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Buruli ulcer disease: Prospects for a vaccine

Scientific Institute of Public Health, Rue Engelandstraat 642, 1180 Brussels, Belgium.
Medical Microbiology and Immunology (Impact Factor: 3.04). 03/2009; 198(2):69-77. DOI: 10.1007/s00430-009-0109-6
Source: PubMed
Buruli ulcer disease (BUD), caused by Mycobacterium ulcerans, is a neglected bacterial infection of the poor in remote rural areas, mostly affecting children. BUD is a mutilating disease leading to severe disability; it is the third most common mycobacterial infection in immunocompetent people after tuberculosis and leprosy. It is most endemic in West Africa, but cases have been reported from more than 30 countries. Treatment with antibiotics is possible, long-lasting and requires injections; there are cases of treatment failures, and the disease is prone to resistance. A vaccine against M. ulcerans would protect persons at risk in highly endemic areas, and could be used as a therapeutic vaccine to shorten the duration of treatment and prevent relapses. There is considerable evidence supporting the notion that generation of a vaccine is feasible. This article reviews the present state of the art with special emphasis on the immunology of the infection and the prospects for development of a vaccine.

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Available from: Caroline Demangel, Apr 18, 2014
Med Microbiol Immunol (2009) 198:69–77
DOI 10.1007/s00430-009-0109-6
Buruli ulcer disease: prospects for a vaccine
Kris Huygen · Ohene Adjei · Dissou AVolabi · Gisela Bretzel · Caroline Demangel · Bernhard Fleischer ·
Roch Christian Johnson · Jorge Pedrosa · Delphin M. Phanzu · Richard O. Phillips · Gerd Pluschke ·
Vera Siegmund · Mahavir Singh · Tjip S. van der Werf · Mark Wansbrough-Jones · Françoise Portaels
Received: 13 January 2009 / Published online: 7 February 2009
© Springer-Verlag 2009
Abstract Buruli ulcer disease (BUD), caused by Myco-
bacterium ulcerans, is a neglected bacterial infection of the
poor in remote rural areas, mostly aVecting children. BUD
is a mutilating disease leading to severe disability; it is the
third most common mycobacterial infection in immuno-
competent people after tuberculosis and leprosy. It is most
endemic in West Africa, but cases have been reported from
more than 30 countries. Treatment with antibiotics is possi-
ble, long-lasting and requires injections; there are cases of
treatment failures, and the disease is prone to resistance. A
vaccine against M. ulcerans would protect persons at risk in
highly endemic areas, and could be used as a therapeutic
vaccine to shorten the duration of treatment and prevent
relapses. There is considerable evidence supporting the
K. Huygen (&)
ScientiWc Institute of Public Health,
Rue Engelandstraat 642, 1180 Brussels, Belgium
O. Adjei
Kumasi Centre for Collaborative Research, Kumasi, Ghana
D. AVolabi
Laboratoire de Référence des Mycobactéries, Cotonou, Benin
G. Bretzel
Department of Infectious Diseases and Tropical Medicine,
Ludwig-Maximilians-University, Munich, Germany
C. Demangel
Institut Pasteur, Paris, France
B. Fleischer
Bernhard Nocht Institute for Tropical Medicine,
Hamburg, Germany
R. C. Johnson
Programme National de Lutte contre l’Ulcère de Buruli,
Cotonou, Benin
J. Pedrosa
Life and Health Sciences Research Institute (ICVS),
School of Health Sciences, University de Minho, Braga, Portugal
D. M. Phanzu
Institut Medical Evangelique, Kimpese, DR Congo
R. O. Phillips
Kwame Nkrumah University of Science
and Technology, Kumasi, Ghana
G. Pluschke
Swiss Tropical Institute, Basel, Switzerland
V. Siegmund
European Research and Project OYce GmbH,
Saarbrücken, Germany
M. Singh
LIONEX Diagnostics and Therapeutics GmbH,
Brunswick, Germany
T. S. van der Werf
University of Groningen Medical Centre,
Groningen, The Netherlands
M. Wansbrough-Jones
St George’s University, London, UK
F. Portaels
Prince Leopold Institute of Tropical Medicine,
Antwerp, Belgium
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70 Med Microbiol Immunol (2009) 198:69–77
notion that generation of a vaccine is feasible. This article
reviews the present state of the art with special emphasis on
the immunology of the infection and the prospects for
development of a vaccine.
