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Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers

Cohen, Alexander A. and Yang, Zhi and Gnanapragasam, Priyanthi N. P. and Ou, Susan and Dam, Kim-Marie A. and Wang, Haoqing and Bjorkman, Pamela J. (2021) Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers. PLoS ONE, 16 (3). Art. No. e0247963. ISSN 1932-6203. PMCID PMC7932532. https://resolver.caltech.edu/CaltechAUTHORS:20200121-113054457

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Abstract

Current influenza vaccines do not elicit broadly protective immune responses against multiple strains. New strategies to focus the humoral immune response to conserved regions on influenza antigens are therefore required for recognition by broadly neutralizing antibodies. It has been suggested that B-cells with receptors that recognize conserved epitopes would be preferentially stimulated through avidity effects by mosaic particles presenting multiple forms of a variable antigen. We adapted SpyCatcher-based platforms, AP205 virus-like particles (VLPs) and mi3 nanoparticles (NPs), to covalently co-display SpyTagged hemagglutinin (HA) trimers from group 1 and group 2 influenza A strains. Here we show successful homotypic and heterotypic conjugation of up to 8 different HA trimers to both VLPs and NPs. We characterized the HA-VLPs and HA-NPs by cryo-electron tomography to derive the average number of conjugated HAs and their separation distances on particles, and compared immunizations of mosaic and homotypic particles in wild-type mice. Both types of HA particles elicited strong antibody responses, but the mosaic particles did not consistently elicit broader immune responses than mixtures of homotypic particles. We conclude that covalent attachment of HAs from currently-circulating influenza strains represents a viable alternative to current annual influenza vaccine strategies, but in the absence of further modifications, is unlikely to represent a method for making a universal influenza vaccine.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1371/journal.pone.0247963DOIArticle
https://doi.org/10.1101/2020.01.18.911388DOIDiscussion Paper
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7932532/PubMed CentralArticle
ORCID:
AuthorORCID
Yang, Zhi0000-0001-8680-3784
Dam, Kim-Marie A.0000-0002-1416-4757
Wang, Haoqing0000-0003-0277-3018
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2021 Cohen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: September 13, 2020; Accepted: February 16, 2021; Published: March 4, 2021. We thank Mark Howarth (Oxford University) for providing plasmids and advice for VLP expression and purification, Jesse Bloom (Fred Hutchinson) for reagents for the infectious virus neutralization assays, Jost Vielmetter and Pauline Hoffmann at the Caltech Beckman Institute Protein Expression Center for help with protein production, Andrey Malyutin and Songye Chen (Caltech) for help with cryo-EM data collection, Rochelle Diamond and Jamie Tijerina at the Caltech Flow Cytometry/Cell Sorting Facility for help in the flow cytometry experiments and analysis, Jennifer Keeffe for implementation of influenza neutralization assays, Claudia Jette for help with figure preparation, Harry Gristick for VLP and NP images for figures, and Andrew Flyak, Jennifer Keeffe, and Claudia Jette for critical reading of the manuscript. EM was done in the Beckman Institute Resource Center for Transmission Electron Microscopy at Caltech. This work was supported in part by grants from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health to P.J.B. (1R01AI129784 and P50 AI150464). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0247963. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Author Contributions: Conceptualization: Alexander A. Cohen, Zhi Yang, Pamela J. Bjorkman. Data curation: Alexander A. Cohen. Formal analysis: Alexander A. Cohen, Zhi Yang, Pamela J. Bjorkman. Investigation: Alexander A. Cohen. Methodology: Alexander A. Cohen, Zhi Yang, Priyanthi N. P. Gnanapragasam, Susan Ou, Kim-Marie A. Dam, Haoqing Wang. Project administration: Alexander A. Cohen, Priyanthi N. P. Gnanapragasam, Susan Ou, Kim-Marie A. Dam. Resources: Alexander A. Cohen. Supervision: Pamela J. Bjorkman. Visualization: Alexander A. Cohen. Writing – original draft: Alexander A. Cohen, Pamela J. Bjorkman. Writing – review & editing: Alexander A. Cohen, Pamela J. Bjorkman.
Funders:
Funding AgencyGrant Number
NIH1R01AI129784
NIHP50 AI150464
Subject Keywords:Influenza virus, Hemagglutinin nanoparticles, Hemagglutinin VLPs, SpyCatcher, Nanoparticle vaccine, Immunizations, Cryo-electron tomography
Issue or Number:3
PubMed Central ID:PMC7932532
Record Number:CaltechAUTHORS:20200121-113054457
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200121-113054457
Official Citation:Cohen AA, Yang Z, Gnanapragasam PNP, Ou S, Dam K-MA, Wang H, et al. (2021) Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers. PLoS ONE 16(3): e0247963. https://doi.org/10.1371/journal.pone.0247963
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100815
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Jan 2020 19:38
Last Modified:26 Aug 2021 19:07

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