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MALARIA VACCINES A tale of two vaccines (and more)

MALARIA VACCINES A tale of two vaccines (and more). Brian Greenwood LSHTM. 40 th Anniversary Tropical Epidemiology Unit March 29 th – 30 th , 2012. WHY WE NEED A MALARIA VACCINE. Malaria has not been controlled by widespread deployment

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MALARIA VACCINES A tale of two vaccines (and more)

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  1. MALARIA VACCINES A tale of two vaccines (and more) Brian Greenwood LSHTM 40th Anniversary Tropical Epidemiology Unit March 29th – 30th, 2012

  2. WHY WE NEED A MALARIA VACCINE • Malaria has not been controlled by widespread deployment • of existing control tools in many endemic areas. • There is increasing concern about the emergence of • resistance to insecticides and antimalarial drugs. • Vaccination is a relatively easy tool to deliver. • Vaccination has played a key role in previous elimination/ • eradication programmes – smallpox, rinderpest, (polio).

  3. WHAT WE EXPECT FROM A MALARIA VACCINE • Provision of direct, individual protection against • malaria infection and its clinical consequences. • Reduction in transmission of malaria infection • (herd immunity).

  4. TYPES OF MALARIA VACCINES Pre-erythrocytic vaccines Vaccines that block transmission Blood-stage vaccines

  5. MALARIA VACCINE DEVELOPMENT • Prevention of malaria in canaries using attenuated sporozoites. • 1960s Vaccination of mice with irradiated sporozoites and discovery of • circumsporozoite protein (CSP). • Prevention of malaria in human volunteers using irradiated sporozoites. • 1990s Clinical trials of the blood stage peptide vaccine SPf66. • 2000s Demonstration of the efficacy of RTS,S in volunteers. • First trials of DNA vaccines. • Development of the prime boost approach using viral vectors. • 2010 - Phase 3 trial of RTSS. • About 30 new vaccines in clinical development.

  6. THE SPf66 VACCINE Dr Manuel Patarroyo

  7. DEVELOPMENT OF THE SPf66 VACCINE • A large number of synthetic • peptides made. • Peptides screened in a • monkey model. • The three peptides giving the • best protection combined to • make SPf66.

  8. TRIALS OF SPf66 IN SOUTH AMERICA Country Age group Subjects Number PE (95% CI) of cases % Spf66 Control Spf66 Control Brazil7- 60 yrs 287 285 107 107 -2 (-32 to 22) Colombia Adults 185 214 2 9 83 Colombia > I year 643 623 53 81 35 (8 to 54) Colombia > 1 year 738 810 168 297 34 (19 to 46)* Ecuador > 1 year 230 238 4 12 67 (3 to 89) Venezuela7- 60 yrs 287 285 102 184 55 (21 to 75)

  9. GETTING THE VACCINE TO AFRICA • Delegations to Colombia. • Visit of Dr Patarroyo to The Gambia. • Dr Patarroyo agreed to donate vaccine • for a trial in Africa. • WHO approval for a trial in Africa. • Opposition of MRC to a Gambian trial. • Trial undertaken in Tanzania.

  10. TRIALS OF SPf66 IN AFRICA AND ASIA Country Age group Subjects Number PE (95% CI) of cases % Spf66 Control Spf66 Control Tanzania 1 - 5 yrs 274 312 73 102 32 (0 to 52) Tanzania < 1 yr (EPI) 550 541 541 547 2 (-16 to 16) Gambia 6 - 11 months 316 231 160 121 8 (-18 to 29) Thailand 2 - 15 yrs 680 668 195 184 - 9 (-33 to 14)

  11. LESSONS LEARNT FROM SPf66 • Malaria vaccine trials require vigorous study design. • Efficacy may be influenced by local epidemiology. • Without an understanding of the mode of action of • a vaccine, unravelling conflicting results is difficult. • Vaccines developed outside the ‘conventional’ system • will be controversial. • The SPf66 trials helped in the design of future malaria • trials and their end-points. • The SPf66 trials provided a key learning experience • for the first generation of malaria field vaccinologists.

  12. CSP VACCINES The Circumsporozoite Protein (CSP) Prof. Ruth Nussensweig

  13. + S HBsAg RTS,S RTS,S The circumsporozoite protein SS RI Repeat NANPRII GPI Target of neutralizing antibodies T cell epitopes R T S HBsAg + Adjuvant (Gordon et al. J Infect Dis1995;171:1576–85)

  14. CHALLENGE STUDY IN AMERICAN VOLUNTEERS Malaria on challenge Control group 6/6 RTS,S + alum + monophosphoryl A 7/8 RTS,S in an oil-in-water emulsion 5/7 RTS,S in an oil-in-water emulsion 1/7 + monophosphoryl A + QS21 (Stoute et al. NEJM 1997;336;86-91)

  15. A TRIAL OF RTS,S/AS02 IN GAMBIAN ADULTS Probability of remaining free of parasitaemia Weeks of surveillance (Bojang et al. Lancet 2001;358:1927-34)

  16. DURATION OF PROTECTION IN GAMBIAN ADULTS % Protection against malaria Overall First 9 weeks Next 6 weeks Following re-vaccination Time after vaccination (Bojang et al., Lancet 2001; 358:1927-34)

  17. RTS,S/ASO2 IN MOZAMBICAN CHILDREN Vaccine Efficacy (VE) Clinical malaria 29.9% (11.0-44.8%) Severe malaria 57.7% (16.2-80,6%) 6 months (Alonso et al Lancet 2004 364:1411-20)

