Protective efficacy of influenza group 2 hemagglutinin stem-fragment immunogen vaccines

Sutton, Troy; Chakraborty, Saborni; Mallajosyula, Vamsee; Lamirande, Elaine W.; Ganti, Ketaki; Bock, Kevin W.; Moore, Ian N.; Varadarajan, Raghavan; Subbarao, Kanta

doi:10.1038/s41541-017-0036-2

Cited by 48 publications

(53 citation statements)

References 44 publications

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“…6E). At present it appears that trimeric stem immunogens have been reported for only H1, H3, H5, and H7 (29,35,(49)(50)(51)(52).…”

Section: Expanding Stem Nanoparticle Design and Expression To More Hamentioning

confidence: 82%

“…Only two immunizations were required and an oil-in-water emulsion adjuvant appears not to increase protection. This will require further studies to understand, since this differs from studies of trimeric antigens, which require adjuvant and, in some cases, require three immunizations (29,35,(49)(50)(51)(52). This design concept can be applied more broadly to other influenza A HA subtypes, as we have demonstrated expression for the majority of influenza A HA subtypes (Fig.…”

Section: Expanding Stem Nanoparticle Design and Expression To More Hamentioning

confidence: 98%

“…It may be challenging to produce traditional trimeric stem immunogens for all subtypes that successfully fold into an immunogenic epitope. Previous studies have shown that stabilizing mutations and trimerization motifs may be required to maintain biological relevance of a trimeric stem epitope (29,35,(49)(50)(51)(52). Consequently, numerous constructs may need to be screened for expression, stability, and structure (29,35).…”

Section: Expanding Stem Nanoparticle Design and Expression To More Hamentioning

confidence: 99%

“…The epitopes of some of these antibodies, including human monoclonal antibodies FI6V3 and CR6261, have also been structurally mapped (17,28,30,36,37,(46)(47)(48). This has facilitated interest in structure-guided efforts to engineer trimeric HA2 stem immunogens that elicit stem antibodies (29,35,(49)(50)(51)(52).…”

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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“…6E). At present it appears that trimeric stem immunogens have been reported for only H1, H3, H5, and H7 (29,35,(49)(50)(51)(52).…”

Section: Expanding Stem Nanoparticle Design and Expression To More Hamentioning

confidence: 82%

Section: Expanding Stem Nanoparticle Design and Expression To More Hamentioning

confidence: 98%

Section: Expanding Stem Nanoparticle Design and Expression To More Hamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2019

Preprint

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“…Although bacterially-produced HA stem-only immunogens from H1, H5, H3 and H7 subtypes have also been reported to protect mice from H3 or H7 influenza, complete protection has only been observed for some homotypic strains (55–57), indicating that the breadth of response is limited. The immunogens in our study more closely mimic the native H3N2 and H7N9 HA stems in that they include native N-linked glycans as well as the membrane proximal region of the HA stem that are both missing in the bacterially-expressed designs.…”

Section: Discussionmentioning

confidence: 99%

Design of nanoparticulate group 2 influenza hemagglutinin stem antigens that activate unmutated ancestor B cell receptors of broadly neutralizing antibody lineages

