Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus

Marcandalli, Jessica; Fiala, Brooke; Ols, Sebastian; Perotti, Michela; Schueren, Willem de van der; Snijder, Joost; Hodge, Edgar A.; Benhaim, Mark A.; Ravichandran, Rashmi; Carter, Lauren; Sheffler, Will; Brunner, Livia; Lawrenz, Maria; Dubois, Patrice; Lanzavecchia, Antonio; Sallusto, Federica; Lee, Kelly K.; Veesler, David; Correnti, Colin; Stewart, Lance; Baker, David; Loré, Karin; Perez, Laurent; King, Neil P.

doi:10.1016/j.cell.2019.01.046

Cited by 395 publications

(449 citation statements)

References 68 publications

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“…In light of our findings, this low spike density might impact the overall avidity between HIV and the immature B cell surface, while having minimal impact on the induction of mature, high affinity receptor signaling during viral encounters. Importantly, the rigid nature of DNA origami nanostructures provides an effective scaffold for precisely defining spatial relationships between immuongens, and as we show here, can be used to define design rules relevant for protein-based virus-like NPs that can be computationally designed to present rigid immunogen arrays following these criteria 36 .…”

Section: Main Textmentioning

confidence: 93%

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

Veneziano

Moyer

Stone

et al. 2020

Preprint

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Arraying vaccine immunogens in a multivalent form on the surface of virus-like particles is an important strategy used to enhance the efficacy of subunit vaccines. However, the impacts of antigen valency, spacing, and spatial organization on B cell triggering remain poorly understood. Here, we use DNA origami nanoparticles to create precise nanoscale organizations of a clinically-relevant HIV gp120 immunogen to systematically interrogate their impact on B cell triggering in vitro. We find that antigen dimers elicit monotonically increasing B cell receptor activation as inter-antigen spacing increases up to ~30 nm, and only 5 immunogens arrayed on the surface of a 3D particle are needed to elicit maximal B cell calcium signaling. Our results reveal design principles of viral and immunogen display that drive functional B cell responses.

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Section: Main Textmentioning

confidence: 93%

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

Veneziano

Moyer

Stone

et al. 2020

Preprint

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“…Much recent effort is being placed on the delivery to, and persistence of antigen in, germinal centers to further promote somatic hypermutation. Continuous delivery of antigen [44,45]**,**, multivalent antigen presentation [46,47]*,* adjuvants, and other technologies, including immune checkpoint modultation to promote germinal center activity, [48] may help overcome the limitations of protein subunits as immunogens. Many of these concepts must now be tested empirically.…”

Section: Somatic Hypermutationmentioning

confidence: 99%

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Ward

Wilson

2020

Current Opinion in Immunology

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Please cite this article as: Ward AB, Wilson IA, Innovations in structure-based antigen design and immune monitoring for next generation vaccines, J o u r n a l P r e -p r o o f Highligthts Immunofocusing as a strategy for structure-based vaccine design. Structure-based vaccine design for RSV F, influenza HA, HIV-1 Env. Structure-based vaccine design translated into the clinic. AbstractThe recent explosion of atomic-level structures of glycoproteins that comprise the surface antigens of human enveloped viruses, such as RSV, influenza, hepatitis C and HIV, provide tremendous opportunities for rational, structure-based vaccine design. Several concepts in structure-based vaccine design have been put into practice and are are well along preclinical and clinical implementation. Testing of these designed immunogens will provide key insights into the ability to induce the desired immune responses, namely neutralizing antibodies. Many of these immunogens in human clinical trials represent only the first wave of designs and will likely require continued tweaking and elaboration to achieve the ultimate result of ever increasingly breadth and potency. Considerable effort is now being invested in germline targeting, epitope focusing, and improved immune presentation such as multivalent nanoparticle incorporation. This review highlights some of the recent advances in these areas as we prepare for the next generation of immunogens for subsequent rounds of iterative vaccine development.

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“…[1][2][3][4] Since 2012, more than a dozen examples of successful cage designs have been validated in atomic detail by X-ray crystallography, [5][6][7][8] and several others have been verified at lower resolution by electron microscopy. 8,9 Recent studies are beginning to generate novel cages with specific applications in mind, including the ability to encapsulate other molecules such as nucleic acids, [10][11][12][13] present viral antigens, 14 or rigidly bind other proteins for cryo-EM imaging. 15,16 Notwithstanding the impressive successes that have been reported for designed protein cages, considerable experimental challenges remain.…”

mentioning

confidence: 99%

Design and structure of two new protein cages illustrate successes and ongoing challenges in protein engineering

et al. 2019

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In recent years, new protein engineering methods have produced more than a dozen symmetric, self‐assembling protein cages whose structures have been validated to match their design models with near‐atomic accuracy. However, many protein cage designs that are tested in the lab do not form the desired assembly, and improving the success rate of design has been a point of recent emphasis. Here we present two protein structures solved by X‐ray crystallography of designed protein oligomers that form two‐component cages with tetrahedral symmetry. To improve on the past tendency toward poorly soluble protein, we used a computational protocol that favors the formation of hydrogen‐bonding networks over exclusively hydrophobic interactions to stabilize the designed protein–protein interfaces. Preliminary characterization showed highly soluble expression, and solution studies indicated successful cage formation by both designed proteins. For one of the designs, a crystal structure confirmed at high resolution that the intended tetrahedral cage was formed, though several flipped amino acid side chain rotamers resulted in an interface that deviates from the precise hydrogen‐bonding pattern that was intended. A structure of the other designed cage showed that, under the conditions where crystals were obtained, a noncage structure was formed wherein a porous 3D protein network in space group I213 is generated by an off‐target twofold homomeric interface. These results illustrate some of the ongoing challenges of developing computational methods for polar interface design, and add two potentially valuable new entries to the growing list of engineered protein materials for downstream applications.

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Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus

Cited by 395 publications

References 68 publications

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

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

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Design and structure of two new protein cages illustrate successes and ongoing challenges in protein engineering

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