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Analysis of a vaccine-elicited anti-H5N1 antibody and its unmutated common ancestor

dc.creatorWinarski, Katie Lynn
dc.description.abstractSeasonal influenza remains a worldwide health concern and recently, the novel avian influenza virus, H5N1, has infected and caused disease in humans, though the virus is not currently capable of human-to-human transmission. Since 2003, 850 human cases of the novel influenza virus H5N1 have been reported with a 50% mortality rate. Recently two labs have shown, very few mutations may be necessary for efficient transmission between humans. In order to examine the immune response to H5N1, a panel of antibodies from subjects in a phase I clinical trial of an experimental H5N1 vaccine were isolated and characterized. We choose a potent and specific anti-H5N1 antibody, H5.3, for further studies in order to determine the molecular mechanism of neutralization used by H5.3 and how the antibody developed. The structure of the H5.3 Fab in complex with the H5 head domain showed H5.3 interacts with the highly conserved receptor binding site and polymorphic residues on the edges of the interface, indicating breadth and potency of the antibody conflict due to variability outside the receptor-binding site. As evidenced by the structures of the H5.3 Fab in complex with H5 respiratory droplet transmissible variants, the receptor preference of the virus may not be critically important for recognition by a receptor binding site directed antibody. The H5N1 vaccine elicited a primarily naïve antibody response, as the H5-specific antibodies had a lower number of somatic mutations than the broadly neutralizing influenza antibodies. The H5.3 somatic mutations do not stabilize the protein conformation, as it remains flexibility after affinity maturation, and do not have a large effect on increasing the affinity of H5.3 for H5. Overall, this research will contribute to influenza vaccine design.
dc.subjectx-ray crystallography
dc.titleAnalysis of a vaccine-elicited anti-H5N1 antibody and its unmutated common ancestor
dc.contributor.committeeMemberJames E. Crowe, Jr.
dc.contributor.committeeMemberMelanie D. Ohi
dc.contributor.committeeMemberJames W. Thomas
dc.contributor.committeeMemberBenjamin W. Spiller
dc.type.materialtext and Immunology University
dc.contributor.committeeChairMark R. Denison

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