Role of nanoscale antigen organization on B-cell activation probed using DNA origami

Abstract

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 displayed 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 found 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.

Conjugation of Native-Like HIV-1 Envelope Trimers onto Liposomes Using EDC/Sulfo-NHS Chemistry: Requirements and Limitations

“…A high density of Env trimers on the surface of liposomes is widely regarded as being critical to bring about the hypothesised benefits of particulate display of immunogens [ 4 , 5 , 7 , 8 ]. Recent studies on the role of nanoscale antigen organisation on the activation of B cells have, however, shed a new light on this much-debated aspect of molecular vaccine design [ 79 ].…”

“…Although several studies have shown that positively charged liposomes can indeed be delivered to lymph nodes, further research is required to assess whether their use within the context of nanoparticle-based HIV-1 vaccines is indicated/useful at all [ 81 , 82 ]. Recent studies on the role of nanoscale antigen organisation on the activation of B cells suggest B-cell signalling to be maximised by as few as five antigens rigidly displayed on the surface of 40-nm nanoparticles [ 79 ]. The low number of Env trimers per liposome achieved by our tag-free EDC/Sulfo-NHS-based conjugation approach may thus be very well sufficient for an enhanced activation of Env-specific/Env-reactive B cells by B-cell receptor crosslinking (BCR crosslinking).…”

Biomarkers of COVID-19 and technologies to combat SARS-CoV-2

“…In a separate study, in vitro tests have shown that DNA origami particles, which are folded intricately to mimic the size and shape of viruses, provoked a strong immune response from human immune cells. 125 The researchers are now working to adapt this approach to develop a potential vaccine for SARS-CoV-2.…”

Nano-based approaches in the development of antiviral agents and vaccines

“…Antibody titers are closely correlated with vaccine effectiveness. Nanovaccines have been shown to induce high antibody titers [ [102] , [103] , [104] , [105] ], probably due to their superiority in target delivery and DC activation as well as the capacity to carry large amounts of antigens [ 106 ]. Nanovaccines can be constructed to carry large quantities of peptides or protein antigens; this provides a high concentration of antigens for efficient B cell receptor (BCR) signaling, consequently improving the B cell response and antibody production ( Fig.…”