Host Genetic Variation Affects Resistance to Infection with a Highly Pathogenic H5N1 Influenza A Virus in Mice

Boon, Adrianus C. M.; DeBeauchamp, Jennifer; Hollmann, A; Luke, Jennifer a.; Kotb, Malak; Rowe, Sarah; Finkelstein, David; Neale, Geoffrey; Lu, Lu; Williams, Robert W.; Webby, Richard J.

doi:10.1128/jvi.00514-09

Cited by 157 publications

(185 citation statements)

References 50 publications

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“…Thus, we performed prophylaxis studies in complement-deficient DBA mice, which are highly sensitive to influenza challenge due to a deficiency in complement (C=5) of the complement pathway (19,20). DBA mice were treated with 1.7 mg/kg of CR9114, CR6261, or CR-JB (isotype control) or vehicle and challenged with 25 MLD 50 of AA60.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Neutralization Is Not Predictive of Prophylactic Efficacy of Broadly Neutralizing Monoclonal Antibodies CR6261 and CR9114 against Lethal H2 Influenza Virus Challenge in Mice

Sutton

Lamirande

Bock

et al. 2017

J Virol

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Influenza viruses of the H1N1, H2N2, and H3N2 subtypes have caused previous pandemics. H2 influenza viruses represent a pandemic threat due to continued circulation in wild birds and limited immunity in the human population. In the event of a pandemic, antiviral agents are the mainstay for treatment, but broadly neutralizing antibodies (bNAbs) may be a viable alternative for short-term prophylaxis or treatment. The hemagglutinin stem binding bNAbs CR6261 and CR9114 have been shown to protect mice from severe disease following challenge with H1N1 and H5N1 and with H1N1, H3N2, and influenza B viruses, respectively. Early studies with CR6261 and CR9114 showed weak in vitro activity against human H2 influenza viruses, but the in vivo efficacy against H2 viruses is unknown. Therefore, we evaluated these antibodies against human-and animal-origin H2 viruses A/Ann Arbor/6/1960 (H2N2) (AA60) and A/swine/MO/4296424/ 06 (H2N3) (Sw06). In vitro, CR6261 neutralized both H2 viruses, while CR9114 only neutralized Sw06. To evaluate prophylactic efficacy, mice were given CR6261 or CR9114 and intranasally challenged 24 h later with lethal doses of AA60 or Sw06. Both antibodies reduced mortality, weight loss, airway inflammation, and pulmonary viral load. Using engineered bNAb variants, antibody-mediated cell cytotoxicity reporter assays, and Fc␥ receptor-deficient (Fcer1g Ϫ/Ϫ ) mice, we show that the in vivo efficacy of CR9114 against AA60 is mediated by Fc␥ receptor-dependent mechanisms. Collectively, these findings demonstrate the in vivo efficacy of CR6261 and CR9114 against H2 viruses and emphasize the need for in vivo evaluation of bNAbs.IMPORTANCE bNAbs represent a strategy to prevent or treat infection by a wide range of influenza viruses. The evaluation of these antibodies against H2 viruses is important because H2 viruses caused a pandemic in 1957 and could cross into humans again. We demonstrate that CR6261 and CR9114 are effective against infection with H2 viruses of both human and animal origin in mice, despite the finding that CR9114 did not display in vitro neutralizing activity against the human H2 virus. These findings emphasize the importance of in vivo evaluation and testing of bNAbs. KEYWORDS H2 influenza virus, broadly neutralizing antibodies, prophylaxis, in vivo evaluation, antibody function, influenza, influenza vaccines I nfluenza pandemics occur when an antigenically novel subtype from the avian reservoir or pigs is introduced and spreads in a susceptible human population. In the last century, H1N1, H2N2, and H3N2 influenza A viruses have caused pandemics. After

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Section: Resultsmentioning

confidence: 99%

In Vitro Neutralization Is Not Predictive of Prophylactic Efficacy of Broadly Neutralizing Monoclonal Antibodies CR6261 and CR9114 against Lethal H2 Influenza Virus Challenge in Mice

Sutton

Lamirande

Bock

et al. 2017

J Virol

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“…Additionally, the DBA mouse has been found to have much higher susceptibility to influenza infection than either C56BL/6 or BALB/c mice (5,6). A variety of influenza viruses, including H5N1 and influenza B viruses, have been shown to be lethal to DBA mice without prior adaptation (7,8).…”

mentioning

confidence: 99%

A broadly neutralizing human monoclonal antibody is effective against H7N9

Tharakaraman

Subramanian

Viswanathan

et al. 2015

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

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Emerging strains of influenza represent a significant public health threat with potential pandemic consequences. Of particular concern are the recently emerged H7N9 strains which cause pneumonia with acute respiratory distress syndrome. Estimates are that nearly 80% of hospitalized patients with H7N9 have received intensive care unit support. VIS410, a human antibody, targets a unique conserved epitope on influenza A. We evaluated the efficacy of VIS410 for neutralization of group 2 influenza strains, including H3N2 and H7N9 strains in vitro and in vivo. VIS410, administered at 50 mg/kg, protected DBA mice infected with A/Anhui/2013 (H7N9), resulting in significant survival benefit upon single-dose (−24 h) or double-dose (−12 h, +48 h) administration (P < 0.001). A single dose of VIS410 at 50 mg/kg (−12 h) combined with oseltamivir at 50 mg/kg (−12 h, twice daily for 7 d) in C57BL/6 mice infected with A/Shanghai 2/2013 (H7N9) resulted in significant decreased lung viral load (P = 0.002) and decreased lung cytokine responses for nine of the 11 cytokines measured. Based on these results, we find that VIS410 may be effective either as monotherapy or combined with antivirals in treating H7N9 disease, as well as disease from other influenza strains.

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“…In this study, lower levels of IFNαβ induced by the 1918 strain are associated with higher levels of IL--6 and other pro--inflammatory cytokines. A more recent study correlates susceptibility or resistance to the same H5N1 virus in back crosses of different mouse strains and describes that susceptibility correlates directly with levels of pro--inflammatory cytokines and inversely with IFNαβ levels [33].…”

Section: Cytokines Involved In the Innate Immune Response Type I And mentioning

confidence: 99%

Contribution of cytokines to pathology and protection in virus infection

Wack¹,

Openshaw

O’Garra³

2011

Current Opinion in Virology

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Acute and chronic viral infections greatly contribute to global health burden.While concerted action of multiple elements of the immune system help the host cope with most viruses, some infections lead to host damage or death. Cytokines are central drivers and controllers of both immune--mediated virus elimination and of immunopathology. Here, we review recent progress in understanding the protective and damaging roles in viral infections of cytokines and chemokines associated with innate, regulatory, and Th1, Th2 and Th17 responses. Addresses:

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Host Genetic Variation Affects Resistance to Infection with a Highly Pathogenic H5N1 Influenza A Virus in Mice

Cited by 157 publications

References 50 publications

In Vitro Neutralization Is Not Predictive of Prophylactic Efficacy of Broadly Neutralizing Monoclonal Antibodies CR6261 and CR9114 against Lethal H2 Influenza Virus Challenge in Mice

In Vitro Neutralization Is Not Predictive of Prophylactic Efficacy of Broadly Neutralizing Monoclonal Antibodies CR6261 and CR9114 against Lethal H2 Influenza Virus Challenge in Mice

A broadly neutralizing human monoclonal antibody is effective against H7N9

Contribution of cytokines to pathology and protection in virus infection

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