Researchers from MIT announced in January 2024 that they have created a vaccine that induces a “strong antibody response” against SARS-CoV-2 through a virus-like delivery particle made from DNA. The work, published in Nature Communications, shows their investigation of thymus-independent DNA origami as an “alternative material” for multivalent antigen display using the receptor binding domain (RBD) of the SARS-CoV-2 spike protein.
The team found that sequential immunisation of mice elicited protective neutralising antibodies “in a manner that depends on the valency of the antigen displayed” and T cell help. However, the immune sera do not contain boosted, class-switched antibodies against the DNA scaffold, which mean that DNA-VLPs offer a good alternative for particulate vaccine design.
P-VLPs
The authors state that protein-based virus-like particles (P-VLPs) have “emerged as an important material platform for multivalent subunit vaccines”, enabling the “rigid display” of TD antigens. They have been used to investigate the effect of valency on B cell activation in vivo, suggesting “early B cell activation and downstream humoral immune responses are improved for some antigens as valency increases”.
However, control over antigen valency in P-VLPs is “constrained to the constituent self-assembled protein scaffold subunits”, which creates a challenge for the investigation of antigen valency without changing the scaffold. On the other hand, if constant protein scaffold geometry is used, investigations are “limited to stochastically controlled antigen valency and spatial positioning”.
“Furthermore, protein-based scaffolds themselves are TD antigens that elicit humoral immunity. This potentially misdirects antibody responses from the target antigens of interest and might also lead to imprinting.”
A final challenge is that scaffold-directed immunological memory may result in “antibody-dependent clearance of the vaccine material”, which would limit sequential or diversified immunisations.
DNA origami
To tackle these challenges, the researchers have developed scaffolds that are made with DNA origami, a method that “offers precise control over the structure of synthetic DNA” and allows them to attach a “variety of molecules”, like viral antigens, at specific locations.
In this study, they found that when they added an antigen consisting of the receptor binding protein of the original strain of SARS-CoV-2, mice who received the vaccine generated high levels of antibodies to the spike protein but not the DNA scaffold. Associate Professor Daniel Lingwood suggests that the DNA nanoparticle “is immunogenically silent”.
An immunological trick
MIT states that the approach, which “strongly stimulates B cells”, could improve vaccine development for viruses that “have been difficult to target”. Associate Professor Lingwood commented that the team is interested in teaching the immune system to “deliver higher levels of immunity against pathogens that resist conventional vaccine approaches”.
“This idea of decoupling the response against the target antigen from the platform itself is a potentially powerful immunological trick that one can now bring to bear to help those immunological targeting decisions move in a direction that is more focused.”
A laser-focus
Professor Mark Bathe, MIT, describes how the DNA scaffold “does not elicit antibodies that may distract away from the protein of interest”.
“What you can imagine is that your B cells and immune system are being fully trained by that target antigen, and that’s what you want – for your immune system to be laser-focused on the antigen of interest.”
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