Structure-based immunogen design — leading the way to the new age of precision vaccines

Sesterhenn, Fabian; Bonet, Jaume; Correia, Bruno E.

doi:10.1016/j.sbi.2018.06.002

Cited by 23 publications

(22 citation statements)

References 53 publications

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“…De novo protein design enables the precise induction of RSV-neutralizing antibodies Fabian Sesterhenn 1,2 *, Che Yang 1,2 *, Jaume Bonet 1,2 †, Johannes T. Cramer 3 †, Xiaolin Wen 4 , Yimeng Wang 5 , Chi-I Chiang 5 , Luciano A. Abriata 1,2 , Iga Kucharska 6,7 , Giacomo Castoro 3 , Sabrina S. Vollers 1,2 ‡, Marie Galloux 8 , Elie Dheilly 9 , Stéphane Rosset 1,2 , Patricia Corthésy 1,2 , Sandrine Georgeon 1,2 , Mélanie Villard 1,2 , Charles-Adrien Richard 8 , Delphyne Descamps 8 , Teresa Delgado 10 , Elisa Oricchio 9 , Marie-Anne Rameix-Welti 11 , Vicente Más 10 , Sean Ervin 12 , Jean-François Eléouët 8 , Sabine Riffault 8 , John T. Bates 13 , Jean-Philippe Julien 6,7 , Yuxing Li 5,14 , Theodore Jardetzky 4 , Thomas Krey 3,15,16,17,18 , Bruno E. Correia 1,2 § De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge.…”

Section: Vaccinologymentioning

confidence: 99%

De novo protein design enables the precise induction of RSV-neutralizing antibodies

Sesterhenn

Yang

Bonet

et al. 2020

Science

Self Cite

165

153

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De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a protein design algorithm called TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. In both mice and nonhuman primates, cocktails of three de novo–designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused preexisting antibody responses toward defined neutralization epitopes. Overall, our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs.

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Section: Vaccinologymentioning

confidence: 99%

De novo protein design enables the precise induction of RSV-neutralizing antibodies

Sesterhenn

Yang

Bonet

et al. 2020

Science

Self Cite

165

153

View full text Add to dashboard Cite

show abstract

“…A recent approach in vaccine design is to use structural methods to understand how critical protective monoclonal antibodies bind to a vaccine target and to then design a synthetic protein which recapitulates the structural features of the antibody epitope (22,23). This has been used in the past to design novel vaccine components and to specifically re-elicit broadly inhibitory antibodies through immunization (24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…A recent advance in structure-guided immunogen design is an approach in which structures are determined for pathogen surface proteins in complex with antibodies with protective or broadly-neutralising properties, followed by the grafting of the epitopes of these antibodies onto smaller scaffolds (22,23). In a number of cases, this has allowed the development of smaller immunogens which can specifically elicit the production of antibodies with desirable properties (24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Structure-guided design of a synthetic mimic of an EPCR-binding PfEMP1 protein

Cky

Turner

et al. 2019

Preprint

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Structure-guided vaccine design provides a route to elicit a focused immune response against the most functionally important regions of a pathogen surface. This can be achieved by identifying epitopes for neutralizing antibodies through structural methods and recapitulating these epitopes by grafting their core structural features onto smaller scaffolds. In this study, we have conducted a modified version of this protocol. We focused on the PfEMP1 protein family found on the surfaces of erythrocytes infected with Plasmodium falciparum. A subset of PfEMP1 proteins bind to endothelial protein C receptor (EPCR), and their expression correlates with development of the symptoms of severe malaria. Structural studies revealed the PfEMP1 to present a helix-kinked-helix motif which forms the core of the EPCR binding site. Using Rosetta-based design we successfully grafted this motif onto a three-helical bundle scaffold. We show that this synthetic binder interacts with EPCR with nanomolar affinity and adopts the expected structure. We also assessed its ability to bind to antibodies found in immunized animals and in humans from malaria endemic regions. Finally, we tested its capacity to effectively elicit antibodies that prevent EPCR binding and analysed the degree of cross-reactivity of these antibodies across a diverse repertoire of EPCR-binding PfEMP1. This provides a case study of immunogen design, assessing the effect of designing a focused immunogen that contains the core features of a ligand binding site, rather than those of a neutralizing antibody epitope.

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“…Multiple strategies have been investigated to focus nAb responses on defined neutralization epitopes ( 47 ). Among them, epitope-scaffolds have been shown to elicit RSV site Il-specific, neutralizing antibody responses in naïve non-human primates.…”

Section: Discussionmentioning

confidence: 99%

Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen

Sesterhenn

Galloux

Vollers

et al. 2018

Preprint

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22Throughout the last decades, vaccination has been key to prevent and eradicate 23 infectious diseases. However, many pathogens (e.g. respiratory syncytial virus (RSV), 24 influenza, dengue and others) have resisted vaccine development efforts, largely due 25 to the failure to induce potent antibody responses targeting conserved epitopes. Deep 26 profiling of human B-cells often reveals potent neutralizing antibodies that emerge 27 from natural infection, but these specificities are generally subdominant (i.e., are 28 present in low titers). A major challenge for next-generation vaccines is to overcome 29 established immunodominance hierarchies and focus antibody responses on crucial 30 neutralization epitopes. Here, we show that a computationally designed epitope-31 focused immunogen presenting a single RSV neutralization epitope elicits superior 32 epitope-specific responses compared to the viral fusion protein. In addition, the 33 epitope-focused immunogen efficiently boosts antibodies targeting the Palivizumab 34 epitope, resulting in enhanced neutralization. Overall, we show that epitope-focused 35 immunogens can boost subdominant neutralizing antibody responses in vivo and 36 reshape established antibody hierarchies. 37 38 elicits superior levels of epitope-specific antibodies compared to prefusion RSVF in 130 naïve mice, indicating that the subdominance of a particular epitope can be altered 131 through its presentation in a distinct molecular context. Repeated immunizations with 132 RSVF failed to increase site II-specific antibodies, and instead further diluted site II 133 specific responses. In contrast, heterologous boosts with an epitope-scaffold 134 nanoparticle enhanced serum responses towards the subdominant site 135 II epitope, and the boosted antibodies neutralized RSV in vitro. For the first time, we 136 provide compelling evidence that synthetic immunogens comprising a single epitope 137 can efficiently redirect specificities in bulk antibody responses in vivo and enhance 138 subdominant neutralizing antibody responses. Such strategy may present an 139

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Structure-based immunogen design — leading the way to the new age of precision vaccines

Cited by 23 publications

References 53 publications

De novo protein design enables the precise induction of RSV-neutralizing antibodies

De novo protein design enables the precise induction of RSV-neutralizing antibodies

Structure-guided design of a synthetic mimic of an EPCR-binding PfEMP1 protein

Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen

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