Malaria vaccine development

Transcription

1 Malaria vaccine development Bernhards Ragama Ogutu Malaria Clinical Trials Alliance INDEPTH-Network 10 AGM 24 Sept 2008 Dar es salaam, Tanzania INDEPTH Network

2 Outline Focus on P. Falciparum Need for malaria vaccine The bottlenecks Some learning milestones Current progress in development Plans for the lead candidate

3 Malaria Disease burden I am growing into a big problem

4 Why Drug resistance Loss of interest and commitment Climatic change Migration and political strife Weak health infrastructure

5 Finger prick for blood slide in a child with non-severe Malaria. Mortality 0.1% A child with severe Malaria in Coma. Mortality 15-20%

6 Why malaria vaccine 2 billion people at risk of infection About million clinical cases annually About 1 million deaths annually No magic bullet yet The E campaign

7 Why malaria vaccine US$ 12 billion lost annually in Africa linked to poverty reduction Drug and insecticide resistance Eradication to result in increased life expectancy Severe malaria licks the marrow but bites the CNS

8 Schizencephaly Normally associated with severe learning difficulties, motor impairments and seizures. Can occur following cerebral malaria

9 Bottlenecks Antigenic Variation Genetic Polymorphism Complex Life cycle Lack of life-long immunity Multiple stages of parasite development Role of animal model Length of protection Host genetic factors

10 Bottlenecks Human Funding Limited understanding Pathogenesis Immunology

11 Challenges Changing malaria epidemiology Large scale deployment of other interventions Host genetic factors

12 Prevalence of sickle traits Haemoglobin Type N Prevalence % AA AS SS S + Hb Kenya A + Hb Kenya AD TOTAL

13 Prevalence of α-thal α-globin genotype Genotypes N Prevalence % Normal a 2a 1 / a 2a Heterozygous _a 1 / a 2 a Homozygous _a 1 / _a

14 The current status Increased funding Increased number of antigen candidate Main targets Human stages Sporozoite Merozoite

15 !"# $ #!%! # $ &!%

16 Dilemmas of Vaccine Trials Outcome measures Adjuvants Length of protection Integration into EPI Local capacity Potential development partners

17 HIV Prevalence, Western Kenya, by Age Group and Sex, (N=1795) ce (%) HIV prevalen All Age group (years) Females Males

18 Learning milestones

19 Failed antigens Spf 66 MSP1 3D7 LSA1 FP9/MVA ME-TRAP

20 MSP1 3D7

21 MSP1 Efficacy 0.8 Proportion of subjects who are malaria-free Time to malaria No. at risk ITT:Rab ITT:FMP1 ATP:Rab ATP:FMP1 D0 D29 D57 D85 D115 D143 D171 D200 D Censored subject

22 MSP1 Efficacy Malaria Case Definitions and vaccine efficacy Definitions of Clinical Cases of Malaria Case Definition Fever a Parasite density b FMP1/AS02A (N=195) Rabipur (N=190) Vaccin e efficacy 95% confidence interval 2 Case Definition (200) 37.5ºC AND c 200K (-64, 30) Definition (100) 37.5ºC AND 100K (-36, 29) 0.9 Primary Case Definition 37.5ºC AND 50K (-26, 28) Case Definition (10) 37.5ºC AND 10K (-22, 29) Case Definition (0) 37.5ºC AND > (-11, 31) Case Definition (0 * ) 37.5ºC OR history of fever in the last 24 hrs AND > (-17, 23) 0.6 p- valu e Definitions of Malaria (Symptomatic or Asymptomatic)* Infection Definition Episode of malaria infection 173 [189] 170 [182] 7.7 (-14, 25) 0.5 Infection above 50K Parasite density > 50K 128 [191] 128 [183] 12.5 (-12, 32) 0.3 * Subjects who met these infection endpoints on the first day of the EFP were excluded from these analyses. Numbers of subjects at risk are shown in brackets.

23 Geometric mean MS SP-1 antibodies (µg/ml) I 0 I 29 I 57 I 85 Study day I 171 FMP1/AS02A RabAvert I 256 Titer data (received: 24APR2006) E:\Proj\MVI\WRAIR\Kenya Phase IIb\Programs\f_antibodies.sas v.004 (last run: 02JUN2006, 12:33)

24 Conclusions FMP1/AS02A safe and highly immunogenic FMP1/AS02A not a promising vaccine candidate Future development should focus on different Future development should focus on different constructs and platforms

