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J&J vaccine plus Gilead immune booster shows promise as HIV fighter
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"The objective of our study was to identify a functional cure for HIV - not to eradicate the virus, but to control it without the need for ART,"said lead author Dan Barouch, M.D., Ph.D., Director of the Center for Virology and Vaccine Research at BIDMC and Professor of Medicine at Harvard Medical Schoo......Janssen, in collaboration with MHRP, recently began in-human studies to evaluate the potential of the HIV therapeutic vaccine in HIV infected patients who initiated ART during acute HIV infection. The Phase I/IIa study is evaluating the safety, immunogenicity of the Ad26/MVA vaccine regimen. The study will also explore the effect on viremic control after interruption of antiretroviral treatment following vaccination. The study will enroll patients who started ART during acute HIV infection and who are currently on stable ART."
New Therapeutic Vaccine Approach in Non-Human Primates Shows Potential as Functional Cure for HIV-1 - (11/09/1)
"The objective of our study was to identify a functional cure for HIV - not to eradicate the virus, but to control it without the need for ART," said lead author Dan Barouch, M.D., Ph.D., Director of the Center for Virology and Vaccine Research at BIDMC and Professor of Medicine at Harvard Medical School.....these data demonstrate the proof-of-concept that the combination of therapeutic vaccination and innate immune stimulation can impact viral rebound following ART discontinuation.In this study, we demonstrate that Ad26/MVA therapeutic vaccination robustly augmented cellular immune magnitude and breadth in ART-suppressed, SIV-infected rhesus monkeys and that the TLR7 agonist GS-986 led to innate immune stimulation and cellular activation. The combination of Ad26/MVA vaccination and GS-986 resulted in a significant 1.74 log reduction in median setpoint viral loads and a 2.5-fold delay in the time to viral rebound following ART discontinuation as compared with sham controls. Moreover, 3 of 9 animals in this group demonstrated virologic control to undetectable levels in the absence of ART. These three animals were characterized by high cellular immune magnitude and breadth and negative viral DNA prior to ART discontinuation.....The present study extends these prior observations by combining therapeutic vaccination with innate immune stimulation. Of note, the combination of Ad26/MVA vaccination and TLR7 stimulation proved more potent than either component alone. This finding is consistent with a prior in vitro study that showed that robust CD8+ T cells may be able to facilitate elimination of the viral reservoir following reactivation11. The present study also demonstrates that the breadth of Gag/Pol/Env-specific T cell responses correlated inversely with setpoint viral loads following ART discontinuation, suggesting that the mechanism underlying the therapeutic efficacy of the vaccine involved expansion of cellular immune breadth and immunologic control of virus rebounding from the reservoir.....Future studies should be performed in SIV-infected monkeys that initiate ART during chronic infection, which would be more representative of the majority of HIV-1-infected individuals. Moreover, future studies could explore longer periods of ART suppression, potentially to reduce residual viral replication, although the majority of animals appear to have a stable reservoir after 24-72 weeks of ART14. The capacity of immunologic interventions to target follicular helper CD4+ T cells in lymph nodes should also be explored20.
Ad26/MVA Therapeutic Vaccination with TLR7 Stimulation in SIV-Infected Rhesus Monkeys - Functional Cure Strategy - (11/09/16).....These data demonstrate the potential of therapeutic vaccination with innate immune stimulation as a strategy aimed at an HIV-1 functional cure.....33% (3 of 9) of the monkeys in the combination intervention group showed effective virologic control to undetectable setpoint viral loads (< 2.30 log copies/ml) following ART discontinuation......Ad26/MVA therapeutic vaccination resulted in a dramatic 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, as well as improved virologic control and delayed viral rebound following ART discontinuation......We infected 36 Indian origin rhesus monkeys (Macaca mulatta) with SIVmac2514,13 by a single intrarectal exposure and initiated daily subcutaneous administration of a pre-formulated ART cocktail (tenofovir disoproxil fumarate, emtricitabine, dolutegravir)14 on day 7 of acute infection. Animals had median plasma SIV RNA levels of 7.10 log copies/ml (range 6.04-7.88 log copies/ml) on the day of ART initiation (Fig. 1a). SIV RNA levels were controlled in the majority of animals by day 56 and in all animals by day 224 (Fig. 1a). SIV RNA levels were comparable among the different groups, and the animals that took longer to control virus had higher starting plasma viral loads on day 7 (P = 0.04; data not shown)......Following 24 weeks of suppressive ART, groups of monkeys received the following interventions: (1) Ad26/MVA vaccines alone, (2) Ad26/ MVA vaccines + TLR7 agonist GS-986, (3) TLR7 agonist GS-986 alone, or (4) sham (N = 9 animals/group)......We next assessed viral DNA in lymph nodes and PBMC using an RT-PCR assay14 with a sensitivity of 3 DNA copies/106 CD4+ T cells (Fig. 2a-b). In sham controls, viral DNA declined slightly between weeks 20 and 48, presumably reflecting the impact of suppressive ART, but no further decline was observed at week 70. In contrast, the two groups that received the Ad26/MVA vaccine demonstrated marked reductions of viral DNA to undetectable levels in the majority of animals by week 70 in both lymph nodes (Fig. 2a) and PBMC (Fig. 2b), suggesting that vaccination led to substantial reductions in SIV-infected CD4+ T cells in these tissue compartments. It is possible that a larger fraction of proviruses might be transcriptionally active following early ART initiation as compared with ART initiation during chronic infection, although this remains to be determined8. Viral outgrowth assays using 20 million PBMC were negative in all animals including controls at week 70 (data not shown), presumably as a result of early initiation of ART.
