Bivalent vaccines derived from measles vaccine

The measles vaccine has been administered to hundreds of millions of children over the last 30 years and has proved both effective and safe, inducing life-long immunity after only one injection. It is produced on a large scale in many countries and is distributed at low cost through the Expanded Program on Immunization of WHO. These characteristics led us to consider its use as a pediatric vector designed to protect children against measles and simultaneously to immunize them against other infections, such as AIDS, malaria or flaviviral diseases. These affordable recombinant vaccines might 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 with standard vaccine. An immunization/challenge experiment performed on macaques using MV-SHIV89.6 vectors demonstrated strong cellular responses and reduction of viral load during primo-infection after a rectal SHIV89.6challenge. A clinical development program is running in collaboration with GlaxoSmithKline to evaluate in phase I/II clinical trials the safety of MV-HIV vector and its capacity to induce immune responses to HIV in humans. The vaccine candidate has been produced and proved to be immunogenic in mice and macaques. A clinical GMP lot is currently evaluated in a large toxcicity study in primates before Phase I testing. New MV vectors promoting the intense budding of assembled HIV1 Gag virus-like-particles coated with HIV1 Env proteins have been produced and proved to be immunogenic. In a similar program, we have constructed a MV vector expressing a new combined dengue antigen derived from the four serotypes of dengue virus and demonstrated its capacity to induce durable specific neutralizing antibodies to dengue virus. The efficacy of this vaccine is currently evaluated in macaques. Other programs are also developed in the laboartory using the same technology, particularly a MV-malaria vaccination program in collaboration with New York University and GlaxoSmithKline.

Proteomics of virus-host interactions

To identify virus-host protein-protein interactions that determine virulence and pathogenesis, we have developed a large-scale mapping project based on high-throughput technologies, including recombination-based cloning and state-of-the-art yeast two-hybrid. Our screening platform is now fully operational and more than 100 screens a year can be performed. Using this tool, we have identified hundreds of virus-host protein-protein interactions, taking advantage of the unique collection of viruses available at Institut Pasteur. Besides collaborative programs developed inside or outside of this institution, our efforts now focus on two viral families of higher interest for our research group : Paramyxoviridae, including measles, Nipah, mumps, human parainfluenza 3 and Tioman viruses, and arboviruses from flavivirus and alphavirus genera including chikungunya, Sindbis, Semliki Forest and yellow fever viruses. Virus-host protein-protein interactions identified by yeast two-hybrid will be validated in the near future using a high-throughput binding assay recently developed in our laboratory. Among identified interactions, we recently demonstrated that the V protein of measles virus targets STAT1, STAT2 and Jak1 to inhibit type I interferon signalling pathway, thereby blocking the innate antiviral immune response. In addition to this fundamental research program, we engaged in the large-scale screening of chemical compound libraries to identify immunostimulators of the antiviral immune response and specific inhibitors of alphavirus virulence factor nsP2.

Keywords: measles, HIV, Chikungunya, dengue, vaccine, interactome, yeast two-hybrid, antiviral molecules

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