25 Some candidates in development RTS,S/AS01B GMZ2 AMA1 MSP3 MSP2 Pf SPZ GLURP LSA3 CSA

26 Adjuvants Alum Emulsions (AS02) Liposome based (AS01) Adenovirus vector

27 Objective of RTS,S malaria vaccine program Develop a vaccine that will protect infants and children, living in endemic regions, from Plasmodium falciparum malaria disease

28 Phase II: The road from proof of concept to Phase III Ongoing safety evaluation Gather additional efficacy data Select Phase III vaccination schedule Select final adjuvant formulation (AS01B vs AS02) Additional data in target age-groups Age de-escalation to young infants Co-administration with EPI vaccines

29 1. Phase II studies Extended efficacy & safety surveillance RTS,S/AS02 Mozambique Adjuvant and schedule optimization Supportive efficacy RTS,S/AS01 & RTS,S/AS02 Gabon Schedule optimization study 0,1 vs 0,1,2 vs 0,1,7 M Ghana Age de-escalation and EPI integration RTS,S/AS02 Infants Mozambique RTS,S/AS02 EPI co-ad Tanzania RTS,S/AS01 Efficacy Tanzania, Kenya RTS,S/AS01 EPI co-ad Ghana,Tanzania, Gabon

30 Efficacy v. clinical malaria over 4 years Time (month) RTS.S CONTROL VE Event PYAR Rate Event PYAR Rate p LL UP 02½_ < VE _time to first episode; the presence of P. falciparum asexual parasitemia > 2500 per µl and the presence of fever? 37.5ºC at the time of presentation and ocuuring in a child who is unwell and brought for treatment to a healthcare facility.

31 Efficacy v. severe malaria over 4 years Time (month) RTS.S CONTROL VE Subjects Subjects % Subjects Subjects % % p LL UP (N) (n) affected (N) (n) affected 2½ Severe Malaria as defined by WHO definition

32 Immunogenicity over 4 years GMTs for anti-cs antibody titers by cohort Cohort 1 RTS,S/AS02 Cohort 2 RTS,S/AS02 Cohort 1 Control Cohort 2 Control Log titers ,1 3 8, months

33 Proof of concept in infants: Efficacy v. infection

34 Estimates of vaccine efficacy Outcome Engerix-B TM RTS,S/AS02D Events PYAR Rate Events PYAR Rate Vaccine efficacy (95%CI) p Malaria infection from 14 days after dose 3 * Parasitaemia > % (42.6%; 79.8%) < Clinical Malaria from 14 days after dose 3 * Fever and parasitaemia > 500 per microliter % (25.3%; 84.4%) Clinical Malaria from dose 1 Fever and parasitaemia > 500 per microliter % (-7.5%; 61.3%) PYAR= Person-years at risk. * Vaccine efficacy estimates adjusted by distance from health facility and community in the ATP cohort. VE First or only P. falciparum infection: 65.9% (42.6%,79.8%)

35 Mal 027 Phase I/IIa Challenge Study Summary of Safety & Immunogenicity Similar reactogenicity typical of AS02A adjuvant Clinically acceptable local pain, redness, swelling Constitutional symptoms (flu-like symptoms) in minority of subjects AEs self limited with no safety concerns Antibody to CSP: AS01B > AS02A (p< 0.008) CSP-specific CD4 T cells: AS01B > AS02A (p=0.07) No CD8 T cell responses observed

36 Mal 027 Phase I/IIa Challenge Study Conclusions RTS,S/AS01B was equally well tolerated RTS,S/AS01B was more immunogenic than RTS,S/AS02A There was a strong trend for greater efficacy with RTS,S/AS01B Further assessment of RTS,S/AS01B in malariaexperienced adults was indicated Kester et al

37 Mal 044 Phase IIb Trial in Kenya Efficacy Results RTS,S pooled 0.50 Rabies control p= Time (Days) Attack rates high, but lower than in previous years Late rains, possible impact of drug clearance? Not powered to show difference between formulations VE ~ 30% consistent with previous challenge trials and Gambia field trial

38 Mal 044 Phase IIb Trial in Kenya Immunogenicity GMC IgG vs CS repeats & 95% CI Day 0 Day 60 Day 90 RTS,S/AS01B p= RTS,S/AS02A Rabies Similarly high anti-hbsag titers in both groups

39 Mal 044 Phase IIb Trial in Kenya Conclusions Safety: Both formulations equally well-tolerated Low Grade 3 AE rates Go for progressing AS01B into pediatric studies Immunogenicity: Better anti-cs responses with AS01B Higher anti-cs responses in those never infected CMI analyses ongoing Efficacy: Confirmation of RTS,S efficacy in high transmission setting in adults

