High-Affinity H7 Head and Stalk Domain–Specific Antibody Responses to an Inactivated Influenza H7N7 Vaccine After Priming With Live Attenuated Influenza Vaccine

Halliley, Jessica L.; Khurana, Surender; Krammer, Florian; Fitzgerald, Theresa; Coyle, Elizabeth M.; Chung, Ka Yan; Baker, Steven F.; Yang, Hongmei; Martínez-Sobrido, Luis; Treanor, John J.; Subbarao, Kanta; Golding, Hana; Topham, David J.; Sangster, Mark Y.

doi:10.1093/infdis/jiv210

Cited by 44 publications

(43 citation statements)

References 41 publications

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“…Interestingly, mice that did not seroconvert to either virus were also protected against homologous and heterologous challenge. This echoes the work of Halliley et al who showed that measuring vaccine responses to LAIV by HAI misses protective efficacy (19).…”

supporting

confidence: 78%

A Single Mutation at PB1 Residue 319 Dramatically Increases the Safety of PR8 Live Attenuated Influenza Vaccine in a Murine Model without Compromising Vaccine Efficacy

Cox

Dewhurst

2016

J Virol

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The live attenuated influenza vaccine (LAIV) is preferentially recommended for use in most children yet remains unsafe for the groups most at risk. Here we have improved the safety of a mouse-adapted live attenuated influenza vaccine containing the same attenuating amino acid mutations as in human LAIV by adding an additional mutation at PB1 residue 319. This results in a vaccine with a 20-fold decrease in protective efficacy and a 10,000-fold increase in safety.T he live attenuated influenza vaccine (LAIV) is preferentially recommended for use in most children and has outperformed its inactivated rival in recent clinical trials (1). However, this vaccine is not approved for use in children under 2 years of age or asthmatics due to safety concerns in the initial licensure trials (2-11). In pursuit of a safer vaccine, we previously developed an experimental animal (mouse) model to study the safety and immunogenicity of LAIV by introducing the attenuating mutations of LAIV (PB2 N265S; PB1 K391E, D581G, and A661T) (Fig. 1A) into the genetic background of the mouse-adapted, highly virulent influenza A virus (IAV) strain, A/PR/8/34 (PR8). This resulted in a modified LAIV that retained virulence in C57BL/6 (B6) mice, such that it is possible to identify additional attenuating mutations that further reduce the virulence of this virus (12). Here we extend that work and show that adding a mutation at residue 319 of PB1 conveys a dramatic safety increase with only a modest decrease in immunogenicity.We replaced the natural (and universally conserved) leucine with glutamine at residue 319 of PB1 (Fig. 1A). This amino acid lies underneath the PA linker region and 30 Å from PB1 residue 391 (the nearest amino acid mutation of LAIV) (13). Mutating

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confidence: 78%

A Single Mutation at PB1 Residue 319 Dramatically Increases the Safety of PR8 Live Attenuated Influenza Vaccine in a Murine Model without Compromising Vaccine Efficacy

Cox

Dewhurst

2016

J Virol

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“…A number of studies have now firmly established that stalk-specific bnAbs, normally present in low quantities, can be boosted substantially in humans following exposure to HA subtypes with antigenically foreign head domains (2)(3)(4)(5)(6)(7)(8). Sequential vaccination of animals with chimeric HAs or with "headless" vaccine constructs have effectively recapitulated the boosting of bnAbs observed in humans after exposure to foreign HAs, and also are protective against heterologous and heterosubtypic IAV challenge (9)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

Tan

Mullarkey

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections. The majority of these antibodies bind to the hemagglutinin (HA) head domain and function by blocking the receptor binding site, preventing infection of host cells. Recently, elicitation of broadly neutralizing antibodies which target the conserved HA stalk domain has become a promising "universal" influenza virus vaccine strategy. The ability of these antibodies to elicit Fc-dependent effector functions has emerged as an important mechanism through which protection is achieved in vivo. However, the way in which Fc-dependent effector functions are regulated by polyclonal influenza virus-binding antibody mixtures in vivo has never been defined. Here, we demonstrate that interactions among viral glycoprotein-binding antibodies of varying specificities regulate the magnitude of antibody-dependent cell-mediated cytotoxicity induction. We show that the mechanism responsible for this phenotype relies upon competition for binding to HA on the surface of infected cells and virus particles. Nonneutralizing antibodies were poor inducers and did not inhibit antibody-dependent cell-mediated cytotoxicity. Interestingly, anti-neuraminidase antibodies weakly induced antibody-dependent cell-mediated cytotoxicity and enhanced induction in the presence of HA stalk-binding antibodies in an additive manner. Our data demonstrate that antibody specificity plays an important role in the regulation of ADCC, and that cross-talk among antibodies of varying specificities determines the magnitude of Fc receptor-mediated effector functions.T he discovery and ongoing characterization of broadly neutralizing antibodies (bnAbs) that bind to the hemagglutinin (HA) stalk domain of influenza A viruses (IAVs) has galvanized promising new efforts to generate a universal influenza virus vaccine (1). A number of studies have now firmly established that stalk-specific bnAbs, normally present in low quantities, can be boosted substantially in humans following exposure to HA subtypes with antigenically foreign head domains (2-8). Sequential vaccination of animals with chimeric HAs or with "headless" vaccine constructs have effectively recapitulated the boosting of bnAbs observed in humans after exposure to foreign HAs, and also are protective against heterologous and heterosubtypic IAV challenge (9-15). These strategies are now being tested as promising "universal" influenza virus vaccine candidates (16).Whereas traditional strain-specific antibodies neutralize virus by inhibiting receptor binding, stalk-binding bnAbs neutralize virus by distinct postbinding mechanisms (17). A direct comparison of in vitro neutralization has revealed that strain-specific mAbs that inhibit receptor binding tend to be more potent at neutralizing virus compared with monoclonal stalk-binding bnAbs (18, 19); however, this difference is minimized in the context of a polyclonal response (18). In addition to virus neutralization,...

