a/h7n9 – ETIDIoH

Highly pathogenic #avian #influenza A/Guangdong/17SF003/2016 is #immunogenic and induces cross-protection against antigenically divergent #H7N9 viruses (npj Vaccines, abstract)

[Source: npj Vaccines, full page: (LINK). Abstract, edited.]

Highly pathogenic avian influenza A/Guangdong/17SF003/2016 is immunogenic and induces cross-protection against antigenically divergent H7N9 viruses

Peter Radvak, Martina Kosikova, Yuan-Chia Kuo, Xing Li, Richard Garner, Falko Schmeisser, Ivan Kosik, Zhiping Ye, Jerry P. Weir, Jonathan W. Yewdell & Hang Xie

npj Vaccines volume 6, Article number: 30 (2021)

Abstract

Avian influenza A(H7N9) epidemics have a fatality rate of approximately 40%. Previous studies reported that low pathogenic avian influenza (LPAI)-derived candidate vaccine viruses (CVVs) are poorly immunogenic. Here, we assess the immunogenicity and efficacy of a highly pathogenic avian influenza (HPAI) A/Guangdong/17SF003/2016 (GD/16)-extracted hemagglutinin (eHA) vaccine. GD/16 eHA induces robust H7-specific antibody responses in mice with a marked adjuvant antigen-sparing effect. Mice immunized with adjuvanted GD/16 eHA are protected from the lethal LPAI and HPAI H7N9 challenges, in stark contrast to low antibody titers and high mortality in mice receiving adjuvanted LPAI H7 eHAs. The protection correlates well with the magnitude of the H7-specific antibody response (IgG and microneutralization) or HA group 2 stem-specific IgG. Inclusion of adjuvanted GD/16 eHA in heterologous prime-boost improves the immunogenicity and protection of LPAI H7 HAs in mice. Our findings support the inclusion of GD/16-derived CVV in the pandemic preparedness vaccine stockpile.

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Keywords: Avian Influenza; H7N9; Vaccines; Pandemic Preparedness.

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Immunogenicity and safety of different dose schedules and #antigen doses of an #MF59-adjuvanted #H7N9 #vaccine in healthy adults aged 65 years and older (Vaccine, abstract)

[Source: Vaccine, full page: (LINK). Abstract, edited.]

Vaccine | Available online 21 January 2021 | In Press, Corrected Proof

Immunogenicity and safety of different dose schedules and antigen doses of an MF59-adjuvanted H7N9 vaccine in healthy adults aged 65 years and older

Patricia Winokur a, Hana M. El Sahly b, Mark J. Mulligan c, Sharon E. Frey d, Richard Rupp e, Evan J. Anderson m, Kathryn M. Edwards f, David I. Bernstein g, Kenneth Schmader h, Lisa A. Jackson i, Wilbur H. Chen j, Heather Hill k, Abigail Bellamy k, the DMID 13-0034 H7N9 Vaccine Study Group

a Division of Infectious Diseases, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, United States; b Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States; c The Hope Clinic of the Emory Vaccine Center, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States; d Department of Medicine, Saint Louis University School of Medicine, Saint Louis, MO, United States; e Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, United States; m Emory Children’s Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States; f Department of Pediatrics, Vanderbilt Vaccine Research Program, Vanderbilt University, Nashville, TN, United States; g Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, United States; h Duke University, United States; i Kaiser Permanente Washington Health Research Institute, Seattle, WA, United States; j Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States; k The Emmes Corporation, Rockville, MD, United States

Received 28 February 2020, Revised 10 November 2020, Accepted 14 November 2020, Available online 21 January 2021.

DOI: https://doi.org/10.1016/j.vaccine.2020.11.051

Abstract

Background

The number of human influenza A (H7N9) infections has escalated since 2013 with high resultant mortality. We conducted a phase II, randomized, partially-blinded trial to evaluate the safety and immunogenicity of an MF59-adjuvanted inactivated, split virion, H7N9 influenza vaccine (H7N9 IIV) administered at various dose levels and schedules in older adults.

Methods

479 adults ≥ 65 years of age in stable health were randomized to one of six groups to receive either 3.75, 7.5 or 15 µg of influenza A/Shanghai/02/2013 (H7N9) IIV adjuvanted with MF59 given as a 3-dose series either on days 1, 28 and 168 or on days 1, 57 and 168. Immunogenicity was assessed using both hemagglutination inhibition (HAI) and microneutralization (MN) assays prior to and 28 days following each dose. Safety was assessed through 1 year following the last dose.

