ABSTRACT
Efficient vaccines against AIDS, Hepatitis C and other persistent virus infections are urgently needed. Vaccine development has been especially hampered by the lack of suitable small animal models to reliably test the protective capacity of candidate vaccines against such chronic viral infections. A natural mouse pathogen such as MHV-68 that persists lifelong after infection, appears to be a particularly promising candidate for a more relevant model system. Here, we investigated infections with recombinant MHV-68 as novel mouse challenge model to test the efficacy of heterologous vaccines based on recombinant modified vaccinia virus Ankara (MVA). To apply ovalbumin (OVA) as a model antigen, we constructed the recombinant virus MHV-68-OVA by BAC technology and characterized genetic stability and replicative capacity of the virus in vitro and in vivo. We demonstrated the ability of MHV-68-OVA to produce ovalbumin upon tissue culture infection. Moreover, the use of MHV-68-OVA-infected target cells allowed for efficient ex vivo amplification of OVA-specific, MHC class I-restricted CD8 T cells derived from MVA-OVA-vaccinated C57BL/6 mice. Finally, we immunized C57BL/6 mice with MVA-OVA and challenged the animals with MHV-68-OVA testing different time points and routes of infection. Vaccinated mice were infected with MHV-68-OVA but showed reduced viral loads in the acute and latent phase of challenge infection. These data strongly suggest the usefulness of the MHV-68 challenge model for further evaluation of recombinant vaccines against persisting virus infections.
Subject(s)
Gammaherpesvirinae/immunology , Herpesviridae Infections/prevention & control , Herpesvirus Vaccines/pharmacology , Ovalbumin/immunology , Vaccinia virus/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Chickens , Disease Models, Animal , Gammaherpesvirinae/genetics , Gammaherpesvirinae/growth & development , Genes, MHC Class I/immunology , Herpesviridae Infections/immunology , Herpesviridae Infections/virology , Herpesvirus Vaccines/genetics , Herpesvirus Vaccines/immunology , Mice , Mice, Inbred C57BL , NIH 3T3 Cells , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology , Vaccines, Synthetic/pharmacology , Vaccinia virus/genetics , Viral LoadABSTRACT
UNLABELLED: Broad T cell and B cell responses to multiple HCV antigens are observed early in individuals who control or clear HCV infection. The prevailing hypothesis has been that similar immune responses induced by prophylactic immunization would reduce acute virus replication and protect exposed individuals from chronic infection. Here, we demonstrate that immunization of naïve chimpanzees with a multicomponent HCV vaccine induced robust HCV-specific immune responses, and that all vaccinees exposed to heterologous chimpanzee-adapted HCV 1b J4 significantly reduced viral RNA in serum by 84%, and in liver by 99% as compared to controls (P=0.024 and 0.028, respectively). However, despite control of HCV in plasma and liver in the acute period, in the chronic phase, 3 of 4 vaccinated animals developed persistent infection. Analysis of expression levels of proinflammatory cytokines in serial hepatic biopsies failed to reveal an association with vaccine outcome. However, expression of IDO, CTLA-4 [corrected] and PD-1 levels in liver correlated with clearance or chronicity. CONCLUSION: Despite early control of virus load, a virus-associated tolerogenic-like state can develop in certain individuals independent of vaccination history.
