Influenza Pathogenesis and Immunity

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

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Overview

Public Health Issue: Although effective influenza vaccines are available, the strain composition of these vaccines must be evaluated annually and updated periodically because of the continuous antigenic drift of HA and NA in circulating influenza viruses. In addition to the ongoing antigenic drift of both influenza A and B viruses, the ever present threat that a new subtype of influenza A will cause a global pandemic has resulted in an urgency to develop new generation vaccines that provide effective protection against circulating influenza strains, of the same (homotypic) and different (heterosubtypic)HA and NA subtypes. Our laboratory supports the development of these vaccines by identification of immune mechanisms that contribute to protection and development of standardized assays to quantify these effector mechanisms. These studies support the evaluation of pre-clinical and clinical studies of influenza vaccines.

Regulatory Contribution: Our research program supports our review of BLA and IND applications that describe the production, pre-clinical and clinical studies of new seasonal and pandemic influenza vaccines.

Research Approach: To accurately evaluate influenza vaccine immunogenicity and efficacy, it is necessary to identify immune correlates of protection against seasonal and pandemic influenza, and to develop practical methods to measure these responses. We support the evaluation of influenza vaccines through the following research approaches: (1) identification of surrogate end-points of protection in animal models, (2) evaluation of human immune responses to influenza vaccines and (3) development of methods to measure vaccine immunogenicity and effectiveness.

Mission Relevance & Outcomes: Our studies are leading to identification of immune mechanisms that contribute to protection against influenza, with development of assays to easily measure these responses after human vaccination. Our current focus includes neuraminidase-inhibiting (NI) antibodies and cytotoxic T lymphocyte (CTL) responses. The outcomes of these studies will be the following: (i) development of high throughput assays to measure NI and influenza-specific CD8+ T cell responses in humans; (ii) determination of the magnitude of the NI and CD8+ T cell response taht correlates with protection in animal models; (iii) evaluation of NI and CD8+ T cell responses following inactivated and live attenuated vaccination.

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Publications

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