DNA origami vaccines program antigen-focused germinal centers

Area of Science:

• Immunology
• Vaccine Development
• Structural Biology

Background:

• Germinal centers (GCs) are crucial for vaccine-induced antibody responses.
• Generating broadly neutralizing antibodies (bnAbs) against HIV requires expansion of rare precursor B cells.
• Protein scaffolds used for multivalent immunogen display can elicit unwanted antibody responses.

Purpose of the Study:

• To design and evaluate DNA origami virus-like particles (VLPs) for optimal display of HIV Env immunogens.
• To assess the capacity of DNA-VLPs to enhance germinal center B cell responses, specifically targeting subdominant bnAb precursors.
• To compare the efficacy of DNA-VLPs against protein nanoparticle platforms in preclinical models.

Main Methods:

• Rational design of T-independent DNA-VLPs displaying the germline-targeting HIV Env immunogen (eOD-GT8).
• Incorporation of T cell help motifs within the DNA-VLP structure.
• Preclinical evaluation in mouse models to assess GC B cell expansion and antibody precursor frequencies.
• Comparison with a clinical-stage protein nanoparticle vaccine.

Main Results:

• DNA-VLPs significantly increased frequencies of epitope-specific GC B cells compared to protein nanoparticles.
• Optimized DNA-VLPs promoted GC responses focused on the target antigen.
• A single immunization with DNA-VLPs rapidly expanded subdominant bnAb precursor B cells for HIV.
• Avoidance of scaffold-specific responses augmented the priming of bnAb precursor B cells.

Conclusions:

• DNA-VLPs represent a promising platform for enhancing vaccine-induced B cell responses against challenging pathogens like HIV.
• Eliminating scaffold immunogenicity improves the expansion of desired antibody precursor populations.
• DNA-VLPs facilitate focused GC responses and expansion of rare, subdominant B cell precursors.