40 4. Comparison of adjuvants: AS01 vs. AS02 formulation Conducted by Albert Schweitzer Hospital, Gabon 180 children aged 18 months to 4 years RTS,S/AS01 was compared to RTS,S/AS02 0, 1, 2-month vaccination schedule Safety and immunogenicity

41 Ratio of Anti-CS geometric mean titer 1-month post dose 3 Immune response is comparable between formulations.

42 Heterologous prime-boost with adenovirus35-vectored CS and recombinant protein RTS,S/AS01B An Adenovirus35-CS/RTS,S Prime-Boost Regimen for Malaria Vaccination is Safe and Enhances Cellular Immunity in the Rhesus Macaque Stewart et al 2007

43 R32LR ELISA results Titer Three months after final immunization R/R/R R/R/AdCS AdCS/R/R AdCS/AdCS Empty Ad35

44 ICS: Frequency of Rhesus monkey CS-C specific CD4 T cells expressing two or more cytokines (IFNγ, IL2, TNFα) Cytokine positive cells / million CD Two weeks after last vaccine

45 Phase III Design of the Phase III RTS,S trial Capacity development for clinical trial sites Establishment of networks of site/investigators/ stakeholders, and implementation issues

46 Design of the Phase III RTS,S trial

47 Phase III efficacy and safety trial of RTS,S/AS01 candidate malaria vaccine Designed to provide: Key safety and efficacy data to support file Full evaluation of relevant disease and public health endpoints to inform implementation planning Primary objective: Efficacy against clinical malaria disease Secondary objectives: Safety of the RTS,S in infants and children Efficacy against severe malaria disease Efficacy in different transmission settings Efficacy of a booster dose Immunogenicity Study start 1Q 09

48 Choice of primary endpoint: Clinical malaria or severe disease? Clinical malaria disease Key disease state on pathway to severe disease Can be achieved reliably in a smaller trial Suitable licensure endpoint Severe malaria disease Rates are falling in study centers, with improvements in malaria control and treatment Remains important secondary objective required by health policy makers

49 Multi-center trial in different transmission areas 10 sites representing different transmission settings Up to children in two age categories: 6 weeks to 12 weeks (6 000 minimum) 5 to 17 months (6 000 minimum)

50 Efficacy data collection Case surveillance at outpatient departments in study area For detection of primary endpoint of clinical malaria disease Case surveillance at inpatient departments in study area For detection of severe malaria disease Clinical evaluation following standardized algorithm Cross-sectional surveys at month 20 and 32 Hemoglobin Parasite prevalence

51 Development of clinical trial sites

52 Clinical Trial Sites: Capacity Strengthening in Africa by MCTA - Bagamoyo

53 Kombewa CRC

54 Capacity of trial site set-up Infrastructure Personnel Procedures Administrative, ethics and regulatory oversight Support structures and stakeholders Community involvement

55 Networking and implementation considerations

56 Networking among African study sites: Clinical Trial Partnership Committee (CTPC) MOROCCO TUNISIA ALGERIA LIBYA EGYPT MAURITANIA MALI NIGER ERITREA THE GAMBIA GUINEA GUINEA BISSAU SIERRA LEONE LIBERIA BURKINA BENIN TOGO COTE GHANA DTVOIRE NIGERIA CAMEROON CHAD CENTRAL AFRICAN REPUBLIC SUDAN ETHIOPIA DJIBOUTI UGANDA The CTPC is made up of members from African centers, GSK, and PATH-MVI, MCTA which was chartered at a meeting in September 2005 for the Phase II / III program for RTS,S EQUATORIAL GUINEA GABON REP. OF THE CONGO ANGOLA NAMIBIA DEMOCRATIC REPUBLIC OF THE CONGO RWANDA ZAMBIA BOTSWANA BURUNDI MALAWI ZIMBABWE KENYA TANZANIA MOZAMBIQUE SWAZILAND LESOTHO SOUTH AFRICA

57 Capacity development by MCTA

58 How do you manage these tasks

59 Considerations in the design & execution of the RTS,S Phase II/III trial in Africa

60 Community participation Community advisory board not political community representatives nor village healthcare workers

61 Blood slide reading and validation Two methods will be implemented: Counting parasites against WBC and RBC counts Counting parasites in a measured blood volume All slides read by two independent readers and a third reader if not meeting agreement criteria Reference panel will be read every 4 months by each reader at each site (WHO methodology with defined criteria for agreement and competency) To ensure comparability of two methodologies To ensure consistency across sites To maintain standards throughout the trial by implementing regular re-accreditation of each reader

