Defining bottlenecks and opportunities for Lassa virus neutralization by structural profiling of vaccine-induced polyclonal antibody responses
Philip J.M. Brouwer,
Hailee R. Perrett,
Tim Beaumont,
Haye Nijhuis,
Sabine Kruijer,
Judith A. Burger,
Ilja Bontjer,
Wen-Hsin Lee,
James A. Ferguson,
Martin Schauflinger,
Helena Müller-Kräuter,
Rogier W. Sanders,
Thomas Strecker,
Marit J. van Gils,
Andrew B. Ward
Affiliations
Philip J.M. Brouwer
Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA
Hailee R. Perrett
Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA
Tim Beaumont
Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands
Haye Nijhuis
Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands
Sabine Kruijer
Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands
Judith A. Burger
Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands
Ilja Bontjer
Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands
Wen-Hsin Lee
Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA
James A. Ferguson
Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA
Martin Schauflinger
Institute of Virology, Philipps University Marburg, 35043 Marburg, Germany
Helena Müller-Kräuter
Institute of Virology, Philipps University Marburg, 35043 Marburg, Germany
Rogier W. Sanders
Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA
Thomas Strecker
Institute of Virology, Philipps University Marburg, 35043 Marburg, Germany
Marit J. van Gils
Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands
Andrew B. Ward
Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA; Corresponding author
Summary: Lassa fever continues to be a major public health burden in West Africa, yet effective therapies or vaccines are lacking. The isolation of protective neutralizing antibodies against the Lassa virus glycoprotein complex (GPC) justifies the development of vaccines that can elicit strong neutralizing antibody responses. However, Lassa vaccine candidates have generally been unsuccessful at doing so, and the associated antibody responses to these vaccines remain poorly characterized. Here, we establish an electron microscopy-based epitope mapping workflow that enables high-resolution structural characterization of polyclonal antibodies to the GPC. By applying this method to rabbits vaccinated with a recombinant GPC vaccine and a GPC-derived virus-like particle, we reveal determinants of neutralization that involve epitopes of the GPC-A competition cluster. Furthermore, by identifying undescribed immunogenic off-target epitopes, we expose the challenges that recombinant GPC vaccines face. By enabling detailed polyclonal antibody characterization, our work ushers in a next generation of more rational Lassa vaccine design.
