Last updated on November 2019

Amsterdam UMC Clinical Trial With a Native-like HIV-1 Envelope Vaccine

Brief description of study

ACTHIVE-001 is a randomised, open-label, uncontrolled phase 1 clinical trial to determine the safety profile of the native-like HIV-1 envelope vaccine, ConM SOSIP.v7, adjuvanted with monophosphoryl lipid A (MPLA) liposomes. The study will furthermore determine the extent to which the vaccine influences the breadth of viruses neutralised by induced antibodies and the associated diversity of B and T cell responses.

The research will also investigate the effect of a within-schedule successive dose level reduction (i.e. fractional dose boosting), aimed to induce higher levels of somatic hypermutation and broadly neutralising antibodies. The primary outcome will be measurement of adverse events. Secondary and exploratory outcomes will include specific viral neutralisation activity of serum antibodies and characterisation of antigen specific blood and lymph node B and T cell responses.

Detailed Study Description

Human immunodeficiency virus (HIV) causes a global pandemic that affects nearly 37 million people and continues to spread at a rate of 1.8 million new infections annually. With currently only 21.7 million people on antiretroviral therapy (ART), a protective vaccine is crucial to reduce HIV spread and eliminate the pandemic. Given their protective capacity, a vaccine that induces neutralising antibodies (NAbs) against the HIV envelope protein (Env) would be a major step forwards. Nevertheless, the design of an effective NAb inducing vaccine has proven to be extremely challenging due to the instability and conformational flexibility of the trimeric Env protein. However, the development of stabilised, native-like trimeric Env proteins, termed SOSIP trimers, has revolutionised the HIV vaccine field by overcoming this obstacle.

The SOSIP prototype, BG505 SOSIP.664, was the first ever Env-based immunogen that consistently induced NAbs against neutralisation-resistant viruses in animals and BG505 trimer immunisation of non-human primates protected against BG505 virus acquisition. Yet, HIV-1 diversity is a major hurdle for generating broad protection by broadly neutralising antibodies (bNAbs). It is thought that consensus-based vaccines might be more amendable for driving neutralisation breadth, because consensus sequences contain less strain-specific antigenic determinants and are closer to individual viral strains than strains are to one another. Therefore, the native-like Env trimer ConM SOSIP.v7 gp140, used in this study, was modelled after the BG505 SOSIP.664 prototype, but based on a consensus sequence of all HIV-1 isolates in group M, responsible for the global HIV epidemic. Previous nonclinical studies in rabbits and non-human primates found the ConM SOSIP.v7 gp140 vaccine to be safe. Moreover, it induced remarkably strong autologous NAb responses and elicited modest levels of cross-neutralisation.

Bearing these promising results in mind, the investigators firstly aim to evaluate the safety and tolerability of the ConM SOSIP.v7 gp140 vaccine, adjuvanted with monophosphoryl lipid A (MPLA) liposomes, in healthy HIV-uninfected individuals. The secondary objective will be to determine whether the ConM SOSIP.v7 gp140 vaccine, adjuvanted in MPLA liposomes, is able to prime human germline (naive) B cells and drive antibody responses towards induction of NAb breadth.

The research will furthermore investigate the effect of a within-schedule successive dose level reduction (i.e. fractional dose boosting), aimed to induce higher levels of somatic hypermutation and bNAbs. It is thought that fractional dose boosting leads to competitive antigen binding in germinal centres, which results in selection and expansion of B cells with surface immunoglobulins showing the highest antigen affinity.

The immunological insights gleaned from this study will be crucial for further design refinement and clinical development. In-depth characterisation of the elicited immune response, accomplished for example by state-of-the-art 'omics techniques such as next generation sequencing (NGS) and transcriptomics, enables us to gain valuable information from just a few human trial subjects. As a part of the European AIDS Vaccine Initiative 2020 Consortium (EAVI2020), this study will aid with the objective to select and refine the best immunogens, adjuvants, prime-boost schedules and determine the impact of host factors such as gender and genetics, increasing the chance of discovery of a definitive vaccine, which most likely will be multi-component.

Clinical Study Identifier: NCT03961438

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