A Study of MVA85A in Healthy Children and Infants
Condition: Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 2

Summary: 
      This study is designed to evaluate the safety of the TB vaccine MVA85A in healthy children
      and infants in South Africa. A single vaccination with MVA85A has been shown to be safe and
      highly immunogenic in a wide range of subjects in previous clinical trials. In this trial,we
      will vaccinate 24 children with 5 x 10^7pfu of MVA85A and three groups of 36 infants with 2.5
      x 10^7, 5 x 10^7 or 1 x 10^8 pfu.

      Participants will be identified from the general population living in Worcester, Western
      Cape, South Africa
    

Detailed description: 
      M.tb is an intracellular organism and protective immunity is dependent on an intact cellular
      immune system. Both Class II-restricted CD4+ and Class I-restricted CD8+ T lymphocytes are
      important for protection. Gamma delta cells and non-classically restricted T cells such as
      CD1-restricted T cells may also play a protective role but knowledge of how to induce these
      to protective levels by vaccination is very limited. Although several vaccine delivery
      systems are capable of inducing T cells, e.g. protein/adjuvant combinations, DNA vaccines and
      recombinant viral vectors, when used alone these delivery systems induce only low-level
      responses. Heterologous prime-boost immunisation strategies involve immunizing with 2 two
      different vaccines, each expressing the same antigen, several weeks apart. These strategies
      induce higher levels of CD4+ and CD8+ T cells than homologous boosting in animal models of
      malaria, HIV and TB.

      Recombinant modified vaccinia virus Ankara expressing antigen 85A (MVA85A). When used in
      heterologous prime-boost strategies, some viral vectors are very good at boosting previously
      primed T cell responses, particularly recombinant adenoviral constructs and recombinant pox
      viruses. Modified vaccinia virus Ankara (MVA) is an attenuated strain of vaccinia virus that
      has been passaged more than 500 times through chick embryo fibroblasts and as a consequence
      has lost both host range genes and cytokine receptor genes. MVA has an excellent safety
      record, as it was used to vaccinate more than 120,000 people at the end of the smallpox
      eradication campaign, with no serious adverse events. In humans, several hundred HIV negative
      volunteers have now been immunized with recombinant MVAs expressing a number of different
      antigens, with no serious adverse events. A recombinant MVA expressing an antigen from
      Plasmodium falciparum has been demonstrated to boost CD4+ and CD8+ T cells in humans.
      Recombinant MVAs are now in clinical trials for several infectious diseases including HIV,
      hepatitis B and malaria. Importantly, for a new TB vaccine, the safety of MVA as a viral
      vector has now been demonstrated in HIV positive patients.

      Including BCG in such heterologous prime-boost regimes allows for the beneficial effects of
      BCG to be retained. We have developed an immunisation strategy using BCG as the priming
      immunisation and a recombinant MVA (rMVA) as the boost. The antigen selected for inclusion in
      the rMVA must be present in all strains of BCG. We have selected Antigen 85A, which forms
      part of the immunodominant antigen 85 complex. Although there are numerous candidate antigens
      for use in a TB vaccine, antigen 85A has long been considered a leading choice. It is a major
      target antigen recognised by T cells from infected individuals and it is protective as a DNA
      vaccine in small animals. Importantly, for use in BCG prime-MVA boost regimes, it is highly
      conserved amongst all mycobacterial species and is present in all strains of BCG. In small
      animals it is a major target of the immune responses induced by BCG and in humans HLA-A2
      restricted CD8 T cells have been found in a high proportion of BCG-immunised individuals.
      Antigen 85A is an enzyme, mycolyl transferase, which is involved in cell wall biosynthesis.

      Pre-clinical data Using this BCG prime-MVA85A boost in BALB/c mice induces higher levels of
      both antigen specific interferon-gamma (IFN-γ) secreting CD4 T and CD8+ T cells and higher
      levels of protection than after BCG alone. This regime has now been further evaluated in the
      more sensitive guinea pig aerosol challenge model with very encouraging results. Guinea pigs
      vaccinated with BCG, followed by MVA85A, and then further boosted with a second recombinant
      viral vector, fowlpox, expressing antigen 85A (FP85A) showed significantly greater protection
      against challenge than guinea pigs vaccinated with BCG alone. This regime is also immunogenic
      and protective in rhesus macaques

      Clinical studies The safety and immunogenicity of this BCG prime-MVA85A boost vaccination
      strategy has now been evaluated in a series of small-scale Phase I studies in the UK. MVA85A
      was the first candidate TB vaccine in clinical trials anywhere in the world in September
      2002, and is currently the only one in clinical trials in Africa . The main immunological
      read-out used in these clinical trials is the ex-vivo IFN-γ Elispot assay, which is used to
      assess specific T cell responses to tuberculin PPD, antigen 85 complex and pools of
      overlapping peptides spanning the length of antigen 85A. The best immunological correlate of
      protection in murine and human TB is the secretion of IFN-γ from sensitised T cells.

