I have developed an extremely simple, innovative, and robust platform technology to present α-helical epitopes from native proteins to the immune system such that the resulting conformation-specific antibodies bind to the native protein target. This procedure involves a process called templating where the helical sequence of interest is inserted into a parallel two-stranded α-helical coiled-coil and disulfide-bridged template which maintains the native helical conformation of the epitope, presents all the surface-exposed residues of the α-helix in the native protein, and optimizes stability of the immunogen.
Viruses that enter cells using Class 1 Viral Fusion Proteins such as Ebola, Influenza A, Respiratory Syncytial Virus and coronaviruses such as SARS-CoV and MERS-CoV are ideal targets for this technology. The stem domains of the fusion glycoproteins of these diverse viruses share a common coiled-coil structure that must be triggered to undergo a massive conformational change in order to induce fusion of the virus envelope with host cell membranes and initiate virus infections in vitro and in vivo. Our templated, two-stranded immunogens elicited stem targeted, virus neutralizing antibodies against SARS-CoV and the hemagglutinin (HA) protein of influenza A.
We have shown that passive administration of rabbit antibodies to a selected immunogen can protect mice against death after intranasal challenge with influenza A. This antibody also recognizes purified HA proteins from different influenza subtypes, suggesting that this stem-targeted immunogen may serve as a “universal” influenza vaccine that can protect against multiple subtypes.
This research is the result of an accumulation of an extensive body of published work on de novo design of coiled-coil proteins from my laboratory. Selected publications are listed.
Jiang, Z., L. Gera, C.T. Mant and R.S. Hodges. Antibody cross-reactivity to hemagglutinin protein antigens demonstrates feasibility for development of a “Universal” Influenza A synthetic peptide vaccine. In Enabling Peptide Research from Basic Research to Drug Discovery, Proceedings of the 24th American Peptide Symposium, Orlando, FL (V. Srivastava, A. Yudin and M. Lebl, editors) pp. 36-39 (2015). Published by the American Peptide Society and Propt Scientific Publishing, 2015.
Yan, Z., W.J. Hartsock, Z. Qian, K.V. Holmes and R.S. Hodges. Strategies for designing peptide immunogens to elicit α-helical conformation specific antibodies reactive with native proteins. In “Small Wonders: Peptides for Disease Control” (K. Rajasekaran, J.W. Cary and J. Jaynes, Eds.) ACS Symposium Series, Chapter 6, pp. 93-136 (2012).
Tripet, B., D. Kao, S. Jeffers, K. Holmes and R.S. Hodges. Template-based Coiled-coil antigens elicit neutralizing antibodies to the SARS-Coronavirus. J. Structural Biology 155: 176-194 (2006).
Tripet, B., M.W. Howard, M. Jobling, R.K. Holmes, K.V. Holmes, and R.S. Hodges. Structural characterization of the SARS-Coronavirus Spike Fusion Protein Core. J. Biol. Chem. 279: 20836-20849 (2004).
I have determined the key adhesin for the attachment of PA to the epithelial cell surface and identified the receptor binding domain as a 17-residue region of the pilin protein. Antibodies to the receptor binding domain (RBD) block adherence of the organism and provide protection against PA in animal models.
We have determined the three-dimensional structures of the receptor binding domains from multiple strains of PA and shown that though sequences vary substantially from one strain to another, there is a common structural motif.
We have shown that a synthetic peptide vaccine is superior to a pilin protein-based vaccine. Using a rational design approach, we have developed a single 17-residue peptide immunogen that generates antibodies that target the RBD of more than one strain of PA.
My present goal is to design a consensus sequence immunogen that will provide maximum antibody cross-reactivity and affinity to all known strains of PA.
Selected publications are listed.
Hartsock, W.J., C. Hackbarth and R.S. Hodges. Antiadhesion synthetic consensus sequence peptide-based vaccines for Pseudmonas aeruginosa. In Handbook of Biologically Active Peptides, 2nd edition, (A.J. Kastin, Editor in Chief) Chapter 77, pp. 563-570 (2013).
Hackbarth, C. and R.S. Hodges. Synthetic Peptide Vaccine Development: Designing Dual Epitopes into a Single Pilin Peptide Immunogen Generates Antibody Cross-reactivity between Two Strains of Pseudomonas aeruginosa. Chem. Biol. & Drug Design 76: 293-304 (2010). (Journal Cover Figure) PMC2949483 PMID20807222
Kao, D. and R.S. Hodges. Advantages of a synthetic peptide immunogen over a protein immunogen in the development of an anti-pilus vaccine for Pseudomonas aeruginosa. Chem. Biol. and Drug Design 74: 33-42 (2009). PMC2756486 PMID19519742
Kao, D., M.E. Churchill, R.T. Irvin and R.S. Hodges. Animal protection and structural studies of a consensus sequence vaccine targeting the receptor binding domain of the type IV pilus of Pseudomonas aeruginosa. J. Mol. Biol.374: 426-442 (2007). PMC3493149 PMID17936788