Supporting the Production of Safe and Effective Influenza Vaccines

Zhiping Ye, M.D., Ph.D.

Office of Vaccines Research and Review
Division of Viral Products
Laboratory of Pediatric and Respiratory Viral Disease

Biosketch

Dr. Zhiping Ye received a Ph.D. degree in Virology from Department of Microbiology, University of Virginia, School of Medicine, Virginia, US and a M.D. degree in Medicine from Shanghai First Medical University, Shanghai, China. In 1980s, he worked in Dr. Chi-Ming Chu’s laboratory in the Institute of Virology, Beijing, China, where he involved in studying epidemiology of influenza virus and development of influenza vaccines. In Dr. Robert Wagner’s laboratory in University of Virginia, he worked extensively with influenza virus and vesicular stomatitis virus.

Dr. Zhiping Ye serves as Chief of Laboratory of Pediatric and Respiratory Vial Diseases in Center for Biologics and Evaluation and Research, Food and Drug Administration (FDA). Dr. Ye has spent over twenty years working on the replication and pathogenesis of influenza viruses. His studies are recognized in the fields of influenza virus as well as influenza vaccines. He is also involved in regulatory work, such as reviewing Investigational New Drug applications and Biological Licensing Applications relating to influenza vaccines for the United States. As a temporary adviser for World Health Organization Global Influenza Program from FDA since 2001, he participates in WHO bi-annual consultation on selection of vaccine viruses for updating the composition of influenza vaccines for Northern and Southern hemispheres.

General Overview

Each year, about 38,000 people in the United States die from influenza infections. In addition, pandemic influenza (worldwide outbreaks) pose a global threat to public health. One of the most effective strategies for preventing seasonal and pandemic influenza infections is vaccination. The need for new vaccines was made more urgent by the emergence of strains of influenza virus that have the pandemic potential, as in the case of the pandemic 2009 H1N1 (swine flu) virus. Production of vaccines against pandemic viruses is slowed by the difficulty in manufacturing of these products, requiring innovative approaches.

Influenza vaccines are designed to trigger immune responses against critical surface proteins called hemagglutinin (HA) and neuraminidase (NA). However, new variants of influenza viruses carrying modified types of HA and NA appear each season. Since existing influenza vaccines would not be able to trigger effective immune responses to these new variants, modified vaccines must be made to protect against an influenza outbreak caused by new variant viruses.

The majority of vaccines used to control annual influenza epidemics in the United States are manufactured using embryonated chicken eggs that are infected with live influenza viruses. These viruses are harvested, inactivated, and used to make vaccines. Most wild-type viruses (i.e., the form that appears in nature) that carry the right HA and NA proteins to make vaccines do not grow in large enough quantities in eggs to support vaccine production. To solve these problems, we modify influenza virus genes in order to produce viruses that grow in large enough quantities to make vaccines and to carry the exact version of HA and NA proteins of that season's influenza virus. In addition, we modify the viruses so they cannot cause disease, reducing the risk to laboratory workers.

We are concentrating our work in these areas on both licensed inactivated influenza virus vaccines and new influenza vaccines that are under clinical development. This research uses state-of-the-art molecular biology techniques to 1) improve production and safe handling during production of pandemic influenza vaccines; and 2) facilitate development of new vaccines for both seasonal and pandemic influenza virus by optimizing the production of vaccine proteins by viral genes. Overall, our research directly impacts the safety, effectiveness, and availability of both seasonal and pandemic influenza vaccines.

Scientific Overview

Our research program addresses several critical and unmet research needs of the influenza vaccine program in the U.S. There are three types of licensed influenza vaccines in U.S.: inactivated, live attenuated, and recombinant vaccines. Currently the inactivated influenza viruses are the major sources for immunization of general population against influenza virus infection in the U.S. Each year manufacturers and federal agencies struggle to identify influenza viruses to be used as vaccine strains, i.e., circulating viruses with appropriate antigenic characteristics and growth properties sufficient to support production of over 150 million inactivated seasonal influenza vaccine doses.

Most wild-type viruses with appropriate antigenic characteristics do not grow to sufficiently high titer in eggs or cells to support vaccine production, and high growth laboratory strains do not contain the appropriate antigenic properties in surface proteins (e.g., HA, NA) of the current year’s circulating wild type strains. Thus, genetic mixtures of the wild type and laboratory strains termed high growth reassortants, are created to contain the growth and immunogenic properties necessary for efficient preparation of commercial quantities of effective new inactivated influenza virus vaccines each year. Understanding how influenza virus proteins control replication is crucial in generating high growth viruses by modifying virus genes.

Although multiple genes of influenza viruses contribute to viral replication and attenuation/virulence properties, we continue to investigate the roles of matrix (M) and NA genes of influenza A virus in viral replication, attenuation, and virulence in vitro and in vivo. Our laboratory focuses particularly on the matrix 1 (M1) protein of influenza A virus and genetic manipulation of the matrix gene of influenza A virus.

Our research program also addresses several critical research needs of the influenza vaccine program by using techniques such as reverse genetics to identify and analyze the functional domains of influenza virus protein(s). Based on our work in this area, we can now modify viruses such as virulent wild-type avian influenza virus to be less pathogenic, or to endow a low-yield virus with high-growth capabilities suitable for preparation of inactivated influenza vaccines.

Important Links

Innovation and Regulatory Science- Research Summary: Influenza candidate vaccine viruses improved by amino acid substitution in hemagglutinin

Publications

Nat Commun 2021 Nov 12;12(1):6559
SARS-CoV-2 B.1.1.7 (alpha) and B.1.351 (beta) variants induce pathogenic patterns in K18-hACE2 transgenic mice distinct from early strains.
Radvak P, Kwon HJ, Kosikova M, Ortega-Rodriguez U, Xiang R, Phue JN, Shen RF, Rozzelle J, Kapoor N, Rabara T, Fairman J, Xie H
Vaccine 2021 Jul 30;39(33):4628-40
Universal influenza vaccine based on conserved antigens provides long-term durability of immune responses and durable broad protection against diverse challenge virus strains in mice.
Lo CY, Misplon JA, Li X, Price GE, Ye Z, Epstein SL
J Med Virol 2021 Jul;93(7):4570-5
SARS-CoV-2 show no infectivity at later stages in a prolonged COVID-19 patient despite positivity in RNA testing.
Wan XF, Tang CY, Ritter D, Wang Y, Li T, Segovia K, Kosikova M, Johnson M, Kwon HJ, Xie H, Hammer RD, McElroy JA, Hamid A, Collins ND, Hang J, Camp S
Clin Infect Dis 2021 Jun 1;72(11):e776-e783
Reduced influenza B-specific post-vaccination antibody cross-reactivity in the B/Victoria lineage predominant 2019/20 season.
Xie H, Xiang R, Wan HJ, Plant EP, Radvak P, Kosikova M, Li X, Zoueva O, Ye Z, Wan XF
PLoS Pathog 2021 Apr 19;17(4):e1009171
Balancing the influenza neuraminidase and hemagglutinin responses by exchanging the vaccine virus backbone.
Gao J, Wan H, Li X, Rakic Martinez M, Klenow L, Gao Y, Ye Z, Daniels R
Vaccines 2021 Apr 14;9(4):383
Research updates for influenza virus and vaccine development.
Plant EP, Xie H
NPJ Vaccines 2021 Feb 26;6(1):30
Highly pathogenic avian influenza A/Guangdong/17SF003/2016 is immunogenic and induces cross-protection against antigenically divergent H7N9 viruses.
Radvak P, Kosikova M, Kuo YC, Li X, Garner R, Schmeisser F, Kosik I, Ye Z, Weir JP, Yewdell JW, Xie H
Vaccines 2020 Mar 11;8(1):125
Immune pressure on polymorphous influenza B populations results in diverse hemagglutinin escape mutants and lineage switching.
Plant EP, Manukyan H, Sanchez JL, Laassri M, Ye Z
Nat Microbiol 2019 Dec;4(12):2216-25
The neuraminidase of A(H3N2) influenza viruses circulating since 2016 is antigenically distinct from the A/Hong Kong/4801/2014 vaccine strain.
Wan H, Gao J, Yang H, Yang S, Harvey R, Chen YQ, Zheng NY, Chang J, Carney PJ, Li X, Plant E, Jiang L, Couzens L, Wang C, Strohmeier S, Wu WW, Shen RF, Krammer F, Cipollo JF, Wilson PC, Stevens J, Wan XF, Eichelberger MC, Ye Z
