HIV Infections Clinical Trial
Official title:
A Phase I Study Evaluating the Safety and Immunogenicity of a New TB Vaccine, MVA85A, in Asymptomatic Volunteers Who Are Infected With Either Mycobacterium Tuberculosis (M.tb.), Human Immunodeficiency Virus (HIV) or Both
This study is designed to evaluate the safety of MVA85A in asymptomatic volunteers in South Africa who are infected with M.tb, HIV or both. A single vaccination with MVA85A, when administered at a dose of 5 x 107pfu intradermally, is safe and highly immunogenic in mycobacterially naïve individuals, BCG vaccinated individuals and M.tb latently infected individuals. We will use the same vaccination regime in this study. Participants will be defined as being infected with M.tb.if they have a positive Elispot response to ESAT6 or CFP10. Participants will be defined as being infected with HIV.if they have a positive HIV rapid test (Determine®, Abbott Laboratories) followed by a positive HIV ELISA result. Participants will be identified from the general population living in Worcester, Western Cape, South Africa
Prime-boost immunization strategies Heterologous prime-boost immunization strategies involve
giving two different vaccines, each encoding the same antigen, several weeks apart. Using a
DNA prime-recombinant modified vaccinia virus Ankara (MVA) boost induces higher levels of
antigen specific CD4+ and CD8+ T cells than using homologous boosting with the same vector
in a number of different disease models (Schneider, 1998; McShane, 2001). Given the
protective efficacy of BCG in childhood, ideally BCG would be the priming immunization in
such a prime-boost strategy. In order to do this, we have focused on antigen 85A as a
candidate antigen. Antigen 85A is highly conserved amongst all mycobacterial species and is
present in all strains of BCG. Antigen 85A is a major secreted antigen from M. tuberculosis
which forms part of the antigen 85 complex (A, B and C). This complex constitutes a major
portion of the secreted proteins of both M.tb and BCG. It is involved in fibronectin binding
within the cell wall and has mycolyltransferase activity. Antigen 85A is immunodominant in
murine and human studies and is protective in small animals (Huygen, 1996).
Recombinant modified vaccinia virus Ankara (rMVA). Many viruses have been investigated as
potential recombinant vaccines. The successful worldwide eradication of smallpox via
vaccination with live vaccinia virus highlighted vaccinia as a candidate for recombinant
use. The recognition in recent years that non- replicating strains of poxvirus such as MVA
and avipox vectors can be more immunogenic than traditional replicating vaccinia strains has
enhanced the attractiveness of this approach. MVA (modified vaccinia virus Ankara) is a
strain of vaccinia virus which has been passaged more than 570 times though avian cells, is
replication incompetent in human cell lines and has a good safety record. It has been
administered to more than 120,000 vaccinees as part of the smallpox eradication programme,
with no adverse effects, despite the deliberate vaccination of high risk groups (Stickl,
1974; Mahnel, 1994). This safety in man is consistent with the avirulence of MVA in animal
models. MVA has six major genomic deletions compared to the parental genome severely
compromising its ability to replicate in mammalian cells (Meher, 1991). No replication has
been documented in non- transformed mammalian cells. Viral replication is blocked late
during infection of cells but importantly viral and recombinant protein synthesis is
unimpaired even during this abortive infection. The viral genome has been proven to be
stable through a large series of passages in chicken embryo fibroblasts.
Replication-deficient recombinant MVA has been seen as an exceptionally safe viral vector.
When tested in animal model studies recombinant MVA's have been shown to be avirulent, yet
protectively immunogenic as vaccines against viral diseases and cancer. Recent studies in
severely immunosuppressed macaques have supported the view that MVA should be safe in
immunocompromised humans (Akira, 2001; Stittelaar, 2001).
Safety of rMVAs in immunosuppression. There is now considerable preclinical and clinical
data demonstrating the safety and immunogenicity of MVA as a viral vector in
immunosuppression and HIV infection. Recombinant MVAs expressing HIV antigens have been
administered to immunosuppressed macaques with no serious adverse events (Stittelaar et al,
2001). In addition, the safety of recombinant MVAs expressing HIV antigens and epitopes have
now been evaluated in several Phase I clinical trials of HIV-infected subjects, both on and
off antiretroviral therapy, with no serious adverse events (Cosma et al, 2003; Harrer et al
2005).
Preclinical data supporting this BCG prime-MVA85A boost strategy In BALB/c mice, using BCG
as the priming immunization and then boosting with MVA85A induces higher levels of both
antigen specific IFN-γ secreting CD4+ and CD8+ T cells and significantly greater levels of
protection against aerosol challenge than after BCG alone (Goonetilleke et al, 2003). 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 and boosted with
MVA85A, and then further boosted with a second recombinant viral vector expressing antigen
85A, fowlpox-85A (FP85A) showed significantly greater protection against challenge than
guinea pigs vaccinated with BCG alone (Williams et al, 2005). This regime is also
immunogenic in rhesus macaques, and protective (Verrek, personal communication).
Clinical data to date with MVA85A UK studies Over the last 3 years HM has established a
clinical trial programme to evaluate the safety and immunogenicity of this BCG prime-MVA85A
boost vaccination strategy in a series of Phase I studies. MVA85A was the first candidate TB
vaccine to enter clinical trials anywhere in the world in September 2002, and is currently
the only one in clinical trials in Africa. The design of these Phase I studies with MVA85A
allowed for sequential vaccination of volunteer groups with a step-wise increase in
mycobacterial exposure, to minimize the possibility of a Koch reaction. Trials were also
conducted sequentially in the UK and The Gambia, as there is a greater degree of exposure to
both environmental mycobacteria and M.tb in The Gambia. A Koch reaction describes the
development of immunopathology in a person or animal with tuberculosis, when an exaggerated
immune response to M.tb is stimulated. It was described in patients with TB disease when
Koch performed his original studies employing mycobacteria as a type of therapeutic
vaccination. It has now been demonstrated in the mouse model of therapeutic vaccination27.
Available animal data suggest that these reactions do not occur in mice latently infected
with M.tb, suggesting that such reactions may correlate with high bacterial load and that
the Koch phenomenon may not pose a problem for vaccination of asymptomatic albeit latently
infected humans25.
In the UK, 14 mycobacterially and BCG naïve, asymptomatic volunteers were recruited. and
vaccinated twice with 5 x 107pfu MVA85A, administered intradermally at 3 week intervals. In
these studies, MVA85A was found to be safe and well tolerated. All subjects experienced some
local side-effects (redness, itching etc) which lasted for 3-7 days after vaccination.
Approximately one third of subjects experienced some transient systemic symptoms (myalgia,
headache) for the first 12-24 hours after vaccination. All local and systemic side-effects
spontaneously resolved. There were no serious or severe adverse events in any of these
studies.
The main immunological outcome used in these ongoing clinical trials is the ex-vivo
interferon-gamma (IFN-γ) Elispot assay, which was used to assess specific T cell responses
to tuberculin PPD, purified antigen 85 complex and pools of overlapping 15mer peptides
spanning the length of antigen 85A. A single vaccination with MVA85A induced remarkably high
levels of specific effector T cell responses 1 week after vaccination (mean IFN-γ Elispot
response to PPD was 460 spots per million PBMC).
Next, the safety of MVA85A in volunteers previously vaccinated with BCG was demonstrated in
17 volunteers. The safety profile of MVA85A in these 17 volunteers was the same as in the
BCG naïve group. These 17 volunteers showed even higher peak levels of antigen specific T
cells (mean response to PPD was 917 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 were previously BCG vaccinated maintained significantly higher levels
of antigen specific T cells after MVA85A for up to 24 weeks after vaccination, when compared
to those volunteers vaccinated with either BCG or MVA85A alone (McShane et al, 2004).
The next trial to be conducted in the UK looked at the boosting efficacy of MVA85A when
administered one month after BCG vaccination. 10 healthy, BCG naïve volunteers were
vaccinated with BCG and one month later were boosted with MVA85A. Comparable safety and
boosting efficacy was seen to the previous trial where the interval between BCG and MVA85A
was 0.5-37 years.
The current ongoing study in the UK is designed to assess the safety and immunogenicity of
MVA85A in asymptomatic volunteers who are latently infected with M.tb. Latent infection with
M.tb describes a state where an individual is presumed to have a very low level persistent
bacterial infection with no clinical or radiological evidence of disease, and yet has a
detectable immune response against M.tb. Latent infection in this study is defined using
specific diagnostic tests based on antigens that are absent from BCG and most environmental
mycobacteria such as ESAT 6 and CFP 10, allowing an accurate diagnosis of latent M.tb
infection to be made. Subjects for this study were recruited from TB contact clinics and
vaccinated with a single dose of MVA85A. Follow-up involved detailed radiological and
clinical assessment of the safety of this vaccine in this group. To date, 11 subjects have
been vaccinated with MVA85A in this study and the safety and immunogenicity profile of
MVA85A is identical to that seen in previous studies. Importantly there has been no
clinical, radiological or immunological evidence of a Koch reaction. The Elispot responses
to PPD, ESAT 6, CFP10, antigen 85A and other mycobacterial antigens are being monitored for
12 months following vaccination.
Gambian studies Following the success of the trials with MVA85A in the UK, a collaboration
with the MRC unit in The Gambia was initiated. MVA85A was first evaluated in Phase I
clinical trials in BCG naïve subjects (n = 11) and subsequently in BCG primed subjects
(n=10). In these studies the safety and immunogenicity profile is comparable to that seen in
the UK studies. 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 is being boosted by
vaccination with MVA85A. When MVA85A is administered to BCG naïve subjects in the Gambia,
the magnitude and kinetics of response resemble the BCG primed group in the UK, a finding
that is likely to represent a greater degree of environmental priming in tropical climates.
South African studies A Phase II study of the safety and immunogenicity of MVA85A in
healthy, M.tb uninfected and HIV uninfected adults in Cape Town commenced in August 2005.
The studies with MVA85A at this site have begun in adults, as a safety requirement despite
the fact that we already have safety and immunogenicity data in adults from both the UK and
the Gambian studies. The population in South Africa is very different from the UK and
Gambian populations in terms of both host genetics and mycobacterial exposure. There is
considerably more M.tb exposure in South Africa than in the Gambia and the exposure to
environmental mycobacterial is believed to be lower in South Africa than the Gambia. The BCG
literature demonstrates wide variation in efficacy across geographical areas and it was
important to confirm our findings in adults in Cape Town before proceeding to a study in
adolescents. We aim to vaccinate 24 adults in total. These studies commenced in August 2005,
and to date, 14 volunteers have been vaccinated. Encouragingly, the safety and
immunogenicity results so far are comparable with the previous studies in the UK and the
Gambia.
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Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention
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