Facilitating Influenza Virus Vaccine Production by Optimizing Vaccine Strains

Principal Investigator: Zhiping Ye, PhD
Office / Division / Lab: OVRR / DVP / LPRVD

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Overview

Public Health Issue: The potentially pandemic strains have appeared with sufficiently different surface appearance of hemagglutinins (HA) and neuraminidases (NA) proteins to generate concerns for the efficacy of current vaccine strains designed to produce an immune response to those proteins. Appearance of these potentially pandemic strains, e.g., avian influenza, has raised the urgent need for public health organizations worldwide to prepare now to develop and test vaccines to protect against these virus strains. The majority of vaccines used to control annual influenza epidemics in US are non-replicating (i.e., inactivated) virus components (HA and NA), manufactured from live viruses infected into eggs. Unlike the seasonal influenza viruses, yields of potentially pandemic virus strains adapted to current manufacturing technologies are considered inadequate to supply the vaccine demand in an emergency situation. In addition, to manufacture these pandemic strains in standard fashion would expose the manufacturing staff and the environment to a risk of infection and virus spread. An alternative way to produce these virus components is to genetically engineer a virus with improved replication properties and low virulence with a stable genetic stability to support manufacture.

Regulatory Contribution: Evaluating new molecular-based approaches to influenza vaccine production will improve vaccine safety, reduce manufacturing risks (and attendant public health risks) and will support the improved availability of effective, safe and high quality influenza vaccines.

Research Approach: Reverse genetics is a recently developed molecular technology that uses DNA plasmids containing the viral genes to control generation of live influenza viruses in cells. This technology makes it possible to manipulate the viral genes and provides a means to take advantage of the role of specific viral proteins in replication for manufacture of influenza vaccines, such as viral growth and in virus virulence, referable to safety issues associated with manufacture. Information from this research can be used to rationally generate vaccine strains with improved growth (better yield in eggs and in cells) and yet ensure virus attenuation (improved safety). We are evaluating influenza virus genes that contribute to viral replication and pathogenesis. The matrix, HA and NA of influenza genes will be modified to optimize attenuating and replication properties. For example, specific genetic manipulations of M1 have the potential to convert a low-growth virus to a relatively high-growth strain, while maintaining the attenuated phenotype, a step that could support enhanced manufacturing capacities for influenza vaccines.

Mission Relevance & Outcomes: These studies will improve FDA's ability to evaluate influenza vaccine's safety and support efficient commercial preparation of effective inactivated virus vaccines.

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Publications

J Virol Methods 2008 Nov;153(2):111-9
Establishment of retroviral pseudotypes with influenza hemagglutinins from H1, H3, and H5 subtypes for sensitive and specific detection of neutralizing antibodies.
Wang W, Butler EN, Veguilla V, Vassell R, Thomas JT, Moos M, Ye Z, Hancock K, Weiss CD

J Neurovirol 2008 Apr;14(2):136-42
Genetic contributions to influenza virus attenuation in the rat brain.
Qi L, Carbone KM, Ye Z, Liu T, Ovanesov M, Pletnikov M, Sauder C, Rubin SA

Vaccine 2007 Nov 1;25(44):7649-55
Evaluating the vaccine potential of an influenza A viral hemagglutinin and matrix double insertion DNA plasmid.
Xie H, Liu T, Chen H, Huang X, Ye Z

Virology 2007 Sep 1;365(2):315-23
Generation of the influenza B viruses with improved growth phenotype by substitution of specific amino acids of hemagglutinin.
Lugovtsev VY, Vodeiko GM, Strupczewski CM, Ye Z, Levandowski RA

Emerg Infect Dis 2007 Mar;13(3):426-35
Matrix protein 2 vaccination and protection against influenza viruses, including subtype H5N1.
Tompkins SM, Zhao ZS, Lo CY, Misplon JA, Liu T, Ye Z, Hogan RJ, Wu Z, Benton KA, Tumpey TM, Epstein SL

Retrovirology 2005 Dec 21;2:80
Targeted infection of HIV-1 Env expressing cells by HIV(CD4/CXCR4) vectors reveals a potential new rationale for HIV-1 mediated down-modulation of CD4.
Ye Z, Harmison GG, Ragheb JA, Schubert M

J Virol 2005 Feb;79(3):1918-23
Attenuating Mutations of the Matrix Gene of Influenza A/WSN/33 Virus.
Liu T, Ye Z

J Neurovirol 2004 Oct;10(5):305-14
Wild-type and attenuated influenza virus infection of the neonatal rat brain.
Rubin S, Liu D, Pletnikov M, McCullers J, Ye Z, Levandowski R, Johannessen J, Carbone K

J Virol 2004 Sep;78(18):9585-91
Introduction of a Temperature-Sensitive Phenotype into Influenza A/WSN/33 Virus by Altering the Basic Amino Acid Domain of Influenza Virus Matrix Protein.
Liu T, Ye Z

Vaccine 2004 Mar 29;22(11-12):1486-93
Mouse neurotoxicity test for vaccinia-based smallpox vaccines.
Li Z, Rubin SA, Taffs RE, Merchlinsky M, Ye Z, Carbone KM