APSUO Rosalind Franklin Young Investigator Award

Damian Ekiert Named Franklin Award Recipient for Studies of Influenza Virus

The APS Users Organization has named Damian C. Ekiert as the winner of the 2012 Rosalind Franklin Young Investigator Award. The prize recognizes Ekiert’s work on broadly neutralizing antibodies, which holds promise for structure-based design of a universal vaccine for influenza.

Current flu vaccines primarily elicit an immune response against the head region of hemagglutinin, a portion of the influenza virus that changes rapidly. Thus, new vaccines must be developed each year, and unanticipated mutations in the virus may lead to the outbreak of an influenza pandemic. Now, thanks to the work of Ekiert and others on broadly neutralizing antibodies, it may be possible for vaccines to target a region of hemagglutinin that does not change. Thus, one vaccine could protect against most types of flu over a much longer term.

The work focused on two antibodies that neutralize many strains of influenza. Ekiert used beamline 23-ID (GM/CA-CAT) to determine the structure of these antibodies in complex with their target antigen, hemagglutinin. The structural data pinpointed the region on the virus that the antibody targets, and further studies showed that the structure of this region is unchanged, or conserved, across many strains of influenza. One of the antibodies tested is now in initial clinical trials in humans for use as a treatment for acute influenza infection.

Ekiert also collaborated with a group led by David Baker (University of Washington) that developed a computational method for designing novel protein-protein interactions. The method was used to design several proteins to target the conserved region of hemagglutinin, and Ekiert solved the structure of one of these proteins when complexed with hemagglutinin from the 1918 pandemic influenza virus.

According to Ekiert, there were some challenges due to the size, flexibility, and heterogeneity of the sample. Hemagglutinin is heavily glycosylated, which can make crystallization challenging, and large regions of the antibodies were disordered in some of the structures. “Tools developed at GM/CA-CAT were crucial for the collection of high-quality diffraction data,” Ekiert said. “Several of the structures would have been difficult or perhaps impossible to obtain at many other beamlines.” Critical to the work were the minibeam (an X-ray beam with a 5-20 µm spot size) and a rastering function developed at GM/CA-CAT. “Together, these tools allowed us to find and center on crystals we were unable to visualize in the mounting loop, collect diffraction data from very small crystals, and to zero in on small, high-quality sections of otherwise unusable crystals,” Ekiert said.

The X-ray structural studies formed the basis of Ekiert’s dissertation work in Ian Wilson’s group at the Scripps Research Institute. The antibody project as a whole was a collaboration between Scripps and the biopharmaceutical company Crucell, of the Netherlands.

Ekiert is now a post-doctoral fellow at the University of California, San Francisco, in the laboratory of Jeffery Cox, where he is working on host-pathogen interactions in M. tuberculosis.

The Franklin Award recognizes an important scientific or technical accomplishment by a young investigator conducted at, or beneficial to, the APS.

Publications:
D.C. Ekiert, R. H. E. Friesen, G. Bhabha, T. Kwaks, M. Jongeneelen, W. Yu, C. Ophorst, F. Cox, H.J.W.M. Korse, B. Brandenburg, R. Vogels, J.P.J. Brakenhoff, R. Kompier, M.H. Koldijk, L.A.H.M. Cornelissen, L.L.M. Poon, M. Peiris, W. Koudstaal, I.A. Wilson, J. Goudsmit. “A highly conserved neutralizing epitope on Group 2 influenza A viruses,” Science, 333, 843 (2011). DOI: 10.1126/science.1204839 http://www.sciencemag.org/content/333/6044/843.short

S.J. Fleishman*, T.A Whitehead*, D.C. Ekiert*, C. Dreyfus, J.E. Corn, E.M. Strauch, I.A. Wilson, D. Baker. "Computational design of proteins targeting the conserved stem region of influenza hemagglutinin." Science, 332, 816 (2011). DOI: 10.1126/science.1202617 http://www.sciencemag.org/content/332/6031/816.abstract

R. Xu*, D.C. Ekiert*, J.C. Krause, R. Hai, J.E. Crowe, Jr., I.A. Wilson. “Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus,” Science, 328, 357 (2010). DOI: 10.1126/science.1186430 http://www.sciencemag.org/content/328/5976/357.abstract

D.C. Ekiert, G. Bhabha, M.A. Elsliger, R.H. Friesen, M. Jongeneelen, M. Throsby, J. Goudsmit, I.A. Wilson. “Antibody recognition of a highly conserved influenza virus epitope.” Science, 324, 246 (2009). DOI: 10.1126/science.1171491 http://www.sciencemag.org/content/324/5924/246.abstract

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