Keywords Buruli ulcer · Mycobacterium ulcerans ·
Mycolactone toxin · Vaccine · Neglected diseases · Review
Buruli ulcer disease (BUD) has emerged since 1980 as an
important cause of human suVering. It is a poverty-
related mutilating disease caused by Mycobacterium
ulcerans. BUD is the third most common mycobacterial
disease in humans after tuberculosis and leprosy and the
most poorly understood of these three diseases. The dis-
ease presents as an indolent necrotizing disease of the
skin, subcutaneous tissue and bone and can aZict all age
groups but children under 15 years represent the largest
part of the BUD disease burden. The disease remained
largely ignored by many national public health programs
for decades [2]. In 1998, the World Health Organization
recognized BUD as an emerging health problem, primar-
ily because of its frequent disabling and stigmatizing
complications [68].
Geographic distribution, incidence and prevalence
The disease is endemic in rural wetlands of tropical coun-
tries of Africa, America, Asia and Australia. Cases have
also been reported in non-tropical areas of Australia, Japan
and China. Known incidence rates are highest in West
Africa, particularly in Benin, Côte d’Ivoire and Ghana
where between 1,000 and 2,000 cases are reported annually
[70]. In some West African countries, the number of BUD
cases may even exceed those of tuberculosis and leprosy
[11]. There is evidence of enormous under-reporting of the
Little is known about the focal epidemiology of BUD.
Incidence, prevalence, and other data are usually reported
at the national or district level. These data show the impor-
tance of the disease but do not reveal the wide variations
that often exist at the village level within a given district
Reservoirs and transmission
BUD is an infectious disease but rarely, if ever, contagious.
There is now suYcient evidence from microbiological and
epidemiological data, including studies of risk factors, to
consider BUD a water-related disease [13]. However, the
exact mode(s) of transmission from the environment and
the ultimate natural reservoir(s) of infection remain
obscure. Humans probably become infected by traumatic
introduction of M. ulcerans into skin from the overlying M.
ulcerans-contaminated surface. Contamination of the skin
could result from direct exposure to stagnant water, aero-
sols arising from ponds and swamp surfaces or fomites
Since the initial discovery of M. ulcerans DNA in water
bugs (Hemiptera) in Benin [39], aquatic insects have been
suspected to play a role in transmission [30, 40]. However,
the ultimate importance of M. ulcerans-colonized aquatic
insect bites in the transmission of BUD remains unproven,
justifying continued investigation of other forms of trans-
mission of M. ulcerans to humans [44, 51]. In an outbreak
in Australia, mosquitoes have been implicated in transmis-
sion [48].
In tropical rural settings where BUD is endemic and scant-
ily dressed people play and work, avoiding contact with the
M. ulcerans contaminated environment is virtually impossi-
ble. Wearing protective clothing when farming [47] and
immediate cleansing of any skin injury [33] may reduce
rates of infection, but achieving these measures is seldom
Use of protected sources of water for domestic purposes
reduces exposure to M. ulcerans contaminated water and
consequently may reduce prevalence rates of BUD [26].
The problem of reducing risk factors for basic agricultural
workers, Wshermen and others who must put themselves at
risk, remains, however, a serious concern.
Clinical manifestations
Mycobacterium ulcerans disease presents a spectrum of
forms related partly to patient delay in admission to hospi-
tal [11]. Mean incubation periods are estimated to be 2–
3 months.
The most common form of disease is a nodule which
enlarges and ulcerates giving rise to a painless ulcer with
undermined edges and edema of the surrounding skin.
