ICF: AbVax Combination vaccination and broadly neutralising antibody therapy in HIV to induce a protective Tcell vaccinal effect, a mechanistic study
Lead Research Organisation:
University of Oxford
Department Name: Experimental Medicine
Abstract
Background
There is no cure for HIV infection. Treatment in the form of 'antiretroviral therapy' (or ART) is widely available, but has to be taken every day for life with issues around side-effects, resistance, adherence and stigma. There is a new therapy called 'broadly neutralising antibodies' (or bNAbs) that appears to work as well as ART and lasts a lot longer - one dose can last 6 months. What is more exciting is that in studies in animals (rhesus macaques), bNAbs have resulted in drug-free suppression for years and, in some cases, possible cures.
There is now early, but compelling, evidence that bNAbs can also achieve sustained HIV virological control in humans. The impact of long-term tablet-free remission for people living with HIV (PWH) is enormous, particularly for hard to reach groups and countries with less developed health infrastructures.
BNAbs appear to work in two stages. An initial direct effect in which the HIV viruses are targeted, followed by a second stage in which the induction of a sustained protective immune response confers longer term control. This immune response appears to be driven by cells called 'T cells', and has been called the 'vaccinal effect'. Understanding the mechanism that drives this effect - and how to maximise it - is the subject of this application.
Aim
Our aim is to determine the mechanism under-pinning the 'vaccinal effect' and to find out how it can be enhanced to induce the strongest and most durable protection for people with HIV. Our hypothesis is that a combination of bNAbs with a vaccine combined with a short period of viraemia (virus in the blood) will produce the most sustained immune protection.
Design
AbVax is an early stage clinical trial designed to understand the biological mechanisms which explain what happens clinically. We aim to recruit 48 participants, who will be randomised across three arms to determine the best combination of bNAbs, vaccination and treatment interruption induced viraemia (TIIV).
In the first arm (Arm A) participants receive the two long-acting bNAbs (called 10-1074-LS and 3BNC117-LS). In Arm B, participants receive the two long-acting bNAbs plus vaccination with the "ChAdOx1-MVA/HIVconsvX" vaccine. The vaccine is a "bivalent conserved mosaic T cell vaccine". This sort of vaccine focuses killer T cells on the most vulnerable parts of HIV. In the third arm (Arm C), participants receive both bNAbs and vaccine but also stop their HIV therapy for a short time to allow the virus to re-enter the blood.
This allows us to see how much the vaccine and treatment interruption add to protection that is provided by the bNAbs. To do this we measure HIV-targeting T cell immunity using the 'activation-induced markers' assay 26 weeks after starting the trial. This is the 'Primary Outcome'. We will also use other measures of T cell immunity (like cell proliferation and cytokine release) to ensure we look at many different measures of response. Other outcomes will include clinical measures such as duration of virological remission following treatment interruption and further detailed immunological, virological and genetic parameters.
Participants have the opportunity to stop their ART six months after the bNAb dosing to determine the clinical impact and to measure how long before any HIV returns to the blood ('rebound').
Delivery
The team are experts in the fields of HIV cure (Fidler, Fox, Frater) and vaccinology (Hanke, Cicconi) and have strong track records in the design and analysis (Liu) of complex clinical trials and high-quality mechanistic laboratory studies.
Impact
If the study demonstrates boosted T cell immunity and sustained virological control following bNAb therapy this has the potential to revolutionise the way we treat HIV (and other persistent infections and cancers). Should the intervention result in long-term remission - or even cure - this would have global impact for people and countries impacted by HIV.
There is no cure for HIV infection. Treatment in the form of 'antiretroviral therapy' (or ART) is widely available, but has to be taken every day for life with issues around side-effects, resistance, adherence and stigma. There is a new therapy called 'broadly neutralising antibodies' (or bNAbs) that appears to work as well as ART and lasts a lot longer - one dose can last 6 months. What is more exciting is that in studies in animals (rhesus macaques), bNAbs have resulted in drug-free suppression for years and, in some cases, possible cures.
There is now early, but compelling, evidence that bNAbs can also achieve sustained HIV virological control in humans. The impact of long-term tablet-free remission for people living with HIV (PWH) is enormous, particularly for hard to reach groups and countries with less developed health infrastructures.
BNAbs appear to work in two stages. An initial direct effect in which the HIV viruses are targeted, followed by a second stage in which the induction of a sustained protective immune response confers longer term control. This immune response appears to be driven by cells called 'T cells', and has been called the 'vaccinal effect'. Understanding the mechanism that drives this effect - and how to maximise it - is the subject of this application.
Aim
Our aim is to determine the mechanism under-pinning the 'vaccinal effect' and to find out how it can be enhanced to induce the strongest and most durable protection for people with HIV. Our hypothesis is that a combination of bNAbs with a vaccine combined with a short period of viraemia (virus in the blood) will produce the most sustained immune protection.
Design
AbVax is an early stage clinical trial designed to understand the biological mechanisms which explain what happens clinically. We aim to recruit 48 participants, who will be randomised across three arms to determine the best combination of bNAbs, vaccination and treatment interruption induced viraemia (TIIV).