Results

Subjects in all groups had only modest immune responses, with the HAI GMT < 20 after the second vaccine dose and <29 after the third vaccine dose. HAI titers ≥ 40 were seen in <37% of subjects after the second dose and <49% after the third dose. There were no significant differences seen between the two dose schedules. MN titers followed similar patterns, although the titers were approximately two-fold higher than the HAI titers. Logistic regression modeling demonstrated no statistically significant associations between the immune responses and age, sex or body mass index whereas recent prior receipt of seasonal influenza vaccine significantly reduced the HAI response [OR 0.13 (95% CI 0.05, 0.33); p < 0.001]. Overall, the vaccine was well tolerated. Two mild potentially immune mediated adverse events occurred, lichen planus and guttate psoriasis.

Conclusions

MF59-adjuvanted H7N9 IIV was only modestly immunogenic in the older adult population following three doses. There were no significant differences in antibody responses noted among the various antigen doses or the two dose schedules.

Keywords: Avian influenza – influenza vaccine – MF59 – H7N9

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Keywords: Avian Influenza; H7N9; Vaccines.

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#Glycosylation generates an efficacious and immunogenic #vaccine against #H7N9 #influenza virus (PLOS Biol., abstract)

[Source: PLOS Biology, full page: (LINK). Abstract, edited.]

OPEN ACCESS | PEER-REVIEWED | RESEARCH ARTICLE

Glycosylation generates an efficacious and immunogenic vaccine against H7N9 influenza virus

Jin Il Kim , Sehee Park , Joon-Yong Bae, Sunmi Lee, Jeonghun Kim, Gayeong Kim, Kirim Yoo, Jun Heo, Yong Seok Kim, Jae Soo Shin, Mee Sook Park, Man-Seong Park

Published: December 23, 2020 | DOI: https://doi.org/10.1371/journal.pbio.3001024

Abstract

Zoonotic avian influenza viruses pose severe health threats to humans. Of several viral subtypes reported, the low pathogenic avian influenza H7N9 virus has since February 2013 caused more than 1,500 cases of human infection with an almost 40% case-fatality rate. Vaccination of poultry appears to reduce human infections. However, the emergence of highly pathogenic strains has increased concerns about H7N9 pandemics. To develop an efficacious H7N9 human vaccine, we designed vaccine viruses by changing the patterns of N-linked glycosylation (NLG) on the viral hemagglutinin (HA) protein based on evolutionary patterns of H7 HA NLG changes. Notably, a virus in which 2 NLG modifications were added to HA showed higher growth rates in cell culture and elicited more cross-reactive antibodies than did other vaccine viruses with no change in the viral antigenicity. Developed into an inactivated vaccine formulation, the vaccine virus with 2 HA NLG additions exhibited much better protective efficacy against lethal viral challenge in mice than did a vaccine candidate with wild-type (WT) HA by reducing viral replication in the lungs. In a ferret model, the 2 NLG-added vaccine viruses also induced hemagglutination-inhibiting antibodies and significantly suppressed viral replication in the upper and lower respiratory tracts compared with the WT HA vaccines. In a mode of action study, the HA NLG modification appeared to increase HA protein contents incorporated into viral particles, which would be successfully translated to improve vaccine efficacy. These results suggest the strong potential of HA NLG modifications in designing avian influenza vaccines.

Citation: Kim JI, Park S, Bae J-Y, Lee S, Kim J, Kim G, et al. (2020) Glycosylation generates an efficacious and immunogenic vaccine against H7N9 influenza virus. PLoS Biol 18(12): e3001024. https://doi.org/10.1371/journal.pbio.3001024

Academic Editor: Sarah L. Rowland-Jones, Weatherall Institute of Molecular Medicine, UNITED KINGDOM

Received: May 6, 2020; Accepted: November 24, 2020; Published: December 23, 2020

Copyright: © 2020 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting information files.

