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Journal of Virology, June 2001, p. 5141-5150, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5141-5150.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Mucosal Delivery of Inactivated Influenza Vaccine Induces B-Cell-Dependent Heterosubtypic Cross-Protection against Lethal Influenza A H5N1 Virus Infection

Terrence M. Tumpey,1,dagger Mary Renshaw,1 John D. Clements,2 and Jacqueline M. Katz1,*

Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333,1 and Department of Microbiology and Immunology, Tulane University Medical Center, New Orleans, Louisiana 701122

Received 20 November 2000/Accepted 14 March 2001

Influenza vaccines that induce greater cross-reactive or heterosubtypic immunity (Het-I) may overcome limitations in vaccine efficacy imposed by the antigenic variability of influenza A viruses. We have compared mucosal versus traditional parenteral administration of inactivated influenza vaccine for the ability to induce Het-I in BALB/c mice and evaluated a modified Escherichia coli heat-labile enterotoxin adjuvant, LT(R192G), for augmentation of Het-I. Mice that received three intranasal (i.n.) immunizations of H3N2 vaccine in the presence of LT(R192G) were completely protected against lethal challenge with a highly pathogenic human H5N1 virus and had nasal and lung viral titers that were at least 2,500-fold lower than those of control mice receiving LT(R192G) alone. In contrast, mice that received three vaccinations of H3N2 vaccine subcutaneously in the presence or absence of LT(R192G) or incomplete Freund's adjuvant were not protected against lethal challenge and had no significant reductions in tissue virus titers observed on day 5 post-H5N1 virus challenge. Mice that were i.n. administered H3N2 vaccine alone, without LT(R192G), displayed partial protection against heterosubtypic challenge. The immune mediators of Het-I were investigated. The functional role of B and CD8+ T cells in Het-I were evaluated by using gene-targeted B-cell (IgH-6-/-)- or beta 2-microglobulin (beta 2m-/-)-deficient mice, respectively. beta 2m-/- but not IgH-6-/- vaccinated mice were protected by Het-I and survived a lethal infection with H5N1, suggesting that B cells, but not CD8+ T cells, were vital for protection of mice against heterosubtypic challenge. Nevertheless, CD8+ T cells contributed to viral clearance in the lungs and brain tissues of heterotypically immune mice. Mucosal but not parenteral vaccination induced subtype cross-reactive lung immunoglobulin G (IgG), IgA, and serum IgG anti-hemagglutinin antibodies, suggesting the presence of a common cross-reactive epitope in the hemagglutinins of H3 and H5. These results suggest a strategy of mucosal vaccination that stimulates cross-protection against multiple influenza virus subtypes, including viruses with pandemic potential.

* Corresponding author. Mailing address: Influenza Branch, Mailstop G-16, DVRD, NCID, Centers for Disease Control and Prevention, 1600 Clifton Road N.E., Atlanta, GA 30333. Phone: (404) 639-3591. Fax: (404) 639-2334. E-mail: JKatz{at}cdc.gov.

dagger Present address: Southeast Poultry Research Laboratory, U.S. Department of Agriculture, Agricultural Research Service, Athens, GA 30605.

Journal of Virology, June 2001, p. 5141-5150, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5141-5150.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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