Design of Novel Antigens and Immunogens to Improve Influenza Vaccines

Abstract

Vaccinology has recently been heavily influenced by advances in structural biology that allow for detailed pathogenic insights, antibody characterization, and the redesign of antigens. Outside of vaccinology, advances in computational protein design have also been accelerating. The ability to design complex oligomeric proteins has been broadly expanded, leading to the design of self-assembling protein nanoparticles of similar sizes to viruses with extensive applications in vaccinology. Here, I present a collection of stories that explore the intersection of vaccine discovery and designed protein self-assembly, involving the translation of designed protein nanoparticles for vaccine development and the use of Rosetta modeling to redesign viral antigens to favor desirable oligomeric or conformational states. The described work most heavily focuses on applications towards influenza vaccines, including the use of particulate display of hemagglutinin (HA) to simultaneously target its head and stem domains, the conformational stabilization of neuraminidase (NA), and the tailored particulate display of the HA head domain in distinct conformational states and/or geometric spacings to alter its immunogenicity. Additional stories are presented involving SARS-CoV-2 and human papillomavirus (HPV), which, respectively, explore stabilization of the SARS-CoV-2 receptor binding domain (RBD) and the presentation of linear peptide HPV epitopes on different designed nanoparticles in diverse arrangements and valencies.