Ulcers develop by perforation of the underlying necrosis
through the epidermis. Ulcers may remain small (minor
ulcers), with a diameter up to 1–2 cm, and self-heal but
usually enlarge (major ulcers) and destroy wide areas of
skin. Major ulcers may self-heal eventually, resulting in
atrophic stellate or symmetric scars with contractures and
disabilities when located over joints which may ankylose
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Med Microbiol Immunol (2009) 198:69–77 71
and become totally immobile. Major ulcers may progress to
involve the subjacent bone and cause osteomyelitis [45].
Laboratory diagnosis
Although the experienced health care worker in endemic
areas usually can make an accurate clinical diagnosis of
BUD, microbiological conWrmation is essential for the
following reasons:
1. To conWrm the precise prevalence and incidence of
BUD in a given area;
2. To conWrm new foci, especially where health care
workers lack experience with BUD;
3. To help manage the disease by surgical and/or
antimycobacterial treatment;
4. To conWrm and diVerentiate relapse and reinfection
after treatment.
Four laboratory tests are currently available to conWrm the
diagnosis of BUD [41, 50]: direct smear examination for
acid-fast bacilli by Ziehl–Neelsen or auramine stain, in
vitro culture, IS2404 PCR and histopathological examina-
tion. PCR represents the gold standard for diagnosis in
research studies because of its high sensitivity and
For decades, excision surgery with primary closure or
skin grafting was the recommended therapy of BUD.
Recurrence rates after surgery vary between 6 and 28%
[5, 12]. In the last few years, the use of oral rifampicin
plus intramuscular streptomycin with or without surgery
has been recommended by WHO [69]. Several centers in
Africa have initiated therapy with antibiotics according
to the WHO guidelines [69], and some studies suggest
that following drug therapy for 8 weeks, most ulcers
may heal without surgery. Recurrence rates within the
year following the end of chemotherapy were less than
2% [6].
However, access to health services in endemic areas is
usually restricted. Due to the painless nature of the lesions,
patients often seek treatment late and tend to turn Wrst to
traditional healers. Thus, treatment is usually delayed, caus-
ing frequent and severe complications, leading to prolonged
and expensive hospitalization.
Moreover, it has been determined for Central Cameroon
that despite free-of-charge medical treatment, the cost
burden of BUD accounts for 25% of households’ yearly
earnings, surpassing the threshold of 10%, which is gener-
ally considered catastrophic for the household economy,
and calling into question the sustainability of current BUD
programs [21].
Pathogenesis and immunity
Mycobacterium ulcerans is genetically very close to
M. marinum [55], an intracellular pathogen that triggers
inXammatory responses and cell-mediated immunity
(CMI) [32] but it is unique among pathogenic mycobacte-
ria since it produces a family of toxic macrolides, the
mycolactones, which are required for virulence [14, 17].
Mycolactones are secreted and diVuse into the infected
tissues and surrounding areas, but the amount and precise
distribution of the toxin in the lesions is not known.
Mycolactones have a potent cytotoxic activity that
induces apoptosis and necrosis of several cell types
including adipocytes, Wbroblasts and leukocytes, and par-
ticipate in the tissue necrosis typical of the disease [1, 23,
36, 65]. Recently, studies using animal models have
shown that mycolactone distributes beyond the sphere of
its cytocidal action and gains access to the blood and lym-
phoid organs, where it concentrates in mononuclear cell
subsets [24].
Cellular immune responses
Resistance to M. ulcerans has been associated with the
development of Th1 type responses [19, 20, 47, 66] and as
BUD disease progresses to healing, granuloma formation
has been reported [22, 27, 54, 63], and the DTH burulin
skin test [53] tends to change from negative to positive [16,
31]. In contrast, disseminated BUD disease and bone
involvement have been reported to be associated with
defects in granuloma formation [28, 34].
