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Development of Malaria Vaccines Development of Malaria Vaccines WHO PDVAC Mee,ng 8-10th June 2016 Salim Abdulla Ifakara health Ins,tute, Tanzania Malaria Burden & exisng Intervenons 214 million malaria cases in 2015, 88% in Africa 438,000 deaths in 2015, 90% in Africa Three biggest risks Financing fragility Artemisinin resistance Insecticide resistance Road Map New Vision “Safe and effecve vaccines against Plasmodium falciparum and Plasmodium vivax that prevent disease and death, and prevent transmission to enable malaria eradica9on.” • Expands to include P. vivax in addi,on to P. falciparum • Expands to all geographical regions rather than sub-Saharan Africa alone • Expands to include target groups beyond children alone depending on goal and risk groups www.who.int/immunization/topics/malaria/vaccine_roadmap/en/ Two new Strategic goals By 2030, license vaccines targe,ng Plasmodium falciparum and Plasmodium vivax that encompass the following two objec,ves, for use by the internaonal public health community: 1. Development of malaria vaccines with protec,ve efficacy of at least 75 percent against clinical malaria suitable for administraon to appropriate at-risk groups in malaria-endemic areas. 2. Development of malaria vaccines that reduce transmission of the parasite and thereby substan,ally reduce the incidence of human malaria infec,on. This will enable eliminaon in mul,ple sengs. Vaccines to reduce transmission should be suitable for administraon in mass campaigns. www.who.int/immuniza9on/topics/malaria/vaccine_roadmap/en Malaria Vaccines design: Points of intervention RTSS Phase 3 Trial in Africa Randomized, controlled, double- blind trial designed to evaluate vaccine efficacy, safety, reactogenicity, and immunogenicity in children up to 32 months after the administration of the first dose of vaccine. Two age categories: – Children 6-12 weeks of age: 7100 – Children 5-17 months of age: 8900 11 centers in 7 African countries Trial implemented with optimized vector control and malaria treatment The co-primary endpoints of the trial are: vaccine efficacy against clinical malaria after 12 months of follow-up in each age category. Impact of RTS,S/AS01 on clinical malaria over 18 months of follow-up Number of cases averted (per 1000 children vaccinated) 0 500 1000 1500 2000 2500 46% VE1° 3000 OVERALL Kilifi Korogwe 941 cases Bagamoyo averted Manhiça (47 to 2356)2° Lambarene months Lilongwe Agogo Kombewa 5-17 Kintampo Nanoro Siaya 27% VE1° OVERALL Kilifi Korogwe 444 cases Bagamoyo averted Manhiça 2° Lambarene, (-12 to 1429) weeks Lilongwe Agogo Kombewa 6-12 Kintampo Nanoro Siaya -20 0 20 40 60 80 0 1 2 3 4 5 6 100Vaccine Efficacy (% and 95%CI) Incidence in control group (number of episodes per person year at risk) Negative binomial regression SwissTPH WHO recommends Large scale Pilot implementa9on of RTSS in Africa • WHO recommends the pilot implementaons of the 4-dose schedule of the RTS,S/AS01 vaccine in 3–5 dis,nct epidemiological sengs in sub-Saharan Africa, at subnaonal level, covering moderate-to-high transmission sengs,” with three doses administered to children between 5 and 9 months of age, followed by a fourth dose 15–18 months later. • Pilots