HIV Infections Clinical Trial
Official title:
A Phase I Study Evaluating the Safety and Immunogenicity of a New TB Vaccine, MVA85A, in Healthy Volunteers Who Are Infected With HIV
This study is designed to evaluate the safety of MVA85A in healthy volunteers in the UK who are infected with HIV. In phase I studies, a single vaccination with MVA85A, when administered at a dose of 5 x 10^7pfu intradermally, has been shown to be safe in both mycobacterially naïve individuals, those previously vaccinated with BCG and latently infected individuals. Additionally, 5 x 10^7 pfu MVA containing HIV antigens administered twice, 4 weeks apart, in HIV positive individuals, is safe. We will use 5 x 107 pfu MVA85A intradermally in this study. Subjects will be identified from HIV clinics in the Oxford Radcliffe Hospitals NHS Trust and also from Swindon and Marlborough NHS Trust and St. Mary's Hospital NHS Trust if our recruitment targets are not met.
The need for new vaccine against tuberculosis 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 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 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 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 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 600 healthy volunteers (adults and children) in Oxford and Africa (The
Gambia and Kenya) without any serious adverse events (Adrian Hill, unpublished, 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 excellent and 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. To date these vaccines have been administered to over 600 people with no
serious adverse events (Hill; personal communication) 40 HIV positive individuals treated
with highly active anti-retroviral therapy (HAART) have been vaccinated with at least 5 x
107 PFU MVA containing HIV antigens with no serious adverse events (Dorrell, unpublished
data; Cosma et al 2003; Harrer et al, 2005). 7 HIV positive individuals have been vaccinated
with MVA containing malaria antigens with no serious adverse events and no significant or
sustained rise in viral load (Bejon at al, CID 2006, in press).
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, 2005).
In rhesus macaques, this BCG prime-MVA85A and Fowlpox85A boost is more immunogenic than any
of the vaccines alone, and is more protective than BCG alone (verrek et al, unpublished
data).
Clinical studies using MVA85A MVA85A (at a dose of 5 x 107pfu) has been administered to 48
healthy volunteers in the UK, 21 healthy volunteers in The Gambia and 18 in South Africa,
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,
Nature Med, 2004) and in The Gambia.
There are two ongoing studies in Oxford. The first is a phase I trial of the safety and
immunogenicity of MVA85A in individuals who are latently infected with M.tb. We have now
vaccinated all 12 volunteers with no serious adverse events. The second is a dose selection
study evaluating the safety and immunogenicity of 2 different doses of MVA85A (1x10^8 and
1x10^7 pfu), in healthy adult volunteers who have previously been vaccinated with BCG. Here
we have vaccinated 11 individuals with the higher dose (1x10^8) with no serious adverse
events, the main side effect being a fever at 24-48 hours post-vaccination, which completely
resolves over 24 hours. Results from the low dose arm will be collected over the next few
months.
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Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention
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