Assessment of Influenza Virus Hemagglutinin Stalk-Based Immunity in Ferrets

Krammer, Florian; Hai, Rong; Yondola, Mark A.; Tan, Gene S.; Leyva-Grado, Victor H.; Ryder, Alex B.; Miller, Matthew S.; Rose, John K.; Palese, Peter; García‐Sastre, Adolfo; Albrecht, Randy A.

doi:10.1128/jvi.03004-13

Cited by 128 publications

(136 citation statements)

References 67 publications

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“…In this study, the ferrets were sequentially infected with sH1N1 isolates via the intranasal route. In contrast, Krammer et al initially infected the ferrets with a cHA-expressing influenza B virus via the intranasal route; but the second virus exposure was via the intramuscular route, and the third virus exposure utilized a replication-deficient viral vector (43). In support of the role(s) for route of administration and infection regimen, the initial production of HA stalk-specific antibody requires viral replication, and the magnitude of the boost correlates with the replication capacity of the second virus (25).…”

Section: Discussionmentioning

confidence: 99%

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Sequential Infection in Ferrets with Antigenically Distinct Seasonal H1N1 Influenza Viruses Boosts Hemagglutinin Stalk-Specific Antibodies

Kirchenbaum

Carter

Ross

2016

J Virol

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Broadly reactive antibodies targeting the conserved hemagglutinin (HA) stalk region are elicited following sequential infection or vaccination with influenza viruses belonging to divergent subtypes and/or expressing antigenically distinct HA globular head domains. Here, we demonstrate, through the use of novel chimeric HA proteins and competitive binding assays, that sequential infection of ferrets with antigenically distinct seasonal H1N1 (sH1N1) influenza virus isolates induced an HA stalk-specific antibody response. Additionally, stalk-specific antibody titers were boosted following sequential infection with antigenically distinct sH1N1 isolates in spite of preexisting, cross-reactive, HA-specific antibody titers. Despite a decline in stalk-specific serum antibody titers, sequential sH1N1 influenza virus-infected ferrets were protected from challenge with a novel H1N1 influenza virus (A/California/07/2009), and these ferrets poorly transmitted the virus to naive contacts. Collectively, these findings indicate that HA stalk-specific antibodies are commonly elicited in ferrets following sequential infection with antigenically distinct sH1N1 influenza virus isolates lacking HA receptor-binding site cross-reactivity and can protect ferrets against a pathogenic novel H1N1 virus. IMPORTANCE The influenza virus hemagglutinin (HA) is a major target of the humoral immune response following infection and The influenza virus is highly contagious and causes an acute respiratory illness, with seasonal epidemics in the human population. Despite global vaccination efforts, influenza remains a major medical issue and is responsible for substantial morbidity and mortality annually. It is estimated that 5 to 20% of the people in the United States contract influenza virus annually, and more than 200,000 people require hospitalization due to influenza-related complications (according to the Centers for Disease Control and Prevention, Atlanta, GA [http://www.cdc.gov/flu/about/qa /disease.htm; accessed 1 September 2015]). The young, the elderly, pregnant females, and those with certain medical conditions are at an increased risk for influenza-associated complications.Current vaccination approaches primarily rely on the induction of antibodies recognizing hemagglutinin (HA) (1). The HA glycoprotein is expressed as a trimeric complex of identical subunits on the surface of influenza virus virions. HA mediates virus attachment and subsequent membrane fusion with target cells (2, 3). Individual HA monomers can be further segregated into the membrane-distal globular head and membrane-proximal stalk domains. The globular head encodes the receptor-binding site (RBS), and the stalk domain encodes the fusion peptide (2).Antibodies directed against HA and, more specifically, to epitopes in close proximity to the RBS within the globular head region are elicited following infection or vaccination (4). These antibodies possess a potent neutralization capacity through the ability to interfere with viral attachment to target cells and a...

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Section: Discussionmentioning

confidence: 99%

“…A variety of approaches for eliciting HA stalkspecific antibody responses have been evaluated in animal models with various degrees of success (43,(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). Collectively, these approaches aim to elicit HA stalk-specific responses through tactics that subvert HA globular head immunodominance.…”

Section: Discussionmentioning

confidence: 99%

Sequential Infection in Ferrets with Antigenically Distinct Seasonal H1N1 Influenza Viruses Boosts Hemagglutinin Stalk-Specific Antibodies

Kirchenbaum

Carter

Ross

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). These strategies are now being tested as promising "universal" influenza virus vaccine candidates (16).…”

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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165

163

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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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“…The stem region is highly conserved among influenza viruses, and anti-stem Abs tend to mediate their neutralization activity by either blocking viral fusion with, or preventing cleavage of, the HA protein (24,25). Vaccine regimens that target the HA stem region have given promising results in mouse models but have yet to be translated into human clinical studies (26)(27)(28).…”

mentioning

confidence: 99%

Influenza-Specific Antibody-Dependent Cellular Cytotoxicity: Toward a Universal Influenza Vaccine

Jegaskanda

Reading

Kent

2014

The Journal of Immunology

116

137

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There is an urgent need for universal influenza vaccines that can control emerging pandemic influenza virus threats without the need to generate new vaccines for each strain. Neutralizing Abs to the influenza virus hemagglutinin glycoprotein are effective at controlling influenza infection but generally target highly variable regions. Abs that can mediate other functions, such as killing influenza-infected cells and activating innate immune responses (termed “Ab-dependent cellular cytotoxicity [ADCC]-mediating Abs”), may assist in protective immunity to influenza. ADCC-mediating Abs can target more conserved regions of influenza virus proteins and recognize a broader array of influenza strains. We review recent research on influenza-specific ADCC Abs and their potential role in improved influenza-vaccination strategies.

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Assessment of Influenza Virus Hemagglutinin Stalk-Based Immunity in Ferrets

Cited by 128 publications

References 67 publications

Sequential Infection in Ferrets with Antigenically Distinct Seasonal H1N1 Influenza Viruses Boosts Hemagglutinin Stalk-Specific Antibodies

Sequential Infection in Ferrets with Antigenically Distinct Seasonal H1N1 Influenza Viruses Boosts Hemagglutinin Stalk-Specific Antibodies

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

Influenza-Specific Antibody-Dependent Cellular Cytotoxicity: Toward a Universal Influenza Vaccine

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