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

Abstract

Throughout the last several decades, vaccination has been key to prevent and eradicate infectious diseases. However, many pathogens (e.g., respiratory syncytial virus [RSV], influenza, dengue, and others) have resisted vaccine development efforts, largely because of the failure to induce potent antibody responses targeting conserved epitopes. Deep profiling of human B cells often reveals potent neutralizing antibodies that emerge from natural infection, but these specificities are generally subdominant (i.e., are present in low titers). A major challenge for next-generation vaccines is to overcome established immunodominance hierarchies and focus antibody responses on crucial neutralization epitopes. Here, we show that a computationally designed epitope-focused immunogen presenting a single RSV neutralization epitope elicits superior epitope-specific responses compared to the viral fusion protein. In addition, the epitope-focused immunogen efficiently boosts antibodies targeting the palivizumab epitope, resulting in enhanced neutralization. Overall, we show that epitope-focused immunogens can boost subdominant neutralizing antibody responses in vivo and reshape established antibody hierarchies.

Convergent selection in antibody repertoires is revealed by deep learning

“…We show that our deep generative model allows us to exhaustively 132 sample from the naturally occurring sequence space of antibody repertoires, resulting in the in silico 133 generation of antibody variants that retain antigen-binding, a procedure that could be used for engineering 134 antibodies with desired therapeutic development properties 25 . Detection of convergent patterns by deep 135 learning may also enable the discovery of functional and protective antibodies in patients with unique 136 immunological phenotypes (e.g., elite neutralizers of HIV), which could be exploited as immunodiagnostics, 137 therapeutic antibodies or for vaccine immunogen design 21,[26][27][28] . all antigens, sequential injections were interspaced by three weeks.…”

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

“…Protein design has sparked hopes in the field of rational vaccinology, particularly to elicit targeted neutralizing antibody (nAb) responses (9,13). Although many potent nAbs have been identified and structurally characterized in complex with their target antigens, the design of immunogens that elicit precise and focused antibody responses remains a major challenge (14,15).…”

“…The difficulty in developing immunogens that can elicit antibodies specific for a restricted subset of epitopes on a single protein continues to be a critical barrier to rational vaccine design. Previous studies have sought to elicit epitope-specific responses using peptidebased approaches (25) or epitope scaffolds (9,13,(26)(27)(28). Leveraging computational design, the antigenic site II of the RSV fusion protein (RSVF), a linear helix-turn-helix motif, was transplanted onto a heterologous protein scaffold, which was shown to elicit nAbs in nonhuman primates (NHPs) after repeated boosting immunizations (9).…”

Hyper-Enriched Anti-RSV Immunoglobulins Nasally Administered: A Promising Approach for Respiratory Syncytial Virus Prophylaxis

“…The efficacy of our anti-RSV Ig could be improved by using the stabilized preF DS-Cav1 as an affinity ligand ( 17 ). An even better approach would be to use epitope-scaffold mimicking the 3D-structure of potent neutralizing F-RSV epitopes ( 27 , 28 ). This latest strategy would ascertain to eliminate from the anti-RSV-Igs, the non-neutralizing antibodies possibly mediating disease enhancement ( 29 ).…”