développement clinique de candidats vaccins antimalariques...
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Développement Clinique de Candidats Vaccins Antimalariques au Mali
Ogobara K. Doumbo, MD, PhD Malaria Research and Training Center (MRTC)/DEAP/FMPOS
International Center of Excellence in clinical Research-USTTB-NIAID/NIH Université des Sciences, Techniques et Technologies de Bamako, MALI
Chaire d’Infectiologie des Docteurs Mérieux
19eme Journees franco-suisses de Pharmacie hospitaliere Macon-Bourgogne le 24 Avril 2015
NIH
Extramural:
NIAID/ DMID/ FIC
MRTC/DEAP/FMPOS
PER-AUF, ICER-NIH
CNRS-IRD-IHU/IP
WRAIR/FDA
CDC
USAID/PMI
Government of
Mali/Uni-
Bko/MOH
EU, EDCTP grants
MalariaGEN
CVD Maryland AUF/CoopFrance
AMANET
AIEA Universities: Marseille, Maryland,
Angers, Bordeaux, Lyon, Paris,
Oxford, LSTMH, Stokholm, Nijmegen,
Tulane, Penn., JHU, ND, Dakar,
Ouagadougou, Bobo, Abidjan,
Conakry, Cotonou, Libreville,
Ndjamina
FMERIEUX
IPP/CNRS
IRD MALI-TULANE
FIC/ITGH Pharma: Sanofi-
Aventis, Novartis, GSK,
Dafra, Pfizer, Mepha, Bio-
Merieux, Guilin
MIM/TDR/WHO
Intramural :
LMIV, LMVR
Professeur Philippe Ranque
Pr C. Soucko F0.1
Professeur ENSUP
Pr A. Diallo
Recteur Univ. Bko
Pr Y.T. Touré
OMS- Geneva
Pr A.Tounkara
Doyen FMPOS
Pr O.K. Doumbo
Directeur PER / MRTC
F1.1 A. Dolo O. Koita A. Djimde S. Doumbia M. Diallo M. Thera A. Toure S. Diop F. Traore S. Sow B. Traore
F1.2
F2.3 F2.4 F2.5 En formation Mali, Afrique, Europe, USA.
A. Dicko O.B Toure I. Sagara M. Diakite B.Poudiougou M S Sissoko K. Kayentao O. Thiero L Sangare A. Bea
Prof ag.
DER SF
FMPOS
Directeur
LBMA Chef Unité
MEDRU
Chef Unité
GIS/RS
Chef Unité
Diag.Parat.
Prof ag.
Chef Unité
MMVDU
Expert
OMS
Chef Unité
Anthro/Serefo
Directeur
CNAM
Directrice
Phar-Priv
Chef Unité
PREMA
Chef Unité
Epi/Biosta/
Data
Chef Unité
BioInformatic
Sc Doctorant
Tulane, USA
Chef Unité
Genomiq
PI -essai Vaccin
Sotuba
PI -essai Vaccin
Bancoumana
Expert
Millienium
Village
PI - Prema
Kambila /
Sikasso
Biostatics
Der SP
FMPOS
Chercheur
LBMA
Chercheur
Guinée
Vision et Stratégies du MRTC-DEAP
• Formation et Développement d’une masse critique de chercheurs au Mali
• Vaccins les plus promoteurs du stade sanguin: MSP1, MSP3, AMA1
• Vaccin bloquant la transmission: Pfs25-Pfs230
• Vaccin de stade pré érythrocytique: PfSPZ
• Capacité d’essais challenge (CHMI)
Phase Ib, IIa, IIb, III et recherche fondamentale
World Diseases Eradication programs
• Failure Hookworm
Yellow fever
Yaws
Schistosomiasis
Filariasis; Geohelminthes
Malaria
• Success Smallpox
Polio (Americas)
Measles (Americas)
• Near success Polio
Guinea worm
Rinderpest
Rubella (Americas)
Adapted from DA Henderson, malERA Zenith Week, March 2010
Vaccines= most efficient public health tools
PARASITE PREVALENCE IN CHILDREN 2-10 YEARS OLD
IN AFRICA 2000 - 2010
(Noor et al. Lancet 2014; 383:1739)
2000 2010
Key antimalarial interventions & strategies (adapted from Robert Newman, GMP/WHO)
Prevention
Insecticide-treated
bednets (ITNs) /
Long-lasting ITNs
(LLINs)
Indoor Residual
Spraying In areas of moderate to high
and stable transmission
IPT in pregnancy
(IPTp),
IPTi (infant)
IPTc (U5 = SMC)
Diagnosis & Treatment Parasite based diagnosis
Microscopy Rapid Diagnostic
Tests
Artemisinin-based combination therapies (ACTs)
Case management:
Health facilities
Community Case
Management (aka HMM)
Private sector
Surveillance, M & E
Routine HMIS
Malaria surveillance
and response systems
Household surveys
ROLE OF SMC, MDA
Malaria Vaccines ?
