scholarly journals Publisher Correction: Natural and directed antigenic drift of the H1 influenza virus hemagglutinin stalk domain

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Christopher S. Anderson ◽  
Sandra Ortega ◽  
Francisco A. Chaves ◽  
Amelia M. Clark ◽  
Hongmei Yang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antigenic Drift ◽  
Influenza Virus Hemagglutinin ◽  
Stalk Domain

scholarly journals Publisher Correction: Natural and directed antigenic drift of the H1 influenza virus hemagglutinin stalk domain

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Christopher S. Anderson ◽  
Sandra Ortega ◽  
Francisco A. Chaves ◽  
Amelia M. Clark ◽  
Hongmei Yang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antigenic Drift ◽  
Influenza Virus Hemagglutinin ◽  
Stalk Domain

scholarly journals Natural and directed antigenic drift of the H1 influenza virus hemagglutinin stalk domain

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Christopher S. Anderson ◽  
Sandra Ortega ◽  
Francisco A. Chaves ◽  
Amelia M. Clark ◽  
Hongmei Yang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Fitness ◽  
Antigenic Drift ◽  
Virus Infections ◽  
Head Region ◽  
Immune Pressure ◽  
Stalk Domain ◽  
Ha Protein

Abstract The induction of antibodies specific for the influenza HA protein stalk domain is being pursued as a universal strategy against influenza virus infections. However, little work has been done looking at natural or induced antigenic variability in this domain and the effects on viral fitness. We analyzed human H1 HA head and stalk domain sequences and found substantial variability in both, although variability was highest in the head region. Furthermore, using human immune sera from pandemic A/California/04/2009 immune subjects and mAbs specific for the stalk domain, viruses were selected in vitro containing mutations in both domains that partially contributed to immune evasion. Recombinant viruses encoding amino acid changes in the HA stalk domain replicated well in vitro, and viruses incorporating two of the stalk mutations retained pathogenicity in vivo. These findings demonstrate that the HA protein stalk domain can undergo limited drift under immune pressure and the viruses can retain fitness and virulence in vivo, findings which are important to consider in the context of vaccination targeting this domain.

scholarly journals Mutations in the Hemagglutinin Stalk Domain Do Not Permit Escape from a Protective, Stalk-Based Vaccine-Induced Immune Response in the Mouse Model

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ericka Kirkpatrick Roubidoux ◽  
Juan Manuel Carreño ◽  
Meagan McMahon ◽  
Kaijun Jiang ◽  
Harm van Bakel ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Mouse Model ◽  
Selection Pressure ◽  
Cross Reactivity ◽  
Antigenic Drift ◽  
Escape Mutant ◽  
Induced Response ◽  
Lethal Challenge ◽  
Stalk Domain

ABSTRACT Current seasonal influenza virus vaccines target regions of the hemagglutinin (HA) head domain that undergo constant antigenic change, forcing the painstaking annual reformulation of vaccines. The development of broadly protective or universal influenza virus vaccines that induce cross-reactive, protective immune responses could circumvent the need to reformulate current seasonal vaccines. Many of these vaccine candidates target the HA stalk domain, which displays epitopes conserved within and across influenza virus subtypes, including those with pandemic potential. While HA head-mediated antigenic drift is well understood, the potential for antigenic drift in the stalk domain is understudied. Using a panel of HA stalk-specific monoclonal antibodies (MAbs), we applied selection pressure to the stalk domain of A/Netherlands/602/2009 (pdmH1N1) to determine fitness and phenotypes of escape mutant viruses (EMVs). We found that HA stalk MAbs with lower cross-reactivity caused single HA stalk escape mutations, whereas MAbs with broader cross-reactivity forced multiple mutations in the HA. Each escape mutant virus greatly decreased mAb neutralizing activity, but escape mutations did not always ablate MAb binding or Fc-Fc receptor-based effector functions. Escape mutant viruses were not attenuated in vitro but showed attenuation in an in vivo mouse model. Importantly, mice vaccinated with a chimeric HA universal vaccine candidate were protected from lethal challenge with EMVs despite these challenge viruses containing escape mutations in the stalk domain. Our study indicates that while the HA stalk domain can mutate under strong MAb selection pressure, mutant viruses may have attenuated phenotypes and do not evade a polyclonal, stalk-based vaccine-induced response. IMPORTANCE Broadly protective or universal influenza virus vaccines target viral epitopes that appear to be conserved. However, it is unclear whether the virus will be able to escape once immunological pressure is applied to these epitopes through vaccination of large proportions of the population. Studies that investigate the fitness and antigenic characteristics of viruses that escape immunological pressure on these conserved epitopes are therefore urgently needed.

scholarly journals Disulfide bond formation during the folding of influenza virus hemagglutinin.