Funding: This study is supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI16C0976; JIK) and from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT, Republic of Korea (Grant No. NRF-2018M3A9H4056537; M-SP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: ANOVA, analysis of variance; Asn, asparagine; BSA, bovine serum albumin; CBER, Center for Biologics Evaluation and Research; DMEM, Dulbecco’s Modified Eagle Medium; dpi, days post-infection; GMT, geometric mean titer; HA, hemagglutinin; HAU, hemagglutination unit; HI, hemagglutination inhibition; HPAI, highly pathogenic avian influenza; hpi, hours post-infection; HRP, horseradish peroxidase; IACUC, Institutional Animal Care and Use Committee; IAV, influenza A virus; MDCK, Madin-Darby canine kidney; MEME, Minimum Essential Medium Eagle; MLD50, 50% mouse lethal dose; MOI, multiplicity of infection; NA, neuraminidase; NCBI, National Center for Biotechnology Information; NLG, N-linked glycosylation; NP, nucleoprotein; PBS, phosphate-buffered saline; PFU, plaque-forming unit; PRNT, plaque-reduction neutralization test; RBS, receptor-binding site; RDE, receptor-destroying enzyme; RT-PCR, reverse transcription polymerase chain reaction; SA, sialic acid; SD, standard deviation; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; SRID, single radial immunodiffusion; TPCK, L-(tosylamido-2-phenyl) ethyl chloromethyl ketone; tRBC, turkey red blood cell; WT, wild-type

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Keywords: Influenza A; Avian Influenza; Pandemic Preparedness; H7N9; Vaccines.

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Efficacy of a cap-dependent #endonuclease #inhibitor and #neuraminidase inhibitors against #H7N9 highly pathogenic #avian #influenza virus causing severe viral #pneumonia in cynomolgus #macaques (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Efficacy of a cap-dependent endonuclease inhibitor and neuraminidase inhibitors against H7N9 highly pathogenic avian influenza virus causing severe viral pneumonia in cynomolgus macaques

Saori Suzuki, Cong Thanh Nguyen, Ayako Ogata-Nakahara, Akihiro Shibata, Hiroyuki Osaka, Hirohito Ishigaki, Masatoshi Okamatsu, Yoshihiro Sakoda, Hiroshi Kida, Kazumasa Ogasawara, Yasushi Itoh

DOI: 10.1128/AAC.01825-20

ABSTRACT

H7N9 highly pathogenic avian influenza virus (HPAIV) infection in a human was first reported in 2017. A/duck/Japan/AQ-HE29-22/2017 (H7N9) (Dk/HE29-22) found in imported duck meat at an airport in Japan possessed hemagglutinin with a multi-basic cleavage site, indicating high pathogenicity in chickens as in the case of other H7 HPAIVs. In the present study, we examined the pathogenicity of Dk/HE29-22 and the effectiveness of a cap-dependent endonuclease inhibitor (baloxavir) and neuraminidase inhibitors (oseltamivir and zanamivir) against infection with this strain in a macaque model (n = 3 for each group). All of the macaques infected with Dk/HE29-22 showed severe signs of disease and pneumonia even after the virus had disappeared from lung samples. Virus titers in macaques treated with baloxavir were significantly lower than those in the other treated groups. After infection, levels of IFN-α and IFN-β in the blood of macaques in the baloxavir group were the highest among the groups, whereas levels of TNF-α and IL-13 were slightly increased in the untreated group. In addition, immune checkpoint proteins including PD-1 and TIGIT were expressed at high levels in the untreated group, especially in one macaque that showed severe signs of disease, indicating that negative feedback responses against vigorous inflammation may contribute to disease progression. In the group treated with baloxavir, the percentages of PD-1, CTLA-4, and TIGIT-positive T lymphocytes were lower than those in the untreated group, indicating that reduction in virus titers may prevent expression of immune checkpoint molecules from downregulation of T cell responses.

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Keywords: Avian Influenza; H7N9; Antivirals; Baloxavir; Oseltamivir; Zanamivir; Animal models.

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A Replication-Defective #Influenza Virus Harboring #H5 and #H7 #Hemagglutinins Provides Protection against #H5N1 and #H7N9 Infection in Mice (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

A Replication-Defective Influenza Virus Harboring H5 and H7 Hemagglutinins Provides Protection against H5N1 and H7N9 Infection in Mice

