Discordant antigenic drift of neuraminidase and hemagglutinin in H1N1 and H3N2 influenza viruses

Sandbulte, Matthew R.; Westgeest, Kim B.; Gao, Jin; Xu, Xinhua; Klimov, Alexander; Russell, Colin A.; Burke, David F.; Smith, Derek J.; Fouchier, Ron A. M.; Eichelberger, Maryna C.

doi:10.1073/pnas.1113801108

Cited by 221 publications

(215 citation statements)

References 28 publications

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“…The wt pH1N1 virus A/California/07/2009 (CA/ 09) and vaccine candidate virus CA/09-X179A were propagated in 9-to 11-day-old embryonated chicken eggs and titrated in eggs or MadinDarby canine kidney (MDCK) cells. H6N1 BR/07 and H6N1 CA/09 reassortant viruses, which contain the hemagglutinin (HA) gene of H6N2 virus A/turkey/Massachusetts/3740/1965 and the NA gene of CA/09 or a seasonal H1N1 virus, A/Brisbane/59/2007 (BR/07), were rescued using reverse genetics (31) and grown in 9-to 11-day-old embryonated chicken eggs for determination of the inhibitory effect of antibodies. The viruses used for enzyme-linked immunosorbent assay (ELISA) were inactivated with ␤-propiolactone (Sigma-Aldrich, St. Louis, MO) and purified by sucrose gradient centrifugation.…”

Section: Methodsmentioning

confidence: 99%

Comparative Efficacy of Monoclonal Antibodies That Bind to Different Epitopes of the 2009 Pandemic H1N1 Influenza Virus Neuraminidase

Jiang

Fantoni

Couzens

et al. 2016

J Virol

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Antibodies against the neuraminidase (NA) of influenza virus correlate with resistance against disease, but the effectiveness of antibodies against different NA epitopes has not been compared. In the present study, we evaluated the in vitro and in vivo efficacies of four monoclonal antibodies (MAbs): HF5 and CD6, which are specific to two different epitopes in the NA of 2009 pandemic H1N1 (pH1N1) virus, and 4E9 and 1H5, which are specific to a conserved epitope in the NA of both H1N1 and H5N1 viruses. In the in vitro assays, HF5 and CD6 inhibited virus spread and growth more effectively than 4E9 and 1H5, with HF5 being the most effective inhibitor. When administered prophylactically at 5 mg/kg of body weight, HF5 and CD6 protected ϳ90 to 100% of DBA/2 mice against lethal wild-type pH1N1 virus challenge; however, at a lower dose (1 mg/kg), HF5 protected ϳ90% of mice, whereas CD6 protected only 25% of mice. 4E9 and 1H5 were less effective than HF5 and CD6, as indicated by the partial protection achieved even at doses as high as 15 mg/kg. When administered therapeutically, HF5 protected a greater proportion of mice against lethal pH1N1 challenge than CD6. However, HF5 quickly selected pH1N1 virus escape mutants in both prophylactic and therapeutic treatments, while CD6 did not. Our findings confirm the important role of NA-specific antibodies in immunity to influenza virus and provide insight into the properties of NA antibodies that may serve as good candidates for therapeutics against influenza. IMPORTANCENeuraminidase (NA) is one of the major surface proteins of influenza virus, serving as an important target for antivirals and therapeutic antibodies. The impact of NA-specific antibodies on NA activity and virus replication is likely to depend on where the antibody binds. Using in vitro assays and the mouse model, we compared the inhibitory/protective efficacy of four mouse monoclonal antibodies (MAbs) that bind to different sites within the 2009 pandemic H1N1 (pH1N1) virus NA. The ability of each MAb to protect mice against lethal pH1N1 infection corresponded to its ability to inhibit NA activity in vitro; however, the MAb that was the most effective inhibitor of NA activity selected pH1N1 escape variants in vivo. One of the tested MAbs, which binds to a conserved region in the NA of pH1N1 virus, inhibited NA activity but did not result in escape variants, highlighting its suitability for development as a therapeutic agent.

