Role of Nanoscale Antigen Organization on B-cell Activation Probed Using DNA Origami
August 15, 2020
Volume and Number
15(8):716-723. doi: 10.1038/s41565-020-0719-0. Epub 2020 Jun 29
Veneziano R, Moyer TJ, Stone MB, Wamhoff EC, Read BJ, Mukherjee S, Shepherd TR, Das J, Schief WR, Irvine DJ, Bathe M
Vaccine efficacy can be increased by arraying immunogens in multivalent form on virus-like nanoparticles to enhance B-cell activation. However, the effects of antigen copy number, spacing and affinity, as well as the dimensionality and rigidity of scaffold presentation on B-cell activation remain poorly understood. Here, we display the clinical vaccine immunogen eOD-GT8, an engineered outer domain of the HIV-1 glycoprotein-120, on DNA origami nanoparticles to systematically interrogate the impact of these nanoscale parameters on B-cell activation in vitro. We find that B-cell signalling is maximized by as few as five antigens maximally spaced on the surface of a 40-nm viral-like nanoparticle. Increasing antigen spacing up to ~25–30 nm monotonically increases B-cell receptor activation. Moreover, scaffold rigidity is essential for robust B-cell triggering. These results reveal molecular vaccine design principles that may be used to drive functional B-cell responses.
- Using DNA origami as a platform for controlling the spatial representation of eOD-GT8 antigens, we identify here several design criteria maximizing early B-cell triggering.
- Future modeling studies may be combined with advanced super-resolution and single-molecule imaging to explore alternative, competing hypotheses such as the presence of actin ‘corrals’ that may also contribute to explaining these experimental observations.
- The relative roles of monomeric versus dimeric binding to individual IgM-BCRs based on the spatial tolerance of IgM would also be interesting to explore with single-particle-based, stochastic models.
- Affinity is also an important determination of BCR responses. We reiterate that the affinity between germline VRCO1 and eOD-GT8 is in the subnanomolar range, placing this system in the regime of mature IgM-BCR antigen affinities, rather than naive affinities.
- In the case of lower-affinity interactions, as explored for the eOD-GT5 and model peptide antigens, higher multivalency might play a more prominent role in B-cell activation.
- It’s been suggested that the low number of Env viral spikes on the viral surface of HIV may help it to evade detection by the immune system.
- Notwithstanding, for the purpose of the rational design of molecular vaccines to trigger robust B-cell responses, DNA origami has offered crucial insight into the spatial relationships between immunogens.
- This may be generalized to other viral pathogens such as SARS-CoV and Zika, and offered important foundations for the rational design of protein-based and other vaccine platforms.