaryBroadly cross-reactive antibodies that protect from SARS-CoV-2 variants are revealed by virus coldspot-driven discovery.

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A neutralizing epitope on the SD1 domain of SARS-CoV-2 spike targeted following infection and vaccination

Cited by 36 publications

References 75 publications

The effect of Omicron breakthrough infection and extended BNT162b2 booster dosing on neutralization breadth against SARS-CoV-2 variants of concern

The effect of Omicron breakthrough infection and extended BNT162b2 booster dosing on neutralization breadth against SARS-CoV-2 variants of concern

Human B Cell Epitope Map of the Lyme Disease Vaccine Antigen, OspA

Human neutralizing antibodies to cold linear epitopes and to subdomain 1 of SARS-CoV-2

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