1992 ◽  
Vol 118 (2) ◽  
pp. 227-244 ◽  
Author(s):  
M S Segal ◽  
J M Bye ◽  
J F Sambrook ◽  
M J Gething
Keyword(s):  
Influenza Virus ◽  
Disulfide Bonds ◽  
Intracellular Transport ◽  
Cellular Protein ◽  
Cysteine Residues ◽  
Mutant Proteins ◽  
Influenza Virus Hemagglutinin ◽  
Stalk Domain ◽  
Do So

To study the importance of individual sulfhydryl residues during the folding and assembly in vivo of influenza virus hemagglutinin (HA), we have constructed and expressed a series of mutant HA proteins in which cysteines involved in three disulfide bonds have been substituted by serine residues. Investigations of the structure and intracellular transport of the mutant proteins indicate that (a) cysteine residues in the ectodomain are essential both for efficient folding of HA and for stabilization of the folded molecule; (b) cysteine residues in the globular portion of the ectodomain are likely to form native disulfide bonds rapidly and directly, without involvement of intermediate, nonnative linkages; and (c) cysteine residues in the stalk portion of the ectodomain also appear not to form intermediate disulfide bonds, even though they have the opportunity to do so, being separated from their correct partners by hundreds of amino acids including two or more other sulfhydryl residues. We propose a role for the cellular protein BiP in shielding the cysteine residues of the stalk domain during the folding process, thus preventing them from forming intermediate, nonnative disulfide bonds.

scholarly journals The Long Road to a Universal Influenza Virus Vaccine

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 125
Author(s):  
Peter Palese
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Influenza A ◽  
Influenza Virus Vaccine ◽  
Antigenic Drift ◽  
Surface Glycoprotein ◽  
Influenza B ◽  
Virus Infections ◽  
Stalk Domain

Seasonal and pandemic influenza virus infections can cause significant disease worldwide. Current vaccines only provide limited, short-lived protection, and antigenic drift/shift in the hemagglutinin (HA) surface glycoprotein necessitates their annual reformulation and re-administration. To overcome these limitations, universal influenza virus vaccine strategies aim at eliciting broadly protective antibodies to conserved epitopes of the HA. We have developed two approaches. (1) The first is based on “chimeric” HA constructs that retain the conserved stalk domain of the HA and have exotic HA heads. Vaccination and boosting with such constructs successfully redirects the immune system in animals and in humans towards the conserved immune sub-dominant domains of the HA stalks; this results in an antigenic silencing of the HA heads and a protective immune response facilitated by the conserved HA stalks. In mice and ferrets, such a strategy protects the animals against homo-subtypic and hetero-subtypic challenge with influenza A strains as well as against influenza B variants. It is hoped that vaccine constructs expressing three components (i.e., conserved group 1 HA stalks, conserved group 2 HA stalks, and conserved influenza B HA stalks) will be protective against all future seasonal and pandemic strains. (2) The “mosaic” HA approach is based on antigenic silencing of the major immunodominant antigenic sites of the HA heads by only replacing those epitopes with corresponding sequences of exotic avian HAs, yielding “mosaic” HAs. In mice, a prime-boost vaccination regime with inactivated viruses expressing “mosaic” HAs elicited highly cross-reactive antibodies against the stalk domain of the HAs that were capable of eliciting Fc-mediated effector functions in vitro. Extensive trials will be necessary in the future in order to identify the optimal vaccination regime (“chimeric” HA-based versus “mosaic” HA-based) in humans.

scholarly journals Pandemic influenza virus vaccines boost hemagglutinin stalk-specific antibody responses in primed adult and pediatric cohorts

npj Vaccines ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Raffael Nachbagauer ◽  
Bruno Salaun ◽  
Daniel Stadlbauer ◽  
Mohammad A. Behzadi ◽  
Damien Friel ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Pandemic Influenza ◽  
Influenza Virus Vaccine ◽  
Cross Reactivity ◽  
Antigenic Drift ◽  
Lethal Challenge ◽  
Cell Responses ◽  
Adults And Children ◽  
Stalk Domain

