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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Helping to Develop Better Influenza Vaccines

Principal Investigator: Maryna Eichelberger, PhD
Office / Division / Lab: OVRR / DVP / LPRVD


General Overview

Vaccination against influenza is an important way to prevent serious illness or even death from this disease because there are very few drugs that are effective in limiting lung infection with influenza viruses.

Our research program aims to develop new methods to identify and quantify important antigens (proteins that are the target of the immune response) in influenza vaccines, and to implement new ways to predict how well the vaccine will protect against disease. We are focusing specifically on the antigens hemagglutinin (HA) and neuraminidase (NA), which are proteins on the surface of the virus: antibodies to these molecules can prevent infection and spread of the virus.

The laboratory uses a modern a protein-identification method called mass spectrometry to measure the amount of HA and NA in vaccine preparations. In addition, we developed new methods to measure antibody responses to these molecules. This technology helps us to understand how different types of influenza vaccines work by identifying the amount of antibody needed to protect animals from infection and by evaluating human responses to vaccines.

Our research is particularly important for public health because it directly contributes to 1) evaluation of seasonal vaccines that use new strategies to induce immunity; and 2) evaluation of vaccines for pandemics (epidemics that spread globally). These studies will have a major impact on the regulatory work of FDA since they provide ways to predict the effectiveness of new vaccines.


Scientific Overview

Our mission is to develop practical methods for measuring the immune correlates of protection against seasonal and pandemic influenza so that vaccine efficacy can be predicted more accurately.

HA is the primary antigen in each influenza vaccine preparation; antibodies that bind to this protein block binding of the virus to host cell receptors and therefore prevent infection. Indeed, vaccine efficacy in persons vaccinated with trivalent inactivated vaccine (TIV) correlates with serum hemagglutination inhibition (HAI) titers of ≥40. This value, however does not accurately predict the efficacy of live attenuated influenza vaccine (LAIV), suggesting that other immune responses contribute to protection against disease.

NA is second in abundance on the surface of virus and plays an essential role in spread of newly formed infectious particles. Antibodies that block NA enzyme activity prevent virus release, thereby limiting infection. Human studies have shown that increased serum NA inhibition (NI) titers correlate with protection, suggesting that this might accurately predict TIV and LAIV vaccine efficacy. Unfortunately, a practical method to routinely measure NI titers is not available; consequently, antibody responses to NA are often overlooked. In addition, there is no test to measure the amount of NA in vaccine preparations. We are therefore developing modern methods to determine the amount of NA in vaccines and NA-specific antibody responses. We use animal models to demonstrate the importance of this antigen to immunity.

Since LAIV induces cell mediated immunity, we expect this vaccine type to protect an individual from disease through a combination of antibody and influenza-specific cells. We are therefore developing practical ways to measure these cellular responses.

Our work will provide additional methods to predict the effectiveness of influenza vaccines. These tests will be very important to our evaluation of vaccines against pandemic influenza strains because direct demonstration of how well the vaccine protects against disease through exposure of vaccinated individuals to a novel virus, particularly one that can result in death, is not possible.

This research program will therefore assist in the development of improved influenza vaccines by establishing ways to measure the amounts of different antigens in the vaccine, and by testing immune responses that provide information about how well the vaccine will protect against influenza.


Publications

J Virol 2013 Mar;87(6):3277-83
In Vivo Selection of H1N2 Influenza Virus Reassortants in the Ferret Model.
Angel M, Kimble JB, Pena L, Wan H, Perez DR

Microb Pathog 2012 Dec 13;55C:9-15
Influenza and respiratory syncytial virus (RSV) vaccines for infants: safety, immunogenicity, and efficacy.
Beeler JA, Eichelberger MC

Viruses 2012 Nov 9;4(11):3012-9
Rapid Detection and Differentiation of Swine-Origin Influenza A Virus (H1N1/2009) from Other Seasonal Influenza A Viruses.
Zhao J, Wang X, Ragupathy V, Zhang P, Tang W, Ye Z, Eichelberger M, Hewlett I