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“…These data, especially for H7-HA1 binding, confirmed that, indeed, all 15 individuals were exposed to H7N7, including those with HI titers of Ͻ10. Sera from H7-unexposed individuals who were enrolled in a previous study of an H7N7 vaccination clinical trial did not react against the H7-HA1 domain (12), confirming the specificity of SPR binding and excluding anti-HA1 antibody cross-reactivity due to prior exposure to seasonal influenza virus strains. A significant correlation was observed between the H7N7 HI titers and total antibody binding to H7-HA1 (r ϭ 0.8797; P Ͻ 0.0001) (Fig.…”

Section: Resultsmentioning

confidence: 66%

“…However, there is a lack of knowledge on the quality of the polyclonal antibody (Ab) responses generated following natural HPAI H7N7 virus infection and how these antibodies protect against severe disease. Current efforts to develop an effective vaccine against H7N7 are hampered by the paucity of information on protective immune responses and poor immune responses in persons vaccinated with either inactivated or live H7N7 vaccines (10)(11)(12).…”

mentioning

confidence: 99%

Antigenic Fingerprinting of Antibody Response in Humans following Exposure to Highly Pathogenic H7N7 Avian Influenza Virus: Evidence for Anti-PA-X Antibodies

Khurana

Chung

Coyle

et al. 2016

J Virol

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Infections with H7 highly pathogenic avian influenza (HPAI) viruses remain a major public health concern. Adaptation of lowpathogenic H7N7 to highly pathogenic H7N7 in Europe in 2015 raised further alarm for a potential pandemic. An in-depth understanding of antibody responses to HPAI H7 virus following infection in humans could provide important insight into virus gene expression as well as define key protective and serodiagnostic targets. Here we used whole-genome gene fragment phage display libraries (GFPDLs) expressing peptides of 15 to 350 amino acids across the complete genome of the HPAI H7N7 A/Netherlands/33/03 virus. The hemagglutinin (HA) antibody epitope repertoires of 15 H7N7-exposed humans identified clear differences between individuals with no hemagglutination inhibition (HI) titers (<1:10) and those with HI titers of >1:40. Several potentially protective H7N7 epitopes close to the HA receptor binding domain (RBD) and neuraminidase (NA) catalytic site were identified. Surface plasmon resonance (SPR) analysis identified a strong correlation between HA1 (but not HA2) binding antibodies and H7N7 HI titers. A proportion of HA1 binding in plasma was contributed by IgA antibodies. Antibodies against the N7 neuraminidase were less frequent but targeted sites close to the sialic acid binding site. Importantly, we identified strong antibody reactivity against PA-X, a putative virulence factor, in most H7N7-exposed individuals, providing the first evidence for in vivo expression of PA-X and its recognition by the immune system during human influenza A virus infection. This knowledge can help inform the development and selection of the most effective countermeasures for prophylactic as well as therapeutic treatments of HPAI H7N7 avian influenza virus. IMPORTANCEAn outbreak of pathogenic H7N7 virus occurred in poultry farms in The Netherlands in 2003. Severe outcome included conjunctivitis, influenza-like illness, and one lethal infection. In this study, we investigated convalescent-phase sera from H7N7-exposed individuals by using a whole-genome phage display library (H7N7-GFPDL) to explore the complete repertoire of post-H7N7-exposure antibodies. PA-X is a recently identified influenza virus virulence protein generated by ribosomal frameshifting in segment 3 of influenza virus coding for PA. However, PA-X expression during influenza virus infection in humans is unknown. We identified strong antibody reactivity against PA-X in most H7N7-exposed individuals (but not in unexposed adults), providing the first evidence for in vivo expression of PA-X and its recognition by the immune system during human infection with pathogenic H7N7 avian influenza virus.A vian influenza viruses (AIVs) are mostly restricted to aquatic birds. On occasion, they acquire the capacity to directly infect the respiratory tract of poultry and mammals. Such cross-species transmission often results in a large number of sick birds (chickens and turkeys), as was reported for H7N1 viruses in Italy in 1999, H7N3 viruses in Canada in 2...

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High-Affinity H7 Head and Stalk Domain–Specific Antibody Responses to an Inactivated Influenza H7N7 Vaccine After Priming With Live Attenuated Influenza Vaccine

Cited by 44 publications

References 41 publications

A Single Mutation at PB1 Residue 319 Dramatically Increases the Safety of PR8 Live Attenuated Influenza Vaccine in a Murine Model without Compromising Vaccine Efficacy

A Single Mutation at PB1 Residue 319 Dramatically Increases the Safety of PR8 Live Attenuated Influenza Vaccine in a Murine Model without Compromising Vaccine Efficacy

Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

Antigenic Fingerprinting of Antibody Response in Humans following Exposure to Highly Pathogenic H7N7 Avian Influenza Virus: Evidence for Anti-PA-X Antibodies

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