Vaccine design via antigen reorientation

Creating universal influenza vaccines is challenging due to the focus of immune responses on the variable head region of hemagglutinin (HA-head) rather than the conserved stem region (HA-stem). This study introduces a method to control antigen orientation using site-specific aspartate residue insertion, enhancing antigen binding to alum. This approach, tested on Ebola, SARS-CoV-2, and influenza antigens, consistently improved neutralizing antibody responses. Reorienting an H2 HA in an ‘upside-down’ configuration increased HA-stem exposure and immunogenicity, inducing stem-directed antibodies cross-reactive with group 1 and 2 influenza A subtypes. Electron microscopy polyclonal epitope mapping confirmed that the reoriented H2 HA elicited cross-reactive antibodies targeting group 2 HA-stems. Antigen reorientation is presented as a generalizable strategy for designing epitope-focused vaccines.

Duo Xu, Joshua J. Carter, Chunfeng Li, Ashley Utz, Payton A. B. Weidenbacher, Shaogeng Tang, Mrinmoy Sanyal, Bali Pulendran, Christopher O. Barnes, Peter S. Kim