Structural basis for potent neutralization of human respirovirus type 3 by protective single-domain camelid antibodies

Nature Communications, vol. 15, pp. 5458

Abstract

Respirovirus 3 is a leading cause of severe acute respiratory infections in vulnerable human populations. Entry into host cells is facilitated by the attachment glycoprotein and the fusion glycoprotein (F). Because of its crucial role, F represents an attractive therapeutic target. Here, we identify 13 F-directed heavy-chain-only antibody fragments that neutralize recombinant respirovirus 3. High-resolution cryo-EM structures of antibody fragments bound to the prefusion conformation of F reveal three distinct, previously uncharacterized epitopes. All three antibody fragments bind quaternary epitopes on F, suggesting mechanisms for neutralization that may include stabilization of the prefusion conformation. Studies in cotton rats demonstrate the prophylactic efficacy of these antibody fragments in reducing viral load in the lungs and nasal passages. These data highlight the potential of heavy-chain-only antibody fragments as effective interventions against respirovirus 3 infection and identify neutralizing epitopes that can be targeted for therapeutic development.

Authors 9

1. Nicole V. Johnson

   The University of Texas at Austin

   Affiliation as printed

   Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA

2. Revina C. van Scherpenzeel

   Janssen (Belgium)

   Affiliation as printed

   Janssen Infectious Diseases and Vaccines, 2340, Beerse, Belgium

3. Mark J. G. Bakkers Aachen Janssen Vaccines & Prevention BV

   Janssen (Netherlands)

   Affiliation as printed

   ForgeBio B.V., Amsterdam, The Netherlands

   Janssen Vaccines & Prevention BV, Leiden, The Netherlands

4. Ajit R. Ramamohan

   The University of Texas at Austin

   Affiliation as printed

   Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA

5. Daan van Overveld Aachen Janssen Vaccines & Prevention BV

   Janssen (Netherlands)

   Affiliation as printed

   Janssen Vaccines & Prevention BV, Leiden, The Netherlands

6. Lam Le Aachen Janssen Vaccines & Prevention BV

   Janssen (Netherlands)

   Affiliation as printed

   Janssen Vaccines & Prevention BV, Leiden, The Netherlands

7. Johannes P. M. Langedijk Aachen Janssen Vaccines & Prevention BV

   Janssen (Netherlands)

   Affiliation as printed

   ForgeBio B.V., Amsterdam, The Netherlands

   Janssen Vaccines & Prevention BV, Leiden, The Netherlands

8. Joost A. Kolkman

   Janssen (Belgium)

   Affiliation as printed

   Janssen Infectious Diseases and Vaccines, 2340, Beerse, Belgium

9. Jason S. McLellan corresponding

   The University of Texas at Austin

   Affiliation as printed

   Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA. jmclellan@austin.utexas.edu

   Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA