DNA origami vaccines program antigen-focused germinal centers.

Area of Science:

• Immunology
• Vaccine Development
• Structural Biology

Background:

• Generating broadly neutralizing antibodies (bnAbs) against HIV requires priming rare precursor B cells in germinal centers (GCs).
• Existing multivalent immunogens on protein nanoparticles can elicit off-target B cell responses, potentially limiting bnAb precursor expansion.
• DNA origami-based virus-like particles (DNA-VLPs) offer a novel scaffold for immunogen display.

Purpose of the Study:

• To design and evaluate DNA-VLPs displaying a germline-targeting HIV envelope immunogen.
• To assess the ability of DNA-VLPs to enhance the expansion of bnAb precursor B cells compared to protein nanoparticles.
• To determine if minimizing scaffold-specific B cell responses improves bnAb priming.

Main Methods:

• Rational design of DNA-VLPs displaying a germline-targeting HIV envelope protein.
• Immunization of a humanized mouse model.
• Analysis of germinal center B cell populations and bnAb-lineage B cell expansion.
• Comparison with a state-of-the-art clinical protein nanoparticle.

Main Results:

• DNA-VLPs elicited no detectable scaffold-specific antibody responses.
• DNA-VLPs increased the expansion of epitope-specific GC B cells relative to off-target B cells.
• DNA-VLPs enhanced the expansion of bnAb-lineage B cells in a CD4 binding site priming model.

Conclusions:

• Minimizing off-target immune responses is crucial for effective bnAb priming.
• DNA-VLPs represent a promising vaccine platform for enhancing bnAb precursor cell expansion.
• This approach could lead to more effective HIV vaccines by improving the generation of bnAbs.