As in tuberculosis and leprosy, the macrophage activat-
ing cytokine IFN- seems to play a pivotal role in the con-
trol of M. ulcerans infection, and PBMC from BUD
patients display a reduced capacity to produce this cytokine
upon in vitro stimulation with whole M. ulcerans bacilli
[18, 47]. Using RT-PCR analysis, Gooding et al. [19] have
described the production of Th2 type cytokines, i.e., IL-4,
IL-5, IL-6 and IL-10 by PBMC from Australian BUD
patients. These Wndings could only be partly conWrmed by
Prévot et al. [47] in French Guyana, who were unable to
detect any IL-4 or IL-13 activity in BUD patients, but who
conWrmed that the production of IL-10 following stimula-
tion with whole, killed M. ulcerans was higher in BUD
patients than in healthy controls. Westenbrink et al. [66]
Wnally failed to detect an association of IL-4 or IL-10 with
changes in IFN- in BUD patients . An extensive real-time
PCR analysis on skin biopsies of 16 patients with early
nodules and 28 patients with late-stage ulcers, showed a
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72 Med Microbiol Immunol (2009) 198:69–77
signiWcantly higher expression of IL-8 and other pro-
inXammatory cytokines in 32 biopsies with neutrophilia
than in those of 12 biopsies without acute inXammation
[38]. As in the Prévot study, expression levels of IL-4 and
IL-5 were below detection level, whereas some IL-10 mes-
sage could be detected.
The M. ulcerans infection-associated reduction of
IFN- responses is not restricted to mycobacterial anti-
gens and resolves after surgical excision of the lesion
[71], suggesting that bacterial factors such as mycolac-
tone may diVuse from bacillar colonies and exert immu-
nosuppressive eVects at the systemic level. This
hypothesis is supported by observations that non-cyto-
toxic doses of mycolactone eYciently suppress the func-
tions of several types of mononuclear cells in vitro. At
nanomolar concentrations, mycolactone inhibits the acti-
vation-induced production of IL-2 by human lympho-
cytes, and of TNF by monocytes and macrophages [7, 37,
61]. Mycolactone also blocks the capacity of dendritic
cells (DCs) to prime cellular responses and produce che-
motactic signals of inXammation [9]. Lymphocytes,
monocytes, DCs and macrophages compose the mononu-
clear cell fraction of blood and lymphoid organs. The fact
that mycolactone targets mononuclear cells in mice
infected with M. ulcerans thus strongly suggests that
these cell subsets are immunosuppressed in infected
hosts, and that mycolactone impairs the development of
cellular immunity. In this model, neutralizing the immu-
nosuppression imposed by mycolactone using inhibitors
of its biosynthesis, or ablating its biological activity in
vivo, would considerably enhance the eYcacy of thera-
peutic vaccines and antibiotic treatments.
So far, nearly all studies of the cellular immune response
against M. ulcerans have used whole bacteria or burulin,
which is a crude, heat-killed bacterial sonicate [38]. IFN-
responses against culture Wltrate antigens 423 and 425 were
similar in pattern but lower than those against M. ulcerans
sonicate [38]. A cross-reactive antigen that has been studied
in some more detail in M. ulcerans infection is the mycolyl
transferase antigen 85 (Ag85), which forms a major frac-
tion of the secreted proteins in mycobacterial culture
Wltrates. This Ag85 is actually a 30–32 kDa family of three
proteins (Ag85A, Ag85B and Ag85C) [67], which all pos-
sess a mycolyl transferase enzymatic activity required for
the integrity of the cell wall [4]. PuriWed Ag85 from BCG
induces strong T cell proliferation and IFN- production in
most healthy individuals infected with M. tuberculosis
M. leprae and in BCG vaccinated mice, whereas in tubercu-
losis and leprosy patients the Ag85 speciWc IFN- produc-
tion is much lower [29, 64]. Similarly, PBMC from BUD
patients demonstrate lower IFN- responses against Ag85
puriWed from BCG than PBMC from healthy BCG vacci-
nated subjects [47].
