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Broadly Neutralizing Antibodies Against Influenza

Infection by influenza virus is a serious public health threat. It is estimated that seasonal epidemics of influenza result in up to a billion infections and 300,000-to-500,000 deaths annually worldwide. Immunization is often quite effective against seasonal infection, usually producing a neutralizing antibody response in an individual, but as seen in the 2014-2015 flu season, the immunization effort did not account for the dominant H3N2 strain, resulting in the vaccine being only 23% effective.

In 2011, Corti et. al. described one of the most broadly neutralizing antibodies against influenza - FI6.  This antibody has the ability to neutralize all influenza strains tested from group 1 and group 2 families, its neutralization potency comes from its ability to bind to the highly conserved stalk region of HA necessary for fusion and it is able to engage Fc receptors to employ FcR-dependent effector functions.  Even with all these impressive features, FI6 is far from being a therapeutic protein and further protein engineering is required.

With funding from DARPA under the ADEPT-PROTECT program, a consortium was established to leverage the skill sets in the Bjorkman, Mayo, Ravetch and Wilson labs.  The Mayo Lab has two main objectives: 1) applying our computational protein design software to investigate antibody-antigen interface residues that can improve binding and neutralization, and 2) developing a high throughput in vitro library mutagenesis protocol to reflect the sequences identified by CPD and then using yeast display to identify improved antibody variants.  Antibodies identified from these methods will then be handed off to the Bjorkman lab for in vivo neutralization assays with top performers then being passed onto the Ravetch and Wilson labs for animal testing.  Better antibodies will lower dosing requirements, in turn lowering manufacturing costs and reducing the potential immune response.    

Jan Kostecki, Ph.D.
Alex Nisthal, Ph.D. 

The Bjorkman Lab, Caltech
The Ravetch Lab, Rockefeller University
The Wilson Lab, UPenn

Funding Agencies: