Why the study?
Developing broadly effective pan-coronavirus countermeasures is an urgent priority, but whether the N-terminal domain is a viable target for universal vaccines and broadly neutralizing antibodies has been unclear, and many receptor binding domain-targeting antibodies are susceptible to viral escape.
Does prophylactic administration of broadly neutralizing antibodies TXG-0078 and CC24.2 prevent weight loss in ACE2 transgenic mice challenged with SARS-CoV-2?
Does prophylactic administration of broadly neutralizing antibodies TXG-0078 and CC24.2 prevent weight loss in ACE2 transgenic mice challenged with SARS-CoV-2?
The discovery of ultra-broad neutralizing antibodies TXG-0078 and CC24.2 provides potential templates for pan-coronavirus vaccine design and variant-resistant therapeutic cocktails.
Answers are grounded in this paper and cite their sources.
NTD may represent a viable target for pan-coronavirus vaccines and antibodies; leaves open clinical utility pending prospective validation.
Summary Development of vaccines and therapeutics that are broadly effective against known and emergent coronaviruses is an urgent priority. Current strategies for developing pan-coronavirus countermeasures have largely focused on the receptor binding domain ( RBD ) and S2 regions of the coronavirus Spike protein; it has been unclear whether the N-terminal domain ( NTD ) is a viable target for universal vaccines and broadly neutralizing antibodies ( Abs ). Additionally, many RBD-targeting Abs have proven susceptible to viral escape. We screened the circulating B cell repertoires of COVID-19 survivors and vaccinees using multiplexed panels of uniquely barcoded antigens in a high-throughput single cell workflow to isolate over 9,000 SARS-CoV-2-specific monoclonal Abs ( mAbs ), providing an expansive view of the SARS-CoV-2-specific Ab repertoire. We observed many instances of clonal coalescence between individuals, suggesting that Ab responses frequently converge independently on similar genetic solutions. Among the recovered antibodies was TXG-0078, a public neutralizing mAb that binds the NTD supersite region of the coronavirus Spike protein and recognizes a diverse collection of alpha- and beta-coronaviruses. TXG-0078 achieves its exceptional binding breadth while utilizing the same VH1-24 variable gene signature and heavy chain-dominant binding pattern seen in other NTD supersite-specific neutralizing Abs with much narrower specificity. We also report the discovery of CC24.2, a pan-sarbecovirus neutralizing mAb that targets a novel RBD epitope and shows similar neutralization potency against all tested SARS-CoV-2 variants, including BQ.1.1 and XBB.1.5. A cocktail of TXG-0078 and CC24.2 provides protection against in vivo challenge with SARS-CoV-2, suggesting potential future use in variant-resistant therapeutic Ab cocktails and as templates for pan-coronavirus vaccine design.
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Hurtado et al. (2023) studied SARS-CoV-2 (n=7). TXG-0078 and CC24.2 vs. ZIKV-1 control antibody was evaluated on Weight loss following SARS-CoV-2 challenge (p=≤0.05).
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