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Title: The influence of the multi-basic cleavage site of the H5 hemagglutinin on the attenuation, immunogenicity and efficacy of a live attenuated influenza A h5N1 cold-adapted vaccine virus

Author
item SUGUITAN, AMORSOLO - National Institutes Of Health (NIH)
item MARINO, MICHAEL - National Institutes Of Health (NIH)
item DESAI, PURVI - National Institutes Of Health (NIH)
item CHEN, LI-MEI - Centers For Disease Control And Prevention (CDC) - United States
item MATSUOKA, YUMIKO - Centers For Disease Control And Prevention (CDC) - United States
item DONIS, RUBEN - Centers For Disease Control And Prevention (CDC) - United States
item JIN, HONG - Medimmune Vaccines, Inc
item Swayne, David
item KEMBLE, GEORGE - Medimmune Vaccines, Inc
item SUBBARAO, KANTA - National Institutes Of Health (NIH)

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/15/2009
Publication Date: 10/14/2009
Citation: Suguitan, A.L., Marino, M.P., Desai, P.D., Chen, L., Matsuoka, Y., Donis, R.O., Jin, H., Swayne, D.E., Kemble, G., Subbarao, K. 2009. The influence of the multi-basic cleavage site of the H5 hemagglutinin on the attenuation, immunogenicity and efficacy of a live attenuated influenza A H5N1 cold-adapted vaccine virus. Virology. 395:280-288.

Interpretive Summary: Various avian influenza viruses have an unknown potential to become human pandemic influenza viruses. This study developed an H5N1 live weakened virus vaccine for humans by using advanced biotechnology with changes in three areas of the virus genetic material. This vaccine had reduced replication in chickens, did not cause disease in mice which are animal models for humans, and only grew at the lower temperatures in the nasal cavity. Administering the vaccine in the nose protected mice against challenge by H5 influenza viruses which support further evaluation of the vaccine in clinical trials.

Technical Abstract: A recombinant live attenuated influenza virus (LAIV) deltaH5N1 vaccine with a modified hemagglutinin (HA) and intact neuraminidase genes from A/Vietnam/1203/04 (H5N1) and the six remaining genome segments from A/Ann Arbor/6/60 (H2N2) cold-adapted (AA ca) virus was attenuated in chickens, mice and ferrets. Evaluation of the recombinant H5N1 viruses in mice indicated that three independent factors contributed to the attenuation of the LAIV deltaH5N1 vaccine: the attenuating mutations specified by the AA ca loci had the greatest influence, followed by the deletion of the multi-basic cleavage site (MBS) of the H5 HA, and the constellation effects of the AA genes acting in concert with the H5N1 glycoproteins. Restoring the MBS in the H5 HA of the vaccine virus improved its immunogenicity and efficacy, likely as a consequence of increased virus replication, indicating that removal of the MBS had a deleterious effect on the immunogenicity and efficacy of the LAIV deltaH5N1 vaccine in mice.