Xingui Tian, Shelby Landreth, Yao Lu, Kannupriya Pandey, Yan Zhou

DOI: 10.1128/JVI.02154-20

ABSTRACT

The recent highly pathogenic avian influenza (HPAI) H5N1 and H7N9 viruses have caused hundreds of human infections with high mortality rates. Although H5N1 and H7N9 viruses have been mainly limited to avian species, there is high potential for these viruses to acquire human-to-human transmission and initiate a pandemic. A highly safe and effective vaccine is needed to protect against a potential H5N1 or H7N9 influenza pandemic. Here, we report the generation and evaluation of two reassortant influenza viruses, PR8-H5-H7NA and PR8-H7-H5NA. These viruses contain six internal segments from A/Puerto Rico/8/1934 (PR8), the HA segment from either A/Alberta/01/2014 (H5N1) [AB14 (H5N1)] or A/British Columbia/01/2015 (H7N9) [BC15 (H7N9)], and a chimeric NA segment with either the BC15 (H7N9) HA gene or the AB14 (H5N1) HA gene flanked by the NA packaging signals of PR8. These viruses expressed both H5 and H7 HAs in infected cells, replicated to high titres when exogenous NA was added to the culture medium in vitro, and were replication-defective and non-virulent when administered intranasally in mice. Moreover, intranasal vaccination with PR8-H5-H7NA elicited robust immune responses to both H5 and H7 viruses, conferring complete protection against both AB14 (H5N1) and BC15 (H7N9) challenges in mice. Conversely, vaccination with PR8-H7-H5NA only elicited robust immune responses towards the H7 virus, which conferred complete protection against BC15 (H7N9) but not against AB14 (H5N1) in mice. Therefore, PR8-H5-H7NA has strong potential to serve as a vaccine candidate against both H5 and H7 subtypes of influenza viruses.

Importance

Avian influenza H5N1 and H7N9 viruses infected human with high mortality rates. A highly safe and effective vaccine is needed to protect against a potential pandemic. We generated and evaluated two reassortant influenza viruses, PR8-H5-H7NA and PR8-H7-H5NA as vaccine candidates. Each virus contains one type of HA in segment 4 and the other subtype of HA in segment 6, thus expressing both H5 and H7 subtypes of HA molecule. The viruses’ replication is dependent in the addition of exogenous NA in cell culture, and are replication-defective in vivo. Vaccination of PR8-H5-H7NA virus confers protection to both H5N1 and H7N9 virus challenge; conversely, vaccination of PR8-H7-H5NA only provides protection to H7N9 virus challenge. Our data revealed when engineering such virus, the H5 or H7 HA in segment 6 affects the immunogenicity. PR8-H5-H7NA has strong potential to serve as a vaccine candidate against both H5 and H7 subtypes of influenza viruses.

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Keywords: Avian Influenza; H5N1; H7N9; Vaccines; Pandemic preparedness.

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#Recombinant #H7 #hemagglutinin expressed in glycoengineered Pichia pastoris forms #nanoparticles that protect mice from challenge with #H7N9 #influenza virus (Vaccine, abstract)

[Source: Vaccine, full page: (LINK). Abstract, edited.]

Vaccine | Available online 31 October 2020 | In Press, Corrected Proof

Recombinant H7 hemagglutinin expressed in glycoengineered Pichia pastoris forms nanoparticles that protect mice from challenge with H7N9 influenza virus

Bo Liu a,1, Pingping Shi a,b,1, Tiantian Wang a,1, Yongkun Zhao c, Shihao Lu a, Xiang Li a,d, Shiqiang Luo a,b, Shaohong Chang a, Sha Wang a, Peng Sun a, Xin Gong a, Yuwei Gao c, Jun Wu a

a Department of Microorganism Engineering, Beijing Institute of Biotechnology, 20 Dongdajie Street, Fengtai District, Beijing 100071, China; b Institute of Physical Science and Information Technology, Anhui University, Hefei 230000, China; c Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130000, China; d School of Life Science, Liaoning University, Shenyang 110036, China

Received 2 March 2020, Revised 15 October 2020, Accepted 19 October 2020, Available online 31 October 2020.

DOI: https://doi.org/10.1016/j.vaccine.2020.10.061

Highlights

The rH7 was expressed successfully in glycoengineered Pichia pastoris system.
The rH7 had complex glycosylation modifications and polymerized to nanoparticles.
The 3.75 µg rH7 was found to protect 100% of the mice with 10LD50 of H7N9 strain.