J Virol 2019 Oct;93(19):e00570-19
A single amino acid substitution at residue 218 of hemagglutinin improves the growth of influenza A(H7N9) candidate vaccine viruses.
Li X, Gao Y, Ye Z
Emerg Microbes Infect 2019;8(1):1146-56
Pregnancy level of estradiol attenuated virus-specific humoral immune response in H5N1-infected female mice despite inducing anti-inflammatory protection.
Finch CL, Zhang A, Kosikova M, Kawano T, Pasetti MF, Ye Z, Ascher JR, Xie H
J Exp Med 2019 Feb 4;216(2):304-16
Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies.
Kosik I, Angeletti D, Gibbs JS, Angel M, Takeda K, Kosikova M, Nair V, Hickman HD, Xie H, Brooke CB, Yewdell JW
J Biol Chem 2018 Dec 14;293(50):19277-89
Comprehensive analysis of N-glycans in IgG purified from ferrets with or without influenza A virus infection.
Zou G, Kosikova M, Kim SR, Kotian S, Wu WW, Shen R, Powers DN, Agarabi C, Xie H, Ju T
Clin Infect Dis 2018 Oct 30;67(10):1523-32
Imprinting of repeated influenza A/H3 exposures on antibody quantity and antibody quality: implications on seasonal vaccine strain selection and vaccine performance.
Kosikova M, Li L, Radvak P, Ye Z, Wan XF, Xie H
Vaccines 2018 Jul 3;6(3):39
The effects of birth year, age and sex on hemagglutination inhibition antibody responses to influenza vaccination.
Plant EP, Eick-Cost AA, Ezzeldin H, Sanchez JL, Ye Z, Cooper MJ
Cell 2018 Apr 5;173(2):417-429.e10
Influenza infection in humans induces broadly cross-reactive and protective neuraminidase-reactive antibodies.
Chen YQ, Wohlbold TJ, Zheng NY, Huang M, Huang Y, Neu KE, Lee J, Wan H, Rojas KT, Kirkpatrick E, Henry C, Palm AE, Stamper CT, Lan LY, Topham DJ, Treanor J, Wrammert J, Ahmed R, Eichelberger MC, Georgiou G, Krammer F, Wilson PC
MBio 2018 Apr 3;9(2):e02332-17
NAction! How can neuraminidase-based immunity contribute to better influenza virus vaccines?
Krammer F, Fouchier RAM, Eichelberger MC, Webby RJ, Shaw-Saliba K, Wan H, Wilson PC, Compans RW, Skountzou I, Monto AS
Sci Rep 2018 Mar 29;8(1):5364
Immunogenicity and protection against influenza H7N3 in mice by modified vaccinia virus Ankara vectors expressing influenza virus hemagglutinin or neuraminidase.
Meseda CA, Atukorale V, Soto J, Eichelberger MC, Gao J, Wang W, Weiss CD, Weir JP
J Virol 2018 Feb;92(4):e01588-17
Comparison of the efficacy of N9 neuraminidase-specific monoclonal antibodies against influenza A(H7N9) virus infection.
Wan H, Qi L, Gao J, Couzens LK, Jiang L, Gao Y, Sheng ZM, Fong S, Hahn M, Khurana S, Taubenberger JK, Eichelberger MC
J Virol 2018 Jan;92(2):e01621-17
A Y161F hemagglutinin substitution increases thermostability and improves yields of 2009 H1N1 influenza A virus in cells.
Wen F, Li L, Zhao N, Chiang MJ, Xie H, Cooley J, Webby R, Wang PG, Wan XF
PLoS Pathog 2018 Jan 18;14(1):e1006796
Influenza A virus hemagglutinin glycosylation compensates for antibody escape fitness costs.
Kosik I, Ince WL, Gentles LE, Oler AJ, Kosikova M, Angel M, Magadán JG, Xie H, Brooke CB, Yewdell JW
Emerg Microbes Infect 2017 Dec 6;6(12):e108
Maintaining pH-dependent conformational flexibility of M1 is critical for efficient influenza A virus replication.
Chiang MJ, Musayev FN, Kosikova M, Lin Z, Gao Y, Mosier PD, Althufairi B, Ye Z, Zhou Q, Desai UR, Xie H, Safo MK
Anal Chem 2017 Sep 5;89(17):9508-9517
