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schistosomiasis vaccination: what are the best approaches?
Dr. Momar Ndao
Director - National Reference Center for ParasitologyResearch Institute of the McGill University Health Centre
Department of Medicine – Div. of Infectious Diseases
VIC Global Health Vaccine - May 10, 2017
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Activities of the National Reference Centre for Parasitology (NRCP)
RANGE OF TESTS: DISEASES
MalariaChagas diseaseHum. African TrypanosomiasisLeishmaniasisBabesiaFilariasisCysticercosisFascioliasisHydatid diseaseTrichinellosisGnathostomiasisToxoplasmosisSchistosomiasisToxocariasisStrongyloidiasisParagonomiasisBaylisascariasisAmoebiasisGiardiasisCryptosporidiosis
BLOOD
FOOD
WATER
DRUG SCREENING
Trypanosoma cruziTrypanosoma bruceiLeishmania spp. (VL and CL)Giardia lambliaCryptosporidium parvum : KO IFNg model
BIOMARKERS DISCOVERY
Chagas disease: Transgenic and KO ApoA1BabesiosisMalariaLeishmaniasis (CL and CL)Dengue (US CDC collaboration)Clostridium difficile infection (US DoD)
VACCINE
SchistosomiasisChagas diseaseLeishmaniasis (CL and VL)Cryptosporidiosis
MODELS
ANTIGENS USED FOR
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RI-MUHC
McGill TDC
NRCP
2017
US
CDC
US
NIH
Am.
Red
CrossUCSF
Can. Blood
Services
Hema
QuebecProv. Lab
Canadian
Forces
London Tropical
Medicine School
Montpellier
WHO Leish. Ref.
Lab.
Inst. Tropical
Medicine Antwerp
WHO/
DNDi
Univ. Fed.
Minas Geiras
Brazil
AviexTechonologies
LLC
Merck
Frosst
Dafra
Pharma
Belgium
B Cell
Design
Limoges
Meridian
Bioscience
Inc.
NRC
Ottawa
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IN VIVO MODELS:CRYPTOSPORIDIOSIS
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Cryptosporidium Oocysts can survivethrough this process
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• Causes of diarrheal outbreaks
• Most at risk: Children, Elderly and
immunosuppressed
❖ 1987 Carrollton, Georgia. 13,000 people infected- Water supply
❖ 1993 South-Eastern Wisconsin, USA. ~ 403,000 people
infected. ~ 4,400 people hospitalized. >100 people died.
Municipality Water supply
❖ 1995 Torbay in Devon, UK, 575 cases.
❖ 1996 Cranbrook, British Columbia, Canada, 2,000 cases. Weeks
later, Cranbrook, British Columbia, Canada, 10,000 to 15,000 cases.
❖ 2001 North Battleford, Saskatchewan, Canada. 1907 cases
❖ 2002 Glasgow, Scotland floods led to 140 000 cases.
❖ 2007 Utah, USA, 1302 cases. Public pools were the cause.
❖ 2008 Northampton, UK, about 250,000 cases. Tap water.
❖ 2010 Östersund, Sweden, over 4000 cases.
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. (A) PO treatment at 35 mg/kg (), 70 mg/kg () and 105 mg/kg (). BID treatment with 1
paromomycin PO at 125 mg/kg (). Infected controls: mock treated () and treated with 0.5% 2
DMSO (). Uninfected controls: mock treated () and treated with 0.5% DMSO PO (). (B) 3
IP treatment at 35 mg/kg (), 52.5 mg/kg () and 70 mg/kg (). Infected controls: mock treated 4
() and treated with 0.5% DMSO IP (). Uninfected controls: mock treated () and treated 5
with 0.5% DMSO (). 6
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ParomomycinMiltefosine OIPC
Front Microbiol. 2015 Sep 23;6:973.
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BIOMARKERS DISCOVERY:Chagas disease
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Chagas Disease: Epidemiology• Infection caused by a protozoan parasite, spread by kissing bugs. Endemic to
Central & South America, Mexico
• Estimated that 16-18 million people are infected
• ~50,000 people die annually from Chagas disease
• Also spread by blood transfusion, organ transplants, mother-child (transplacental), and from contaminated food.
Kissing bug
Apical Aneurysm of
heart
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Estimated Number of Immigrants with T. cruzi
Infection in Non-Endemic Countries
The Lancet 2010, 375:1388
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8500 9000 9500 10000
8500 9000 9500 10000
Chagas Venezuela
Chagas Guatemala
Toxoplasma
Sleeping sickness
Babesia
Leishmania
Malaria
8500 9000 9500 10000
8500 9000 9500 10000
8500 9000 9500 10000
8500 9000 9500 10000
8500 9000 9500 10000
8500 9000 9500 10000
8500 9000 9500 10000
8500 9000 9500 10000
8500 9000 9500 10000
Chagas Venezuela
Chagas Guatemala
Toxoplasma
Sleeping sickness
Babesia
Leishmania
Malaria
0
5
10
15
20
8500 9000 9500 10000
9304.1+H
0
5
10
15
20
8500 9000 9500 10000
9302.8+H
0
5
10
15
20
8500 9000 9500 10000
0
5
10
15
20
8500 9000 9500 10000
0
5
10
15
20
8500 9000 9500 10000
0
5
10
15
20
8500 9000 9500 10000
0
5
10
15
20
8500 9000 9500 10000
85009000950010000
85009000950010000
Chagas Venezuela
Chagas Guatemala
Toxoplasma
Sleeping sickness
Babesia
Leishmania
Malaria
85009000950010000
85009000950010000
85009000950010000
85009000950010000
85009000950010000
85009000950010000
85009000950010000
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SCHISTOSOMIASIS Vaccine: Classical approaches
https://www.emaze.com/@ACQRRIQW/Schistosomiasis
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Epidemiology• 700 million people at risk
• Over 200 million people infected
• 750,000 deaths per year
• Most important human helminth infection
• Important public health impact
S. mansoniS. haematobium S. japonicum S. mekongiS. intercalatum
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Start here
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Schistosoma mansoni Cathepsin B
Ingestion
~104 erythrocytes/h
~105 erythrocytes/h
Hg
Oligopeptides
Amino Acids
Oe
sop
hag
us
Gas
tro
de
rmis
He
mo
lysi
nP
ep
tid
ase
s
Cathepsins
B1
F(L1)
L(L2)?
