Development of a Pan-H1 Influenza Vaccine

Darricarrère, Nicole; Pougatcheva, Svetlana; Duan, Xiaochu; Rudicell, Rebecca S.; Chou, Te-hui W.; DiNapoli, Joshua; Ross, Ted M.; Alefantis, Tim; Vogel, Thorsten U.; Kleanthous, Harry; Wei, Chih‐Jen; Nabel, Gary J.

doi:10.1128/jvi.01349-18

Cited by 45 publications

(36 citation statements)

References 29 publications

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“…1a). LuS and ferritin have served as scaffolds for nanoparticle immunogens in several clinical studies: for LuS see https ://www.clini caltr ials.gov/ct2/show/NCT03 69924 1 28 ; for ferritin, see https ://www.clini caltr ials.gov/ct2/show/NCT03 54724 5 10,29,30 . The N termini of both ferritin and LuS are exposed to the nanoparticle surface and are thus accessible for SpyTag or SpyCatcher attachment (Fig.…”

Section: Expression Of Lus-and Ferritin-nanoparticle Scaffolds With Smentioning

confidence: 99%

A platform incorporating trimeric antigens into self-assembling nanoparticles reveals SARS-CoV-2-spike nanoparticles to elicit substantially higher neutralizing responses than spike alone

Zhang

Chao

Tsybovsky

et al. 2020

Sci Rep

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Antigens displayed on self-assembling nanoparticles can stimulate strong immune responses and have been playing an increasingly prominent role in structure-based vaccines. However, the development of such immunogens is often complicated by inefficiencies in their production. To alleviate this issue, we developed a plug-and-play platform using the spontaneous isopeptide-bond formation of the SpyTag:SpyCatcher system to display trimeric antigens on self-assembling nanoparticles, including the 60-subunit Aquifex aeolicus lumazine synthase (LuS) and the 24-subunit Helicobacter pylori ferritin. LuS and ferritin coupled to SpyTag expressed well in a mammalian expression system when an N-linked glycan was added to the nanoparticle surface. The respiratory syncytial virus fusion (F) glycoprotein trimer—stabilized in the prefusion conformation and fused with SpyCatcher—could be efficiently conjugated to LuS-SpyTag or ferritin-SpyTag, enabling multivalent display of F trimers with prefusion antigenicity. Similarly, F-glycoprotein trimers from human parainfluenza virus-type 3 and spike-glycoprotein trimers from SARS-CoV-2 could be displayed on LuS nanoparticles with decent yield and antigenicity. Notably, murine vaccination with 0.08 µg of SARS-CoV-2 spike-LuS nanoparticle elicited similar neutralizing responses as 2.0 µg of spike, which was ~ 25-fold higher on a weight-per-weight basis. The versatile platform described here thus allows for multivalent plug-and-play presentation on self-assembling nanoparticles of trimeric viral antigens, with SARS-CoV-2 spike-LuS nanoparticles inducing particularly potent neutralizing responses.

show abstract

Section: Expression Of Lus-and Ferritin-nanoparticle Scaffolds With Smentioning

confidence: 99%

A platform incorporating trimeric antigens into self-assembling nanoparticles reveals SARS-CoV-2-spike nanoparticles to elicit substantially higher neutralizing responses than spike alone

Zhang

Chao

Tsybovsky

et al. 2020

Sci Rep

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show abstract

“…Epitope accessibility, proper folding of the antigen, and stability are also important considerations in any strategy for antigen presentation. Several reports have utilized non-viral, naturally occurring protein scaffolds, such as self-assembling ferritin ( Kanekiyo et al, 2013 ; Sliepen et al, 2015 ; Darricarrère et al, 2018 ), lumazine synthase ( Sanders and Moore, 2017 ; Abbott et al, 2018 ), or encapsulin ( Kanekiyo et al, 2015 ) nanoparticles, to present a variety of complex oligomeric or engineered antigens. These studies have illustrated the advantages of using self-assembling proteins as scaffolds for antigen presentation ( López-Sagaseta et al, 2016 ; Kanekiyo et al, 2019 ), including enhanced immunogenicity and seamless integration of antigen and scaffold through genetic fusion.…”

Section: Introductionmentioning

confidence: 99%

Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens

Ueda

Antanasijevic

Fallas

et al. 2020

eLife

135

150

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Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. To enable a new generation of anti-viral vaccines, we designed self-assembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. We first de novo designed trimers tailored for antigen fusion, featuring N-terminal helices positioned to match the C termini of the viral glycoproteins. Trimers that experimentally adopted their designed configurations were incorporated as components of tetrahedral, octahedral, and icosahedral nanoparticles, which were characterized by cryo-electron microscopy and assessed for their ability to present viral glycoproteins. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles presented antigenically intact prefusion HIV-1 Env, influenza hemagglutinin, and RSV F trimers in the predicted geometries. This work demonstrates that antigen-displaying protein nanoparticles can be designed from scratch, and provides a systematic way to investigate the influence of antigen presentation geometry on the immune response to vaccination.

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“…Attributes such as epitope accessibility, proper folding of the antigen, and overall stability are additional considerations that must be taken into account in any design strategy for antigen presentation. Several reports have utilized non-viral, naturally occurring protein scaffolds, such as self-assembling ferritin [8][9][10] , lumazine synthase 5,11 , or encapsulin 12 nanoparticles, to present a variety of complex oligomeric or engineered antigens. These studies collectively highlight several of the key advantages of using self-assembling proteins as scaffolds for multivalent antigen presentation 13,14 , including the formation of stable, highly monodisperse immunogens, the existence of scalable manufacturing methods, and seamless integration of antigen and scaffold via genetic fusion.…”

Section: Introductionmentioning

confidence: 99%

Tailored Design of Protein Nanoparticle Scaffolds for Multivalent Presentation of Viral Glycoprotein Antigens

Ueda

Antanasijevic

Fallas

et al. 2020

Preprint

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The adaptive immune system is highly sensitive to arrayed antigens, and multivalent display of viral glycoproteins on symmetric scaffolds has been found to substantially increase the elicitation of antigen-specific antibodies. Motivated by the considerable promise of this strategy for next-generation anti-viral vaccines, we set out to design new self-assembling protein nanoparticles with geometries specifically tailored to scaffold ectodomains of different viral glycoproteins. We first designed and characterized homo-trimers from designed repeat proteins with N-terminal helices positioned to match the C termini of several viral glycoprotein trimers. Oligomers found to experimentally adopt the designed configuration were then used to generate nanoparticles with tetrahedral, octahedral, or icosahedral symmetry. Examples of all three target symmetries were experimentally validated by cryo-electron microscopy and several were assessed for their ability to display viral glycoproteins via genetic fusion. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles display conformationally intact native-like HIV-1 Env, influenza hemagglutinin, and prefusion RSV F trimers in the predicted geometries. This work demonstrates that novel nanoparticle immunogens can be designed from the bottom up with atomic-level accuracy and provides a general strategy for precisely controlling epitope presentation and accessibility.

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Development of a Pan-H1 Influenza Vaccine

Cited by 45 publications

References 29 publications

A platform incorporating trimeric antigens into self-assembling nanoparticles reveals SARS-CoV-2-spike nanoparticles to elicit substantially higher neutralizing responses than spike alone

A platform incorporating trimeric antigens into self-assembling nanoparticles reveals SARS-CoV-2-spike nanoparticles to elicit substantially higher neutralizing responses than spike alone

Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens

Tailored Design of Protein Nanoparticle Scaffolds for Multivalent Presentation of Viral Glycoprotein Antigens

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