2026-02-05 マサチューセッツ工科大学(MIT)
<関連情報>
- https://news.mit.edu/2026/new-vaccine-platform-promotes-rare-protective-b-cells-0205
- https://www.science.org/doi/10.1126/science.adx6291
- https://www.nature.com/articles/s41467-024-44869-0
DNA折り紙ワクチンは抗原に焦点を当てた胚中心をプログラムする DNA origami vaccines program antigen-focused germinal centers
Anna Romanov, Grant A. Knappe, Larance Ronsard, Christopher A. Cottrell, […] , and Darrell J. Irvine
Science Published:5 Feb 2026
DOI:https://doi.org/10.1126/science.adx6291
Editor’s summary
Vaccines that can elicit broadly neutralizing antibodies (bnAbs) help to provide immunity against multiple strains of the same virus. One approach to boost the rare B cells that generate bnAbs is to vaccinate with a particle that presents many copies of the same antigen; however, protein scaffolds may also induce immune responses. Romanov et al. used DNA origami to generate virus-like particles (DNA-VLPs) and optimized multivalent presentation of an antigen belonging to HIV alongside synthetic T cell epitopes (see the Perspective by Bannard and Howarth). Immunization with the DNA-VLP produced limited nonspecific B cell responses, unlike vaccination with a protein nanoparticle, and boosted antigen-specific, bnAb-producing B cells to a greater extent. —Sarah H. Ross
Structured Abstract
INTRODUCTION
Generating broadly neutralizing antibodies (bnAbs) is a key aim of HIV vaccine design, but germline-encoded bnAb precursors are immunologically subdominant and rare in the human immune repertoire, making it difficult to reproducibly expand them in primary vaccination. Multivalent display of germline-targeting immunogens on protein nanoparticles is a well-established method to enhance vaccine-induced B cell responses. However, such nanoparticle scaffolds themselves become targets of an antibody response. It has remained unclear whether and to what degree antiscaffold responses may limit the expansion of rare B cells specific to the desired bnAb epitopes.
RATIONALE
DNA origami technology provides an immunologically inert vaccine scaffold that also offers precise engineering of biomolecule display. We hypothesized that the immune tolerance toward DNA could render these particles capable of testing the impact of antiscaffold responses on the development of epitope-specific responses. We therefore optimized the design of DNA origami–based virus-like particles (DNA-VLPs) displaying a germline-targeting HIV envelope protein immunogen, engineered outer domain GT8 (eOD-GT8), that could be compared with a protein nanoparticle scaffold presenting the same antigen.
RESULTS
We found that priming of robust germinal center (GC) responses in mice required that DNA-VLPs display antigen at a high density on the particle surface, which promoted activation of complement and led the particles to be captured in B cell follicles after immunization. Further, optimized DNA-VLPs required the incorporation of synthetic T cell epitopes to ensure sufficient T cell help for the vaccine. These rationally designed DNA-VLPs expanded threefold more antigen-specific GC B cells compared with a clinical state-of-the-art protein nanoparticle of the same size and antigen valency, eOD-GT8 60mer. In a humanized mouse model of bnAb priming with physiologically relevant frequencies of precursor B cells, DNA-VLPs primed highly epitope-specific GC B cells, whereas protein nanoparticles induced GCs where both epitope-specific and scaffold-specific B cells were present at comparable frequencies. Moreover, a single prime vaccination of DNA-VLPs effectively primed and expanded rare bnAb precursors in GCs, whereas the protein nanoparticle failed to prime these rare cells at early time points.
CONCLUSION
Antigen-displaying DNA-VLPs can be engineered to promote accumulation in B cell follicles and elicit strong, antigen-focused GC responses in vivo. Optimized DNA-VLPs produced epitope-focused GCs with fewer scaffold-specific competitor B cells relative to protein VLPs displaying the same antigens and drove the expansion of subdominant broadly neutralizing precursor B cells after a single immunization.
Atomic model of DNA-VLPs.
A molecular model of an optimized DNA-VLP (pink), displaying 60 copies of eOD-GT8-PADRE (gold; PADRE, pan-HLA DR-binding epitope).
Abstract
Priming rare subdominant precursor B cells in germinal centers (GCs) is a central goal of vaccination to generate broadly neutralizing antibodies (bnAbs) against HIV. Multivalent immunogen display on protein nanoparticle scaffolds can promote such responses, but it also generates scaffold-specific B cells that could theoretically limit bnAb precursor expansion in GCs. We rationally designed DNA origami–based virus-like particles (DNA-VLPs) displaying a germline-targeting HIV envelope protein immunogen, which elicited no scaffold-specific antibody responses. Compared with a state-of-the-art clinical protein nanoparticle, these DNA-VLPs increased the expansion of epitope-specific GC B cells relative to off-target B cells and enhanced expansion of bnAb-lineage B cells in a humanized mouse model of CD4 binding site priming. Thus, minimizing off-target responses enhances bnAb priming and indicates that DNA-VLPs are a promising vaccine platform.
胸腺非依存性DNAオリガミ足場における多価抗原提示による抗体反応の増強 Enhancing antibody responses by multivalent antigen display on thymus-independent DNA origami scaffolds
Eike-Christian Wamhoff,Larance Ronsard,Jared Feldman,Grant A. Knappe,Blake M. Hauser,Anna Romanov,James Brett Case,Shilpa Sanapala,Evan C. Lam,Kerri J. St. Denis,Julie Boucau,Amy K. Barczak,Alejandro B. Balazs,Michael S. Diamond,Aaron G. Schmidt,Daniel Lingwood & Mark Bathe
Nature Communications Published:30 January 2024
DOI:https://doi.org/10.1038/s41467-024-44869-0
Abstract
Protein-based virus-like particles (P-VLPs) are commonly used to spatially organize antigens and enhance humoral immunity through multivalent antigen display. However, P-VLPs are thymus-dependent antigens that are themselves immunogenic and can induce B cell responses that may neutralize the platform. Here, we investigate 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 primary target of neutralizing antibody responses. Sequential immunization of mice with DNA-based VLPs (DNA-VLPs) elicits protective neutralizing antibodies to SARS-CoV-2 in a manner that depends on the valency of the antigen displayed and on T cell help. Importantly, the immune sera do not contain boosted, class-switched antibodies against the DNA scaffold, in contrast to P-VLPs that elicit strong B cell memory against both the target antigen and the scaffold. Thus, DNA-VLPs enhance target antigen immunogenicity without generating scaffold-directed immunity and thereby offer an important alternative material for particulate vaccine design.
