Vaccine design via antigen reorientation

Area of Science:

• Vaccinology
• Immunology
• Structural Biology

Background:

• Developing universal vaccines requires targeting conserved viral epitopes, such as the influenza hemagglutinin stem (HA-stem), away from variable regions like the HA-head.
• Current vaccine strategies often struggle to elicit immune responses focused on these conserved, immunogenic regions.

Purpose of the Study:

• To introduce and validate a novel antigen reorientation strategy for enhancing immune responses against conserved viral epitopes.
• To demonstrate the generalizability of this approach across different viral antigens, including influenza, Ebola, and SARS-CoV-2.

Main Methods:

• Site-specific insertion of aspartate residues to control antigen orientation and facilitate binding to alum adjuvants.
• Reorientation of H2 hemagglutinin (H2 HA) into an 'upside-down' configuration (reoH2HA) to enhance HA-stem exposure and immunogenicity.
• Assessment of neutralizing antibody responses and epitope mapping using Electron Microscopy Polyclonal Epitope Mapping (EMPEM).

Main Results:

• Antigen reorientation enhanced neutralizing antibody responses against Ebola, SARS-CoV-2, and influenza virus antigens.
• The reoriented H2 HA (reoH2HA) induced potent stem-directed antibodies.
• These antibodies demonstrated cross-reactivity against both group 1 and group 2 influenza A subtypes, as confirmed by EMPEM.

Conclusions:

• Antigen reorientation is a versatile strategy for designing epitope-focused vaccines.
• This approach can effectively direct immune responses toward conserved viral epitopes, potentially leading to broadly protective vaccines.
• The study provides a new platform for developing next-generation vaccines against highly variable viruses like influenza.