In the first arm (Arm A) participants receive the two long-acting bNAbs (called 10-1074-LS and 3BNC117-LS). In Arm B, participants receive the two long-acting bNAbs plus vaccination with the "ChAdOx1-MVA/HIVconsvX" vaccine. The vaccine is a "bivalent conserved mosaic T cell vaccine". This sort of vaccine focuses killer T cells on the most vulnerable parts of HIV. In the third arm (Arm C), participants receive both bNAbs and vaccine but also stop their HIV therapy for a short time to allow the virus to re-enter the blood.
This allows us to see how much the vaccine and treatment interruption add to protection that is provided by the bNAbs. To do this we measure HIV-targeting T cell immunity using the 'activation-induced markers' assay 26 weeks after starting the trial. This is the 'Primary Outcome'. We will also use other measures of T cell immunity (like cell proliferation and cytokine release) to ensure we look at many different measures of response. Other outcomes will include clinical measures such as duration of virological remission following treatment interruption and further detailed immunological, virological and genetic parameters.
Participants have the opportunity to stop their ART six months after the bNAb dosing to determine the clinical impact and to measure how long before any HIV returns to the blood ('rebound').
Delivery
The team are experts in the fields of HIV cure (Fidler, Fox, Frater) and vaccinology (Hanke, Cicconi) and have strong track records in the design and analysis (Liu) of complex clinical trials and high-quality mechanistic laboratory studies.
Impact
If the study demonstrates boosted T cell immunity and sustained virological control following bNAb therapy this has the potential to revolutionise the way we treat HIV (and other persistent infections and cancers). Should the intervention result in long-term remission - or even cure - this would have global impact for people and countries impacted by HIV.
Technical Summary
The Need
For people with HIV (PWH), viral control can only be achieved by life-long daily
antiretroviral medication. Broadly neutralising antibodies (bNAbs) can achieve
treatment-free HIV control for over 6 months by inducing a sustained cell-mediated
immune response, the 'vaccinal effect'.
We aim to understand the mechanism of the vaccinal effect and how to maximise it
to extend drug-free HIV control. Our hypothesis is that the ChAdOx1/MVA HIVcons
T-cell vaccine combined with a brief period of treatment interruption-induced
viraemia (TIIV) and the bNAbs 10-1074-LS and 3BNC117-LS will induce a stronger
T-cell response than bNAbs alone.
Proposed Solution
AbVax is a mechanistic open label phase II clinical trial powered on 48 participants,
initially randomised across three arms to determine the best combination of bNAbs,
vaccination (ChAdOx/MVA) and TIIV.
Primary outcome is T-cell immunity by activation-induced marker assay 26 weeks
after bNAb dosing. Secondary outcomes include duration of remission following TI
and other detailed immunological, virological and genetic parameters.
Rationale
Non-human primate studies show that bNAbs induce a T cell immune response that
is associated with long-term protection, even cure - the first time an intervention has
induced clinically protective T cell immunity. Early human studies show similar
induction of T cell immunity after bNAb treatment. There is therefore a rationale that
T cell immunity can provide protection in humans, but the optimal mechanistic
approach remains untested.
Development Plan
The team are internationally recognised in HIV therapeutics (Fidler, Fox, Frater),
vaccinology (Hanke, Cicconi) and vaccine trial design (Liu). Working with community
advisors with HIV, AbVax will answer the questions above using an experienced
clinical trials unit, clinical sites with experience at recruiting HIV bNAb studies and
internationally-recognised laboratories to run mechanistic outcome assays.
For people with HIV (PWH), viral control can only be achieved by life-long daily
antiretroviral medication. Broadly neutralising antibodies (bNAbs) can achieve
treatment-free HIV control for over 6 months by inducing a sustained cell-mediated
immune response, the 'vaccinal effect'.
We aim to understand the mechanism of the vaccinal effect and how to maximise it
to extend drug-free HIV control. Our hypothesis is that the ChAdOx1/MVA HIVcons
T-cell vaccine combined with a brief period of treatment interruption-induced
viraemia (TIIV) and the bNAbs 10-1074-LS and 3BNC117-LS will induce a stronger
T-cell response than bNAbs alone.
Proposed Solution
AbVax is a mechanistic open label phase II clinical trial powered on 48 participants,
initially randomised across three arms to determine the best combination of bNAbs,
vaccination (ChAdOx/MVA) and TIIV.
Primary outcome is T-cell immunity by activation-induced marker assay 26 weeks
after bNAb dosing. Secondary outcomes include duration of remission following TI
and other detailed immunological, virological and genetic parameters.
Rationale
Non-human primate studies show that bNAbs induce a T cell immune response that
is associated with long-term protection, even cure - the first time an intervention has
induced clinically protective T cell immunity. Early human studies show similar
induction of T cell immunity after bNAb treatment. There is therefore a rationale that
T cell immunity can provide protection in humans, but the optimal mechanistic
approach remains untested.
Development Plan
The team are internationally recognised in HIV therapeutics (Fidler, Fox, Frater),
vaccinology (Hanke, Cicconi) and vaccine trial design (Liu). Working with community
advisors with HIV, AbVax will answer the questions above using an experienced
clinical trials unit, clinical sites with experience at recruiting HIV bNAb studies and
internationally-recognised laboratories to run mechanistic outcome assays.
