Effective Multivalent Oriented Presentation of Meningococcal NadA Antigen Trimers by Self-Assembling Ferritin Nanoparticles

被引:7
作者
Veggi, Daniele [1 ]
Dello Iacono, Lucia [1 ]
Malito, Enrico [2 ,4 ]
Maruggi, Giulietta [2 ]
Giusti, Fabiola [1 ]
Goswami, Panchali [3 ]
Pansegrau, Werner [1 ]
Marchi, Sara [1 ]
Tomei, Sara [1 ]
Luzzi, Enrico [1 ]
Bottomley, Matthew James [2 ,5 ]
Fontani, Federico [1 ]
Ferlenghi, Ilaria [1 ]
Scarselli, Maria [1 ]
机构
[1] GSK, Via Fiorentina 1, I-53100 Siena, Italy
[2] GSK, 14200 Shady Grove Rd, Rockville, MD 20850 USA
[3] GSK, Gunnels Wood Rd, Stevenage SG1 2NY, England
[4] Struct Biol Schrodinger, 1540 Broadway, New York, NY 10036 USA
[5] Dynavax Technol, 2100 Powell St,Suite 720, Emeryville, CA 94608 USA
关键词
nanoparticles; ferritin; bacterial antigen; NEISSERIA-MENINGITIDIS NADA; STRUCTURE-BASED DESIGN; VACCINE; PROTEIN; RESPONSES; EPITOPE; ORGANIZATION;
D O I
10.3390/ijms24076183
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The presentation of viral antigens on nanoparticles in multivalent arrays has emerged as a valuable technology for vaccines. On the nanoparticle surface, highly ordered, repetitive arrays of antigens can mimic their geometric arrangement on virion surfaces and elicit stronger humoral responses than soluble viral antigens. More recently, bacterial antigens have been presented on self-assembling protein nanoparticles and have elicited protective antibody and effective T-helper responses, further supporting the nanoparticle platform as a universal approach for stimulating potent immunogenicity. Here, we present the rational design, structural analysis, and immunogenicity of self-assembling ferritin nanoparticles displaying eight copies of the Neisseria meningitidis trimeric adhesin NadA. We engineered constructs consisting of two different NadA fragments, head only and head with stalk, that we fused to ferritin and expressed in Escherichia coli. Both fusion constructs self-assembled into the expected nanoparticles as determined by Cryo electron microscopy. In mice, the two nanoparticles elicited comparable NadA antibody levels that were 10- to 100-fold higher than those elicited by the corresponding NadA trimer subunits. Further, the NadAferritin nanoparticles potently induced complement-mediated serum bactericidal activity. These findings confirm the value of self-assembling nanoparticles for optimizing the immunogenicity of bacterial antigens and support the broad applicability of the approach to vaccine programs, especially for the presentation of trimeric antigens.
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页数:15
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