Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability

Burnett, Deborah L.; Jackson, Katherine; Langley, David B.; Aggrawal, Anupria; Stella, Alberto Ospina; Johansen, Matt D.; Balachandran, Harikrishnan; Lenthall, Helen; Rouet, Romain; Walker, G. J.; Saunders, Bernadette M.; Singh, Mandeep; Li, Hui; Henry, Jake Y.; Jackson, Jennifer; Stewart, Alastair G.; Witthauer, Franka; Spence, Matthew A.; Hansbro, Nicole G.; Jackson, C.J.; Schofield, Peter; Milthorpe, Claire; Martinello, Marianne; Schulz, Sebastian; Roth, Edith; Kelleher, Anthony D.; Emery, Sean; Britton, Warwick J.; Rawlinson, William D.; Karl, Rudolfo; Schäfer, Simon; Winkler, Thomas; Brink, Robert; Bull, Rowena A.; Jäck, Hans‐Martin; Turville, Stuart; Christ, Daniel; Goodnow, Christopher C.

doi:10.1016/j.immuni.2021.10.019

Cited by 47 publications

(55 citation statements)

References 78 publications

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“…Thus, even with the 17.3-fold decrease in neutralisation titre, boosting with mRNA vaccines is predicted to provide signi cant protection from infection with Omicron (Table 1 The Omicron variant contains several mutations at RBD sites, previously thought to be highly conserved, that are the target of antibody therapeutics. For example, S371L, S373P, and S375F form part of the class 4 epitope, affecting previously described class 4 antibodies such as Ab-3467 that broadly neutralise sarbecoviruses 13,14 . Additional mutations unique to Omicron at sites 417, 440, 446, and 493 are likely to contribute to the lack of the neutralisation of other therapeutic antibodies.…”

Section: Modelling On Vaccine E Cacy Based On Omicron Fold Evasion Fr...mentioning

confidence: 92%

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SARS-CoV-2 Omicron: evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

Aggarwal

Stella²,

Walker

et al. 2022

Preprint

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Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. Over this time global vaccine programs have been introduced, contributing to lowered COVID-19 hospitalisation and mortality rates, particularly in the first world. In late 2021, the Omicron (B.1.1.529) virus variant emerged, with significant genetic differences and clinical effects from other variants of concern (VOC). This variant a demonstrated higher number of polymorphisms in the gene encoding the Spike (S) protein, and there has been displacement of the dominant Delta variant. We assessed the impact of Omicron infection on the ability of: serum from vaccinated and/or previously infected individuals; concentrated human IgG from plasma donors, and licensed monoclonal antibody therapies to neutralise the virus in vitro. There was a 17 to 27-fold reduction in neutralisation titres across all donors who had a detectable neutralising antibody titre to the Omicron variant. Concentrated pooled human IgG from convalescent and vaccinated donors had greater breadth of neutralisation, although the potency was still reduced 16-fold. Of all therapeutic antibodies tested, significant neutralisation of the Omicron variant was only observed for Sotrovimab, with other monoclonal antibodies unable to neutralise Omicron in vitro. These results have implications for ongoing therapy of individuals infected with the Omicron variant.

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Section: Modelling On Vaccine E Cacy Based On Omicron Fold Evasion Fr...mentioning

confidence: 92%

“…For monoclonal antibodies, DNA sequences encoding the variable domain sequences of the therapeutic monoclonal antibodies Sotrovimab, Casirivimab, Imdevimab, Bamlanivimab, Cilgavimab and Tixagevimab were generated by gene synthesis, cloned into human IgG1 expression vectors, and produced in CHO cells 13 .…”

Section: Other Immunoglobulin Productsmentioning

confidence: 99%

SARS-CoV-2 Omicron: evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

Aggarwal

Stella²,

Walker

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Casirivimab, Imdevimab, Bamlanivimab, Cilgavimab, and Ab-3467 did not neutralize at the highest concentrations tested (Table 2 The Omicron variant contains several mutations at RBD sites previously thought to be highly conserved that are the target of antibody therapeutics. For example, S371L, S373P, and S375F form part of the class 4 epitope, affecting previously described class 4 antibodies such as Ab-3467 that broadly neutralize sarbecoviruses 7,8 . Additional mutations unique to Omicron at sites 417, 440, 446, and 493 are likely to contribute to the lack of the neutralisation of other therapeutic antibodies.…”

Section: Sotrovimab Retains Activity Against Omicronmentioning

confidence: 92%

SARS-CoV-2 Omicron: evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

Aggarwal

Stella

Walker

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

From late 2020 the world observed the rapid emergence of many distinct SARS-CoV-2 variants. At the same time, pandemic responses resulted in significant global vaccine rollouts that have now significantly lowered Covid-19 hospitalisation and mortality rates in the developed world. Unfortunately, in late 2021, the variant Omicron (B.1.1.529) emerged and it eclipsed the other variants of concern (VOC) in its number of Spike polymorphisms, and its ability to compete with and displacement of the dominant VOC Delta. Herein we accessed the impact of Omicron to humoral neutralisation in vaccinated, convalescent cohorts, in concentrated human IgG from thousands of plasma donors and also alongside many clinically used monoclonal antibodies. Overall, we observed a 17 to 22 fold drop in neutralisation titres across all donors that reached a titre to Omicron. Concentrated pooled human IgG from convalescent and vaccinated donors had greater breadth but was still reduced by 16-fold. In all therapeutic antibodies tested, significant neutralization was only observed for Sotrovimab, with other monoclonals unable to neutralize B.1.1.529.

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“…Mucosal IgA reduces colonisation of the mucosa by other respiratory pathogens 2 , including when induced by i.n vaccination 30,40 . There is scope to explore the addition of de ned Spike epitopes to the vaccine that may induce cross-reactive nAb against SARS-CoV-2 variants, or other pathogenic coronaviruses 41 . Mucosal vaccination also increased lung Spike-speci c CD4 + T-cell responses (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mucosal TLR2-activating protein-based vaccination induces potent pulmonary immunity and protection against SARS-CoV-2 in mice

Ashhurst

Johansen

Maxwell

et al. 2022

Preprint

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Current vaccines against SARS-CoV-2 substantially reduce mortality, but protection against infection is less effective. Enhancing immunity in the respiratory tract, via mucosal vaccination, may provide protection against infection and minimise viral spread. We tested a novel subunit vaccine in mice, consisting of SARS-CoV-2 Spike protein with a TLR2-stimulating adjuvant, delivered to mice parenterally or mucosally. Both routes of vaccination induced substantial neutralising antibody (nAb) titres, however, mucosal vaccination uniquely generated anti-Spike IgA, increased nAb in the serum and airways, and increased lung CD4+ T-cell responses. TLR2 is expressed by respiratory epithelia and immune cells. Using TLR2 deficient chimeric mice, we determined that TLR2 expression in either compartment facilitated early innate responses to mucosal vaccination. By contrast, TLR2 on hematopoietic cells was essential for optimal lung-localised, antigen-specific responses. In a K18-hACE2 mice, vaccination provided complete protection against disease and sterilising lung immunity against SARS-CoV-2. These data support mucosal vaccination as a strategy to improve protection in the respiratory tract against SARS-CoV-2 and other respiratory viruses.

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Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability

Cited by 47 publications

References 78 publications

SARS-CoV-2 Omicron: evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

SARS-CoV-2 Omicron: evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

SARS-CoV-2 Omicron: evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

Mucosal TLR2-activating protein-based vaccination induces potent pulmonary immunity and protection against SARS-CoV-2 in mice

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