Thermostable measles fusion glycoprotein as a new vaccine strategy

Measles (MeV) causes disease worldwide despite efforts towards eradication by vaccine, primarily because it is readily spread between people. Acute MeV infection causes immune amnesia, increasing susceptibility to other infectious diseases. In addition, rare but severe neurological complications can develop several years after measles due to persistent MeV infection of the central nervous system. People with impaired cellular immunity are at increased risk of developing severe measles but often cannot be vaccinated since the vaccine virus itself can lead to fatal illness. There is no specific therapy for acute or persistent MeV manifestations. A successful vaccination campaign could have eradicated MeV more than 20 years ago. As of today, eradication is not in sight, and the resurgence of measles highlights the need for a vaccination strategy that is safe for immune-compromised people and easy to be delivered around the world without the need for a cold chain. We have designed a thermostable measles fusion protein and shown that it induces protective immunity and neutralizing antibodies in vivo. We have obtained structural data showing that our stabilized MeV F is in the expected pre-fusion state. The recent approval of a stabilized respiratory syncytial virus fusion protein as a subunit vaccine highlights the clinical validity of our strategy. This application will test whether we can design a thermostable measles F that elicits protection in immune-compromised individuals and that can be delivered worldwide. We propose to capitalize on our structural and functional knowledge of the MeV F to optimize and assess the efficacy of thermostable forms of the F to elicit neutralizing antibodies and induce a protective immune response in vivo. The proposed work will address two Specific Aims: 1. Engineering a thermostable measles F protein immunogen. 2. Evaluate the protection afforded by anti-F protein immune responses. The impact of our application will be significant for the growing number of severely immune-compromised individuals who cannot be vaccinated with the current live MeV vaccine and may contribute to worldwide eradication of MeV.