.....To evaluate the therapeutic efficacy of the interventions, we discontinued ART at week 72. Viral rebound was observed in all animals (Fig. 3a). All sham controls rebounded by day 10-14 following ART discontinuation in a stereotypical fashion and exhibited median set point plasma SIV RNA levels of 4.89 log copies/ml (range 4.27-5.57 log copies/ml) on day 168 following ART discontinuation. The monkeys that received GS-986 alone did not demonstrate any discernible delay or control of viral rebound, indicating that TLR7 stimulation alone exerted no detectable antiviral effect in this study. Animals that received the Ad26/MVA vaccine alone exhibited a 0.66 log reduction of median setpoint plasma SIV RNA levels to 4.23 log copies/ml (range 2.70-4.91 log copies/ml) (P = 0.002, Wilcoxon rank-sum test) but only a marginal delay of viral rebound (P = 0.01, Wilcoxon rank-sum test) as compared with controls (Fig. 3b-c). In contrast, monkeys that received both the Ad26/MVA vaccine and GS-986 showed a striking 1.74 log reduction of median setpoint plasma SIV RNA levels to 3.15 log copies/ml (range < 2.30-4.09 log copies/ml) (P < 0.0001) and a 2.5-fold delay of viral rebound from a median of 10 to 25 days as compared with controls (P = 0.003) (Fig. 3b-c). Moreover, 33% (3 of 9) of the monkeys in the combination intervention group showed effective virologic control to undetectable setpoint viral loads (< 2.30 log copies/ml) following ART discontinuation. These data demonstrate that the combination of Ad26/ MVA vaccination and TLR7 stimulation improved virology control and delayed viral rebound following ART discontinuation.
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J&J vaccine plus Gilead immune booster shows promise as HIV fighter
By Julie Steenhuysen | CHICAGO
http://mobile.reuters.com/article/idUSKBN134364
An experimental HIV vaccine from Johnson & Johnson combined with an immune system booster from Gilead Sciences Inc showed promise at keeping the virus at bay in monkeys even after treatments had stopped, marking yet another step toward the development of a so-called functional cure for HIV.
Both companies are currently testing the products separately in early-stage trials in people with HIV.
The study, published on Wednesday in the journal Nature, evaluated monkeys infected with simian immunodeficiency virus, the monkey version of HIV, and showed the treatments were much more effective when used together than separately.
All nine monkeys that got both treatments showed significantly reduced viral loads. In three of them, the combination therapy has kept the virus at bay for six months after antiretroviral therapy or ART drugs were stopped.
The study is part of ongoing efforts to develop a so-called functional cure for HIV that would allow people infected with the virus to stop taking daily antiretroviral therapy. [L1N1CJ134]
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"Current antiretroviral drugs, although they're lifesaving, do not cure HIV. They merely hold it in check. We are trying to develop strategies to achieve ART-free, long-term viral suppression," said study author Dr. Dan Barouch, a vaccine researcher at Harvard-affiliated Beth Israel Deaconess Medical Center in Boston.
For the study, the team used what is known as a "kick and kill" approach. The two-punch strategy is designed to lure dormant HIV-infected immune cells out of hiding places in the body and then attempt to eradicate them.
The trial evaluated a therapeutic vaccine called Ad26/MVA, which J&J and partners are testing in early-stage human trials. The vaccine works by provoking a broad immune response from the adaptive immune system, the part that recognizes specific pathogens and produces lasting immunity.
They combined this with Gilead's experimental drug called GS-986, a so-called TLR-7 agonist that kickstarts the innate immune system, a more generalized line of defense that mounts the body's initial response to infection. Gilead is also testing this in trials of HIV-infected patients.
In the study, they evaluated 36 monkeys infected with SIV that had been treated with ART for six months to get the virus under control. They then divided the group into four arms, with one getting the Ad26/MVA vaccine alone, another getting the TLR-7 agonist alone, a third getting the combination of the two, and a fourth getting a placebo.
Then, they discontinued ART in all of the animals and monitored levels of the virus in their blood and lymph nodes. Animals that got Gilead's TLR-7 agonist saw no benefit and the virus quickly rebounded. Those that got the vaccine alone showed some reduction of viral load and a modest delay in viral rebound. The biggest effect was in the combination group, which saw a 2.5 times longer delay in viral rebound compared to the control group.
In this group, levels of virus in the blood were 50 times lower than in the controls, and the virus fell to undetectable levels in three of the animals, which have been off ART for six months with no viral rebound.
"If all the animals' viral loads had been undetectable, that would have been a home run," said Barouch. "But the fact that all animals showed a reduction in viral load and three out of nine were undetectable, that's a solid base hit. It's definitely something that we can work from."
Barouch said his team has been in talks with both companies to test the combination therapy in patients with HIV.
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