Human antibody targeting of coronavirus spike S2 subunit is associated with protection mediated by Fc effector functions
Bibliographic record
Abstract
ABSTRACT Over the past two decades, betacoronaviruses (β-CoVs) have caused two epidemics and a pandemic and remain a high risk for future outbreaks through zoonotic transmissions, highlighting the need for broad biomedical countermeasures. Here, we describe a convalescent human monoclonal antibody (mAb 1871) that targets the S2 subunit of the coronavirus spike protein, with broad β-CoVs binding and sarbecovirus neutralization. Cryo-electron microscopy analysis revealed that mAb 1871 binds the upstream helix of the S2 subunit, interacting with partially conserved residues, providing a molecular basis for its cross-reactivity. Though less potent than receptor-binding domain-directed antibodies—approximately 500-fold lower neutralization potency than the emergency use authorized receptor-binding domain (RBD)-directed Pemgarda mAb against wild-type SARS-CoV-2—mAb 1871 provides protective efficacy in a mouse model. Notably, Fc effector functions are critical for its in vivo protection. This study further highlights the Fc dependence of S2-directed antibodies for in vivo protection and identifies a conserved epitope in the S2 subunit as a potential target of broad-β-CoVs countermeasures. IMPORTANCE Bats and pangolins are natural reservoirs of betacoronaviruses (β-CoVs) and continue to pose a significant risk for future outbreaks through zoonotic transmissions. This highlights the need for effective countermeasures to prevent future pandemics. While neutralizing antibodies targeting the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) received emergency use authorization, many have lost efficacy as the virus evolved, and authorizations have been revoked. In contrast to the S1 subunit, the spike protein S2 subunit is more conserved across β-CoVs, making it an attractive target for the development of broadly neutralizing antibodies. Here, we describe a human mAb that targets a conserved epitope in the S2 subunit, demonstrating broad β-CoV binding, sarbecovirus neutralization, and in vivo protection mediated by Fc effector functions in a mouse model. These findings have important implications for pan-β-CoVs therapeutics and vaccine development.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".