Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses

Ray, Rashmi; Nait Mohamed, Faez Amokrane; Maurer, Daniel P.; Huang, Jiachen; Alpay, Berk A.; Ronsard, Larance; Xie, Zhenfei; Han, Julianna; Fernandez-Quintero, Monica; Phan, Quynh Anh; Ursin, Rebecca L.; Vu, Mya; Kirsch, Kathrin H.; Prum, Thavaleak; Rosado, Victoria C.; Bracamonte-Moreno, Thalia; Okonkwo, Vintus; Bals, Julia; McCarthy, Caitlin; Nair, Usha; Kanekiyo, Masaru; Ward, Andrew B.; Schmidt, Aaron G.; Batista, Facundo D.; Lingwood, Daniel

doi:10.1016/j.immuni.2024.03.022

Cited by 3 publications

References 114 publications

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Conserved sites on the influenza H1 and H3 hemagglutinin recognized by human antibodies

Maurer,

Vu,

Ramos

et al. 2024

Preprint

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Monoclonal antibodies (mAbs) targeting the influenza hemagglutinin (HA) have the potential to be used as prophylactics or templates for next-generation vaccines that provide broad protection. Here, we isolated broad, subtype-neutralizing mAbs from human B cells targeting the H1 or H3 HA head as well as a unique mAb targeting the stem. The H1 mAbs target the previously defined lateral patch epitope on H1 HAs and recognize HAs from 1933 to 2021 in addition to a swine H1N1 virus with pandemic potential. Using directed evolution, we improved the neutralization potency of these H1 mAbs towards a contemporary H1 strain. Using deep mutational scanning of four antigenically distinct H1N1 viruses, we identified potential viral escape pathways. For the H3 mAbs we used cryo-EM to define the targeted epitopes: one mAb recognizes the side of the H3 head, accommodating the N133 glycan and a pocket underneath the receptor binding site. The other H3 mAb recognizes an epitope in the HA stem that overlaps with previously characterized mAbs, but with distinct antibody variable genes and mode of recognition. Collectively, these mAbs identify common sites recognized by broad, subtype-specific mAbs that may be elicited by next-generation vaccines.

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Conserved sites on the influenza H1 and H3 hemagglutinin recognized by human antibodies

Maurer,

Vu,

Ramos

et al. 2024

Preprint

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Functional and epitope specific monoclonal antibody discovery directly from immune sera using cryoEM

Ferguson,

Raghavan,

Peña Alzua

et al. 2024

Preprint

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Antibodies are crucial therapeutics, comprising a significant portion of approved drugs due to their safety and clinical efficacy. Traditional antibody discovery methods are labor-intensive, limiting scalability and high-throughput analysis. Here, we improved upon our streamlined approach combining structural analysis and bioinformatics to infer heavy and light chain sequences from electron potential maps of serum-derived polyclonal antibodies (pAbs) bound to antigens. Using ModelAngelo, an automated structure-building tool, we accelerated pAb sequence determination and identified sequence matches in B cell repertoires via ModelAngelo derived Hidden Markov Models (HMMs) associated with pAb structures. Benchmarking against results from a non-human primate HIV vaccine trial, our pipeline reduced analysis time from weeks to under a day with higher precision. Validation with murine immune sera from influenza vaccination revealed multiple protective antibodies. This workflow enhances antibody discovery, enabling faster, more accurate mapping of polyclonal responses with broad applications in vaccine development and therapeutic antibody discovery.

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Immunity and Protective Efficacy of a Plant-Based Tobacco Mosaic Virus-like Nanoparticle Vaccine against Influenza a Virus in Mice

Madapong,

Petro-Turnquist,

Webby

et al. 2024

Vaccines

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Background: The rapid production of influenza vaccines is crucial to meet increasing pandemic response demands. Here, we developed plant-made vaccines comprising centralized consensus influenza hemagglutinin (HA-con) proteins (H1 and H3 subtypes) conjugated to a modified plant virus, tobacco mosaic virus (TMV) nanoparticle (TMV-HA-con). Methods: We compared immune responses and protective efficacy against historical H1 or H3 influenza A virus infections among TMV-HA-con, HA-con protein combined with AddaVax™ adjuvant, and whole-inactivated virus vaccine (Fluzone®). Results: Immunogenicity studies demonstrated robust IgG, IgM, and IgA responses in the TMV-HA-con and HA-con protein vaccinated groups, with relatively low induction of interferon (IFN)-γ+ T-cell responses across all vaccinated groups. The TMV-HA-con and HA-con protein groups displayed partial protection (100% and 80% survival) with minimal weight loss following challenge with two H1N1 strains. The HA-con protein group exhibited 80% and 100% survival against two H3 strains, whereas the TMV-HA-con groups showed reduced protection (20% survival). The Fluzone® group conferred 20–100% survival against two H1N1 strains and one H3N1 strain, but did not protect against H3N2 infection. Conclusions: Our findings indicate that TMV-HA and HA-con protein vaccines with adjuvant induce protective immune responses against influenza A virus infections. Furthermore, our results underscore the potential of plant-based production using TMV-like nanoparticles for developing influenza A virus candidate vaccines.

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Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses

Cited by 3 publications

References 114 publications

Conserved sites on the influenza H1 and H3 hemagglutinin recognized by human antibodies

Conserved sites on the influenza H1 and H3 hemagglutinin recognized by human antibodies

Functional and epitope specific monoclonal antibody discovery directly from immune sera using cryoEM

Immunity and Protective Efficacy of a Plant-Based Tobacco Mosaic Virus-like Nanoparticle Vaccine against Influenza a Virus in Mice

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