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Title: MUCOSAL DELIVERY OF INACTIVATED INFLUENZA VACCINE INDUCES B CELL-DEPENDENT HETEROSUBTYPIC CROSS-PROTECTION AGAINST LETHAL INFLUENZA A H5N1 VIRUS INFECTION

Author
item Tumpey, Terrence
item RENSHAW,, MARY - CDC - ATLANTA, GEORGIA
item CLEMENTS,, JOHN - TULANE UNIV, NEW ORLEANS
item KATZ,, JACQUELINE - CDC - ATLANTA, GEORGIA

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/14/2001
Publication Date: 6/15/2001
Citation: N/A

Interpretive Summary: In 1997 in Hong Kong, 18 human cases of respiratory illness were caused by an avian influenza A H5N1 virus. Although avian influenza viruses had not previously been known to cause respiratory illness in humans, the H5N1 viruses caused severe illness and death, primarily in individuals aged >12 years. The purpose of this research was to design a vaccine strategy that would be cross-reactive to multiple subtypes of Influenza A and could be a important first line of prevention against a novel subtype, allowing time for the development of a pandemic strain-specific vaccine. We have compared mucosal versus traditional parenteral administration of an inactivated influenza vaccine for the ability to induce cross-protection in mice. Mice that received mucosal immunizations of the H3N2 vaccine were completely protected against lethal challenge with a highly pathogenic human H5N1 virus. In contrast, mice that received vaccinations of H3N2 vaccine subcutaneously were not protected against lethal challenge. Mucosal, but not parenteral vaccination induced subtype cross-reactive antibodies. These results suggest a strategy of mucosal vaccination that stimulates cross-protection against multiple influenza subtypes, including viruses with pandemic potential.

Technical Abstract: Influenza vaccines that induce greater cross-reactive or heterosubtypic immunity 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 heterosubtypic immunity in mice and evaluated an enterotoxin adjuvant LT for augmentation of heterosubtypic immunity. Mice that received intranasal immunizations of H3N2 vaccine in the presence of LT were completely protected against lethal challenge with a highly pathogenic human H5N1 virus. In contrast, mice that received three vaccinations of H3N2 vaccine subcutaneously in the presence or absence of LT did not survive lethal challenge. The functional role of B and CD8 T cells in heterosubtypic immunity were evaluated by using gene targeted B cell or CD8 cell deficient mice, respectively. CD8 but not B cell deficient tvaccinated mice were protected by heterosubtypic immunity, suggesting that B cells, but not CD8 T cells, were vital for protection of mice against heterosubtypic challenge. Mucosal, but not parenteral vaccination induced subtype cross-reactive lung IgG, IgA and serum IgG anti-HA antibodies, suggesting the presence of a common cross-reactive epitope in the HA of H3 and H5. These results suggest a strategy of mucosal vaccination that stimulates cross-protection against multiple influenza subtypes.