Influenza immunogen design
We are attempting to design immunogens that elicit broadly neutralizing antibodies against influenza virus, a re-emerging global health threat. In 2010, we carried out the design and bacterial expression of an immunogen consisting of the conserved stem region of the viral surface protein HA from H3N2 influenza. Since this region of the protein is in a metastable pre-fusion conformation, it had not been previously possible to express it in a soluble form at neutral pH. This problem was overcome by introducing mutations to destabilize the post-fusion conformation of the protein. In collaborative studies with Merck, the immunogen was shown to confer protection against pathogenic viral challenge in mice. This was one of the first successful examples of structure guided immunogen design.
Subsequently we have used similar mutations to stabilize the stem region of other clades of influenza, thus this approach may serve as the foundation for a universal flu vaccine, that might replace current seasonal vaccines or more likely, find application during a pandemic. We are currently attempting to stabilize these stem immunogens through mutation as well as by nanoparticle display. We are also exploring how soluble ectodomains of HA and the other major surface protein of influenza virus, Neuraminidase might be stabilized and incorporated in improved influenza vaccine formulations. Much of this work is done in collaboration with the Bengaluru based startup Mynvax.