Virology 2012 Oct 10;432(1):39-44
Protection against a lethal H5N1 influenza challenge by intranasal immunization with virus-like particles containing 2009 pandemic H1N1 neuraminidase in mice.
Easterbrook JD, Schwartzman LM, Gao J, Kash JC, Morens DM, Couzens L, Wan H, Eichelberger MC, Taubenberger JK

Front Cell Infect Microbiol 2012 May;2:74
Development of a murine nose-only inhalation model of influenza: comparison of disease caused by instilled and inhaled A/PR/8/34.
Bowen LE, Rivers K, Trombley JE, Bohannon JK, Li SX, Boydston JA, Eichelberger MC

Clin Infect Dis 2011 Dec;53(12):1179-87
Revisiting the 1976 "swine flu" vaccine clinical trials: cross-reactive hemagglutinin and neuraminidase antibodies and their role in protection against the 2009 H1N1 pandemic virus in mice.
Xie H, Li X, Gao J, Lin Z, Jing X, Plant E, Zoueva O, Eichelberger MC, Ye Z

Proc Natl Acad Sci U S A 2011 Dec 20;108(51):20748-53
Discordant antigenic drift of neuraminidase and hemagglutinin in H1N1 and H3N2 influenza viruses.
Sandbulte MR, Westgeest KB, Gao J, Xu X, Klimov AI, Russell CA, Burke DF, Smith DJ, Fouchier RA, Eichelberger MC

Influenza Other Respir Viruses 2011 Nov;5(6):438-42
Confronting the next pandemic-Workshop on lessons learned from potency testing of pandemic (H1N1) 2009 influenza vaccines and considerations for future potency tests, Ottawa, Canada, July 27-29, 2010.
Hardy S, Eichelberger M, Griffiths E, Weir JP, Wood D, Alfonso C

Expert Opin Drug Metab Toxicol 2011 Sep;7(9):1117-27
Animal models to assess the toxicity, immunogenicity and effectiveness of candidate influenza vaccines.
Eichelberger MC, Green MD

AIDS 2011 Jun 1;25(9):1229-32
Seroincidence of 2009 H1N1 infection in HIV-infected and HIV-uninfected women prior to vaccine availability.
Althoff KN, Eichelberger M, Gange SJ, Sharp GB, Gao J, Glesby MJ, Young M, Greenblatt RM, French AL, Villacres MC, Minkoff H

Virol J 2011 May 21;8:251
Intramuscular immunization of mice with live influenza virus is more immunogenic and offers greater protection than immunization with inactivated virus.
Harris K, Ream R, Gao J, Eichelberger MC

Influenza Other Respir Viruses 2011 May;5(3):198-205
Immunization with 1976 swine H1N1- or 2009 pandemic H1N1-inactivated vaccines protects mice from a lethal 1918 influenza infection.
Easterbrook JD, Kash JC, Sheng ZM, Qi L, Gao J, Kilbourne ED, Eichelberger MC, Taubenberger JK

Vaccine 2011 Mar 21;29(14):2601-6
Influenza neuraminidase-inhibiting antibodies are induced in the presence of zanamivir.
Sultana I, Gao J, Markoff L, Eichelberger MC

Anal Biochem 2011 Feb 15;409(2):202-12
Label-free mass spectrometry-based relative quantification of proteins separated by one-dimensional gel electrophoresis.
Getie-Kebtie M, Lazarev A, Eichelberger M, Alterman M

J Infect Dis 2010 Dec 1;202(11):1634-8
Inactivated seasonal influenza vaccines increase serum antibodies to the neuraminidase of pandemic influenza A(H1N1) 2009 virus in an age-dependent manner.
Marcelin G, Bland HM, Negovetich NJ, Sandbulte MR, Ellebedy AH, Webb AD, Griffin YS, Debeauchamp JL, McElhaney JE, Webby RJ

Clin Infect Dis 2010 May 1;50(9):1252-5
Rapid selection of oseltamivir- and peramivir-resistant pandemic H1N1 virus during therapy in 2 immunocompromised hosts.
Memoli MJ, Hrabal RJ, Hassantoufighi A, Eichelberger MC, Taubenberger JK

J Infect Dis 2010 May 1;201(9):1397-403
Rapid selection of a transmissible multidrug-resistant influenza A/H3N2 virus in an immunocompromised host.
Memoli MJ, Hrabal RJ, Hassantoufighi A, Jagger BW, Sheng ZM, Eichelberger MC, Taubenberger JK

Vaccine 2010 Jan 8;28(3):790-7
A practical influenza neutralization assay to simultaneously quantify hemagglutinin and neuraminidase-inhibiting antibody responses.
Hassantoufighi A, Zhang H, Sandbulte M, Gao J, Manischewitz J, King L, Golding H, Straight TM, Eichelberger MC

Influenza Other Respir Viruses 2009 Sep;3(5):233-40
A miniaturized assay for influenza neuraminidase-inhibiting antibodies utilizing reverse genetics-derived antigens
Sandbulte MR, Gao J, Straight TM, Eichelberger MC

J Recept Signal Transduct Res 2009;29(3-4):202-10
Interrogation of phosphor-specific interaction on a high-throughput label-free optical biosensor system-Epic system.
Wu M, Long S, Frutos AG, Eichelberger M, Li M, Fang Y

Proteomics Clin Appl 2009 Aug 1;3(8):979-88
Proteomics-based characterization of hemagglutinins in different strains of influenza virus.
Getie-Kebtie M, Chen D, Eichelberger M, Alterman M

BMC Pulm Med 2009 Jun 10;9:28
Comparison of airway measurements during influenza-induced tachypnea in infant and adult cotton rats.
Trias EL, Hassantoufighi A, Prince GA, Eichelberger MC

Virol J 2008 Sep 26;5:109
Neuraminidase activity provides a practical read-out for a high throughput influenza antiviral screening assay.
Eichelberger MC, Hassantoufighi A, Wu M, Li M

Vaccine 2008 Aug 12;26(34):4299-303
FDA/NIH/WHO public workshop on immune correlates of protection against influenza A viruses in support of pandemic vaccine development, Bethesda, Maryland, US, December 10-11, 2007.
Eichelberger M, Golding H, Hess M, Weir J, Subbarao K, Luke CJ, Friede M, Wood D

Front Biosci 2008 May 1;13:4912-24
Influenza vaccines.
Webby RJ, Sandbulte MR

Virol J 2008 Mar 20;5:44
Antibody contributes to heterosubtypic protection against influenza A-induced tachypnea in cotton rats.
Straight TM, Ottolini MG, Prince GA, Eichelberger MC

Microb Pathog 2007 Nov-Dec;43(5-6):208-16
Co-infection of the cotton rat (Sigmodon hispidus) with Staphylococcus aureus and influenza A virus results in synergistic disease.
Braun LE, Sutter DE, Eichelberger MC, Pletneva L, Kokai-Kun JF, Blanco JC, Prince GA, Ottolini MG

Viral Immunol 2007 Summer;20(2):243-9
The cotton rat as a model to study influenza pathogenesis and immunity.
Eichelberger MC

Clin Exp Immunol 2007 May;148(2):218-29
Respiratory syncytial virus replication is prolonged by a concomitant allergic response.
Hassantoufighi A, Oglesbee M, Richter BW, Prince GA, Hemming V, Niewiesk S, Eichelberger MC

Cell Immunol 2006 Oct;243(2):67-74
Distinct cellular immune responses following primary and secondary influenza virus challenge in cotton rats.
Eichelberger MC, Bauchiero S, Point D, Richter BW, Prince GA, Schuman R

 

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