Strengthening health systems, Research and Human
Resources for scientific evidences: “evidences based public
health strategies
IMPACT DE LA MALARIA SUR LA QUALITE DE LA SCOLARISATION AU MALI ET IMPORTANCE DE LA PARASITEMIE SUB-MICROSCOPICQUE
(Josselin et al., Soc. Sci. Med., 2010
Vaccins antipaludiques: Stades et Impact
Pré-érythrocytique Vaccins pour prévenir l’infection
et impacter sur la maladie
Stade Sanguins Vaccins pour éliminer la maladie
Bloquant la Transmission Vaccins pour prévenir la transmission
Vaccins qui interrompent la Transmission du Paludisme
• 1920s-40s Experiments in bird malaria models
• 1960s Irradiated sporozoites protect in mice
• 1970s Irradiated sporozoites protect in man (Clyde, et.al. University of Maryland)
• 1980s Recombinant DNA techniques – Heterologous expression systems
• Viruses, bacteria, yeast transformed with Plasmodia DNA
– Sub-unit peptide vaccine candidates
• 1990s DNA vaccines
• 2000s Live attenuated whole organism vaccines
Malaria vaccines: History
Malaria Parasite Biologic Complexity
Organism Genome (Mb) HIV 0.01
Polio 0.08
Haemophilus influenzae 1.8
Streptococcus pneumoniae 2.2
Saccharomyces cerevisiae 13
Plasmodium falciparum 30
14 chromosomes, 5200 genes,
epigenetics?
MALARIA SPECIES IN HOMO SAPIENS
• 1] Plasmodium falciparum (Africa)
• 2] Plasmodium malaria (Africa)
• 3] Plasmodium vivax (Africa)
• 4] Plasmodium ovale (Africa)
– Plasmodium ovale wallikeri
– Plasmodium ovale curtisi
• 5] Plasmodium knowlesi (SEA)
growth
mg
hc
What new in Plasmodium biology, transmission and building of natural
immunity in vertebral host
Hafalla et al., 2011
BIOLOGY OF PREGNANCY ASSOCIATED MALARIA and Vaccines developt
Receptors
• CSA -
Thrombomodulin
Betaglycan
• Hyaluronic Acid
• Fc IgG
• others receptors ?
Placenta, CSA Phenotypes
/var2CSA
Micro vessel, CD36, ICAM1….
Adhesion molecules
CD36, ICAM-1, E-Selectin,
VECAM, PECAM-1/CD31 etc..
Fried & Duffy, 1996, 1998, 2000 and others from field
to labs and toward PAM vaccines candidates, PhaseIa,b
Kaplan-Meier curves for the cumulative proportion of children with ⩾1
episode of clinical malaria.
Sacarlal J et al. J Infect Dis. 2009;200:329-336
Sustained efficacy of RTS,S (VE=~50%
Efficacy 30-60% against clinical disease and infection
2010 2011 2012 2013 2014 2015 2016
1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4
Timeline for RTS,S Phase 3 trial and data
availability (adapted from the RTS,S Consortium)
1
1 2
3 2
1 2 3
Phase 3
trial ends
Legend
= Study reports completed
= Projected submissions to EMEA for Scientific Opinion
= Projected submissions to NRAs
3
Community Permission/Consent, Diallo, Doumbo et al., CID 2005
Steps
Procedures
Time, Personnel, and
resources
Study of the community
Elucidate community’s
sociocultural structure and
health system
Identify political and traditional
leadership
9 months for initial study, then
yearly
PI, Medical Anthro, Local
guides, driver
Car
Introductory meeting with
leaders
Introduce research team
Explain the project
Identify best way for community
permission
2-3 hours meeting
PI, local health director, local
guides, driver
car
Formal meeting with leaders
Explain project, risks, benefits,
etc.
