Technical Report | Published:

Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity

Nature Medicine volume 16, pages 339345 (2010) | Download Citation


Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8+ T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine antigens to create replication-defective vaccine vectors. These rLCMV vaccines elicited CTL responses that were equivalent to or greater than those elicited by recombinant adenovirus 5 or recombinant vaccinia virus in their magnitude and cytokine profiles, and they exhibited more effective protection in several models. In contrast to recombinant adenovirus 5, rLCMV failed to elicit vector-specific antibody immunity, which facilitated re-administration of the same vector for booster vaccination. In addition, rLCMV elicited T helper type 1 CD4+ T cell responses and protective neutralizing antibodies to vaccine antigens. These features, together with low seroprevalence in humans, suggest that rLCMV may show utility as a vaccine platform against infectious diseases and cancer.

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We thank H. Hengartner and R. Zinkernagel for critical comments, suggestions, discussions and long-term support; E. Horvath for technical assistance; S.A. Rosenberg and J.R. Wunderlich for samples from patients with melanoma; M. Roederer and K. Foulds for reagents and flow cytometry support; A. Oxenius, R. Spörri and N. Joller for providing access to their flow cytometry facility; A. Pegu, R. Roychoudhuri and C. Cheng for discussions and advice on human DC cultures; D. von Laer (Georg-Speyer-Haus) for plasmid M369 and GP-expressing 293T cells; H. Shen (University of Pennsylvania School of Medicine) for rLM-OVA; M. Groettrup (University of Constance) for VACC-OVA, originally generated by J. Yewdell (National Institute of Allergy and Infectious Diseases); and R. Schirmbeck (University of Ulm) for StT-OVA-G cDNA. L.F. was supported by a fellowship of the Schweizerische Stiftung für medizinisch-biologische Stipendien. A.N.H. is a fellow of GRAKO1121 of the German Research Foundation. M.L. is a Lichtenberg fellow funded by the Volkswagen Foundation. A.B. was supported by a PhD scholarship of the Boehringer Ingelheim Fonds and by a post-doctoral fellowship of the Roche Research Foundation. D.D.P. holds a stipendiary professorship of the Swiss National Science Foundation (PP00A-114913) and was supported by grant 3100A0-104067/1 of the Swiss National Science Foundation.

Author information

Author notes

    • Frédéric Lévy

    Present address: Debiopharm, Lausanne, Switzerland.

    • Ahmed N Hegazy
    • , Andreas Bergthaler
    •  & Admar Verschoor

    These authors contributed equally to this work.


  1. Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.

    • Lukas Flatz
    • , Andreas Bergthaler
    • , Marylise Fernandez
    • , Susan Johnson
    • , Claire-Anne Siegrist
    •  & Daniel D Pinschewer
  2. Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland.

    • Lukas Flatz
    • , Ahmed N Hegazy
    • , Andreas Bergthaler
    • , Admar Verschoor
    • , Maries van den Broek
    • , Max Löhning
    •  & Daniel D Pinschewer
  3. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Lukas Flatz
    •  & Gary J Nabel
  4. Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité–University Medicine, Berlin, Germany.

    • Ahmed N Hegazy
    • , Andreas Radbruch
    •  & Max Löhning
  5. Deutsches Rheuma-Forschungszentrum, Berlin, Germany.

    • Ahmed N Hegazy
    • , Andreas Radbruch
    •  & Max Löhning
  6. Institute for Systems Biology, Seattle, Washington, USA.

    • Andreas Bergthaler
  7. Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany.

    • Admar Verschoor
  8. Tumor Immunology, Department of Clinical Research, University of Berne, Berne, Switzerland.

    • Christina Claus
    •  & Adrian F Ochsenbein
  9. World Health Organization Collaborating Center for Neonatal Vaccinology, University of Geneva, Geneva, Switzerland.

    • Marylise Fernandez
    • , Susan Johnson
    • , Paul-Henri Lambert
    • , Claire-Anne Siegrist
    •  & Daniel D Pinschewer
  10. Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Luca Gattinoni
    •  & Nicholas P Restifo
  11. Division of Gene Therapy, University of Ulm, Ulm, Germany.

    • Florian Kreppel
    •  & Stefan Kochanek
  12. Oncology, University Hospital of Zurich, Zurich, Switzerland.

    • Maries van den Broek
  13. Ludwig Institute for Cancer Research, Epalinges, Switzerland.

    • Frédéric Lévy
  14. Department of Pediatrics, University of Geneva, Geneva, Switzerland.

    • Claire-Anne Siegrist


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L.F., A.N.H., A.B., A.V., C.C., M.F., L.G., S.J., F.K. and D.D.P. performed experiments; L.F., A.N.H., A.B., A.V., C.C., L.G., P.-H.L., C.-A.S., N.P.R., M.L., A.F.O., G.J.N. and D.D.P. designed experiments; S.K., M.v.d.B., A.R. and F.L. contributed reagents; and L.F., G.J.N. and D.D.P. wrote the manuscript.

Competing interests

L.F., A.B. and D.D.P. are listed as co-inventors on a patent held by the University of Zurich on arenavirus vectors and thus they will be recipients of potential future revenues from this intellectual property. C.A.S. has received honoraria for participation in scientific advisory boards and research grants from several vaccine manufacturers, none related to this work.

Corresponding authors

Correspondence to Lukas Flatz or Daniel D Pinschewer.

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