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
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Abstract
A recombinant live attenuated influenza virus DeltaH5N1 vaccine with a modified hemagglutinin
(HA) and intact neuraminidase genes from A/Vietnam/1203/04 (H5N1) and six remaining
genome segments from A/Ann Arbor/6/60 (H2N2) cold-adapted (AA ca) virus was previously
shown to be 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 DeltaH5N1 vaccine: the attenuating mutations specified by the AA ca loci had
the greatest influence, followed by the deletion of the H5 HA multi-basic cleavage
site (MBS), 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 DeltaH5N1 vaccine in mice.