Defining bottlenecks and opportunities for Lassa virus neutralization by structural profiling of vaccine-induced polyclonal antibody responses.

Autor:	Brouwer PJM; Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA., Perrett HR; Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA., Beaumont T; Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam 1105 AZ, the Netherlands., Nijhuis H; Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam 1105 AZ, the Netherlands., Kruijer S; Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam 1105 AZ, the Netherlands., Burger JA; Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam 1105 AZ, the Netherlands., Lee WH; Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA., Müller-Kraüter H; Institute of Virology, Philipps University Marburg, 35043 Marburg, Germany., Sanders RW; Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam 1105 AZ, the Netherlands.; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA., Strecker T; Institute of Virology, Philipps University Marburg, 35043 Marburg, Germany., van Gils MJ; Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam 1105 AZ, the Netherlands., Ward AB; Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA.; Lead contact.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 23. Date of Electronic Publication: 2023 Dec 23.
DOI:	10.1101/2023.12.21.572918
Abstrakt:	Lassa fever continues to be a major public health burden in endemic countries in West Africa, yet effective therapies or vaccines are lacking. The isolation of potent and protective neutralizing antibodies against the Lassa virus glycoprotein complex (GPC) justifies the development of vaccines that can elicit strong neutralizing antibody responses. However, Lassa vaccines candidates have generally been unsuccessful in doing so and the associated antibody responses to these vaccines remain poorly characterized. Here, we establish an electron-microscopy based epitope mapping pipeline that enables high-resolution structural characterization of polyclonal antibodies to 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 which involve epitopes of the GPC-C, GPC-A, and GP1-A competition clusters. Furthermore, by identifying previously undescribed immunogenic off-target epitopes, we expose 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. Competing Interests: Declaration of interests The authors declare no competing interests.
Databáze:	MEDLINE
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