Conformationally Specific Viral Immunogens

Abstract

The present invention provides methods of making engineered viral proteins and protein complexes that are useful as vaccine immunogens, engineered viral proteins and protein complexes made using such methods, and pharmaceutical compositions comprising such engineered viral proteins and protein complexes. Such engineered viral proteins and protein complexes may comprise one or more cross-links that stabilize the conformation of an antibody epitope, such as a quaternary neutralizing antibody, and may exhibit an enhanced ability to elicit a protective immune response when administered to a subject as a component of a vaccine.

1 . A method for stabilizing envelope proteins and protein complexes of pathogenic viruses to enhance their effectiveness as vaccine immunogens, the method comprising: stabilizing the tertiary structure of a polypeptide and quarternary structure of a protein complex by crosslinking, whereby the crosslinking is stable under physiologically relevant conditions, does not lead to aggregate formation of the polypeptides or proteins during expression or when they are stored in high concentrations, and stabilizes the folds of the polypeptides of the complex in particular conformations that increase the effectiveness of the complex as a vaccine immunogen by stabilizing epitopes in such conformations that can be recognized by antibodies and activate B cell receptors upon binding.