Tuberculosis Clinical Trial
Official title:
A Phase I Study Evaluating the Safety and Immunogenicity of a New TB Vaccine, MVA85A, in Healthy Volunteers Who Are Latently Infected With Mycobacterium Tuberculosis.
This study is designed to evaluate the safety of MVA85A in healthy volunteers in the UK who are latently infected with M.tb. A single vaccination with MVA85A, when administeredat a dose of 5 x 107pfu intradermally, is safe in both mycobacterially naïve individuals and those previously vaccinated with BCG. We will use the same vaccination regime in this study. Subjects will be defined as being latently infected if they have a positive elispot response to ESAT6 or CFP10. Subjects will be identified from TB contact clinics.
Tuberculosis (TB) kills about three million people annually. It is estimated that one third
of the world’s population are latently infected with Mycobacterium tuberculosis (M.tb) (Dye,
1999). These latently infected individuals are at risk of reactivation of infection, should
they become immunosuppressed. Worldwide, coinfection with HIV is the commonest cause of
immunosuppression and increases the chances of reactivation from a 10% lifetime risk to a
10% annual risk (Corbett, 1996). The currently available vaccine, M. bovis BCG, is largely
ineffective at protecting against adult pulmonary disease in endemic areas and it is widely
agreed that a new more effective tuberculosis vaccine is a major global public health
priority (Colditz, 1994). However, it may be unethical and impractical to test and deploy a
vaccine strategy that does not include BCG, as BCG does confer worthwhile protection against
TB meningitis and leprosy. An immunisation strategy that includes BCG is also attractive
because the populations in which this vaccine candidate will need to be tested will already
have been immunised with BCG. Given the high prevalence of infection with M.tb, a vaccine
that could be administered to latently infected individuals and eradicate latent infection
would have an enormous impact on the mortality and morbidity from TB.
M.tb is an intracellular organism. CD4+ Th1-type cellular responses are essential for
protection and there is increasing evidence from animal and human studies that CD8+ T cells
also play a protective role (Flynn, 2001). However, it has generally been difficult to
induce strong cellular immune responses in humans using subunit vaccines. DNA vaccines,
recombinant viral vectors and protein/adjuvant combinations all induce both CD4+ and CD8+ T
cells, however none of these antigen delivery systems induce high levels of antigen specific
T cells, when used alone. Heterologous prime-boost immunisation strategies involves 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 immunisation 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 nonreplicating 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 nontransformed 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 MVAs have been shown to be avirulent, yet protectively immunogenic as vaccines
against viral diseases and cancer. Recent studies in severely immuno-suppressed macaques
have supported the view that MVA should be safe in immuno-compromised humans (Akira, 2001;
Stittelaar, 2001). There is now safety data from a number of recombinant MVAs that are
currently in Phase I/II trials in both the UK and Africa. Useful data on the safety and
efficacy of various doses of a recombinant MVA vaccine comes from clinical trial data with a
recombinant MVA expressing a number of CTL epitopes from Plasmodium falciparum
pre-erythrocytic antigens fused to a complete pre-erythrocytic stage antigen, Thrombospondin
Related Adhesion Protein (TRAP). To date MVA ME-TRAP has been administered to over 250
healthy volunteers in Oxford and The Gambia without any serious adverse events (Adrian Hill,
personal communication). Volunteers have received one to three doses of from 3 to 15 x 107
pfu per dose of intra-dermal vaccine at three-week intervals. All subjects have temporary
local redness with typically a 5mm central red area with a paler pink surrounding area that
ranges in size from about 1 –7cm in diameter and peaks at 48 hours post vaccination. At
seven days post vaccination generally only the central red area remains. This fades over the
next few weeks and is usually not apparent at 2 months after vaccination. The emerging
safety profile of recombinant MVA vaccine is supported by data from clinical studies of
three other MVA recombinants made in Oxford and currently in clinical studies using MVAs for
HIV, HBV and melanoma. Recombinant MVA encoding antigen 85A MVA85A induces both a CD4+ and a
CD8+ epitope when used to immunise mice. When mice are primed with BCG and then given MVA85A
as a boost, the levels of CD4+ and CD8+ T cells induced are higher than with either BCG or
MVA85A alone, and this regime is more protective than either vaccine alone (Goonetilleke et
al, 2003). In the more sensitive guinea pig model, guinea pigs vaccinated with BCG, and then
MVA85A, and then a second viral vector, fowlpox expressing antigen 85A, 6/6 guinea pigs are
alive at the end of the experiment, compared with 2/6 guinea pigs vaccinated with BCG alone,
and 0/6 control animals (Williams et al, submitted). In rhesus macaques, this BCG
prime-MVA85A and Fowlpox85A boost is more immunogenic than any of the vaccines alone.
Clinical studies using MVA85A MVA85A (at a dose of 5 x 107pfu) has been administered to 40
healthy volunteers in the UK and 15 healthy volunteers in The Gambia, with no serious
adverse events. We have designed our Phase I studies to allow for a vaccination of volunteer
groups sequentially with a step-wise increase in mycobacterial exposure, in order to
minimize the possibility of a Koch reaction. 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 vaccination (Taylor, 2003). 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 healthy albeit latently infected
humans. We started these studies in healthy volunteers who were as mycobacterially naïve as
possible. They were skin test negative and Elispot negative for PPD, ESAT 6 and CFP10, and
had not had previously been vaccinated with BCG. We have now completed studies in the UK
vaccinating volunteers previously vaccinated with BCG (McShane, submitted). These volunteers
are excluded if their Heaf test is greater than grade II. These studies are ongoing in The
Gambia. The next group we then plan to vaccinate on this increasing mycobacterial spectrum
are healthy volunteers who are latently infected with M.tb. Rationale This study is designed
to evaluate the safety of MVA85A in healthy volunteers in the UK who are latently infected
with M.tb. A single vaccination with MVA85A, when administered at a dose of 5 x 107pfu
intradermally, is safe in both mycobacterially naïve individuals and those previously
vaccinated with BCG. We will use the same vaccination regime in this study. Subjects will be
defined as being latently infected if they have a positive elispot response to ESAT6 or
CFP10. Subjects will be identified from TB contact clinics.
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Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
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