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.
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.
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rm 3E13C.1, 33 North Drive, MSC 3203, Bethesda, MD 20892-3203, USA. suguitanjra@medimmune.com
authors.forename: Amorsolo L
authors.initials: AL
authors.lastname: Suguitan
authors.forename: Michael P
authors.initials: MP
authors.lastname: Marino
authors.forename: Purvi D
authors.initials: PD
authors.lastname: Desai
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Chen
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Ruben O
authors.initials: RO
authors.lastname: Donis
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.forename: David E
authors.initials: DE
authors.lastname: Swayne
authors.forename: George
authors.initials: G
authors.lastname: Kemble
authors.forename: Kanta
authors.initials: K
authors.lastname: Subbarao
mesh_terms: D000222:Adaptation, Physiological; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002645:Chickens; D003080:Cold Temperature; D004279:DNA, Viral; D004334:Drug Administration Schedule; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry*; D053124:Influenza A Virus, H5N1 Subtype / Q000502:physiology*; D007252:Influenza Vaccines / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D011994:Recombinant Proteins; D014613:Vaccines, Attenuated / Q000276:immunology*; D014764:Viral Proteins
chemical_list: D004279:DNA, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D011994:Recombinant Proteins; D014613:Vaccines, Attenuated; D014764:Viral Proteins; C109963:hemagglutinin, avian influenza A virus