to involve sufficiently large populaons also to assess, 1. feasibility of providing all four doses of RTS,S to the target age group through exis,ng health services; 2. impact of RTS,S on child mortality; 3. evidence of any causal relaonship between RTS,S and either meningi,s or cerebral malaria, in the context of surveillance of adverse events; as well as the compilaon of evidence on the func,oning of country immunizaon programs and the use of currently recommended malaria control measures. 9 Malaria Vaccine Multi-component Four Stages for Vaccines to Target 1. Sporozoite Stage 2. Liver Stage schizonts R21 VLP viral vectors RBC 4. Mosquito Stage 3. Blood Stage PfRH5 VLP Pfs25 VLP R21 compared to RTS,S RTS,S R21 • Produced in P. pastoris • Produced in S. cerevisiae • Very high immunogenicity in mouse model • In Phase III trial • 100% efficacy in transgenic • Efficacy << 50% in field challenge in mice trials • Phase I trials (matrix M, AS01) Inial R21 Clinical Trial Data 5-fold dose sparing with R21 in matrix-M compared to RTS,S in AS01 Phase IIa challenge trial planned for September 2016 Ventakraman, Bowyer et al. unpublished Liver-Stage Vaccines Two advances entering trials 1. More protec,ve an,gens • LSA1 and LSAP2 (in viral vectors) 2. Prime & Target Immunizaon • Adenoviral vector administered i.m. followed by targe,ng immunisaon that redirects CD8+ T cells to the liver • Greater efficacy observed pre-clinically Clinical Progression of PfRH5 Vaccine Candidates 1. ChAd and MVA vectors phase I • Complete 2. Protein PfRH5 • GMP manufacture complete • Phase I/IIa planned 3. VLP for PfRH5 • Pre-clinical 22 193 A Protein Pfs25 (aa 22-194) His6 22 193 Protein nanoparticle His6 Pfs25 (aa 22-194) IMX313 22 193 ChAd63/MVA-Pfs25 tPA Pfs25 (aa 22-194) 22 193 ChAd63/MVA-Pfs25-IMX313 tPA Pfs25 (aa 22-194) IMX313 [Phos] Pfs25 (aa 22-194) His B 6 KpnI [Phos] His Pfs25 (aa 22-194) IMX313 6 KpnI KpnI Induce Linearise MeOH Purification DNA metabolism column Electroporate into P. pastoris Pfs25 soluble protein or Pfs25-IMX313 protein Clone gene of nanoparticle interest CPfs25-IMX313 Nanopar9cle An,gen fused to IMX313 self-assembles to form a heptamer Significantly bejer transmission-blocking ac,vity in the Standard Membrane Feeding Assay 120 Log improvement in an,body ,tre 100 10000 80 1000 60 100 40 No. of oocysts permosquito oocysts of No. 20 10 Pfs25 Antibody Unit (AU) Antibody Pfs25 0 1 Pfs25 Pfs25 Control Pfs25 Pfs25-IMX313 Pfs25-IMX313 Pfs25-IMX313 375 µg/ml 188 µg/ml 5 ug protein in Alhydrogel i.m. • Phase I trial of Pfs25-IMX313 in viral vectors underway • GMP manufacture of Pfs25-IMX313 nanopar,cle funded Deploying a Multi-Stage Malaria Vaccine Virus-Like Particles + Vectors in Infants A Regime for Deployment in Infants in Developing Countries 0 1 2 3 4 5 6 7.5 9 months Ad MVA R+ R+ R+ Ad = ChAd63 MeTRAP MVA = MVA MeTRAP R+ = R21 + RH5 + Pfs25 all VLPs in adjuvant Whole Malaria Sporozoite Vaccine approaches Irradiated infected mosquitoes showed > 90% protection 40 years ago Whole sporozoite vaccines • Radiation attenuated • Chemo attenuated • Genetically attenuated Currently using mosquitoes to produce the sporozoites in the future by invitro culture Irradiated purified sporozoite provide Short