Persistent Antibody Clonotypes Dominate the Serum Response to Influenza over Multiple Years and Repeated Vaccinations

Lee, Jiwon; Paparoditis, Philipp; Horton, Andrew P.; Frühwirth, Alexander; McDaniel, Jonathan R.; Jung, Jiwon; Boutz, Daniel R.; Hussein, Dania A.; Tanno, Yuri; Pappas, Leontios; Ippolito, Gregory C.; Corti, Davide; Lanzavecchia, Antonio; Georgiou, George

doi:10.1016/j.chom.2019.01.010

Cited by 104 publications

(103 citation statements)

References 58 publications

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“…An important pathogen from this category is influenza, where the challenge is to overcome immunodominance hierarchies (37), which have been established during repeated natural infections, and that favour strain-specific antibody specificities, rather than cross-protecting nAbs found in the hemagglutinin stem region (38). The ability to selectively boost subdominant nAbs targeting defined, broadly protective epitopes that are surrounded by strain-specific epitopes could overcome long-standing challenges in vaccine development, given that crossneutralizing antibodies can persist for years once elicited (39). A tantalizing future application for epitope-focused immunogens could marry this technology with engineered components of the immune system, which could be used to stimulate antibody production of adoptively transferred, engineered B-cells that express monoclonal therapeutic antibodies in vivo (40).…”

Section: Resultsmentioning

confidence: 99%

“…Four sequences were experimentally tested (S0_1. [37][38][39][40]. The best variant according to binding, S0_1.39, bound with 5 nM affinity to antibody D25, and, importantly, also gained binding to the 5C4 antibody (KD = 5 nM).…”

Section: Computational Design Of Template-based Epitope-focused Immunmentioning

confidence: 98%

“…An illustrative example on how a template-based design approach can fail to fulfil these criteria is the comparison between the quaternary environment of the site 0 epitope in preRSVF and S0_1. 39 showing that this topology does not mimic such environment, albeit allowing the binding of several monoclonal antibodies ( Fig S6).…”

Section: Figmentioning

confidence: 99%

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De novo protein design enables precise induction of functional antibodies in vivo

Sesterhenn

Yang

Cramer

et al. 2019

Preprint

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De novo protein design has been increasingly successful in expanding beyond nature's sequence and structural space. However, most de novo designed proteins lack biological function, in part due to the structural complexity required for functional purposes. An important domain where protein design has raised expectations was on the induction of precise antibody responses that may lead to improved vaccines. Here, we showcase two computational design approaches to stabilize irregular and discontinuous binding motifs in de novo designed immunogens and tested them for the induction of respiratory syncytial virus neutralizing antibodies in vivo. The designs mimic the native conformations of the neutralization epitopes with sub-angstrom accuracy. In vivo, cocktail formulations of the immunogens induce robust neutralizing serum responses targeting three epitopes, and re-focus pre-existing antibody responses towards bona fide neutralization epitopes. Our work provides a blueprint for epitope-centric vaccine design for pathogens that have frustrated traditional vaccine development efforts, and a general methodological pipeline to create novel proteins with functional sites within tailored protein topologies.Recently, Correia and colleagues (12) have shown that computationally designed immunogens could elicit epitope-specific responses. The RSVF antigenic site II, a linear helixturn-helix motif, was transplanted onto a heterologous protein scaffold, which elicited nAbs in non-human-primates (NHPs) after repeated boosting immunizations. Despite being a proofof-principle for the induction of functional antibodies using a computationally designed immunogen, several major caveats emerged; namely, the lack of applicability of the computational approach to structurally complex epitopes, and the inconsistent neutralization titers observed in the immunogenicity studies.

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Section: Resultsmentioning

confidence: 99%

Section: Computational Design Of Template-based Epitope-focused Immunmentioning

confidence: 98%

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De novo protein design enables precise induction of functional antibodies in vivo

Sesterhenn

Yang

Cramer

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Many studies have analyzed the distributions of the number of SHMs across all individual antibodies (Wendel et al, 2017;Lee et al, 2019) or across all clonal lineages (Ellebedy et al, 2016;Nielsen et al, 2019;Horns et al, 2019) in an antibody repertoire. These approaches, while valuable, face the difficulty of finding the closest D genes and identifying non-genomic insertions, leading to complications in deriving SHMs in CDR3s.…”