Abstract

Cases of H7N9 human infection caused by an avian-origin H7N9 virus emerged in eastern China in 2013, leading to the urgent requirement of developing an effective vaccine to reduce its pandemic potential. In this report, the full-length recombinant H7 protein (rH7) of A/Hangzhou/1/2013 (H7N9) virus was expressed by a glycoengineered Pichia pastoris system. The rH7 protein underwent complex glycosylation modifications and polymerized to nanoparticles of 30–50 nm in diameter. Recombinant H7 (1.9 µg) elicited a > 1:40 hemagglutination inhibition titer, and 3.75 µg rH7 protected 100% of the mice in the mice challenge model with 10-fold 50% lethal dose of the A/Shanghai/2/2013 (H7N9) rat lung-adapted strain. In conclusion, rH7 produced by the glycoengineered P. pastoris can be used for vaccination against the H7N9 virus, and provides an effective platform for the rapid production of future influenza vaccines.

Keywords: Influenza – H7N9 – Influenza vaccine – Subunit vaccine – rH7

1 These authors contributed equally to this work.

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Keywords: Avian Influenza; H7N9; Vaccines; Animal models.

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Dynamic #PB2-E627K #substitution of #influenza #H7N9 virus indicates the in vivo #genetic #tuning and rapid #host #adaptation (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Dynamic PB2-E627K substitution of influenza H7N9 virus indicates the in vivo genetic tuning and rapid host adaptation

William J. Liu, Jun Li, Rongrong Zou, Jingcao Pan, Tao Jin, Liqiang Li, Peipei Liu, Yingze Zhao, Xinfen Yu, Haoqiu Wang, Guang Liu, Hui Jiang, Yuhai Bi, Lei Liu, Kwok-Yung Yuen, Yingxia Liu, and George F. Gao

PNAS first published September 1, 2020 https://doi.org/10.1073/pnas.2013267117

Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved August 5, 2020 (received for review July 6, 2020)

Significance

Deep-sequencing of viral genomes based on original specimens from H7N9-infected patients and the surrounding poultry/environment has provided the first in-depth data on virus adaptation at the interface between poultry and humans. In contrast to the consistent dominance of 627E in poultry-derived H7N9, diverse but longitudinally changing ratios of the mammalian signature substitution PB2-E627K from patient specimens indicate a dynamic viral adaptation during infection, termed “genetic tuning” of avian influenza viruses in new hosts. Furthermore, the correlation between rapid host adaptation of H7N9 PB2-627 and the disease severity in patients is brought to light. Of note, under a one-health vision, our study provides direct big data evidence that “genetic tuning” of PB2-E627K is associated with H7N9 pathogenicity during human infection.

Abstract

Avian-origin influenza viruses overcome the bottleneck of the interspecies barrier and infect humans through the evolution of variants toward more efficient replication in mammals. The dynamic adaptation of the genetic substitutions and the correlation with the virulence of avian-origin influenza virus in patients remain largely elusive. Here, based on the one-health approach, we retrieved the original virus-positive samples from patients with H7N9 and their surrounding poultry/environment. The specimens were directly deep sequenced, and the subsequent big data were integrated with the clinical manifestations. Unlike poultry/environment-derived samples with the consistent dominance of avian signature 627E of H7N9 polymerase basic protein 2 (PB2), patient specimens had diverse ratios of mammalian signature 627K, indicating the rapid dynamics of H7N9 adaptation in patients during the infection process. In contrast, both human- and poultry/environment-related viruses had constant dominance of avian signature PB2-701D. The intrahost dynamic adaptation was confirmed by the gradual replacement of 627E by 627K in H7N9 in the longitudinally collected specimens from one patient. These results suggest that host adaptation for better virus replication to new hosts, termed “genetic tuning,” actually occurred in H7N9-infected patients in vivo. Notably, our findings also demonstrate the correlation between rapid host adaptation of H7N9 PB2-E627K and the fatal outcome and disease severity in humans. The feature of H7N9 genetic tuning in vivo and its correlation with the disease severity emphasize the importance of testing for the evolution of this avian-origin virus during the course of infection.

host adaptation – dynamic substitution – next-generation sequencing – H7N9 virus –
PB2-627

Footnotes

1 W.J.L., J.L., R.Z., and J.P. contributed equally to this work.

2 To whom correspondence may be addressed. Email: yingxialiu@hotmail.com or gaofu@chinacdc.cn.

Author contributions: W.J.L., J.P., and G.F.G. designed research; J.L., R.Z., Y.Z., and X.Y. performed research; W.J.L., J.L., R.Z., T.J., L. Li, P.L., H.W., G.L., H.J., Y.B., and L. Liu analyzed data; and W.J.L., K.-Y.Y., Y.L., and G.F.G. wrote the paper.