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Section: Methodsmentioning

confidence: 99%

Comparative Efficacy of Monoclonal Antibodies That Bind to Different Epitopes of the 2009 Pandemic H1N1 Influenza Virus Neuraminidase

Jiang

Fantoni

Couzens

et al. 2016

J Virol

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“…The narrow specificity of influenza NAbs, particularly those directed against the immunodominant hemagglutinin (HA) head, is problematic for protection against influenza viruses (14,15). However, in addition to neutralization, Abs can also mediate several functions through their Fc region, including complement-dependent cytotoxicity (CDC) (16,17), Ab-dependent cellular cytotoxicity (ADCC) (18)(19)(20)(21), and Ab-dependent phagocytosis (ADP) (22).…”

Section: Introductionmentioning

confidence: 99%

Fc functional antibodies in humans with severe H7N9 and seasonal influenza

Vanderven¹,

Liu²,

Ana-Sosa-Batiz³

et al. 2017

JCI Insight

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“…Vaccination with trivalent influenza vaccines (comprising split inactivated preparations of appropriate H1N1, H3N2, and type B virus strains) primarily induces protective hemagglutinin (HA)-specific neutralizing Abs (5,6). However, influenza surface HA proteins are highly susceptible to mutations, leading to loss of immune recognition overtime (antigenic drift), and therefore are required to be generated yearly (7,8). Additionally, vaccination is thought to provide weak protection against emerging reassortant influenza viruses with novel HA proteins (antigenic shift), which has historically led to significant worldwide influenza pandemics (9).…”

mentioning

confidence: 99%

Cross-Reactive Influenza-Specific Antibody-Dependent Cellular Cytotoxicity Antibodies in the Absence of Neutralizing Antibodies

Jegaskanda

Job

Kramski

et al. 2013

The Journal of Immunology

203

202

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A better understanding of immunity to influenza virus is needed to generate cross-protective vaccines. Engagement of Ab-dependent cellular cytotoxicity (ADCC) Abs by NK cells leads to killing of virus-infected cells and secretion of antiviral cytokines and chemokines. ADCC Abs may target more conserved influenza virus Ags compared with neutralizing Abs. There has been minimal interest in influenza-specific ADCC in recent decades. In this study, we developed novel assays to assess the specificity and function of influenza-specific ADCC Abs. We found that healthy influenza-seropositive young adults without detectable neutralizing Abs to the hemagglutinin of the 1968 H3N2 influenza strain (A/Aichi/2/1968) almost always had ADCC Abs that triggered NK cell activation and in vitro elimination of influenza-infected human blood and respiratory epithelial cells. Furthermore, we detected ADCC in the absence of neutralization to both the recent H1N1 pandemic strain (A/California/04/2009) as well as the avian H5N1 influenza hemagglutinin (A/Anhui/01/2005). We conclude that there is a remarkable degree of cross-reactivity of influenza-specific ADCC Abs in seropositive humans. Targeting cross-reactive influenza-specific ADCC epitopes by vaccination could lead to improved influenza vaccines.

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Discordant antigenic drift of neuraminidase and hemagglutinin in H1N1 and H3N2 influenza viruses

Cited by 221 publications

References 28 publications

Comparative Efficacy of Monoclonal Antibodies That Bind to Different Epitopes of the 2009 Pandemic H1N1 Influenza Virus Neuraminidase

Comparative Efficacy of Monoclonal Antibodies That Bind to Different Epitopes of the 2009 Pandemic H1N1 Influenza Virus Neuraminidase

Fc functional antibodies in humans with severe H7N9 and seasonal influenza

Cross-Reactive Influenza-Specific Antibody-Dependent Cellular Cytotoxicity Antibodies in the Absence of Neutralizing Antibodies

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