Term Homologous Protec9on - CHMI 3 Weeks Post Last Dose, Pf3D7 by Mosquito Bite)- Number of Dosage Regimen Volunteers Protecti Study PfSPZ/ Numbe Total No. ve Protect Challeng Dose (x r of PfSPZ Efficacy ed ed 105) Doses (x 105) VRC 314/ WRAIR 2.7 3 8.1 3 10* 20% 2080 VRC 314 (R. Seder, 2.7 4 10.8 7 9** 73% K. Lyke) WRAIR 2080 2.7 5 13.5 12 13*** 92% (J. Epstein) 4.5 WRAIR (8 week 3 13.5 13 15*** 87% 2080 interval) 7/8*, 5/6**, and 6/6*** controls developed parasitemia WRAIR and Sanaria18 Irradiated Sporozoites provide durable Homologous and Heterologous Protecon CHMI 6 months after Last Dose Number of Protective Dosage Regimen Volunteers at Efficacy 23-24 Weeks Study Total PfSPZ/ Numb No. Protecte Challeng 3 23-24 Dose (x er of PfSPZ d ed Weeks Weeks 105) Doses (x 105) VRC 314 2.7 4 10.8 6 11 ND 55%* WRAIR 2.7 5 13.5 7 10 92% 70% 2080 WRAIR 4.5 3 13.5 8 14 87% 57% 2080 *All Protected at 12 Months 9.0 x 105 PfSPZ three Nmes at 8 week intervals • 9/14 (64%) vaccinees and 0/6 controls were protected: Pf3D7 CHMI (homologous) at 19 weeks aZer last dose of PfSPZ Vaccine • 5/6 (83%) vaccinees who were protected at 19 weeks and 0/6 controls were protected: Pf7G8 CHM (heterologous at 33 weeks WRAIR and Sanaria Irradiated Sporozoites provide durable Heterologous Protecon in adults in Africa Sample size (N) Protecve Efficacy Follow-up From Last Study Aack Vaccine Vaccine Time-to-Event Proporonal Locaon Rate Significance Significance Controls Immunized Dose Analysis* Analysis** (p-value) (p-value) (weeks) (95% C.I.) (95% C.I.) 8.8% RTS,S/ 29.5% Kenya 75 74 49.3% 16 0.164 (-23.4%-35.6% 0.624 AS01B (-15.4%-56.9%) ) PfSPZ 52.1% 28.5% Mali 44 42 93.2% 24 0.0031 0.004 Vaccine (21.9%-70.6%) (9.0%-46.4%) * Time to Event Analysis = Vaccine efficacy based on survival analysis/Cox hazard rao ** Propor,onal Analysis = [(ARC - ARV)/ ARC]*100%, where AR = aack rate MRTC and Sanaria *** Polhemus et al., 2009 PLoS ONE 4(7): e6465. doi:10.1371/journal.pone.0006465 20 Chemoprophylaxis with Sporozoites (CPS) Roestenberg NEJM 2009 • Pf sporozoites administered by bite of mosquitoes • 3 sequential monthly doses of 12-15 mosquito bites (total of only 36-45 infected mosquito bites) • Weekly chloroquine • 100% protection after malaria challenge 21 Purified Sporozoites with Chloroquine Results - Tübingen B. Mordmueller, P. Kremsner Dosage Regimen Number of Volunteers Protective Group Total No. PfSPZ/Dose Number Efficacy PfSPZ Protected Challenged (x 103) of Doses (x 103) 1 3.2 3 9.6 3 9 33% 2 12.8 5 38.4 6 9 67% 3 51.2 3 153 9 9 100% U.Tubingen and Sanaria 22 Malaria Vaccine Evaluaon Models CHMI models Sporozoite – Sporozoite – injec,on Blood-stage mosquito bite Mimicking natural Yes No No route of infec,on Ability to control +/− ++ +++ inoculum size Life-cycle stages Sporozoite (skin and Sporozoite (blood) Blood-Stage amenable to study blood) Liver-Stage Liver-Stage Blood-Stage Blood-Stage Availability Limited trial centers Poten,al for Poten,al for widespread use widespread use Duraon of blood- Short Variable Longer stage parasite (2–4 d) (2–8 d) (8–9 d) exposure Reliably achieves +++ ++ +++ 100% infecon Sheehy et al Hum Vaccin Immunother 2013 Some issues with Controlled Human
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