Charani RanasingheMolecular Mucosal Vaccine Immunology Group, Dept Immunology
The John Curtin School of Medical ResearchThe Australian National University
Novel HIV IL-4R antagonist vaccine strategy can induce both high avidity CD8 and excellent B cell immunity
2
Mucosal vaccination induces high quality/avidity HIV-specific CD8 T cells
Induction of high quality/avidity HIV-specific CD8 T cells following mucosal vaccination is associated with lower expression of IL-4/IL-13 by CD8 T cells
Ranasinghe et al. J. Immunol 2007
Ranasinghe et al. Euro J Immunol 2009
Ranasinghe et al. Mucosal Immunology 2013
Absence of IL-4/IL-13 induces high avidity HIV-specific CD8 T cells
Construction of poxviral vector-based vaccines that co-express IL-4R antagonist using homologous recombination
IL-4R antagonist HIV gag/pol/env
Recombinant vaccinia virus (rVV) or Modified Vaccinia Ankara (rMVA) - booster vaccine
Recombinant fowlpox virus (rFPV) - priming vaccine
HIV gag/polIL-4R antagonist
Jackson Boyle Ranasinghe Methods in Molecular Biology (2014)
intranasal/ intramuscular (i.n./i.m.) combined mucosal/systemic strategy
IL-4
Rα
γc IL-4
Rα
IL-1
3Rα
1
IL-13Rα2m
STAT6
IL-4 IL-13
4
Novel IL-4R antagonist adjuvanted vaccine will bind to IL-4R and transiently block IL-4/IL-13 signaling via the STAT6 pathway
Ranasinghe et al Cytokine and Growth Factor Reviews (In press)
96 hrs
12 hrs
Jackson Worley Trivedi Ranasinghe (submitted)
5Jackson Worley Trivedi Ranasinghe (submitted)
i.n./i.m. IL-4R antagonist adjuvanted vaccine strategy can induce HIV-specific CD8 T cells of high avidity
Inclusion of the inhibitor in the priming vaccination is crucial to induce the high avidity T cell repertoire
6.9% 9.8% 21.8% 19.6%
0.38% 1.16% 0.76% 0.98%
FPV HIVIL-4C118/VVHIVIL-4C118
Spleen
Genito-rectal nodes
FPV HIV/VV HIV FPV HIVIL-4C118/VV HIV
CD8
Kd
-Gag
Inclusion of the inhibitor in the i.n. rFPV priming vaccination is crucial to induce high avidity CD8 T cell repertoire
FPV HIV/VV HIVIL-4C118
Jackson Worley Trivedi Ranasinghe (submitted)
( i)
FP
V H
IV∆
10/ V
V H
IV∆
10(i
i) F
PV
HIV
VV
HIV
Spleen Iliac nodes Lung Lung nodes
Ranasinghe Mucosal Immunology 2013
Novel vaccines can enhance both systemic & mucosal HIV-specific poly-functional HIV-specific CD8 T cell immunity
8Jackson Worley Trivedi Ranasinghe (submitted)Ranasinghe et al Mucosal Immunology 2013;
i.n./i.m. IL-4R antagonist adjuvanted HIV vaccine strategy induces excellent CD8 T cell mediated protective immunity
* * *
P < 0.05 compared to control vaccination
* 0.0567
i.n./i.m. IL-4R antagonist adjuvanted vaccine strategy can induce Gag-specific antibody class switching
Statistics were calculated using Mann – Whitney U test
* 0.0256*** 0.0006* 0.0566
* 0.0256
6 weeks 12 weeks
IgG1
IgG2a
9Jackson Worley Trivedi Ranasinghe (submitted)
10Ranasinghe et al Mucosal Immunology 2013 ; Trivedi Jackson Ranasinghe (Submitted)
100 101 102 103 104
cd103 FITC-A
DC_1 fpv balbc.fcs
100 101 102 103 104
cd103 FITC-A
DC_1 fpv balbc.fcs
100 101 102 103 104
cd103 FITC-A
DC_3 fpv c118.fcs
100 101 102 103 104
cd103 FITC-A
DC_3 fpv c118.fcs
CD
11b
CD103
FPV-HIV - unadjuvanted FPV-HIV IL-4RC118 (IL-4R antagonist)
73.5%
1.03%
45.1%
1.92%
i.n. delivery of FPV-HIV IL-4R antagonist adjuvanted vaccine recruits unique antigen presenting cells to the lung mucosae responsible for
the induction of high avidity CD8 T and excellent B cell immunity
CD11C+ CD11b+ CD103-
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Unique features of the novel i.n./i.m. HIV IL-4R antagonist adjuvanted vaccine strategy.
Help recruit unique antigen presenting cell subsets to the lung mucosae
Induce enhanced high quality/avidity mucosal & systemic HIV Gag-specific CD8 T cell immunity*
HIV Gag-specific antibody class switching (IgG1 and IgG2a)* Env-specific IgG1 following a second i.m. Env protein booster**
Induce triple action immunity
The immune responses induced are consistent with • HIV controllers* and • Features of partial protective efficacy in the RV144 trial**
=> Platform technology against other chronic pathogens
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Acknowledgements
Molecular Mucosal Vaccine Immunology Group:Ronald JacksonAnnette BuchananLisa Pavlinovic, Megan Glidden, Sherry Tu
Students: Danushka Wijsundara, Shubhanshi
Trivedi, Matthew Worley
ANU/BRF - Kerong Zhang
JCSMR/MCRF - Harpreet Vohra, Mick Devoy
ANU/Animal services staffCollaborators:
David Boyle - CSIRO AAHL
John Stambas - Deakin Uni/ CSIRO AAHL
Robert Center - Burnet Institute/ Uni of Melbourne