Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses

Kanekiyo, Masaru; Joyce, Michael; Gillespie, Rebecca A.; Gallagher, John R.; Andrews, Sarah F.; Yassine, Hadi M.; Wheatley, Adam K.; Fisher, B. L.; Ambrozak, David R.; Creanga, Adrian; Leung, Kwanyee; Yang, Eun Sung; Boyoglu-Barnum, Seyhan; Georgiev, Ivelin S.; Tsybovsky, Yaroslav; Prabhakaran, Madhu; Andersen, Hanné; Kong, Wing-Pui; Baxa, Ulrich; Zephir, Kathryn L; Ledgerwood, Julie E.; Koup, Richard A.; Kwong, Peter D.; Harris, Audray K.; McDermott, Adrian B.; Mascola, John R.; Graham, Barney S.

doi:10.1038/s41590-018-0305-x

Cited by 254 publications

(289 citation statements)

References 73 publications

(97 reference statements)

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“…There are also ongoing efforts to broaden immune responses against the conserved receptor binding site within the more variable influenza HA head. A recently described strategy wherein HAs from 8 different strains were presented on a single mosaic VLP effectively promoted cross-reactive responses against the receptor binding domain [22]**.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…An emerging strategy in vaccine development is to use symmetrical nanoparticles to display a viral antigen with multiple copies of the antigen displayed to the immune system (31,32,(57)(58)(59). Repetitive antigen arrangements on nanoparticle surfaces is thought to facilitate B cell receptor co-aggregation, triggering, and activation (60).…”

Section: Epitope Selection and Copy Number On Nanoparticle Scaffoldsmentioning

confidence: 99%

“…Repetitive antigen arrangements on nanoparticle surfaces is thought to facilitate B cell receptor co-aggregation, triggering, and activation (60). Studies have shown that multivalent viral proteins displayed on nanoparticles are more immunogenic than other platforms (31,57,58,61,62). Although the nanoparticle display of epitopes appears to be an emerging solution to invoke multivalent display, several factors must be considered, such as the identity, molecular size, density/spacing, and copy number of the epitope, as well as the size and type of nanoparticle scaffold.…”

Section: Epitope Selection and Copy Number On Nanoparticle Scaffoldsmentioning

confidence: 99%

“…The ability to stockpile such a vaccine would aid in pandemic preparedness. One emerging strategy for the development of a universal influenza vaccine has been to focus on producing antigens, such as engineered proteins and nanoparticles, that elicit antibodies to conserved epitopes of HA and lead to broader protection (27)(28)(29)(30)(31)(32)(33)(34)(35). It has been speculated that this may require an iterative approach to antigen design and evaluation in order to develop a more efficacious vaccine (24).…”

Section: Introductionmentioning

confidence: 99%

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Designed Nanoparticles Elicit Cross-Reactive Antibody Responses To Conserved Influenza Virus Hemagglutinin Stem Epitopes

et al. 2019

Preprint

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Despite the availability of seasonal vaccines and antiviral medications, influenza virus continues to be a major health concern and pandemic threat due to the continually changing antigenic regions of the major surface glycoprotein, hemagglutinin (HA). One emerging strategy for the development of more efficacious seasonal and universal influenza vaccines is structure-guided design of nanoparticles that display conserved regions of HA, such as the stem. Using the H1 HA subtype to establish proof of concept, we found that an alpha-helical fragment (helix-A) from the conserved stem region can be displayed on nanoparticles. The stem region of HA on these nanoparticles is immunogenic and the nanoparticles are biochemically robust in that heat exposure did not destroy the particles and immunogenicity was retained. Furthermore, H1nanoparticles protected mice from lethal challenge with H1N1 influenza virus. Importantly, antibodies elicited by these nanoparticles demonstrated homosubtypic and heterosubtypic crossreactivity. The helix-A stem nanoparticle design represents a novel approach to display several hundred copies of non-trimeric conserved HA stem epitopes on vaccine nanoparticles. This design concept provides a new approach to universal influenza vaccine development strategies and opens up opportunities for the development of nanoparticles with broad coverage over many antigenically diverse influenza HA subtypes. SignificanceInfluenza virus is a public health issue that affects millions of people globally each year.Commercial influenza vaccines are based on the hemagglutinin (HA) surface glycoprotein, which can change antigenically every year, demanding the manufacture of newly matched vaccines annually. HA stem epitopes have a higher degree of conservation than HA molecules contained in conventional vaccine formulations and we demonstrate that we are able to design nanoparticles that display hundreds of HA stem fragments on nanoparticles. These designed nanoparticles are heat-stable, elicit antibodies to the HA stem, confer protection in mouse challenge models, and show cross-reactivity between HA subtypes. This technology provides promising opportunities to improve seasonal vaccines, develop pandemic preparedness vaccines, and facilitate the development of a universal influenza vaccine.

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“…As a result, seasonal influenza virus infections or vaccinations typically provide limited protection against antigenically drifted strains. New ‘universal’ vaccine antigens are currently being developed to elicit broadly-reactive antibodies against conserved epitopes in the HA receptor binding site (RBS) (Giles and Ross, 2011; Kanekiyo et al, 2019) as well as the HA stalk region (Impagliazzo et al, 2015; Krammer et al, 2013; Yassine et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Identification of antibodies targeting the H3N2 hemagglutinin receptor binding site following vaccination of humans

Zost

Lee

Gumina

et al. 2019

Preprint

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word count: 136 20 Text word count: 5424 21 22 23 *Correspondence: hensley@pennmedicine.upenn.edu 24 SUMMARY 25Antibodies targeting the receptor binding site (RBS) of the influenza virus hemagglutinin (HA) 26 protein are usually not broadly-reactive because their footprints are typically large and extend to 27 nearby variable HA residues. Here, we identified several human H3N2 HA RBS-targeting 28 monoclonal antibodies (mAbs) that were sensitive to substitutions in conventional antigenic sites 29 and were not broadly-reactive. However, we also identified one H3N2 HA RBS-targeting mAb 30 that was exceptionally broadly reactive despite being sensitive to substitutions in residues 31 outside of the RBS. We determined that similar antibodies are present at measurable levels in 32

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Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses

Cited by 254 publications

References 73 publications

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

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

Designed Nanoparticles Elicit Cross-Reactive Antibody Responses To Conserved Influenza Virus Hemagglutinin Stem Epitopes

Identification of antibodies targeting the H3N2 hemagglutinin receptor binding site following vaccination of humans

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