D
•Most abundant cysteine peptidase in parasite gut
•Involved in hemoglobin digestion
•Needed for parasite development
Modified from Kasny (2009) Adv Paraitol39kDA
Pichia Pastoris expression system (Invitrogen)
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Sm-CB + CpG Challenge: Worm & Egg Burden
56% Eggs burden reduction in liver
54% Eggs burden reduction in intestine
59% worms burden reduction
▪TDR/WHO committee established threshold: 40%▪CathB + CpG: 59% reduction worm number; 56% & 54% reductions in liver and intestinal eggs, respectively
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Sm-Cathepsin B + CpG: Antibody Production
▪The formulation generated robust CathB-specific total IgG endpoint titers (>120,000 at week 9)▪IgG2c greater than IgG1▪This may be a marker of the immune environment pre-challenge
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Sm-CB + CpG Challenge: Cytokine Production
Th1
▪ Th1 cytokines (IFNɣ & TNFα) were increased in the experimental group ▪Th1 responses are believed to be crucial for protection▪Sm-CB + CpG: Th1 biased response
Th2
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▪ CathB + Mont: 60% reduction worm number; 62% & 56% reductions in liver and intestinal eggs respectively
▪ The formulation generated robust CathB-specific total IgG endpoint titers (>120,000 at week 9)▪ IgG1 greater than IgG2c
▪ Th1 (IFNɣ & TNFα) and Th2 (IL-4 & IL-5) cytokines were increased in the experimental group▪ Sm-CB + Mont: Mixed Th1/Th2 response
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In vitro parasite killing assay
*Combinations1)Media2)Sera3)Lung cells4)Lung cells + pre-immune sera5)Lung cells + immune sera
•Plate 60 schistosomula•Add the various combinations*•Incubate 24 hours at 37°C•Assess viability•Supernatant collection
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Immune Mechanisms Involved in Sm-cathepsin B + MontanideMediated Protection in mice
•Highest parasite killing (63%) in the presence of lung cells and immune serum from experimental animals•Suggesting an antibody dependant effect
•CD4 depletion reduced parasite killingfrom 63% to 36% in experimental group•Addition of immune serum did not •contribute to a significant change in •parasite killing
•NK cell depletion reduced parasite killing from 63% to 34% in Exp. group•Addition of immune serum did not contribute to a significant change in parasite killing•Killing maintained after CD8+ or F4/80+ cell depletion
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SCHISTOSOMIASIS vaccine:New approaches
Repurposing an Attenuated Salmonella typhimurium YS1646Strain to Develop a Novel Mucosal Schistosomiasis Vaccine
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PLos NTD, September 2011 | Volume 5 | Issue 9 | e1313
S. japonicum burden in mice immunizedwith heterologous prime-boost vaccination.
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OUTCOMESWeight loss
Behavioral changesAdult worm burden
Eggs/gram of liver-intestineHumoral and cellular responses
Memory T cells.
B cells
Sm-Cath B -YS1646
IgG
IgAPro-inflammatoryCytokines
Colonic Epithelium
T cells Memory B cells
NKT Cell
Plasma cells
Effector & Helper
T cells
DendriticCell
Colonic Epithelium
Colonic Epithelium
DendriticCell
Sm-Cath B -YS646Sm-Cath B -YS1646
S. mansoni Cat B-YS1646
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1000bp
Cathepsin B
Empty Plasmids
LEC LHC NEC NHC PEC PHC
• lac-sopE2-SmCathepsin B → LEC; lac-sspH1-SmCathepsin B → LHC
• nirB-sopE2-SmCathepsin B → NEC; nirB-sspH1-SmCathepsin B → NHC
• pagC-sopE2-SmCathepsin B → PEC; pagC-sspH1-SmCathepsin B → PHC
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Immunogenicity and Challenge Studies
Day 0 2 6 10 weeks
SACChallenge
3 weeks 6 weeks
Oral Doses
150 Cercaria
Sm-Cath B -YS1646
Immunogenicity Challenge
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Day 0 2 4 13 weeks
SACIM
3 weeks 6 weeks
Oral Doses
3 weeks
Challenge
Prime-Boost Model
20 μg Recomb.CatB
150 Cercaria
109 CFUs
Sm-Cath B -YS1646
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Day 0 21 23 25 13 weeks
SACIM
3 weeks 6 weeks
Oral Doses
3 weeks
Challenge
20 μg Recomb.CatB
150 Cercaria
109 CFUs
Prime-Boost Model
Sm-Cath B -YS1646
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Acknowledgements
Dr. Brian Ward
Alessandra Ricciardi
Nicholas Zelt
Cynthia Santamaria
Elizabeth Rius Lancheros
Qianqian Miao
Connie Krawczyk
Ward’s Lab Members
Ndao’s Lab Members