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

Lukas Flatz; Ahmed N. Hegazy; Andreas Bergthaler; Admar Verschoor; Christina Claus; Marylise Fernandez; Luca Gattinoni; Susan Johnson; Florian Kreppel; Stefan Kochanek; Maries Van Den Broek; Andreas Radbruch; Frédéric Lévy; Paul Henri Lambert; Claire Anne Siegrist; Nicholas P. Restifo; Max Löhning; Adrian F. Ochsenbein; Gary J. Nabel; Daniel D. Pinschewer

doi:10.1038/nm.2104

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

Lukas Flatz^*, Ahmed N. Hegazy, Andreas Bergthaler, Admar Verschoor, Christina Claus, Marylise Fernandez, Luca Gattinoni, Susan Johnson, Florian Kreppel, Stefan Kochanek, Maries Van Den Broek, Andreas Radbruch, Frédéric Lévy, Paul Henri Lambert, Claire Anne Siegrist, Nicholas P. Restifo, Max Löhning, Adrian F. Ochsenbein, Gary J. Nabel, Daniel D. Pinschewer

^*Corresponding author for this work

Institute of Systemic Inflamation Research

90 Citations (Scopus)

Abstract

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⁺ 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.

Original language	English
Journal	Nature Medicine
Volume	16
Issue number	3
Pages (from-to)	339-345
Number of pages	7
ISSN	1078-8956
DOIs	https://doi.org/10.1038/nm.2104
Publication status	Published - 03.2010

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/nm.2104

Cite this

Flatz, L., Hegazy, A. N., Bergthaler, A., Verschoor, A., Claus, C., Fernandez, M., Gattinoni, L., Johnson, S., Kreppel, F., Kochanek, S., Broek, M. V. D., Radbruch, A., Lévy, F., Lambert, P. H., Siegrist, C. A., Restifo, N. P., Löhning, M., Ochsenbein, A. F., Nabel, G. J., & Pinschewer, D. D. (2010). Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8⁺ T cell immunity. Nature Medicine, 16(3), 339-345. https://doi.org/10.1038/nm.2104

@article{7592dc378dba4dccac839c3b3722c0b1,

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

abstract = "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+ 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.",

author = "Lukas Flatz and Hegazy, {Ahmed N.} and Andreas Bergthaler and Admar Verschoor and Christina Claus and Marylise Fernandez and Luca Gattinoni and Susan Johnson and Florian Kreppel and Stefan Kochanek and Broek, {Maries Van Den} and Andreas Radbruch and Fr{\'e}d{\'e}ric L{\'e}vy and Lambert, {Paul Henri} and Siegrist, {Claire Anne} and Restifo, {Nicholas P.} and Max L{\"o}hning and Ochsenbein, {Adrian F.} and Nabel, {Gary J.} and Pinschewer, {Daniel D.}",

note = "Funding Information: Swiss National Science Foundation (PP00A-114913) and was supported by grant 3100A0-104067/1 of the Swiss National Science Foundation. Funding Information: 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. Sp{\"o}rri 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 f{\"u}r 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 Copyright: Copyright 2010 Elsevier B.V., All rights reserved.",

year = "2010",

month = mar,

doi = "10.1038/nm.2104",

language = "English",

volume = "16",

pages = "339--345",

journal = "Nature Medicine",

issn = "1078-8956",

number = "3",

}

Flatz, L, Hegazy, AN, Bergthaler, A, Verschoor, A, Claus, C, Fernandez, M, Gattinoni, L, Johnson, S, Kreppel, F, Kochanek, S, Broek, MVD, Radbruch, A, Lévy, F, Lambert, PH, Siegrist, CA, Restifo, NP, Löhning, M, Ochsenbein, AF, Nabel, GJ & Pinschewer, DD 2010, 'Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8⁺ T cell immunity', Nature Medicine, vol. 16, no. 3, pp. 339-345. https://doi.org/10.1038/nm.2104

TY - JOUR

T1 - Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity

AU - Flatz, Lukas

AU - Hegazy, Ahmed N.

AU - Bergthaler, Andreas

AU - Verschoor, Admar

AU - Claus, Christina

AU - Fernandez, Marylise

AU - Gattinoni, Luca

AU - Johnson, Susan

AU - Kreppel, Florian

AU - Kochanek, Stefan

AU - Broek, Maries Van Den

AU - Radbruch, Andreas

AU - Lévy, Frédéric

AU - Lambert, Paul Henri

AU - Siegrist, Claire Anne

AU - Restifo, Nicholas P.

AU - Löhning, Max

AU - Ochsenbein, Adrian F.

AU - Nabel, Gary J.

AU - Pinschewer, Daniel D.

N1 - Funding Information: Swiss National Science Foundation (PP00A-114913) and was supported by grant 3100A0-104067/1 of the Swiss National Science Foundation. Funding Information: 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 Copyright: Copyright 2010 Elsevier B.V., All rights reserved.

PY - 2010/3

Y1 - 2010/3

N2 - 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+ 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.

AB - 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+ 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.

UR - http://www.scopus.com/inward/record.url?scp=77949275849&partnerID=8YFLogxK

U2 - 10.1038/nm.2104

DO - 10.1038/nm.2104

M3 - Journal articles

C2 - 20139992

AN - SCOPUS:77949275849

SN - 1078-8956

VL - 16

SP - 339

EP - 345

JO - Nature Medicine

JF - Nature Medicine

IS - 3

ER -