Development of VAX128, a recombinant hemagglutinin (HA) influenza-flagellin fusion vaccine with improved safety and immune response

Taylor, David N.; Treanor, John J.; Sheldon, Eric; Johnson, Casey; Umlauf, Scott; Song, Langzhou; Kavita, Uma; Liu, Ge; Tussey, Lynda; Ozer, Karen; Hofstaetter, Thomas; Shaw, Alan

doi:10.1016/j.vaccine.2012.06.086

Cited by 116 publications

(97 citation statements)

References 11 publications

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“…We show that the bacterially expressed HA1, which was originally expressed as a fusion protein with flagellin, is properly refolded and is recognized by broadly neutralizing human antibody 5J8. As such, these results provide further evidence that this strategy of producing recombinant HA in E. coli is suitable for vaccination, as also noted from the ferret experiments (48) and human studies (49,50). The structural knowledge of how 5J8 functions, in combination with the other RBS-targeted antibodies, will potentially further aid and inform vaccine and therapeutic design against the influenza A H1 subtype.…”

Section: Discussionsupporting

confidence: 67%

“…Moreover, E. coli-expressed HA1 has been shown to elicit a protective immune response in ferrets (48), suggesting that a protective antibody response can be generated despite the lack of glycan shielding on the surface of HA, at least in the case of the 2009 H1 pandemic strain. In support of this, E. coli-expressed fusions of flagellin and Cali07/2009-H1 HA1 or A/Solomon Islands/3/1986 HA1 have been shown to elicit protective antibody titers in hu- mans (49,50). We show that the bacterially expressed HA1, which was originally expressed as a fusion protein with flagellin, is properly refolded and is recognized by broadly neutralizing human antibody 5J8.…”

Section: Discussionmentioning

confidence: 62%

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Antibody Recognition of the Pandemic H1N1 Influenza Virus Hemagglutinin Receptor Binding Site

Hong

Lee

Hoffman

et al. 2013

J Virol

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148

165

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Influenza virus is a global health concern due to its unpredictable pandemic potential. This potential threat was realized in 2009 when an H1N1 virus emerged that resembled the 1918 virus in antigenicity but fortunately was not nearly as deadly. 5J8 is a human antibody that potently neutralizes a broad spectrum of H1N1 viruses, including the 1918 and 2009 pandemic viruses. Here, we present the crystal structure of 5J8 Fab in complex with a bacterially expressed and refolded globular head domain from the hemagglutinin (HA) of the A/California/07/2009 (H1N1) pandemic virus. 5J8 recognizes a conserved epitope in and around the receptor binding site (RBS), and its HCDR3 closely mimics interactions of the sialic acid receptor. Electron microscopy (EM) reconstructions of 5J8 Fab in complex with an HA trimer from a 1986 H1 strain and with an engineered stabilized HA trimer from the 2009 H1 pandemic virus showed a similar mode of binding. As for other characterized RBS-targeted antibodies, 5J8 uses avidity to extend its breadth and affinity against divergent H1 strains. 5J8 selectively interacts with HA insertion residue 133a, which is conserved in pandemic H1 strains and has precluded binding of other RBS-targeted antibodies. Thus, the RBS of divergent HAs is targeted by 5J8 and adds to the growing arsenal of common recognition motifs for design of therapeutics and vaccines. Moreover, consistent with previous studies, the bacterially expressed H1 HA properly refolds, retaining its antigenic structure, and presents a low-cost and rapid alternative for engineering and manufacturing candidate flu vaccines.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 62%

Antibody Recognition of the Pandemic H1N1 Influenza Virus Hemagglutinin Receptor Binding Site

Hong

Lee

Hoffman

et al. 2013

J Virol

Self Cite

148

165

View full text Add to dashboard Cite

show abstract

“…In addition, like mammalian cell culture processes, the scale‐up potential of the insect cell/baculovirus vector system may offer advantages for rapid antigen change and response to a pandemic situation 18. Some of these potential advantages may also apply to other novel recombinant protein vaccines that are being developed 19, 20. Regulatory challenges for novel influenza vaccines include the determination of the most appropriate potency assay for a particular vaccine product.…”

Section: Regulatory Experience and Challenges With New And Novel Inflmentioning

confidence: 99%

An overview of the regulation of influenza vaccines in the United States

Weir

Gruber

2016

Influenza Resp Viruses

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Influenza virus vaccines are unique among currently licensed viral vaccines. The vaccines designed to protect against seasonal influenza illness must be updated periodically in an effort to match the vaccine strain with currently circulating viruses, and the vaccine manufacturing timeline includes multiple, overlapping processes with a very limited amount of flexibility. In the United States (U.S.), over 150 million doses of seasonal trivalent and quadrivalent vaccine are produced annually, a mammoth effort, particularly in the context of a vaccine with components that usually change on a yearly basis. In addition, emergence of an influenza virus containing an HA subtype that has not recently circulated in humans is an ever present possibility. Recently, pandemic influenza vaccines have been licensed, and the pathways for licensure of pandemic vaccines and subsequent strain updating have been defined. Thus, there are formidable challenges for the regulation of currently licensed influenza vaccines, as well as for the regulation of influenza vaccines under development. This review describes the process of licensing influenza vaccines in the U.S., the process and steps involved in the annual updating of seasonal influenza vaccines, and some recent experiences and regulatory challenges faced in development and evaluation of novel influenza vaccines.

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“…Therefore, inducing a full immune response that is close to a natural infection response is only possible to attain in the case of vaccination with live attenuated vaccines or with vectors that assure the synthesis of the viral proteins in cytoplasm. Moreover, the induction of the effective T-cell response could be achieved by the cross-priming mechanism using such adjuvant as the Toll-like receptors (TLR) ligands [46].…”

Section: The Cell Immunity To the Influenza Infectionmentioning

confidence: 99%

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2016

MIR journal

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Development of VAX128, a recombinant hemagglutinin (HA) influenza-flagellin fusion vaccine with improved safety and immune response

Cited by 116 publications

References 11 publications

Antibody Recognition of the Pandemic H1N1 Influenza Virus Hemagglutinin Receptor Binding Site

Antibody Recognition of the Pandemic H1N1 Influenza Virus Hemagglutinin Receptor Binding Site

An overview of the regulation of influenza vaccines in the United States

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