Barney S. Graham, Jean-François Eléouët, Patricia Corthésy, Bruno E. Correia, Pablo Gainza, Che Yang, Fabian Sesterhenn, Marie Galloux, Marie-Anne Rameix-Welti, Sabrina Vollers, Stéphane Rosset, Delphyne Descamps, Jaume Bonet, Sabine Riffault, Man Chen, Simon Friedensohn, Sai T. Reddy, Lucia Csepregi, Institute of Bioengineering [Lausanne, Suisse], Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics (SIB), Swiss Institute of Bioinformatics, Molecular Immunology and Virology (VIM-UR892), Institut National de la Recherche Agronomique (INRA), Department of Biosystems Science and Engineering [ETH Zürich] (D-BSSE), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Viral Pathogenesis Laboratory [Bethesda, MD, États-Unis], Vaccine Research Center [Bethesda, MD, États-Unis], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH)-National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Infection et inflammation chronique (2I), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Laboratoire de Microbiologie [Boulogne-Billancourt], Hôpital Ambroise Paré, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), FS was supported by the Swiss initiative for systems biology (SystemsX.ch). BEC was supported by the European Research Council (Starting grant - 716058) and the Swiss National Science Foundation (Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, 310030_163139)., Bodescot, Myriam, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Ambroise Paré [AP-HP], and Université de Lausanne (UNIL)
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., A computationally designed epitope-focused immunogen presenting a single neutralization epitope from Respiratory Syncytial Virus elicits superior epitope-specific responses compared to the viral fusion protein. Furthermore, epitope-focused immunogens can reshape established antibody hierarchies., Author summary Vaccines are one of the most valuable instruments to prevent and control infectious diseases. Their primary correlate of protection is the level of induction of neutralizing antibodies that target critical antigenic sites and thereby block infection. Natural infections with pathogens such as the respiratory syncytial virus (RSV) or influenza induce a broad repertoire of antibodies that target multiple epitopes. Among those, functional antibodies with key specificities are often subdominant (present in low titers). Thus, a central goal for vaccine development is to focus antibody responses on such neutralization epitopes. Here, we show that a computationally designed, epitope-focused immunogen mimicking an important RSV neutralization epitope (site II) can focus antibodies onto this well-defined epitope. In a scenario of preexisting immunity, in which site II–specific antibodies were subdominant, the epitope-focused immunogen selectively boosted site II–specific antibodies, resulting in an increased viral neutralization through this epitope. We propose that rationally designed immunogens spotlighting defined epitopes have a unique potential to focus antibody responses on functionally conserved sites in cases of preexisting immunity. Our results have broad implications for vaccine design as a strategy to steer preexisting antibody responses away from immunodominant, variable epitopes and toward subdominant epitopes that confer broad and potent neutralization.