Receive and answer questions
2-3 hours meeting
PI, Local health director, local
guides
Broadcasting by local radio
($3.0)
Personal visits to leaders
Visit leaders personally in their
homes for further explanation
and opportunity to answer
specific questions
30 mn – 1 hour
PI, local director, local guides
Car, “Cola-nuts”
Meeting with traditional health
providers
Develop formal agreement with
them for collaboration on the
project
30mn – 1 hour meeting
PI, local health director, local
guides
Car, cola-nuts
Obtaining permission/consent
as a dynamic process
Conduct a modified consultation
process with leaders at each
modification in the protocol or
new research project
2 -3 hours meeting
PI, local health director, local
guides
Broadcasting by local radio
17 malaria vaccine trials completed by MRTC
investigators & collaborators 2003-2015
Site and vaccine Trial design Primary funder Publication
Bandiagara
MSP1 AS02A Phase 1 adults NIAID Mali-Maryland contract Thera et al. PLoS Clin Trials 2006
AMA1 AS02A Phase 1 adults NIAID Mali-Maryland contract Thera et al. PLoS ONE 2008
AMA1 AS02A Phase 1 children NIAID Mali-Maryland ICIDR Thera et al. PLoS ONE 2010
AMA1 AS02A Phase 2 children NIAID Mali-Maryland ICIDR Thera et al. in NEJM 2011
AMA1 Alhydrogel Phase 1 adults AMANET Coulibaly et al. in preparation
Doneguebougou
AMA1C1 Alhydrogel Phase 1 adults Intramural NIAID MVDB Dicko et al. PLoS ONE 2007
AMA1C1 Alhydrogel Phase 1 children Intramural NIAID MVDB Dicko et al. PLoS ONE 2008
AMA1C1 Alhydrogel/CPG MSP 3-Alam Pf-SPZ IV -SANARIA
Phase 1 adults Phase IIb children Phase Ib adults
Intramural NIAID MVDB Pierre Druilhe NIAID-SANARIA
Sagara et al. Vaccine 2009 2011-2012 On Going 2014
Bancoumana
AMA1C1 Alhydrogel/CPG Pf25-EBA et Pfs25-230
Phase 1/2 children Phase Ib adults
Intramural NIAID NIAID/LMIV
Sagara et al. Vaccine 2009 On going 2014-2015
Sotuba
MSP3 Alhydrogel Phase 2 Children AMANET/IPP Cissoko et al., in preparation
Doneguebougou
Malaria Research Center
Site of 3 intramural NIAID malaria vaccine trials Extramural NIAID Tropical Medicine Research Center 1995-2000 Malaria Vaccine Development Branch (MVDB), LMIV-NIH
Site of 1 Vac-4-All consortium malaria vaccine trial (MSP3)
Bougoula Clinical Research Center
• Site of 2 malaria vaccine trials
• Site of several malaria drug trials
– WANECAM consortium
– Vacc-4-All consortium
Bandiagara Malaria Project
• Site of 5 malaria vaccine trials
– Mali-Maryland contract 1998-2006
– Mali-Maryland ICIDR* 2005-2015
*International Center for Infectious Diseases Research
MRTC Support Facilities
• Biostatistics and Medical Informatics Training Lab
• Data Management and Epidemiology Unit
• Clinical lab: CAP/CSLI certified in 2011
FMP2.1/AS02A
– Preuve du concept de protection clinique par un vaccin de stade sanguins établi
– Démonstration efficacité spécifique de souche
• A prendre en compte pour la mise au point des vaccins de seconde génération
AMA-1:
protéine de 83 kD exprimée au
niveau des micronèmes
34 MA THERA, MRTC/DEAP/FMOS - ISFRA
Antigène de la Membrane Apicale 1 (8/10)
Tolérance et Immunogénicité d’un vaccin basé sur AMA-1 chez l’adulte: Phase Ib
35 MA THERA, MRTC/DEAP/FMOS - ISFRA
Méthodologie
• Essai randomisé en double aveugle
• Dose croissante • 25µg FMP2.1/0,25ml AS02A
• 50µg FMP2.1/0,5ml AS02A
• Vaccin témoin: vaccin antirabique (RabAvert®)
• 3 immunisations à 0, 1 et 2 mois d’intervalle dans le deltoïde gauche