Competing interest statement: T.J., L. Li., G.L., and H.J. were employees of BGI-Shenzhen during the project.

This article is a PNAS Direct Submission.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2013267117/-/DCSupplemental.

Data Availability. All study data are included in the main text and SI Appendix.

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Keywords: Avian Influenza; H7N9; Human; Poultry; Evolution.

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L226Q #mutation on #influenza #H7N9 virus #hemagglutinin increases receptor-binding avidity and leads to biased #antigenicity evaluation (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

L226Q mutation on influenza H7N9 virus hemagglutinin increases receptor-binding avidity and leads to biased antigenicity evaluation

Yang Wang, Yunhua Lv, Xuefeng Niu, Ji Dong, Pei Feng, Qinming Li, Wei Xu, Jiashun Li, Chufang Li, Jiahui Li, Jia Luo, Zhixia Li, Yichu Liu, Yee-Joo Tan, Weiqi Pan, Ling Chen

DOI: 10.1128/JVI.00667-20

ABSTRACT

Since the first outbreak in 2013, the influenza A (H7N9) virus has continued emerging and caused over five epidemic waves. Suspected antigenic changes of the H7N9 virus based on hemagglutination inhibition (HI) assay during the fifth outbreak have prompted the update of H7N9 candidate vaccine viruses (CVVs). In this study, we comprehensively compared the serological cross-reactivity induced by the hemagglutinins (HAs) of the earlier CVV A/Anhui/1/2013 (H7/AH13) and the updated A/Guangdong/17SF003/2016 (H7/GD16). We found that although H7/GD16 showed poor HI cross-reactivity to immune sera from mice and rhesus macaques vaccinated with either H7/AH13 or H7/GD16, the cross-reactive neutralizing antibodies between H7/AH13 and H7/GD16 were comparably high. Passive transfer of H7/AH13 immune sera also provided complete protection against the lethal challenge of H7N9/GD16 virus in mice. Analysis of amino acid mutations in the HAs between H7/AH13 and H7/GD16 revealed that L226Q substitution increases the HA binding avidity to sialic acid receptors on red blood cells, leading to decreased HI titers against viruses containing HA Q226 and thus resulted in a biased antigenic evaluation based on HI assay. These results suggest that amino acids located in the receptor-binding site could mislead the evaluation of antigenic variation by solely impact on the receptor-binding avidity to red blood cells without genuine contribution to antigenic drift. Our study highlights that viral receptor-binding avidity and combination of multiple serological assays should be taken into consideration in evaluating and selecting a candidate vaccine virus of H7N9 and other subtypes of influenza viruses.

IMPORTANCE

The HI assay is a standard method for profiling the antigenic characterization of influenza viruses. Suspected antigenic changes based on HI divergency in H7N9 viruses during the 2016-2017 wave prompted the recommendation of new H7N9 candidate vaccine viruses (CVVs). In this study, we found that the L226Q substitution in HA of A/Guangdong/17SF003/2016 (H7/GD16) increased the viral receptor-binding avidity to red blood cells with no impact on the antigenicity of H7N9 virus. Although immune sera raised by an earlier vaccine strain (H7/AH13) showed poor HI titers against H7/GD16, the H7/AH13 immune sera had potent cross-neutralizing antibody titers against H7/GD16 and could provide complete passive protection against H7N9/GD16 virus challenge in mice. Our study highlights that receptor-binding avidity might lead to biased antigenic evaluation by using HI assay. Other serological assays, such as MN assay, should be considered as a complementary indicator for analysis of antigenic variation and selection of influenza CVVs.

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Keywords: Avian Influenza; H7N9; Vaccines.