Antibody responses
In studies with M. ulcerans culture Wltrates, IgG antibody
responses against the secreted M. ulcerans proteins were
frequently found in BUD patients, but also in TB patients
from BUD non-endemic regions [16, 35]. The IgM
responses of BUD patients against the Wltrate proteins were
more distinct than those of healthy family members living
in the same village [35] indicating B cell stimulation. Diaz
et al. used the highly immunogenic M. ulcerans 18 kD
small heat shock protein, which has no homologs in
M. bovis and M. tuberculosis to monitor M. ulcerans spe-
ciWc IgG responses in BUD patients and household contacts
from Ghana. Under stringent assay conditions 75% of
patients, independent of disease stage, but also 38% of
household contacts showed reactivity, whereas samples
from Europeans and non-exposed Africans remained nega-
tive [15]. This indicates that speciWc humoral responses
against M. ulcerans develop in exposed, but otherwise
healthy individuals. Immune responses in healthy house-
hold contacts have also been described by immunoblot
analysis in Australian samples [19], where a lower back-
ground staining than with African sera facilitated analysis
with M. ulcerans cell extracts. The control of M. ulcerans
infection may be primarily dependent on cell-mediated
immunity involving activated macrophages, T cells, and
Th1 type cytokines, as is thought to be the case for
M. tuberculosis and M. leprae infection. However, antibod-
ies could provide additional protective mechanisms against
the largely extracellular M. ulcerans. Opsonisation might
improve phagocytosis and killing by neutrophils, increase
intracellular killing by macrophages or improve antigen
presentation and induction of protective T cell responses.
Vaccination against M. ulcerans
Although signiWcant progress has been made in manage-
ment of this disease in endemic countries during the last
decade, BUD remains a major economic and social burden
for developing countries [21]. Therefore, vaccination pro-
grams remain the only viable prevention alternative. Evi-
dence that a protective immune response can develop in
humans is incomplete but, as described above, two serolog-
ical studies have indicated that some household contacts of
BUD patients have been exposed to M. ulcerans without
developing disease. This may be because they developed a
protective immune response or because of unrelated issues
such as in inadequate infective dose of the organism or the
wrong conditions for bacterial proliferation in exposed
skin. In addition, there is much anecdotal evidence that
some people develop pathological lesions after infection
with M. ulcerans which heal in a short time without any
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Med Microbiol Immunol (2009) 198:69–77 73
treatment. This was, for example, documented in the con-
trol group of a placebo-controlled trial of clofazimine for
treatment of early BUD lesions from which 30% healed
without going on to ulcerate [49]. This strongly suggests
that the disease can be controlled by an appropriate host
response, although there is no evidence that such individu-
als were protected against infection on future exposure.
The fact that a bimodal age distribution of M. ulcerans
disease has been observed with peaks at 5–15 years and
75–79 years raises the possibility that latent infection can
reactivate as immunity declines with age [11]. There is,
however, no hard evidence to support this notion of reacti-
vation at present.
Molecular and immunological tools have started to give
us more insight into the mechanism of M. ulcerans infec-
tion, the progression to BUD and immune responses
involved. However, a key question with respect to the
development of an eVective vaccine remains to be
answered: is M. ulcerans essentially an intracellular or
extracellular pathogen? In the former case, antibodies are
likely to play little role in protection and vaccination should
focus on the stimulation of cellular immune responses, par-
ticularly those conferred by the Th1 type helper T cell pop-
ulation. If extracellular, a vaccine aimed at stimulating
antibody responses would be a more obvious and perhaps
easier option. The third, and perhaps most probable, possi-
bility is that both arms of the immune response are required
for optimal protection, as is the case for a number of viral
and parasite pathogens.
Experimental infections in mice have shown that
M. ulcerans is eYciently internalized by mouse phagocytes
in vitro [7, 61] and that it proliferates inside macrophages
[61]. This intracellular phase is transient [7], except in the
edges of the lesion [61]. Following injection in the dermis
of the ears, bacilli are indeed internalized by professional
cells and transported to the draining lymph nodes within
host cells [7]. The inoculation site eventually becomes
ulcerated with tissue necrosis and extracellular bacteria
appear at later stages of the infection.
