Depletion of Serum Amyloid P Component to Enhance the Immune Response to DNA Vaccination
Condition: HIV
MeSH terms: Amyloidosis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This is a clinical proof-of-concept (PoC) study of DNA vaccination after SAP depletion. The
      investigators will measure the immune responses to DNA vaccination against HIV-1 in healthy
      adult male volunteers, comparing a group in whom SAP has been completely depleted at the time
      of DNA vaccination and a control group vaccinated without SAP depletion.
    

Detailed description: 
      Vaccination is one of the most important achievements of medicine. Injection of modified
      germs, or materials from them, induces protective immunity against the infections which they
      cause. Successful immunisation induces a protective immune response against particular
      component(s) of the target germ, the so-called immunogen(s). For some diseases the immunogens
      are not known and for others they are difficult and expensive to produce, transport and
      administer, for example influenza vaccine must be produced in millions of chicken eggs. A
      very attractive potential solution is to inject the deoxyribose nucleic acid (DNA) gene
      encoding the immunogen rather than the immunogen itself. In this process, known as DNA
      vaccination, the DNA enters cells, predominantly at the site of injection, and causes them to
      produce the immunogen locally within the body. DNA vaccination works well and stimulates
      excellent protective immunity against a variety of different infections, and even some
      cancers, in mice, horses, dogs, rabbits and pigs. But in humans and other primates, and in
      cows and sheep, the immune response to DNA vaccination is very feeble. Despite enormous
      academic and pharmaceutical industry efforts, the reasons for this failure have not been
      understood or overcome. The investigators previously discovered that a protein in human
      blood, known as serum amyloid P component (SAP), is the only normal blood protein which binds
      strongly to DNA. The investigators have now found that, in each of the animal species in
      which DNA vaccination is effective, this protein is either absent or, if it is present, it
      binds only weakly to DNA. In contrast, nonhuman primates, cows and sheep share with humans
      the presence of SAP proteins which strongly bind to DNA. The investigators believe that
      binding of DNA by SAP may be responsible for blocking induction of immune responses by DNA
      and that removal of SAP may overcome this inhibition. SAP contributes to important human
      diseases, amyloidosis and Alzheimer's disease, and the investigators have previously
      developed a drug,
      (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxohexanoyl]pyrrolidine-2-carboxylic acid (CPHPC),
      which safely removes almost all SAP from the blood in humans. Another laboratory has recently
      reported that the presence of human SAP inhibits DNA vaccination in mice and that this effect
      is reversed by the investigators drug, CPHPC. These observations confirm the investigators
      hypothesis. The investigators now propose to undertake the first human clinical study of DNA
      vaccination after SAP depletion. The investigators will measure the immune responses to human
      immunodeficiency virus (HIV)-1 DNA vaccination in 40 healthy adult men, comparing a group in
      whom SAP has been completely depleted at the time of DNA vaccination and a control group
      vaccinated without SAP depletion. The investigators predict that SAP depletion at the time of
      DNA vaccination will enhance the immune response.

      Development of an effective, accessible vaccine is the only realistic hope for halting the
      human immunodeficiency virus type 1 (HIV-1)/AIDS epidemic. Ideally, such a vaccine should
      induce broadly neutralizing antibodies and effective T cells at the same time. Both of these
      goals face substantial and very different challenges, with one major roadblock in common: the
      enormous HIV-1 genome plasticity, i.e. ability to change and escape immune responses. There
      is a need to develop vaccines which may be used both prophylactically and therapeutically to
      either prevent HIV-1 acquisition, control its replication without HAART and/or eventually
      eradicated the virus from the body completely.

      The approach taken in this clinical study aims to overcome the antigenic variation of HIV-1
      by focusing induced T cell responses on the functionally conserved regions of HIV-1 proteins,
      which HIV-1 cannot change without a significant cost to its fitness. Thus, the HIVconsv
      immunogen is a chimaeric protein assembled from the 14 most conserved regions of the HIV-1
      proteome alternating among the four most common HIV-1 clades: A, B, C and D. The gene coding
      for HIVconsv was made synthetically and was inserted into three safe non-replicating vaccine
      vectors: plasmid DNA to construct pSG2.HIVconsv, attenuated chimpanzee adenovirus (ChAdV63)
      to construct ChAdV63.HIVconsv and recombinant modified vaccinia virus Ankara (MVA) to
      construct MVA.HIVconsv. These three vectors facilitate delivery of the immunogen gene into
      host cells, which then express the HIVconsv protein and initiate a series of processes
      leading to the presentation of HIVconsv-derived peptides to the cells of the host immune
      system and induction of the HIVconsv-specific host T cell responses.

      Volunteers will receive the vaccine candidates ChAdV63.HIVconsv (C), MVA.HIVconsv (M) and
      pSG2.HIVconsv DNA (D) in a DDDCM regimen at weeks 0, 4, 8, 12 and 16. CPHPC or placebo is
      given by 26 hours infusion prior to the pSG2.HIVconsv vaccinations.
    

Intervention name(s): pSG2.HIVconsv DNA vaccine; ChAdV63.HIVconsv booster vaccine; MVA.HIVconsv booster vaccine; CPHPC; Placebo
Intervention type(s): Biological; Biological; Biological; Drug; Other
Intervention description(s): pSG2.HIVconsv DNA 4 mg at weeks 0, 4 and 8.; ChAdV63.HIVconsv 5 x 10^10 vp at week 12.; MVA.HIVconsv 2 x 10^8 pfu at week 20; 40 mg CPHPC IV infusion for 26 hours at weeks 0, 4 and 8 during which pSG2.HIVconsv is administered after 24 hours.; Placebo IV infusion for 26 hours at weeks 0, 4 and 8 during which pSG2.HIVconsv is administered after 24 hours.
Other intervention name(s): (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxohexanoyl] pyrrolidine-2-carboxylic acid; 0.9% saline
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Vaccine; DNA; HIV-1; Serum amyloid P component (SAP); Clinical trial; Vaccination; Prophylaxis; Adult male