AbstractLicensed influenza virus vaccines target the head domain of the hemagglutinin (HA) glycoprotein which undergoes constant antigenic drift. The highly conserved HA stalk domain is an attractive target to increase immunologic breadth required for universal influenza virus vaccines. We tested the hypothesis that immunization with a pandemic influenza virus vaccine boosts pre-existing anti-stalk antibodies. We used chimeric cH6/1, full length H2 and H18 HA antigens in an ELISA to measure anti-stalk antibodies in recipients participating in clinical trials of A/H1N1, A/H5N1 and A/H9N2 vaccines. The vaccines induced high titers of anti-H1 stalk antibodies in adults and children, with higher titers elicited by AS03-adjuvanted vaccines. We also observed cross-reactivity to H2 and H18 HAs. The A/H9N2 vaccine elicited plasmablast and memory B-cell responses. Post-vaccination serum from vaccinees protected mice against lethal challenge with cH6/1N5 and cH5/3N4 viruses. These findings support the concept of a chimeric HA stalk-based universal influenza virus vaccine. clinicaltrials.gov: NCT02415842.

scholarly journals Identification and Characterization of Novel Antibody Epitopes on the N2 Neuraminidase

mSphere ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ericka Kirkpatrick Roubidoux ◽  
Meagan McMahon ◽  
Juan Manuel Carreño ◽  
Christina Capuano ◽  
Kaijun Jiang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Vaccine Development ◽  
Viral Fitness ◽  
Antigenic Drift ◽  
H3n2 Virus ◽  
Escape Mutant ◽  
Influenza Virus Hemagglutinin ◽  
Influenza Virus Neuraminidase ◽  
Antibody Epitopes

ABSTRACT The influenza virus neuraminidase (NA) is becoming a focus for novel vaccine designs. However, the epitopes of human anti-NA antibodies have been poorly defined. Using a panel of 10 anti-N2 monoclonal antibodies (MAbs) that bind the H3N2 virus A/Switzerland/9715293/2013, we generated five escape mutant viruses. These viruses contained mutations K199E/T, E258K, A272D, and S331N. We found that mutations at K199 and E258 had the largest impact on MAb binding, NA inhibition and neutralization activity. In addition, a natural isolate from the 2017-2018 season was found to contain the E258K mutation and was resistant to numerous antibodies tested. The mutation S331N, was identified in virus passaged in the presence of antibody; however, it had little impact on MAb activity and greatly decreased viral fitness. This information aids in identifying novel human MAb epitopes on the N2 and helps with the detection of antigenically drifted NAs. IMPORTANCE The influenza virus neuraminidase is an emerging target for universal influenza virus vaccines. However, in contrast to influenza virus hemagglutinin, we know little about antibody epitopes and antigenic sites on the neuraminidase. Characterizing and defining these sites is aiding vaccine development and helping to understand antigenic drift of NA.

scholarly journals The influenza virus hemagglutinin head evolves faster than the stalk domain

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Ericka Kirkpatrick ◽  
Xueting Qiu ◽  
Patrick C. Wilson ◽  
Justin Bahl ◽  
Florian Krammer
Keyword(s):  
Influenza Virus ◽  
Influenza Virus Hemagglutinin ◽  
Stalk Domain

scholarly journals Original antigenic sin priming of influenza virus hemagglutinin stalk antibodies

2020 ◽  
Vol 117 (29) ◽  
pp. 17221-17227 ◽  
Author(s):  
Claudia P. Arevalo ◽  
Valerie Le Sage ◽  
Marcus J. Bolton ◽  
Theresa Eilola ◽  
Jennifer E. Jones ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antibody Response ◽  
Influenza A ◽  
Influenza Viruses ◽  
Antibody Responses ◽  
Virus Infections ◽  
Universal Vaccine ◽  
Influenza Virus Hemagglutinin ◽  
Stalk Domain ◽  
Original Antigenic Sin

Immunity to influenza viruses can be long-lived, but reinfections with antigenically distinct viral strains and subtypes are common. Reinfections can boost antibody responses against viral strains first encountered in childhood through a process termed “original antigenic sin.” It is unknown how initial childhood exposures affect the induction of antibodies against the hemagglutinin (HA) stalk domain of influenza viruses. This is an important consideration since broadly reactive HA stalk antibodies can protect against infection, and universal vaccine platforms are being developed to induce these antibodies. Here we show that experimentally infected ferrets and naturally infected humans establish strong “immunological imprints” against HA stalk antigens first encountered during primary influenza virus infections. We found that HA stalk antibodies are surprisingly boosted upon subsequent infections with antigenically distinct influenza A virus subtypes. Paradoxically, these heterosubtypic-boosted HA stalk antibodies do not bind efficiently to the boosting influenza virus strain. Our results demonstrate that an individual’s HA stalk antibody response is dependent on the specific subtype of influenza virus that they first encounter early in life. We propose that humans are susceptible to heterosubtypic influenza virus infections later in life since these viruses boost HA stalk antibodies that do not bind efficiently to the boosting antigen.

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