Solid-phase chemical modification for sialic acid linkage analysis: application to glycoproteins of host cells used in influenza virus propagation.
Yang S, Jankowska E, Kosikova M, Xie H, Cipollo J
Virus Res 2017 Aug 15;240:81-6
Influenza virus NS1 protein mutations at position 171 impact innate interferon responses by respiratory epithelial cells.
Plant EP, Ilyushina NA, Sheikh F, Donnelly RP, Ye Z
Sci Rep 2017 Jul 12;7(1):5258
Different repeat annual influenza vaccinations improve the antibody response to drifted influenza strains.
Plant EP, Fredell LJ, Hatcher BA, Li X, Chiang MJ, Kosikova M, Xie H, Zoueva O, Cost AA, Ye Z, Cooper MJ
PLoS One 2017 Jun 29;12(6):e0179939
Automated interpretation of influenza hemagglutination inhibition (HAI) assays: is plate tilting necessary?
Wilson G, Ye Z, Xie H, Vahl S, Dawson E, Rowlen K
Methods Mol Biol 2017;1602:205-38
Reverse genetics of influenza B viruses.
Nogales A, Perez DR, Santos J, Finch C, Martínez-Sobrido L
Emerg Microbes Infect 2017 Apr 12;6(4):e17
Pathogenicity and transmission of a swine influenza A(H6N6) virus.
Sun H, Kaplan BS, Guan M, Zhang G, Ye J, Long LP, Blackmon S, Yang CK, Chiang MJ, Xie H, Zhao N, Cooley J, Smith DF, Liao M, Cardona C, Li L, Wang GP, Webby R, Wan XF
PLoS One 2016 Sep 22;11(9):e0163175
Sensitive detection and simultaneous discrimination of influenza A and B viruses in nasopharyngeal swabs in a single assay using next-generation sequencing-based diagnostics.
Zhao J, Liu J, Vemula SV, Lin C, Tan J, Ragupathy V, Wang X, Mbondji-Wonje C, Ye Z, Landry ML, Hewlett I
Sci Rep 2016 Jun 30;6:29110
Iron overload by superparamagnetic iron oxide nanoparticles is a high risk factor in cirrhosis by a systems toxicology assessment.
Wei Y, Zhao M, Yang F, Mao Y, Xie H, Zhou Q
Influenza Other Respir Viruses 2016 Mar;10(2):134-40
A novel approach for preparation of the antisera reagent for potency determination of inactivated H7N9 influenza vaccines.
Schmeisser F, Jing X, Joshi M, Vasudevan A, Soto J, Li X, Choudhary A, Baichoo N, Resnick J, Ye Z, McCormick W, Weir JP
Viruses 2016 Feb 2;8(2):33
Pandemic influenza A (H1N1) virus infection increases apoptosis and HIV-1 replication in HIV-1 infected Jurkat cells.
Wang X, Tan J, Biswas S, Zhao J, Devadas K, Ye Z, Hewlett I
J Virol 2016 Jan;90(1):117-28
Comparative efficacy of monoclonal antibodies that bind to different epitopes of the 2009 pandemic H1N1 influenza virus neuraminidase.
Jiang L, Fantoni G, Couzens L, Gao J, Plant E, Ye Z, Eichelberger MC, Wan H
Sci Rep 2015 Oct 16;5:15279
H3N2 mismatch of 2014-15 northern hemisphere influenza vaccines and head-to-head comparison between human and ferret antisera derived antigenic maps.
Xie H, Wan XF, Ye Z, Plant EP, Zhao Y, Xu Y, Li X, Finch C, Zhao N, Kawano T, Zoueva O, Chiang MJ, Jing X, Lin Z, Zhang A, Zhu Y
PLoS One 2015 Sep 25;10(9):e0138650
Deep sequencing for evaluation of genetic stability of influenza A/California/07/2009 (H1N1) vaccine viruses.
Majid L, Zagorodnyaya T, Plant EP, Petrovskaya S, Bidzhieva B, Ye Z, Simonyan V, Chumakov K
J Gen Virol 2015 Apr;96(Pt 4):752-5
Chimeric NA and mutant PB1 gene constellation improves growth and yield of H5N1 vaccine candidate virus.
Plant EP, Ye Z
Emerg Infect Dis 2015 Mar;21(3):400-8
Nanomicroarray and multiplex next-generation sequencing for simultaneous identification and characterization of influenza viruses.
Zhao J, Ragupathy V, Liu J, Wang X, Vemula SV, El Mubarak HS, Ye Z, Landry ML, Hewlett I