36 MA THERA, MRTC/DEAP/FMOS - ISFRA
Tolérance et Immunogénicité d’un vaccin basé sur AMA-1 chez l’enfant: Phase IIa
39 MA THERA, MRTC/DEAP/FMOS - ISFRA
Tolérance, Immunogénicité et Efficacité d’un vaccin basé sur AMA-
1 chez l’enfant en fonction de la diversité antigénique: Phase IIb
42 MA THERA, MRTC/DEAP/FMOS - ISFRA
Génotypage à Bandiagara
• 748 séquences – 506 infections uniques ou prédominantes
– 242 infections multiples
• 77 SNPs – 62 positions polymorphiques des amino acides
• Domaine I – 36; Domaine II – 11; Domaines III – 8
• 214 haplotypes/506 infections uniques ou prédominantes – Fréquence des haplotypes : 0.2% - 3.6%
– 3.0% correspondent exactement à 3D7
44 MA THERA, MRTC/DEAP/FMOS - ISFRA
Modifications d’aas au niveau c1L sont associées à un risque accru d’épisode clinique de paludisme
46 Takala et al 2009, Dutta et al 2007 MA THERA, MRTC/DEAP/FMOS - ISFRA
Efficacité du vaccin candidat FMP2.1/AS02A contre le premier épisode clinique de paludisme
Efficacité 17,4% IC à 95% [-8,9 – 37,4] p=0,175
47 MA THERA, MRTC/DEAP/FMOS - ISFRA
Impact FMP2.1/AS02A sur parasitémie A
ire
so
us la
co
urb
e d
e l
a p
ara
sit
ém
ie t
ota
le c
um
ulé
e
Tro
ph
ozo
ïtes
de
P.
falc
ipa
rum
/mm
3
Jour d’étude
Efficacité spécifique d’allèle contre l’épisode clinique de paludisme causé par des parasites similaires à 3D7 au niveau des 8 positions
polymorphiques d’aminoacides
Efficacité 64,3% IC à 95% [14,0 – 91,6]
Protection upon follow-up in 2 cohorts of MSP3 immunized children
Vs control (engerix): Sirima et al., NEJM 2011; Phase Iib enfant au Mali
NEXT GENERATION OF MALARIA VACCINES
1-WHOLE PARASITES Organism VACCINES
a-ATTENUATED SPOROZOITES: SANARIA=S.HOFFMAN, USA
b-SPZ+CQ: CVAC: ROBERT S, NJEMEGEN, NETHERLANDS.
C-ATTENUATED SCHIZONES: M. GOOD, AUSTRALIA
2-COMBINE HAPLOTYPES OF DIFFERENTS PARASITES POPULATION
3- Transmission Blocking Vaccines: Pfs25-230
3-COMBINE STAGES OF PARASITES LIFE CYCLE
PERV + BSV + TBV
Phase 1b Trial to Assess the Safety and Immunogenicity of Direct Venous
Inoculation with Radiation Attenuated Plasmodium falciparum NF54 Sporozoites (PfSPZ Vaccine) in Healthy Malian Adults
Sara A. Healy, Mahamadou S. Sissoko, Freda Omaswa, Abdoulaye Katile, Bourama Kamate, Yacouba Samake, Kourane Sissoko, Amagana Dolo, Karamoko Niare, Amadou Niangaly, Merepen A. Guindo, Erin Gabriel, Michael Fay, Irfan Zaidi, Eric James, Anita Manoj, Anusha Gunasekera,
B. Kim Lee Sim, Peter Billingsley, Stephen L. Hoffman, Ogobara Doumbo, Michael Walther, Patrick Duffy
November 2014
Background Whole Organism Clinical Trials:
Irradiated Sporozoites via Mosquito Bite
1950 1960 1970 1980 1990 2000 2010 1940
Established that human volunteers could be
protected against controlled human malaria
infection(CHMI) with infectious mosquitoes
after being bitten by mosquitoes carrying
irradiated sporozoites
Clyde et al. Am J Med Sci. 1973; Clyde et al. Am J Med Sci. 1973; Clyde et al. Am J Trop Med Hyg. 1975;
Rieckmann et al. Trans R Soc Trop Med Hyg. 1974; Rieckmann et al. Bull World Health Organ. 1979;
Rieckmann et al. Bull World Health Organ. 1990’; McCarthy and Clyde. Exp Parasitol. 1977
2014
Background Whole Organism Clinical Trials:
Irradiated Sporozoites via Mosquito Bite
1950 1960 1970 1980 1990 2000 2010 1940
Continued validation and definition of
the irradiated sporozoite model as
protective – various degrees of
irradiation, heterologous challenge,
and number of immunizing bites.
