CBER Expertise
Development and Evaluation of Influenza Vaccines Using Molecular Approaches
Principal Investigator: Zhiping Ye, PhD
Office / Division / Lab: OVRR / DVP / LPRVD
Overview
Public Health Issue: In recent years, new influenza virus strains (i.e., 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 antibodies to those proteins. Appearance of these 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. However, to manufacture these pandemic strains in standard fashion would expose the manufacturing staff and the environment to a significant risk of infection and virus spread. An alternative way to produce these virus components is to genetically engineer a virus of low virulence and improved replication properties to support manufacture.
Regulatory Contribution: Developing and 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 synthesis 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) and yet ensure virus attenuation (improved safety). Although multiple genes of influenza virus contribute to viral replication, specifically we are evaluating the role of the matrix protein (M1), which has a major impact on attenuating properties of the virus. For example, specific genetic manipulations of M1 have the potential to convert a low-growth virus to a relatively high-growth strain, a step that could support enhanced manufacturing capacities for influenza vaccine.
Mission Relevance and Outcomes: These studies will improve FDA's ability to evaluate influenza vaccine's safety and support efficient commercial preparation of effective new inactivated virus vaccines.
Publications
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