ICF: AbVax Combination vaccination and broadly neutralising antibody therapy in HIV to induce a protective Tcell vaccinal effect, a mechanistic study

Background

There is no cure for HIV infection. Antiretroviral therapy (or ART) is a widely available treatment, but has to be taken daily, for life, causing issues around side-effects, resistance, adherence and stigma. A new therapy called 'broadly neutralising antibodies' (or bNAbs) appears to work as well as ART and lasts much longer - one dose can last 6 months.

Excitingly, in studies with animals (rhesus macaques), bNAbs have resulted in drug-free suppression for years and, in some cases, possible cures.

There is now compelling early evidence showing that bNAbs can 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 by cells called 'T cells' confers longer term control - called the 'vaccinal effect'. 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 PWH. 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 vaccination, treatment interruption induced viraemia (TIIV) and bNAbs.

All participants will receive a single dose of the two long-acting bNAbs (called 10-1074-LS and 3BNC117-LS). In the first arm (Arm A) participants will stop HIV therapy for a short time (about 4 weeks - this is the 'TIIV') to allow the virus to re-enter the blood before the bNAbs are given. This may induce a stronger vaccinal effect.

In the second arm (Arm B), participants will receive vaccination with the "ChAdOx1-MVA/HIVconsvX" vaccines before bNAb infusions. These vaccines are "bivalent conserved mosaic T cell vaccines" which focus killer T cells on the most vulnerable parts of HIV. We hypothesise that the bNAbs vaccinal effect will enhance the T cell specific response to the vaccines, which will contribute to a stronger HIV immune control.

In the third arm (Arm C), participants have both the TIIV and the vaccines with the bNAbs. Once dosed, all participants then stop therapy to see how long the virus can be controlled off any drugs, using just the interventions in the three arms of the study.

This design allows us to see how much the vaccine and TIIV add to protection provided by bNAbs. To do this we measure HIV-targeting T cell immunity 26 weeks after starting the trial using a test called an ELISpot. This is the 'Primary Outcome'.

We also use other tests of T cell immunity to look at many different measures of the response. Other outcomes include clinical measures such as duration of virological remission following treatment interruption and further detailed immunological, virological and genetic parameters. 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 could 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.