  18. DURATION OF PROTECTION IN MOZAMBICAN CHILDREN Vaccine Efficacy (VE) Clinical malaria – all episodes 25.6 % (11.9,37.1%) 42 months (Sacaral et al. JID 2009; 200:329-36) (Sacaral et al. JID 2009:200:329-36)

  19. A BETTER ADJUVANT - AS01 A trial in Kenyan children Vaccine Efficacy (VE) Clinical malaria 56% (31.0-72%) (Bejon et al. NEJM 2008:359:2521-32)

  20. THE PHASE 3 RTS,S/AS01 TRIAL Design Study groups: children 5 - 17 months (RTS,S separate from EPI vaccines)(6,000) infants 2 - 4 months (RTS,S given with EPI vaccines)(6,000)

  21. THE PHASE 3 RTS,S/AS01 TRIAL Study centres 7 countries 11 centres

  22. TRIAL END-POINTS • Primary • Efficacy against clinical malaria 12 months after vaccination in the • 5 -17 month group. • Efficacy against clinical malaria 12 months after vaccination in the • 6 - 12 week group. • Secondary • Efficacy against severe malaria, anaemia and hospital admissions. • Efficacy against malaria 30 months after completion ofvaccination. • Efficacy against malaria infection and impact on parasite population. • Efficacy of a booster immunisation. • The effect of the level of transmission on efficacy. • Immunogenicity. • Safety.

  23. THE PHASE 3 RTS,S/AS01 TRIAL Efficacy after 12 months in the 5-17 month group 6,000 children Uncomplicated malaria VE = 50.4% (48.5-54.6%) Severe malaria VE = 45.1% (23.8-60.5%) (RTS,S Clinical Trials partnership NEJM 2011;365:1863-75.)

  24. RTS,S/ASO1 PHASE 3 TRIAL Next steps • 2012Analysis of efficacy in infants at 12 months. • 2013/14 Analysis of - duration of protection. • - impact by level of transmission. • - impact on additional end-points. • 2014/15 Potential licensure. • 2015 Possible deployment in routine immunisation • programmes (Phase 4 programmes). Where and how should RTS,S/AS01 be used if licensed?

  25. SECOND GENERATION VACCINES Malaria Road Map Target for 2025 - 80% protection against clinical malaria - persistence of protection for 4 years Achieving the Target - vaccines that are more efficacious than RTS,S/AS01 - combination vaccines - stages of the lifecycle - different proteins

  26. TYPES OF MALARIA VACCINES Pre-erythrocytic vaccines Vaccines that block transmission Blood-stage vaccines

  27. PRE-ERYTHROCYTIC VACCINES Second generation • Irradiated sporozoites (PfSPZ)(Sanaria) • Produced to GMP standards. • May need to be given intravenously. • Need to be stored in liquid nitrogen. • Would be expected to give a high level of protection. • Challenge and treatment • Two years of protection following inoculation • whilst receiving chloroquine treatment. • Viral vectored vaccines • Pox viruses and adenoviruses (human and chimp). • Work best using the ‘prime boost’ strategy. • Induce strong T cell responses. • Some protection seen in challenge studies.

  28. BLOOD STAGE VACCINES Second generation • MSP1 - First malaria blood stage antigen to be investigated. • - Many constructs have failed to give protection. • AMA1 -Involved in red cell invasion – very variable antigen. • - Some protection found against one variant in Mali trial. • - AMA1 virosome + CSP gave protection in Tanzania. • MSP 3- Induces a specific kind of immune response. • - Protection achieved in one pilot study in Burkina Faso. • GMZ2 - A combination of MSP3 and GLURP. • - A large multicentre trial currently underway in Africa. • SE36 - Based on the blood stage antigen SERA. • - Gave protection in children in Uganda.

  29. TRANSMISSION BLOCKING VACCINES • Pf s25 -Immune response directed at the parasite in in the mosquito. • - Little antigenic variability. • - No boosting. • Pvs 25 - Related antigen in Plasmodium vivax. • - In clinical trials. • Pf45/48 - Antibody directed at the gametocytes. • - Has been very difficult to produce in an immunogenic form. • - Some success with conjugation to EPA. • AnAPN1 - Attacks the mosquito midgut. • - Could provide cross-species protection. Membrane feeding assay

  30. VACCINES FOR ELIMINATION (MalERA consultative group on vaccines. PloS Med 2011;8:e1000398)

  31. WHO RAINBOW CHART WHO.int/entity/vaccine_research/documents/rainbow_table 28

  32. CHALLENGES FOR SECOND GENERATION MALARIA VACCINES • Trial design - need to compare with RTS,S ? • - inferiority or superiority? • - how to test combinations? • Transmission blocking vaccines • - need for community randomised trials? • - ethics of randomised trials ? • - licensure on immunogencity?

  33. SUMMARY • Malaria control is threatened by resistance to artemisinins • and pyrethroids and so malaria vaccines will be needed for • control in some areas and probably for elimination. • Many more candidate malaria vaccines will reach the stage of • clinical trials in endemic areas in the next decade. • Evaluation of second generation vaccines will be challenging • and expensive. • Substantial funds will be needed to ensure deployment of • malaria vaccines once they have been licensed.

  34. Dr Owusu and the first child to receive RTS,S/AS01, Kintampo, Ghana

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