As of now, there is no speciWc vaccine against M. ulcerans,
but some evidence in the literature has suggested a cross-
reactive protective role of the M. bovis BCG vaccine used
against tuberculosis. Two large randomized controlled tri-
als of BCG vaccination for the prevention of BUD were
conducted in Uganda during the late 1960s and early 1970s.
The Wrst study was performed in a population of approx-
imately 2,500 Rwandan refugees in the Kinyara refugee
camp in the Bunyoro district of Uganda [62]. At the com-
mencement of the study the entire population was surveyed
and divided into groups according to whether they had pre-
viously had BUD, prior BCG or no prior BCG. Those with-
out prior BCG were randomized to receive or not to receive
a single dose of BCG, provided their tuberculin skin test
result (TST) was <6 mm. The population was followed for
16 months. Overall eYcacy of BCG was 47%. Protection
rate was 72% in the Wrst 6 months, but almost 0% in the
second 6 months. In non-randomized subjects, prior BUD
disease (healed lesion) and a positive TST were protective.
The protective eVect of a positive TST also declined during
the study period. Protection aVorded by BCG was not inXu-
enced by age at vaccination or TST conversion. In those
who developed BUD, BCG and positive TST were associ-
ated with “reactive” histology and a higher proportion of
“pre-ulcerative” lesions.
The second study was performed in a rural area along the
south-east bank of the Nile in central Uganda [52]. The
study population consisted of 9,396 people who lived in
Wve administrative parishes. At the commencement of the
study, the population was surveyed and o
Vered TSTs. BCG
was given at random to 50% of all these persons, irrespec-
tive of previous BUD lesions, BCG scar or tuberculin-sta-
tus. The main Wndings were: overall protection rate of 47%
during the Wrst year of study. Protection appeared to decline
beyond this time. BCG only provided protection in those
with initial TST <4 mm and BCG reduced the size of BUD
lesions at diagnosis. Healed BUD lesion or BCG scar
oVered some protection, but subsequent BCG vaccination
did not show additional protection.
Taken together, both studies were consistent with BCG
producing a signiWcant but only short-lasting protection
against BUD. Moreover, the results in the tuberculin-posi-
tive subjects suggested that a cross-protective immune
response could also be induced by previous exposure to
M. tuberculosis. Conversely, in 1987 Bahr et al. [3] described
a cross-reactive skin test response to M. ulcerans in BCG
vaccinated school children from Kuwait, a region where
M. ulcerans has not been reported so far. All this is not
really surprising in the light of the close phylogenetic rela-
tionship of mycobacteria from the M. tuberculosis complex
(M. tuberculosisbovisafricanum) on the one hand and
M. ulcerans-marinum on the other [60].
One manifestation of BUD, against which BCG vaccina-
tion seems to exert a sustained, immunoprophylactic eVect,
is the disseminated osteomyelitic form. In 2002, Portaels
et al. [42] reported a protective eVect of BCG vaccination
against osteomyelitis in children suVering from BUD in
Benin. In her study, only 7.7% of the children younger than
15 years of age with BCG scars had this severe, dissemi-
nated form of BUD, whereas in the group of unvaccinated
children, 33% suVered from osteomyelitis. Also in adults,
BCG vaccination confers a certain degree of protection
against osteomyelitis [43].
In experimental foot pad infection of C57BL/6 mice
with M. ulcerans, M. bovis BCG vaccine oVers only a
short-term protection and the duration of this protection
cannot be prolonged by a booster vaccination [58]. These
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74 Med Microbiol Immunol (2009) 198:69–77
Wndings seem to indicate that the limited protection con-
ferred by BCG against M. ulcerans is not so much caused
by a waning of the immune protection, but rather that the
quality of immune response induced by the vaccine is not
optimal. It is possible that the cross-reactive immune
response induced by the M. bovis BCG vaccine is not suY-
cient and that species-speciWc immune responses are
required to eVectively control the infection. A comparative
study of the protective eYcacy of two DNA vaccines
encoding Ag85A from BCG and from M. ulcerans, respec-
tively, indicates that this might indeed be the case [59].
Mycolactone is an obvious candidate for a vaccine, but
by virtue of its chemical structure, the polyketide is not in
itself immunogenic, and so far antibodies against mycolac-
tone have not been detected either in healthy contacts or in
BUD patients. The enzymes involved in the mycolactone
biosynthesis are alternative vaccine candidates. In addition
to the giant mlsA1, mlsA2 and mlsB genes encoding the
polyketide synthases (PKS), other genes have been identi-
Wed that are involved in the synthesis of the toxin: three
putative transcriptional regulatory genes: fur, Ws and tetR,
and two genes encoding enzymes involved in the synthesis
of mycolactone precursor molecules: acetate kinase (ack)
and 3-ketoacyl acyl carrier protein synthase III (fabH).
Although M. ulcerans and M. tuberculosis/bovis BCG
share a large number of highly conserved antigens, even
small sequence changes can result in the loss of immuno-
dominant epitopes. Therefore, it has been argued that an
attenuated, live vaccine based on M. ulcerans could oVer a
better and more speciWc protection than BCG [25]. Myco-
lactone negative isolates of M. ulcerans have been identi-
Wed, both as spontaneous mutants that lack the yellow
pigmentation of the mycolactone, and more recently by
screening of kanamycin resistance in isolates generated by
transposon mutagenesis [56].
Adjuvanted subunit based protein vaccines are an alter-
native to live attenuated vaccines. Subunit vaccines have
the advantage of being well characterized and of posing no
danger for application in HIV-positive populations. On the
other hand, their antigenic repertoire is obviously limited,
and the induced immune responses and memory are gener-
ally weak, requiring repeated boosting. So far only two sub-
unit-based vaccines have been tested in experimental
models. Tanghe et al. [57] were the Wrst to report that vacci-
nation with plasmid DNA encoding the mycolyl-transferase
85A from BCG could signiWcantly reduce the bacterial load
in the foot pads of M. ulcerans infected mice. Vaccination
with recombinant Ag85A protein from M. ulcerans con-
ferred also some protection and a DNA prime-protein boost
immunization protocol resulted in a protective eYcacy
comparable to the one induced by the BCG vaccine [59].
The genes encoding the GroEL-2 protein Hsp65 are highly
conserved among mycobacterial species, with 96 and 95%
identity at the amino-acid level between the M. ulcerans
antigen and the homologous proteins in M. tuberculosis and
M. leprae, respectively. Hsp65 is very immunogenic and
vaccination of mice with a plasmid encoding hsp65-encod-
ing DNA vaccine was also signiWcantly protective against
M. ulcerans infection, as demonstrated by the reduced bac-
terial loads in tails of infected BALB/c mice. In this mouse
model, the protection levels conferred by DNA vaccines
expressing hsp65, Ag85B, or both antigens were compara-
ble, but nevertheless inferior to the one aVorded by vaccina-
tion with BCG [8]. Although hsp65 is not currently
considered as a vaccine candidate in humans because of its
strong homology with human hsp60 and the risk of promot-
ing auto-immune diseases, this experiment further demon-
strates the possible role of subunit antigens in vaccination
against BUD.
In recent years, impressive progress has been made in
research activities with respect to epidemiology, transmis-
sion, pathogenesis, immunology, diagnosis and treatment
of BUD infection. Priority has been given to increased sur-
veillance, early detection and treatment of the disease and
there is still much to be done: antimycobacterial treatment
has to be shortened and adapted to avoid injections, and the
role, extent and timing of debridement surgery and skin
grafting subsequent to antibiotic treatment have to be deW-
ned. However, good surveillance, detection and treatment
tools will not be suYcient to decrease the incidence and
prevalence of BUD. Prevention tools are mandatory and
identiWcation and development of vaccine candidates have
now become a priority for better control of BUD. Gener-
ally, a vaccine against any neglected bacterial infection will
only be used in highly endemic regions within endemic
countries. A vaccine against M. ulcerans will be useful to
protect children in hyperendemic foci but it may also have a
role in therapy by shortening the duration of antibiotic
treatment and preventing recurrences and severe forms of
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  • Source
    • "Given the deficient cross-reactive immune response elicited by BCG vaccination during M. ulcerans infection, it has been argued that an M. ulcerans-specific immunization would be more efficient at controlling infection. Indeed, there are differences in genetic and antigenic mycobacterial composition that can result in variations of immunodominant epitopes [38]. Therefore, we evaluated the efficacy of a vaccination protocol with a mycolactone-negative strain of M. ulcerans. "
    [Show abstract] [Hide abstract] ABSTRACT: Buruli ulcer (BU) is an emerging infectious disease caused by Mycobacterium ulcerans that can result in extensive necrotizing cutaneous lesions due to the cytotoxic exotoxin mycolactone. There is no specific vaccine against BU but reports show some degree of cross-reactive protection conferred by M. bovis BCG immunization. Alternatively, an M. ulcerans-specific immunization could be a better preventive strategy. In this study, we used the mouse model to characterize the histological and cytokine profiles triggered by vaccination with either BCG or mycolactone-negative M. ulcerans, followed by footpad infection with virulent M. ulcerans. We observed that BCG vaccination significantly delayed the onset of M. ulcerans growth and footpad swelling through the induction of an earlier and sustained IFN-γ T cell response in the draining lymph node (DLN). BCG vaccination also resulted in cell-mediated immunity (CMI) in M. ulcerans-infected footpads, given the predominance of a chronic mononuclear infiltrate positive for iNOS, as well as increased and sustained levels of IFN-γ and TNF. No significant IL-4, IL-17 or IL-10 responses were detected in the footpad or the DLN, in either infected or vaccinated mice. Despite this protective Th1 response, BCG vaccination did not avoid the later progression of M. ulcerans infection, regardless of challenge dose. Immunization with mycolactone-deficient M. ulcerans also significantly delayed the progression of footpad infection, swelling and ulceration, but ultimately M. ulcerans pathogenic mechanisms prevailed. The delay in the emergence of pathology observed in vaccinated mice emphasizes the relevance of protective Th1 recall responses against M. ulcerans. In future studies it will be important to determine how the transient CMI induced by vaccination is compromised.
    Full-text · Article · Mar 2012 · PLoS ONE
  • [Show abstract] [Hide abstract] ABSTRACT: Major trends in science and technology policy reform in Vietnam have been reviewed in this paper. Based upon this analysis, some suggestions have been made to improve endogenous capacity through policy options relating to technology planning with participation, technology evaluation, utilization of local experts, promotion of rural areas, and development of technology services and environmental integration
    No preview · Conference Paper · Feb 1999
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Mycobacterium ulcerans infection is an emerging disease that causes indolent, necrotizing skin lesions known as Buruli ulcer (BU). Approximately 10% of patients develop reactive osteitis or osteomyelitis beneath skin lesions or metastatic osteomyelitis from lymphohematogenous spread of M. ulcerans. The most plausible mode of transmission is by skin trauma at sites contaminated by M. ulcerans. Pathogenesis is mediated by a necrotizing, immunosuppressive toxin produced by M. ulcerans called mycolactone. The incidence of BU is highest in children up to 15 years old and is a public health problem in countries of endemicity due to disabling scarring and bone destruction. Today, most BU occurs in West Africa, but the disease has been reported in over 30 countries. Treatment options for BU are antibiotics and surgery. BCG vaccination provides short-term protection against BU and prevents osteomyelitis. HIV seropositivity may increase the risk for BU and render BU osteomyeletis highly aggressive.
    Full-text · Article · Aug 2009 · Clinical Microbiology Newsletter
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