Outflanking immunodominance to target subdominant broadly neutralizing epitopes

Area of Science:

• Virology
• Immunology
• Vaccinology

Background:

• Antigenically variable viruses pose vaccination challenges due to antibody responses favoring variable epitopes.
• Influenza virus hemagglutinin (HA) head immunodominance hinders responses to the conserved stem region.
• Developing effective vaccines requires strategies to elicit broadly protective immunity against conserved viral components.

Purpose of the Study:

• To investigate the mechanisms underlying antibody response skewing in influenza hemagglutinin (HA).
• To identify strategies for enhancing immune responses to the conserved HA stem region.
• To explore implications for improving human influenza vaccination.

Main Methods:

• Investigated the role of physical attachment between HA head and stem on immunodominance.
• Assessed strategies to enhance stem immunogenicity, including stem-only constructs and altered local antigen concentration.
• Analyzed the impact of coimmunization on stem-specific antibody class switching.

Main Results:

• HA head immunodominance is dependent on its physical linkage to the stem.
• Stem-only constructs and increased local HA concentration significantly enhance stem immunogenicity.
• Coimmunization with full-length HA and stem impacts stem-antibody class switching.

Conclusions:

• Strategies targeting the physical structure and presentation of viral antigens can overcome immunodominance.
• Enhancing responses to conserved regions like the HA stem is achievable.
• Findings provide a roadmap for developing more effective influenza vaccines and vaccines against other variable viruses.