Section: Methodsmentioning

confidence: 99%

IgEvolution: clonal analysis of antibody repertoires

Safonova

Pevzner

2019

Preprint

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Constructing antibody repertoires is an important error-correcting step in analyzing immunosequencing datasets that is important for reconstructing evolutionary (clonal) development of antibodies. However, the state-of-the-art repertoire construction tools typically miss low-abundance antibodies that often represent internal nodes in clonal trees and are crucially important for clonal tree reconstruction. Thus, although repertoire construction is a prerequisite for follow up clonal tree reconstruction, the existing repertoire reconstruction algorithms are not well suited for this task. Since clonal analysis has the potential to reveal errors in the constructed repertoires and contribute to constructing more accurate repertoires, we advocate a tree-guided construction of antibody repertoires that combines error correction and clonal reconstruction as interconnected (rather than independent) tasks. We developed the IgEvolution algorithm for simultaneous repertoire and clonal tree reconstruction and applied it for analyzing multiple immunosequencing datasets representing antigen-specific immune responses. We demonstrate that analysis of clonal trees reveals highly mutable positions that correlate with antigen-binding sites and light-chain contacts in crystallized antibody-antigen complexes. We further demonstrate that this analysis leads to a new approach for identifying complementarity determining regions (CDRs) in antibodies.

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“…It has become clear that exposure to viruses that differ significantly from those circulating, can 309 select responses to epitopes in both HA and NA that are shared between the incoming virus 310 and the seasonal viruses in circulation, derived from the memory B cell population (Henry et 311 al., 2018). While antibodies against new epitopes can also be generated, even in the elderly 312 , it appears that they are initially at a disadvantage but may overtake and 313 become dominant with time (Lee et al, 2019, Henry et al, 2019. It is these high affinity and 314 relatively specific antibodies that are mainly detected in serological surveys (Fonville et al,…”

mentioning

confidence: 99%

Broadly inhibiting anti-neuraminidase monoclonal antibodies induced by trivalent influenza vaccine and H7N9 infection in humans

Rijal

Wang

Tan

et al. 2019

Preprint

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24 original antigenic sin, H7N9 25 26 Highlights of the paper 27 • Antibodies that inhibit influenza viruses with N1 neuraminidase (NA), with broad reactivity 28 for viruses isolated between 1918-2018, can be isolated from human recipients of 29 seasonal influenza vaccine 30 • Antibodies targeting N1 NA of human seasonal H1N1 viruses can cross-react with a 31 variety of avian N1 neuraminidases 32 • Acute H7N9 infection can recall memory B cells to N1 NA and elicit cross-reactive 33 antibodies to the group 1 N1 and group 2 N9 NAs 34 • Antibodies to N1 NA with this broad reactivity protect against lethal virus challenge 35 36 Abstract 37The majority of antibodies induced by influenza neuraminidase (NA), like those against 38 hemagglutinin (HA), are relatively specific to viruses isolated within a limited time-window as 39 seen in serological studies and the analysis of many murine monoclonal antibodies. We report 40 three broadly reactive human monoclonal antibodies (mAbs) targeting N1 NA. Two were 41 isolated from a young adult vaccinated with trivalent influenza vaccine (TIV), which inhibited 42 N1 NA from viruses isolated from human over a period of a hundred years. The third antibody 43 isolated from a child with acute mild H7N9 infection inhibited both group 1 N1 and group 2 N9 44 2 NAs. In addition, the antibodies cross-inhibited the N1 NAs of highly pathogenic avian H5N1 45 influenza viruses. These antibodies are protective in prophylaxis against seasonal H1N1 46 viruses in mice. This study demonstrates that human antibodies to N1 NA with exceptional 47 cross-reactivity can be recalled by vaccination and highlights the importance of standardizing 48 the NA antigen in seasonal vaccines to offer optimal protection. 50Importance 51 Antibodies to the influenza NA can provide protection against influenza disease. Analysis of 52 human antibodies to NA lags behind that for HA. We show that human monoclonal antibodies 53 against NA induced by vaccination and infection can be very broadly reactive and able to 54 inhibit a wide spectrum of N1 NAs between 1918 and 2018. This suggests that antibodies to 55

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Persistent Antibody Clonotypes Dominate the Serum Response to Influenza over Multiple Years and Repeated Vaccinations

Cited by 104 publications

References 58 publications

De novo protein design enables precise induction of functional antibodies in vivo

De novo protein design enables precise induction of functional antibodies in vivo

IgEvolution: clonal analysis of antibody repertoires

Broadly inhibiting anti-neuraminidase monoclonal antibodies induced by trivalent influenza vaccine and H7N9 infection in humans

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