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Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys

Abstract

The development of immunologic interventions that can target the viral reservoir in HIV-1-infected individuals is a major goal of HIV-1 research1,2. However, little evidence exists that the viral reservoir can be sufficiently targeted to improve virologic control following discontinuation of antiretroviral therapy. Here we show that therapeutic vaccination with Ad26/MVA (recombinant adenovirus serotype 26 (Ad26) prime, modified vaccinia Ankara (MVA) boost)3,4 and stimulation of TLR7 (Toll-like receptor 7) improves virologic control and delays viral rebound following discontinuation of antiretroviral therapy in SIV-infected rhesus monkeys that began antiretroviral therapy during acute infection. Therapeutic vaccination with Ad26/MVA resulted in a marked increase in the magnitude and breadth of SIV-specific cellular immune responses in virologically suppressed, SIV-infected monkeys. TLR7 agonist administration led to innate immune stimulation and cellular immune activation. The combination of Ad26/MVA vaccination and TLR7 stimulation resulted in decreased levels of viral DNA in lymph nodes and peripheral blood, and improved virologic control and delayed viral rebound following discontinuation of antiretroviral therapy. The breadth of cellular immune responses correlated inversely with set point viral loads and correlated directly with time to viral rebound. These data demonstrate the potential of therapeutic vaccination combined with innate immune stimulation as a strategy aimed at a functional cure for HIV-1 infection.

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Figure 1: SIV RNA and vaccine immunogenicity before ART discontinuation.
Figure 2: SIV DNA before ART discontinuation.
Figure 3: SIV RNA following ART discontinuation.
Figure 4: Correlations of cellular immune breadth with set point viral loads and time to viral rebound.

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Acknowledgements

We thank C. Linde, T. Broge, T. Barnes, D. van Manen, F. Wegmann, C. Shaver, W. Wagner, M. Boyd, R. Nityanandam, K. Smith, S. Blackmore, L. Parenteau, P. Giglio, M. Shetty, S. Levin, J. Shields, G. Neubauer, and F. Stephens for generous advice, assistance, and reagents. We acknowledge support from the US Army Medical Research and Materiel Command and the Military HIV Research Program, Walter Reed Army Institute of Research through its cooperative agreement with the Henry M. Jackson Foundation (W81XWH-11-2-0174); the National Institutes of Health (AI096040, AI124377, AI126603, OD019851); the Ragon Institute of MGH, MIT, and Harvard. Mathematical model fitting was performed on the Orchestra High Performance Compute Cluster at Harvard Medical School. The views expressed in this manuscript are those of the authors and do not represent the official views of the Department of the Army or the Department of Defense.

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Authors and Affiliations

Authors

Contributions

D.H.B, N.L.M., J.H.K., M.L.R., M.G.P., H.S., and R.G. designed the studies. J.H. and R.G. developed the ART formulation and TLR7 agonist. E.N.B., C.C., K.E.S., J.L., J.P.N., A.L.B., L.P., B.C.L., J.J., D.J., J.M., S.M., A.C., K.M., and G.A. performed the immunologic assays. P.A. and D.N. conducted the virologic assays. J.M.G. and A.L.H. performed the viral dynamics modelling. M.G.L. led the clinical care of the rhesus monkeys. D.H.B. wrote the paper with all co-authors.

Corresponding author

Correspondence to Dan H. Barouch.

Ethics declarations

Competing interests

M.G.P. and H.S. are employees of Janssen Infectious Diseases and Vaccines. J.H. and R.G. are employees of Gilead Sciences.

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Reviewer Information

Nature thanks S. Lewin and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data figures and tables

Extended Data Figure 1 Activation of CD8+ T cells following GS-986 administration.

Representative data on days 0, 1, and 2 following GS-986 administration. Activation was assessed by CD69 expression on CD3+CD8+ T cells. Red bars represent mean values for each group.

Extended Data Figure 2 Activation of CD4+ T cells following GS-986 administration.

Representative data on days 0, 1, and 2 following GS-986 administration. Activation was assessed by CD69 expression on CD3+CD4+ T cells.

Extended Data Figure 3 Innate immune stimulation following GS-986 administration.

Plasma IFN-α (pg ml−1) levels are shown on day 1 following GS-986 administration. Red bars represent mean values for each group. Data points reflect all animals following all GS-986 administrations combined with pre-dose levels subtracted.

Extended Data Figure 4 CD8+ T cells following Ad26/MVA vaccination.

SIVmac239 Gag-, Pol- and Env-specific, IFN-γ+CD3+CD8+ central memory T cells were assessed by multiparameter intracellular cytokine staining assays.

Extended Data Figure 5 CD4+ T cells following Ad26/MVA vaccination.

SIVmac239 Gag-, Pol- and Env-specific, IFN-γ+CD3+CD4+ central memory T cells were assessed by multiparameter intracellular cytokine staining assays.

Extended Data Figure 6 Cellular immune breadth.

Responses to subpools of 10 peptides spanning SIVmac239 Gag, Pol, and Env are shown before vaccination (week 20, blue), after Ad26 prime (week 29, red), and after MVA boost (week 50, green). Coloured squares indicate positive responses. ‘x’ indicates missing data as a result of insufficient PBMCs.

Extended Data Figure 7 Correlations of cellular immune breadth to day 7 SIV RNA.

Correlations are shown for the breadth of Gag, Pol, Env and total (Gag+Pol+Env) cellular immune responses at the time of ART discontinuation at week 72 and pre-ART day 7 log SIV RNA. P value indicates two-sided Spearman rank-correlation test. R value indicates correlation coefficient.

Extended Data Figure 8 Correlations of cellular immune breadth to set point viral loads.

Correlations are shown for the breadth of Gag, Pol, Env and total (Gag+Pol+Env) cellular immune responses at peak immunity at week 50 and set point log SIV RNA following ART discontinuation. P values indicate two-sided Spearman rank-correlation tests. R values indicate correlation coefficients.

Extended Data Figure 9 Correlations of cellular immune breadth to time to viral rebound.

Correlations are shown for the breadth of Gag, Pol, Env and total (Gag+Pol+Env) cellular immune responses at peak immunity at week 50 and time to viral rebound following ART discontinuation. P values indicate two-sided Spearman rank-correlation tests. R values indicate correlation coefficients.

Extended Data Figure 10 Rebound kinetic parameters estimated from viral dynamics modelling.

Viral load values following ART discontinuation in each animal were fit to a viral dynamics model using a Bayesian framework. ad, Plots show the median and 95% credible intervals for estimations of the rate of reactivation of cells from the latent reservoir (a), the initial exponential growth rate (b), the immune proliferation rate (c), and the time at which viral load reaches the detection threshold of 200 copies per ml for each treatment group (d). Monkeys treated with both the vaccine and TLR7 agonist exhibited slower viral growth rates and stronger immune responses than all other groups (P < 0.01 for each comparison). These monkeys and monkeys treated with only the vaccine exhibited a lower reservoir exit rate than untreated monkeys (P < 0.05 for each comparison).

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Borducchi, E., Cabral, C., Stephenson, K. et al. Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys. Nature 540, 284–287 (2016). https://doi.org/10.1038/nature20583

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