Herrington et al. Am J Trop Med Hyg. 1991; Edelman et al. J Infect Dis. 1993; Egan et al. Am J Trop Med
Hyg. 1993.
2014
>1,000 mosquito bites <1 year from last dose to challenge
Protected/Tested Volunteers
P falciparum homologous challenge
14/15
P falciparum heterologous challenge
4/4
Background Irradiated Sporozoites via Mosquito Bite
• Development had not been previously pursued due to:
– Considered technically impractical or impossible
– Considered unnecessary since modern subunit vaccines would solve the problem
Background Irradiated Sporozoites via Injection:
PfSPZ Vaccine • Sanaria, Inc.
– Harvest sporozoites from the salivary glands of irradiated mosquitoes
– Purified and cryopreserved the irradiated sporozoites from aseptic mosquitoes in the quantities necessary for vaccination
Background Clinical Trials: PfSPZ DVI Trial
1950 1960 1970 1980 1990 2000 2010 1940
Open-label evaluation of the safety,
tolerability, immunogenicity and protective
efficacy against CHMI of the PfSPZ
vaccine at successively higher dosages.
Subjects are enrolled in a step-wise, dose-
escalation manner
2014
Seder et al. Science. 2013
• 57 subjects enrolled, 44 underwent CHMI: – Group 1: 2,000 SPZ dose (n=3); 1-2 doses – safety – Group 2: 7,500 SPZ dose (n=6); 4-6 doses – Group 3: 30,000 SPZ dose (n=11); 4-6 doses – Group 4: 135,000 SPZ dose (n=15); 4-5 doses
• Well tolerated and safe • Sterile immunity at highest doses
– 6/6 subjects with 5 doses of 135K sporozoites protected – PfSPZ Vaccine is potent and highly protective in humans.
Seder et al. Science. 2013
• Donéguébougou & Surrounding villages – 30 km NE of Bamako
– ~ 7,000 inhabitants
• Malaria transmission is highly seasonal, with a transmission season taking place from June until December.
• Entomological inoculation rates is > 100 infectious bites per person/ transmission season.
PfSPZ Trial Site in Mali
Dicko A. t al. Am J Trop Med Hyg. Dec 2007;77(6):1028-1033
Primary Objective
• To test Sanaria, Inc. product in malaria endemic African population, we are conducting a Phase Ib, double blind, randomized, controlled clinical trial:
– to assess the repeated DVI PfSPZ Vaccine’s safety in malaria exposed healthy adults, 18-35 years, Malians.
Trial profile Community Consent (n=4)
Screened (n=296)
Enrolled (n=109)
Pilot Safety Group
Vac #1 (Day 0) -- 1.35x105 PfSPZ Vaccine (n=12)
Vac #2 (Day 14) – 2.7x105 PfSPZ Vaccine (n=12)
Vac #3 (Day 84) – 2.7x105 PfSPZ Vaccine (n=9)
Vac #4 (Day 112) – 2.7x105 PfSPZ Vaccine (n=9)
Vac #5 (Day 140) – 2.7x105 PfSPZ Vaccine (n=9)
Main Phase
Vac #1 (Day 0) – 2.7x105 PfSPZ Vaccine or placebo (n=93)
Vac #2 (Day 28) – 2.7x105 PfSPZ Vaccine or placebo (n=90)
Vac #3 (Day 56) – 2.7x105 PfSPZ Vaccine or placebo (n=90)
Vac #4 (Day 84) – 2.7x105 PfSPZ Vaccine or placebo (n=90)
Vac #5 (Day 112) – 2.7x105 PfSPZ Vaccine or placebo (n=88)
199 screen
failures: EKG,
HBS+, Sickle cell
trait, ABP,…
Total Vaccine Dose: 12.15 x 105 PfSPZ
Vaccine
Total Vaccine Dose:13.5 x 105 PfSPZ
Vaccine
PfSPZ Vaccine Coordination and Administration
• PfSPZ Vaccine is cryopreserved in aliquots of 20 microL in 0.5 mL cryovials and stored in LNVP at below -150oC.