Corbett

Moin

Yassine

et al. 2018

Preprint

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30Influenza vaccines targeting the highly-conserved stem of the hemagglutinin (HA) surface 31 glycoprotein have the potential to protect against pandemic and drifted seasonal influenza viruses 32 not covered by current vaccines. While HA stem-based immunogens derived from group 1 33 influenza A have been shown to induce intra-group heterosubtypic protection, HA stem-specific 34 antibody lineages originating from group 2 may be more likely to possess broad cross-group 35 reactivity. We report the structure-guided development of mammalian cell-expressed candidate 36 vaccine immunogens based on influenza A group 2 H3 and H7 HA stem trimers displayed on 37 self-assembling ferritin nanoparticles using an iterative, multipronged approach involving helix 38 stabilization, loop optimization, disulfide bond addition, and side chain repacking. These 39 immunogens were thermostable, formed uniform and symmetric nanoparticles, were recognized 40 by cross-group-reactive broadly neutralizing antibodies (bNAbs) with nanomolar affinity, and 41 elicited protective, homosubtypic antibodies in mice. Importantly, several immunogens were 42 able to activate B cells expressing inferred unmutated common ancestor (UCA) versions of 43 cross-group-reactive human bNAbs from two multi-donor classes, suggesting they could initiate 44 elicitation of these bNAbs in humans. 45 46 47 48 common ancestor (UCA) versions of human antibody lineages associated with cross-group 59 reactive, broadly neutralizing antibodies (bNAbs). Immunization of mice led to protection 60 against a lethal homosubtypic influenza challenge. These candidate vaccines are now being 61 manufactured for clinical evaluation. 62 63 Influenza continues to be a significant global health burden, typically resulting in about 65 500,000 deaths worldwide annually (1), even though the technology for conventional egg-grown, 66 whole inactivated influenza virus vaccines was developed more than 70 years ago. Constant 67 antigenic drift of the influenza virus hemagglutinin (HA) coupled with immunodominant strain-68 specific antibody responses directed to the variable HA head domain results in conventional 69 vaccine effectiveness ranging from 10-60% (2) and the need for seasonal updates of virus strains 70 included in licensed vaccines. Furthermore, current vaccine approaches provide minimal 71 protection against pandemic influenza strains (3, 4). Improved influenza vaccines would not be 72 produced in eggs, would be designed to induce broad immunity against future drifted and 73 pandemic strains without seasonal reformulation, and elicit durable immune responses avoiding 74 the need for annual vaccination (4). One approach for achieving broadly cross-reactive 75 influenza-specific antibodies is to target highly conserved neutralization-sensitive epitopes in the 76 stem region of the influenza A HA surface glycoprotein (5). Monoclonal antibodies have been 77 identified that bind conserved HA stem epitopes and possess broad neutralizing activity across 78 diverse HA subtypes within an infl...

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Extending the Breadth of Influenza Vaccines: Status and Prospects for a Universal Vaccine

Fox

Quinn

Subbarao

2018

Drugs

Self Cite

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Despite the widespread use of seasonal influenza vaccines, there is urgent need for a universal influenza vaccine to provide broad, long-term protection. A number of factors underpin this urgency, including threats posed by zoonotic and pandemic influenza A viruses, suboptimal effectiveness of seasonal influenza vaccines, and concerns surrounding the effects of annual vaccination. In this article, we discuss approaches that are being investigated to increase influenza vaccine breadth, which are near-term, readily achievable approaches to increase the range of strains recognized within a subtype, or longer-term more challenging approaches to produce a truly universal influenza vaccine. Adjuvanted and neuraminidase-optimized vaccines are emerging as the most feasible and promising approaches to extend protection to cover a broader range of strains within a subtype. The goal of developing a universal vaccine has also been advanced with the design of immunogenic influenza HA-stem constructs that induce broadly neutralizing antibodies. However, these constructs are not yet sufficiently immunogenic to induce lasting universal immunity in humans. Advances in understanding how T cells mediate protection, and how viruses are packaged, have facilitated the rationale design and delivery of replication-incompetent virus vaccines that induce broad protection mediated by lung-resident memory T cells. While the lack of clear mechanistic correlates of protection, other than haemagglutination-inhibiting antibodies, remains an impediment to further advancing novel influenza vaccines, the pressing need for such a vaccine is supporting development of highly innovative and effective strategies.

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Protective efficacy of influenza group 2 hemagglutinin stem-fragment immunogen vaccines

Cited by 48 publications

References 44 publications

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

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

Design of nanoparticulate group 2 influenza hemagglutinin stem antigens that activate unmutated ancestor B cell receptors of broadly neutralizing antibody lineages

Extending the Breadth of Influenza Vaccines: Status and Prospects for a Universal Vaccine

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