      In the UK, 14 mycobacterially and BCG naïve, healthy volunteers have been vaccinated with 5 x
      10^7pfu MVA85A, administered intradermally. We find that MVA85A is safe and well tolerated. A
      single vaccination with MVA85A induces remarkably high levels of specific effector T cell
      responses (median IFN- γ Elispot response to Antigen 85A summed peptide pools 1153 spots per
      million PBMC). In addition, the safety of MVA85A in volunteers previously vaccinated with BCG
      has now been demonstrated in 17 volunteers. These 17 volunteers show even higher peak levels
      of antigen specific T cells (median response 2455 spots per million PBMC) 1 week
      post-vaccination than those immunized with MVA85A alone. Perhaps more importantly for the
      induction of T cell memory, volunteers who have been previously BCG vaccinated maintain
      higher levels of antigen specific T cells after MVA85A for up to 24 weeks after vaccination,
      when compared to those volunteers vaccinated with MVA85A alone. In contrast to this viral
      vector boost, the magnitude of T cell responses seen after vaccination with a leading
      protein/adjuvant vaccine (for malaria), RTS,S/AS02, is around 200 spots per million PBMC.

      This series of Phase I studies have also replicated in The Gambia, and the results from The
      Gambia are equally promising. In both the UK and The Gambian studies, MVA85A induces 5-10
      fold higher immune responses than any other recombinant MVA in clinical trials. The most
      likely explanation for this is that the volunteers have some weak pre-existing
      anti-mycobacterial immunity induced by exposure to environmental mycobacteria, and this
      specific anti-mycobacterial immunity is being boosted by MVA85A. We have some preliminary
      data to support this hypothesis, and other groups have also found pre-existing immunity to
      environmental mycobacteria in healthy UK adults. Vaccines that are good at boosting
      previously primed T cell responses, such as MVA85A, are potentially good candidates for a
      post-exposure vaccine designed to boost the immune response and prevent the development of
      disease in those latently infected. If the high levels of specific T cells seen after a
      single immunisation with MVA85A are attributable to the boosting of pre-existing
      environmentally induced responses, then this makes MVA85A an extremely promising candidate
      for a boosting vaccine, given as a post-exposure vaccine in latent infection.

      The next study, which completed enrolment in the UK in February 2006, assessed the safety and
      immunogenicity of MVA85A in healthy volunteers who were latently infected with M.tb. Twelve
      latently infected healthy subjects were vaccinated with a single dose of 5 x 10^7pfu MVA85A.
      In this study, latent M.tb infection was determined by tuberculin skin testing and ex-vivo
      IFN-γ Elispot responses to two M.tb specific antigens, ESAT6 and CFP10. Follow-up involved
      detailed radiological and clinical assessment of the safety of this vaccine in M.tb infected
      subjects. We found that MVA85A is equally safe and equally immunogenic in this latently
      infected population as it is in the population vaccinated with BCG (Sander et al, unpublished
      data). We have also conducted a dose finding study looking at two further doses of MVA85A, 1
      x 10^7pfu and 1 x 10^8 pfu. Twelve subjects were vaccinated with each dose. The preliminary
      results show the vaccine is significantly more immunogenic at the higher (1 x 10^8 pfu) dose
      but the immunogenicity of the lower (1 x 10^7 pfu) dose is comparable with the standard (5 x
      10^7pfu) dose.

      We have just started enrolment into an HIV study where antiretroviral naïve, HIV infected
      adults with a CD4 count greater than 350 are vaccinated with MVA85A. To date, there have been
      no safety concerns with this study.

      MVA85A is being trialled in a series of Phase I and II studies in the Western Cape province,
      South Africa, where the prevalence of tuberculosis is extremely high (annual incidence of
      disease ~1%). In August 2005, enrolment commenced into trial 008 and it continued until July
      2006. 24 healthy TB naïve and HIV uninfected adults were vaccinated. The preliminary results
      of this arm of the trial were presented in Vienna (Hawkridge et al, TB Vaccines for the
      World; April 2006) and Paris the vaccine was shown to be safe and highly immunogenic.
      Enrolment into the adolescent arm of this study commenced in November 2006 once it was clear
      that the day 84 safety results in the adults were satisfactory.

      This protocol forms the second part of these age de-escalation studies in South Africa, which
      are necessary before we commence a Phase IIb proof-of-concept efficacy trial with MVA85A in
      this population in 2008.
    

Intervention name(s): MVA85A; Prevenar
Intervention type(s): Biological; Biological
Intervention description(s): Modified vaccinia virus Ankara expressing antigen 85A from M. tuberculosis; Streptococcus pneumoniae vaccine
Other intervention name(s): Modified vaccinia virus Ankara
Intervention MeSH terms: Heptavalent Pneumococcal Conjugate Vaccine
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention