Transcript S. mansoni - York College of Pennsylvania

The Impact of Helminthic Infection on the Efficacy of the
Bacille Calmette-Guérin (BCG) Vaccine Against Pulmonary Tuberculosis
Sadie Forrester
Department of Biological Sciences, York College of Pennsylvania
PROJECT SUMMARY
REVIEW OF LITERATURE
OBJECTIVES
EXPECTED RESULTS
The efficacy of bacille Calmette-Guérin (BCG), the
only vaccine prescribed against tuberculosis, varies
from 0% to 80%. That variability has not been
explained, although low protection characterizes
regions endemic for helminths. This proposal intends
to test the impact of helminthic infection on BCG
efficacy through a two-phase study. Rhesus monkeys
in phase one will be infected with the helminth
Schistosoma mansoni before or after BCG vaccination,
and subsequently challenged with Mycobacterium
tuberculosis. If clinical assessments, cellular
proliferation analyses, cytokine assays, bacterial
counts, and pathologic examinations indicate that
helminthic infection reduces efficacy, phase two will be
conducted. Monkeys in phase two will be infected with
S. mansoni and treated with the antihelminthic drug
praziquantel before or after BCG vaccination, followed
by exposure to M. tuberculosis. Should pretreatment
with praziquantel appear to improve immune
responsiveness to BCG, administering antihelminthics
before vaccination may be a cost-effective way to
protect worm-burdened peoples from tuberculosis.
 The immune system is dominated by one of two
divergent responses during the course of an infection.
 To conduct a controlled study that characterizes the
effect of schistosomiasis on the cytokine profile of the
immune system
 A prominent Th2 immune profile in monkeys
with schistosomiasis
 The other is primarily humoral and is induced by
T helper type 2 (Th2) cytokines (Gallagher 1997).
 Ethiopian immigrants to Israel with helminthic
infections had highly activated immune systems
characterized by a Th2 cytokine profile
(Borkow et al. 2000) (Figure 1).
 The Th1 response to tetanus toxoid is suppressed
in humans with schistosomiasis (Sabin et al. 1996).
 To determine how the efficacy of the BCG vaccine is
impacted by an altered immune response
 To test whether antihelminthic treatment is able to
restore the immune response and improve the efficacy
of the BCG vaccine against challenge
RESEARCH DESIGN AND METHODS
Table 1. Phase I summary protocol
Group Primary
Secondary a
Treatment Treatment
I
Saline
-II
S. mansoni -III
BCG
-IV
S. mansoni BCG
V
BCG
S. mansoni
 A short-term study revealed that humans treated
with antihelminthics before BCG vaccination had
elevated in vitro responses compared to vaccinated
individuals infected with helminths (Elias et al. 2001)
(Figure 2).
Figure 1.
Helminths
 Bacille Calmette-Guérin (BCG) is the only vaccine
administered against tuberculosis.
IL-2
IFN-γ
Th1 cytokines
 Cases of pulmonary tuberculosis infection continue
to rise in developing countries because the vaccine’s
efficacy is highly variable.
IL-4
IL-10
Th2 cytokines
 The reason for the variability is not understood.
 The study will also test the ability of the
antihelminthic drug praziquantel to restore the immune
profile and improve the efficacy of the BCG vaccine
upon eradication of helminthic infection.
Figure 2.
(a)
250
250
(b)
5000
5000
*
200
200
150
150
100
100
**
50
50
IFN- γ (pg/ml)
 The proposed study will determine whether the
helminthic infection Schistosoma mansoni alters the
underlying immune profile of rhesus monkeys and
whether that shift in turn reduces the efficacy of the
BCG vaccine.
Figure 1. The shift of the immune system towards a Th2 cytokine profile
as a result of helminthic infection (Adapted from Bentwich et al. 1999).
Stimulation index
 Helminthic infections may reduce the efficacy of the
BCG vaccine because they alter the underlying
immune profile.
of the six monkeys in each group will be challenged
with M. tuberculosis after secondary treatments.
Cytokine
network
INTRODUCTION
 Examination of the impact of helminthic infections,
which are common in areas where efficacy is low, has
largely been overlooked.
a Three
PHA
PHA
PHA
PPD
PPD
PPD
VI
VII
VIII
IX
Praziquantel
S. mansoni
BCG
Praziquantel
S. mansoni
Praziquantel
Praziquantel
BCG
-----
X
S. mansoni
BCG
Praziquantel
XI
S. mansoni
Praziquantel
BCG
of the six monkeys in each group will be challenged with M. tuberculosis after
tertiary treatments.
**
3000
3000
 Clinical assessments will be conducted daily to
monitor for signs of tuberculosis such as coughing
 Cellular proliferation analysis will be executed
regularly to measure the response to tuberculin PPD
2000
2000
1000
1000
00
0
Tertiary a
Treatment
a Three
**
4000
4000
Table 2. Phase II summary protocol
Group Primary
Secondary
Treatment
Treatment
PHA
PHA
PPD
PPD
Figure 2. Proliferative responses (a) and IFN-γ secretion (b) to
mycobacterial antigen in humans treated with antihelminthics prior to
vaccination with BCG. Peripheral blood mononuclear cells (PBMC)
obtained 8 weeks after the first dose of placebo ( ) or antihelminthic ( )
were stimulated with phytohaemagglutinin (PHA) or tuberculin purified
protein derivative (PPD). Data are means + s.e.m. *P<0.001 **P<0.05
(Reproduced from Elias et al. 2001).
 Trap ELISA and flow cytometry will detect cytokine
levels in regularly collected unstimulated venous
blood samples
 Pathologic examinations upon sacrifice will verify
S. mansoni and tuberculosis infections
 Bacterial counts from lung tissue samples will
indicate the intensity of tuberculosis infections
 Reduced cellular proliferation in monkeys with
schistosomiasis at the time of BCG vaccination
 Increased cellular proliferation and a restored
Th1 immune profile in S. mansoni-infected
monkeys treated with praziquantel prior to
vaccination (Figure 3)
 Vaccinated monkeys never infected with
S. mansoni or that were infected but received
praziquantel prior to vaccination will be more
resistant to challenge with M. tuberculosis
Figure 3. 18
Stimulation index
 One response is primarily cell-mediated and is
induced by T helper type 1 (Th1) cytokines.
16
14
12
10
8
6
4
2
0
S
S+BCG
P
P+BCG
Figure 3. Expected proliferative response to PPD in S. mansoni
infected (S) and praziquantel treated (P) groups before and after
BCG vaccination (+BCG). Unstimulated PBMC will be analyzed
1 week before ( ) and 8 weeks after ( ) vaccination.
Data are means (Adapted from Elias et al. 2001).
LITERATURE CITED
Bentwich, Z., Kalinkovich, A., Weisman, Z., Borkow, G.,
Beyers, N. and Beyers, A.D. 1999. Can eradication of
helminthic infections change the face of AIDS and
tuberculosis? Trends in Immunology Today 20:485-487.
Borkow, G., Leng, Q., Weisman, Z., Stein, M., Galai, N.,
Kalinkovich, A. and Bentwich, Z. 2000. Chronic immune
activation associated with intestinal helminth infections
results in impaired signal transduction and anergy. Journal of
Clinical Investigation [serial online] 106:1053-1060. Available
from: HighWire Press.
Elias, D., Wolday, D., Akuffo, H., Petros, B., Bronner, U. and
Britton, S. 2001. Effect of deworming on human T cell
responses to mycobacterial antigens in helminth-exposed
individuals before and after bacille Calmette-Guérin (BCG)
vaccination. Clinical and Experimental Immunology
123:219-225.
Gallagher, R. 1997. Tagging T cells Th1 or Th2? Science
275:1615-1620.
Sabin, E.A., Araujo, M.I., Carvalho, E.M. and Pearce, E.J.
1996. Impairment of tetanus toxoid-specific Th1-like immune
responses in humans infected with Schistosoma mansoni.
Journal of Infectious Diseases 173:269-72.
Acknowledgements:
Carolyn Mathur, PhD, YCP Research Mentor
Deborah Ricker, PhD