• Diluent : PBS and HSA. Stored in controlled room.
• Normal saline as Placebo for the control Group
Safety: Incidence & Severity of Local/Systemic AEs
#OF AE’S
FOLLOWING
Vac #1
(N=105)
#OF AE’S
FOLLOWING
Vac #2
(N=102)
#OF AE’S
FOLLOWING
Vac #3
(N=99)
#OF AE’S
FOLLOWING
Vac #4
(N=99)
#OF AE’S
FOLLOWING
Vac #5
(N=97)
TOTAL 3 4 5 4 6
Mild 3 4 5 4 6
Moderate 0 0 0 0 0
Severe 0 0 0 0 0
Potential Life
threatening
0 0 0 0 0
•4 local reactogenicity: all local injection site pain
•18 solicited systemic reactogenicity: Headache (11), Fatigue (3), Myalgia
(2), Pyrexia (2) •All solicited AEs are deemed possibly/probably/definitely related to the
investigational product given the timing of their occurrence post
vaccination.
Safety: Unsolicited AEs
Number of
Unsolicited AEs
Related
TOTAL 181 47 (26.1%)
Mild 151 43 (28.5%)
Moderate 25 4 (16.0%)
Severe 5 0 (0.0%)
Potential Life
threatening
0 0 (0.0%)
•The most commonly reported AEs have been :
•Lab AEs (Grade 1 ): leukopenia (20), granulocyte count decreased (13), and hemoglobin decreased
(11).
•Clinical AEs (Grade 1): rhinitis (16), headache (13), and clinical malaria (12).
•25 reported Grade 2 AEs (14%): among them 4 AEs were deemed related to the investigational product given
the timing of their occurrence post vaccination.
•5 reported Grade 3 AEs (2.8%): influenza-like illness, sinobronchitis, and malaria in three subjects. All
deemed by the investigator to be not related to the investigational product.
Conclusion and future of PfSPZ in Mali
• MS Sissoko et al., results of PhaseI1/2 Mali in NEJM 2015 in preparation
• Phase II in 2015 Mali in preparation
• CHMI vs Heterologous natural challenge
• International Vaccinology course in Africa 2015: Oxford university, CICM/FMerieux, MRTC: Bamako Octobre 2015
Model for “exhausted” memory B cells in persistent infections.
Moir et al, JEM 2008 (CD20hi/ CD27-/ CD21lo/FcRL4+)
‘Exhausted’ or ‘atypical’ memory B cells are greatly expanded in children and adults in malaria-endemic Mali.
Weiss et al, J Immunol, 2009
Differential susceptibility to malaria in sympatric
ethnic groups in Mali: Dogon vs Fulani A
Farouk, Dolo et al., 2005
↑ DC activation ↑ IFN-g normal TLR responses → Potent T cell activation? ↑ humoral immunity
Impaired DC activation ↓ IFN-g
impaired TLR responses → poor T cell activation? ↓ humoral immunity
Disease Protection
Fulani Dogon
Possible mechanism of protection against
malaria: the Fulani-Dogon in Mali
P. falciparum
Charles Arama, MRTC & Wenner-Gren Institute, Department of Immunology 15-03-2012
New tools in Infectious Diseases studies: Serological profiling against many falciparum peptides: Arrays/OMICs
Crompton P D et al. PNAS 2010;107:6958-6963
THE CHARMS OF THE MRTC
LUNCH AT THE BANCOMANO FIELD STATION, 1997:
H Varmus , LH Miller, and MRTC team