Bivalent vaccines derived from measles vaccine

The measles vaccine is one of the best vaccines currently available. Over the last 30 years, it has been administered to hundreds of millions of children and has proved both effective and safe. This attenuated live virus induces life-long immunity after only one or two injections. It is produced on a large scale, with ease, in many countries and is distributed at low cost. These characteristics led us to consider its use as a pediatric vector designed to simultaneously protect children against measles and to immunize them against other infections, such as AIDS, malaria or flaviviral diseases. Such affordable recombinant vaccines may be attractive for the developing word.

With this aim, we cloned the genome of the attenuated Schwarz strain of the measles virus (MV) and made it into a vector by inserting new transcriptional units. We demonstrated the strong and stable expression from this vector of genes encoding proteins from HIV, West Nile or dengue viruses. These vectors are immunogenic in mice transgenic for MV receptor and in macaques. Recombinant vaccines expressing the HIV Env gene with deletions of the hypervariable sequences induced neutralizing antibodies and T-cell responses after a single injection. Pre-existing immunity to the vector did not affect the immunogenic potential of the vectors, since two successive injections led to the induction of anti-HIV antibodies in mice and macaques previously vaccinated one year before with the standard vaccine.

An immunization/challenge experiment performed on macaques using vectors expressing the Gag, Env, Tat, and Nef proteins of SHIV89.6 demonstrated strong cellular responses and reduction of viral load during primo-infection after a rectal challenge with SHIV89.6. Similarly, a single injection of MV vector expressing the Env protein of West Nile virus induced protection against experimental challenge in mice and monkeys.

This work has led to plans for phase I/II clinical trials in collaboration with GlaxoSmithKline, aiming to test the safety of this vector and its capacity to induce immune responses to HIV in humans.

Proteomics of virus-host interactions

To identify virus-host protein-protein interactions that determine virulence and pathogenesis, we initiated a large-scale mapping project based on high-throughput technologies, including recombination-based cloning and state-of-the-art yeast two-hybrid.

Our first goal was to identify and compare the cellular proteins targeted by Paramyxoviridae. Using our proteomics platform, we characterized 80 cellular proteins as direct interactors of measles, Nipah, mumps and Tioman viruses. This network of virus-host interactions, which interfaces virulence factors and cellular mediators of innate immune response, will be used to identify potential targets for generic antiviral drugs. Functional assays are currently under development to validate these interactions and isolate interaction-disrupting peptides with antiviral activity.

In addition, we collaborate with several groups from the Virology Department to extend this strategy to other virus families, including Chikungunya virus, and eventually obtain a comprehensive map of human viruses-host interactions.