62 Microscopy training lab in Kisumu

63 Take home messages An elaborate program has been developed to establish the safety and efficacy of the RTS,S candidate malaria vaccine for regulatory licensure Capacity is being developed across Africa to support the Phase III trial and offer improved quality of care Establishment of networks of site/investigators/stakeholders will accelerate the process of evaluation and uptake of new products Work is ongoing on harmonization and quality control of methodologies and procedures

64 Product development roadmap: From investigational vaccine to product registration and implementation

65 Preparing for introduction Implementation of the Clinical Development Plan (GSK, PATH- Malaria Vaccine Initiative, collaborators) Production scaling-up and manufacturing facility (GSK Bio, Rixensart - Belgium) Regulatory strategy developed (GSK, MVI-PATH, European Reg. authorities, WHO, national Rrg. authorities) Implementation strategy: integration with EPI and other malaria control measures [GSK and partners, international health authorities (WHO, UNICEF, GAVI) and national heath Authorities] GSK Bio Rixensart, Belgium

66 Scaling-up and preparing for commercial manufacturing Large-scale manufacturing plant has been established at GSK Capacity to produce tens of millions of doses per year Plant validated by European regulatory authorities Scaling up of RTS,S antigen manufacturing initiated in June 2007 Scaling-up of adjuvant manufacturing ongoing Consistency lots planned for 2009 RTS,S manufacturing facility, Rixensart

67 Regulatory pathway Recommendation for inclusion into National Immunization Programs (NIP) Vaccine sourcing for NIP United Nations procurement agencies (e.g., UNICEF) with support from international funders (e.g.,gavi, GFATM) Licensure by African national regulatory authorities Local marketing authorization! "" Prequalification by WHO UN procurement Licensure by African national regulatory authorities Prequalification by WHO Local marketing authorization UN procurement

68 Implementation of Artemisinin-Based Combination Therapies (ACTs) Millions of treatme ent courses Cumulative no. of coun ntries adopting ACT ACT procured No countries adopting ACT No countries implementing Graph courtesy of WHO GMP, MMV, 2007

69 Status of regulatory pathway Ongoing dialogue with regulatory agencies and global health authorities on: Overall quality of the vaccine development program EMEA: Scientific advice obtained in June 07 (manufacturing, preclinical package, clinical) FDA: Input and comments on manufacturing, preclinical package and clinical protocols WHO: continuous dialogue on various aspects of program, e.g., discussion and consensus of measures of malaria vaccine efficacy Expedited & innovative regulatory procedures EMEA, FDA, WHO, African NRAs: ongoing dialogue African NRAs engaged through WHO-sponsored African Vaccine Regulators Forum (AVAREF) to prepare for review of Phase III and licensure

70 MVI-GSK Strategic Vision for Implementation To ensure that robust evidence and resources are available to all countries in sub-saharan Africa, allowing each to take a decision if they want to adopt, defer, or not adopt RTS,S into their EPI and/or wider health systems, within 1-3 years of legal and physical availability

71 Economics & Financing Addressing the needs of policymakers and potential funders Foreseeing cost-effectiveness data needs Developing models in collaboration with Swiss Tropical Institute Public sector return on investment Utilizing vaccines in the context of complementary malaria control interventions and finite resources Initiating discussions with key potential funding partners (e.g., GAVI, GFATM)

72 RTS,S Policy Pathway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

73 Clinical Trial Partnership Committee: Collaboration of academic groups, MVI, GSK, MCTA Institut de Recherche en Science de la Santé, Burkina Faso Kumasi Centre for Collaborative Research, Ghana School of Medical Sciences Kumasi, Ghana Kintampo Health Research Centre, Ghana Albert Schweitzer Hospital, Gabon Kenya Medical Research Institute, Kisumu, Kenya Wellcome Collaborative Research Programme, Kilifi, Kenya University of North Carolina Project, Malawi Centro de Investigação em Saude de Manhiça, Mozambique Ifakara Health Research Development, Tanzania National Institute of Medical Research, Tanzania Northern Southern Prince Leopold Institute of Tropical Medicine, Belgium University of Copenhagen, Denmark University of Tuebingen, Germany Bernhard Nocht Institute, Germany University of Barcleona, Spain Swiss Tropical Institute, Switzerland London School of Hygiene & Tropical Medicine, UK University of North Carolina at Chapel Hill, USA Walter Reed Army Institute of Research, USA Centers for Disease Control and Prevention, USA

74 Looking at the horizon with confidence

75 THE ULTIMATE SMILE

76 Acknowledgements They, we, them, you Site leaders PATH-Malaria Vaccine Initiative Bill & Melinda Gates Foundation GlaxoSmithKline Biologicals INDEPTH/MCTA

77