We have shown that defective viral-like particles (VLPs) associating retroviral capsids and envelope glycoproteins derived from several enveloped viruses, such as HCV1 and avian influenza2, are potent inducers of neutralising antibodies in mice1,2. Particularly, VLPs displaying the HCV E1 glycoprotein (E1-VLPs) elicit a neutralising antibody response of broad specificity against the major HCV genotypes1, which is not attenuated by high-density lipoproteins and human serum3. Aiming to vectorise these novel immunogens, we have generated recombinant viruses derived from live measles vaccine (MV, Schwarzstrain4) that express the E1 glycoprotein (MV-E1). The immunogenicity of MV-E1 in a heterologous "prime-boost" protocol, using E1-VLPs in the boosts, was compared to an immunisation scheme that only uses E1-VLPs as immunogen. Transgenic mice, expressing huCD46+ and KO for the type I interferon receptor, were inoculated twice with MV-E1 at a 4 weeks interval. These mice were then inoculated with either E1-VLPs at a 21 days interval ("MV-E1/E1-VLP" group) or RD114-VLP, expressing a control glycoprotein derived from the RD114 retrovirus ("control" group). A third group of mice ("E1-VLP" group) was inoculated at 3 weeks intervals with E1-VLPs only, without MV-E1 priming. We show that mice from the "MV-E1/E1-VLP" and "E1-VLP" groups elicit anti-VHC antibodies that neutralise both HCVpp and HCVcc. Moreover, a robust response was detected after the second boost with E1-VLPs in mice of the "MV-E1/E1-VLP" group in contrast to mice of the "E1-VLP" group that slowly mounted a neutralising response. Finally, antibodies purified from these sera cross-neutralised HCVpp of several genotypes and were not attenuated by HDL. In conclusion, we propose a novel HCV immunisation protocol that induces strong and potent humoral responses, via an heterologous "prime-boost" protocol combining a recombinant measles virus-derived vector and VLPs displaying the HCV-E1 glycoprotein.

1: Granier C, Verney G, Bartosch B, Cosset FL. Potent cross-neutralising antibody responses induced by hepatitis C virus (HCV) pseudo-particles displaying the HCV E1 glycoprotein. 2004. Unpublished results.
2: Szecsi J, Boson, B, CossetFL. A novel fast and robust method to measure titres of neutralising antibodies raised against pathogenic avian influenza viruses. 2005. Unpublished results.
3: Dreux M et al. High density lipoprotein inhibits hepatitis C virus neutralising antibodies by stimulating cell entry via activation of the scavenger receptor BI. 2006. J Biol Chem. In press.
4: Combredet, C et al. A molecularly cloned Schwarz strain of measles virus vaccine induces strong immune responses in macaques and transgenic mice. 2003, J. Virology, 77, 11546-554.
5: Bartosch B, Dubuisson J, Cosset FL. Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. 2003. J Exp Med.197:633-642