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Immune escape #adaptive #mutations in the #H7N9 #avian #influenza #hemagglutinin protein increase virus #replication #fitness and decrease #pandemic #potential (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Immune escape adaptive mutations in the H7N9 avian influenza hemagglutinin protein increase virus replication fitness and decrease pandemic potential

Pengxiang Chang, Joshua E. Sealy, Jean-Remy Sadeyen, Sushant Bhat, Deimante Lukosaityte, Yipeng Sun, Munir Iqbal

DOI: 10.1128/JVI.00216-20

ABSTRACT

H7N9 avian influenza viruses (AIVs) continue to evolve and remain a huge threat to human health and the poultry industry. Previously, serially passaging the H7N9 A/Anhui/1/2013 virus in the presence of homologous ferret antiserum resulted in immune escape viruses containing amino acid substitutions alanine to threonine at residues 125 (A125T), 151 (A151T) and leucine to glutamine at residue 217 (L217Q) in the hemagglutinin (HA) protein. These HA mutations have also been found in the field isolates in 2019. To investigate the potential threat of the serum escape mutant viruses to humans and poultry, the impact of these HA substitutions, either individually or in combination, on receptor binding, pH of fusion, thermal stability and virus replication were investigated. Our results showed the serum escape mutant formed large plaques in Madin-Darby canine kidney (MDCK) cells and grew robustly in vitro and in ovo. They had a lower pH of fusion and increased thermal stability. Of note, the serum escape mutant completely lost the ability to bind to human-like receptor analogues. Further analysis revealed that N-linked glycosylation, as a result of A125T or A151T substitutions in HA, resulted in reduced receptor binding avidity toward both human and avian-like receptor analogues, and the A125T+A151T mutations completely abolished human-like receptor binding. The L217Q mutation enhanced the H7N9 acid and thermal stability while the A151T mutation dramatically decreased H7N9 HA thermal stability. To conclude, H7N9 AIVs that contain A125T+A151T+L217Q mutations in HA protein might pose a reduced pandemic risk but remain a heightened threat for poultry.

IMPORTANCE

Avian influenza H7N9 viruses have been causing disease outbreaks in poultry and humans. We previously determined that propagation of H7N9 virus in the virus-specific antiserum give rise to mutant viruses carrying mutations A125T+A151T+L217Q in their hemagglutinin protein, enabling the virus to overcome vaccine-induced immunity. As predicted, these immune escape mutations were also observed in the field viruses that likely emerged in the immunised or naturally exposed birds. This study demonstrates that the immune escape mutants also (i) gained greater replication ability in cultured cells and in chick embryo as well as (ii) increased acid and thermal stability, but (iii) lost preferences for binding to human-type receptor while maintaining binding for the avian-like receptor. Therefore, they potentially pose reduced pandemic risk. However, the emergent virus variants containing indicated mutations remain a significant risk to the poultry due to antigenic drift and improved fitness for poultry.

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Keywords: Avian Influenza; H7N9; Poultry; Evolution.

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#Evolution and #Antigenic #Drift of #Influenza A (#H7N9) Viruses, #China, 2017–2019 (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 26, Number 8—August 2020 | Dispatch

Evolution and Antigenic Drift of Influenza A (H7N9) Viruses, China, 2017–2019

Jiahao Zhang1, Hejia Ye1, Huanan Li1, Kaixiong Ma, Weihong Qiu, Yiqun Chen, Ziwen Qiu, Bo Li, Weixin Jia, Zhaoping Liang, Ming Liao , and Wenbao Qi

Author affiliations: College of Veterinary Medicine, South China Agricultural University, Guangzhou, China (J. Zhang, H. Li, K. Ma, Y. Chen, Z. Qiu, B. Li, W. Jia, M. Liao, W. Qi); National Avian Influenza Para-Reference Laboratory, Ministry of Agriculture and Rural Affairs of the People’s Republic of China, Guangzhou (J. Zhang, H. Li, W. Jia, M. Liao, W. Qi); Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs of the People’s Republic of China, Guangzhou (J. Zhang, W. Jia, M. Liao, W. Qi); National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, National Development and Reform Commission, Guangzhou (J. Zhang, W. Jia, M. Liao, W. Qi); Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou (J. Zhang, W. Jia, M. Liao, W. Qi); Guangzhou South China Biological Medicine Co., Ltd, Guangzhou (H. Ye, W. Qiu, Z. Liang); Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou (W. Jia, M. Liao, W. Qi)

Abstract

After a sharp decrease of influenza A(H7N9) virus in China in 2018, highly pathogenic H7N9 viruses re-emerged in 2019. These H7N9 variants exhibited a new predominant subclade and had been cocirculating at a low level in eastern and northeastern China. Several immune escape mutations and antigenic drift were observed in H7N9 variants.

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Keywords: Avian Influenza; H7N9; China.

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