Amsterdam UMC Clinical Trial With a Native-like HIV-1 Envelope Vaccine
Condition: HIV-1-infection
MeSH terms: Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      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 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.
    

Intervention name(s): ConM SOSIP.v7 gp140, adjuvanted with MPLA liposomes; ConM SOSIP.v7 gp140, adjuvanted with MPLA liposomes
Intervention type(s): Biological; Biological
Intervention description(s): Vaccine administration will be done at months 0, 2 and 6 by intramuscular injection into the deltoid muscle of the non-dominant arm. The immunogen will be used at the dosage of 100 μg and will be admixed with 500 μg MPLA formulated in liposomes.; Vaccine administration will be done at months 0, 2 and 6 by intramuscular injection into the deltoid muscle of the non-dominant arm. The immunogen will be used at the dosage of 100 μg at months 0 and 2, and 20 μg at month 6. All immunogen dosages will be admixed with 500 μg MPLA formulated in liposomes.
Other intervention name(s): Recombinant HIV-1 trimeric gp140 Env protein: ConM SOSIP.v7.; Recombinant HIV-1 trimeric gp140 Env protein: ConM SOSIP.v7.
Intervention MeSH terms: Monophosphoryl lipid A
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants will be randomised in a 1:1 ratio between two treatment groups with a different dosing regimen. The randomisation will be stratified for gender.
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Neutralizing antibody responses; Antibodies; HIV-infection; Vaccine