Malaria and Helminth - euvaccine.eu · Malaria and helminths co-infection •Several associations...
Transcript of Malaria and Helminth - euvaccine.eu · Malaria and helminths co-infection •Several associations...
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OVERVIEW
• Objectives
• Background
• Hypothesis
• Litterature review
• Malaria and Helminthiasis in Gabon – Epidemiology
– vaccinology
• Conclusion
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OBJECTIVES
• Reported effect of helminths infection on malaria
– Effect of helminths on epidemiology of malaria
– Effet of helminth on malaria vaccine candidates
– Effect of helminths on malaria sexual stage
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- Malnutrition -Learning/memory - Anemia -Weight loss -Skin symptoms - Immunopathology - Permanent disability
Examples: - Blood flukes (Schistosomes, filaria) - Geohelminths (hookworm, Trichuris, Ascaris)
Helminths cause Heavy morbidity
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Helminth infections and Immunology
Danilowicz-Luebert et al., 2011 Co-infection EDR 5
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Antigen specific
T cell responses
Worm burden or time after infection
Chronic infection
Spill over
suppression
Helminths induce immune hyporesponsiveness
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Malaria cause heavy mortality
• 207 million cases of malaria in 2012
• 627000 deaths caused by malaria in 2012
• 90% of cases occur in Africa
• Control is limited to:
– ITNs
– Indoor spray
– Prompt case managment treatment
– No vaccine several underdevelopment
• RTS‘S in 2015???
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Immunology of malaria
Co-infection EDR 8
Source : www-dsv.cea.fr
• Evidence in both humans and mice suggests: Early stage: type Th1 (IFN-G) Later stage : type Treg
IgG1 et IgG3
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Geographical distribution of malaria and
helminthiasis
Co-infection EDR 9
Helminth
Malaria
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Malaria and helminths co-infection
• How helminths infections affects malaria
– Epidemiology?
– Clinical features?
– Vaccine candidates?
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Malaria and helminths co-infection
• Several associations reported with different helminths species:
– Hookworm
– A. lumbricoides
– T. trichiura
– M. Perstans
– S. mansoni
– S. hematobium
RELACS launch meeting Cotonou 23-24
January 2014
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• Good worms
– There is a trend towards a protective effect of A. lumbricoides and S. hematobium on incidence and pathogenesis of malaria
• Bad worms
– Hookworm and S. mansoni are positively associated with malaria incidence and pathogenesis.
• In general helminths protect against severe manifestations of malaria.
RELACS launch meeting Cotonou 23-24
January 2014
Good worms, bad worms?
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Good worms, bad worms?
The observed Immunological trends:
Hookworms
Trichuris trichiura
S. haematobium
Associated with decreased level of antibody responses to P. falciparum
Courtin D
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Ateba-Ngoa et al, submitted
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Vaccinations
• Current malaria vaccine candidates are aiming to trigger a Th1 type immune response
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TB
TT
INFLUENZA
HIV
Malaria
Helminths and vaccines
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GMZ2 is a subunit vaccine of a fusion protein of
MSP3 and GLURP in alum
Previous phase I clinical trials:
• European adults (Esen et al. 2009)
• African malaria-exposed adults (Mordmuller et al 2011)
• African malaria exposed children (1-5yrs) (Belard et al. 2011)
GMZ-2 trial developpement
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Wednesday, January 7, 2015 Impact of helminth infections on
vaccination
Antigen (GMZ2, GLURP & MSP3) specific antibodies are suppressed in A. lumbricoides and T. trichiura positive children
(Esen et at 2012, In Press).
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Total IgG: infected versus uninfected
Wednesday, January 7, 2015 Impact of helminth infections on
vaccination
(A.lumbricoides & T.trichiura ) Any helminth infection
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Comments
• T. trichiura negatively affects IgG production
• A. lumbricoides seems to not affect IgG production
• Combined infection with both species has a stronger negative effect on IgG production
Wednesday, January 7, 2015 Impact of helminth infections on
vaccination
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NEED FOR LARGE SAMPLE SIZE AND WELL DESIGNED STUDIES
IDEA STUDY
IDEA
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Malaria vaccine candidate and helminths
General objective To determine the modulation by worm co-infections on vaccination and vaccine-induced immune responses
Specific objectives To assess the effect of worm co-infection on the efficacy of the malaria vaccine candidate (GMZ-2) To assess the effect of worm co-infection on the humoral and cellular immune responses to GMZ-2
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Method (1) Design
Observationnal study nested into a phase IIb, randomized, controlled, double-blind, study to evaluate the efficacy, safety, and immunogenicity of GMZ2 malaria vaccine candidate
Study population
Children aged from 1 to 5 years old living in Lambaréné and surrounding villages
Vaccine allocation
1:1 randomization of either 3 doses of 100ug GMZ2 or HDC rabies vaccine at Day 0, 28 and 56
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Method (3) Study flow chart
D -14 D0 D28
D56
D84 D168 D224 D365 D588 D730
Urine and stool examination Humoral response Cell mediated immunity Functionnal assay
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Update on the work (1)
GMZ2 trials
512
IDEA worm and GMZ-2 study
411
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Update on the work (3)
Preliminaries results/Microscopy
Any helminth infection: 32%
Schistosomiasis: 9%
Intestinal helminth: 31%
•T. trichura: 23%
•A. lumbricoides: 12%
•Hookworm: 2%
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Samples collected and stored
dark blue n = 411, light blue n = 100; ELISA = serum/plasma
Type and volume of samples collected at each timepoint
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update
• Efficacy?????
• Immunogenicity????
Final analysis => 2014 ????
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Acknowledgments