Division of Malaria Research Institute for Global Health University of Maryland School of Medicine Safety tolerability and efficacy of a metabolically active nonreplicating whole organism malaria vaccine PfSPZ Vaccine in malariaexperienced adults in Burkina Faso ID: 1047558
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1. Matt Laurens, MD MPHon behalf of the PfSPZ Vaccine in Burkina Faso study teamDivision of Malaria ResearchInstitute for Global HealthUniversity of Maryland School of MedicineSafety, tolerability and efficacy of a metabolically active, non-replicating, whole organism malaria vaccine (PfSPZ Vaccine) in malaria-experienced adults in Burkina Faso
2. BackgroundSanaria® PfSPZ Vaccine: radiation attenuated, aseptic, purified, cryopreserved NF54 Plasmodium falciparum (Pf) sporozoites (SPZ)PfSPZ Vaccine: safe and well tolerated in >1130 subjects. Vaccine efficacy (VE) against controlled human malaria infection (CHMI):Homologous CHMI:>90% at 3-11 weeks in the U.S. (Seder, 2013, Epstein 2017), Tanzania, Mali, and Germany (Jongo, Sissoko, and Mordmueller, unpublished)55% at 14 months in the U.S. (Ishizuka, 2017) Heterologous CHMI: 55% at 8 months in U.S. (Lyke, 2017)VE against intense, heterogeneous Pf transmission during 6 months in Mali:Time-to-event: 48%; proportional: 29% (Sissoko & Healy, 2017)Antibodies to PfSPZ and PfCSP significantly lower in malaria-experienced Malian adults than malaria-naïve U.S. adults
3. Dose escalation study of Sanaria® PfSPZ Vaccine, followed by a randomized, double-blind, placebo-controlled clinical trial to evaluate the safety, immunogenicity, and protective efficacy of PfSPZ Vaccine in malaria-experienced adults in Burkina Faso
4. Centre National de Recherche et de Formation sur le PaludismePI: Sodiomon SIRIMA
5. Primary Objective: Safety and reactogenicity of PfSPZ Vaccine in malaria-experienced healthy adults Secondary Objective:Vaccine-induced immune responsesExploratory Objectives:PfSPZ Vaccine efficacy against naturally-occurring P. falciparum infectionsStrain-specific efficacy and vaccine selection for non-vaccine variant strainsAntibody responses, T cell responses or mRNA expression profilesObjectivesPfSPZ Vaccine in malaria-experienced adults in Burkina Faso
6. Study Site: Balonghin, Saponé region47 km south of OuagadougouPart of the health district of SaponéStudy SitePfSPZ Vaccine in malaria-experienced adults in Burkina Faso
7. Adults aged 21-40Dose escalationCohort 1 (n=8): 4.5x105 dose x 2Cohort 2 (n=8): 9.0x105 dose x 2Cohort 3 (n=8): 1.8x106 dose x 2Cohort 4 (n=8): 2.7x106 dose x 2Cohort 5 (n=80): 2.7x106 dose x 3 (efficacy cohort) or saline placebo (1:1 ratio)7-day artesunate before first and last vaccinationsVaccine doses are given 8 weeks apartStudy DesignPfSPZ Vaccine in malaria-experienced adults in Burkina Faso
8. Study DesignPfSPZ Vaccine in malaria-experienced adults in Burkina Faso
9. Current status:32 participants in Cohorts 1-4 completed80 participants in Cohort 5 (efficacy cohort) enrolled in early 2017 and completed vaccinations in July 2017Efficacy against malaria infection by thick blood smear for 2017 malaria transmission season availablePfSPZ Vaccine in malaria-experienced adults in Burkina Faso
10. Number and Percentage of Participants Experiencing Solicited Systemic Eventsa with 95% CI by Symptom and CohortPfSPZ Vaccine in malaria-experienced adults in Burkina Faso*Cohort 5 participants remain blinded
11. Number and Percentage of Participants Experiencing Solicited Local Eventsa with 95% CI by Symptom and CohortPfSPZ Vaccine in malaria-experienced adults in Burkina Faso
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13. Serious Adverse EventsPfSPZ Vaccine in malaria-experienced adults in Burkina Faso5 total Serious Adverse Events (SAEs)Severe MalariaPulmonary TuberculosisLoss of consciousnessAppendicular abscessCranial subcutaneous hematomaNone related to study productPhoto: PATH/Gabe Bienczycki
14. Safety Laboratory ResultsCohorts 1-4PfSPZ Vaccine in malaria-experienced adults in Burkina Faso
15. Post-immunization minus pre-immunization anti-PfCSP antibody level (Net 0D 1.0) by ELISA (serum dilution at which the optical density was 1.0 – OD 1.0) by cohort from baseline to 14 days after second immunization
16. Net OD 1.0 anti-PfCSP antibody by cohort from baseline to 14 days after last immunization: Two doses of 2.7x106 SPZ induces >antibody than five doses of 2.7x105 SPZ From Sissoko et al., Lancet ID 2017PfSPZ Vaccine 2.7x105 dose x 5
17. Ratio of post-immunization to pre-immunization anti-PfCSP antibody level (OD 1.0) by cohort from baseline to 14 days after second immunization
18. Ratio of OD 1.0 anti-PfCSP antibody level by cohort from baseline to 14 days after last immunization: Two doses of 2.7x106 SPZ induces >antibody than five doses of 2.7x105 SPZ From Sissoko et al., Lancet ID 2017PfSPZ Vaccine 2.7x105 dose x 5
19. Efficacy Against P. falciparum Infection by Thick Blood Smearduring the 6 months After Last Dose of PfSPZ Vaccine; Cohort 5 (n=80)PfSPZ Vaccine in malaria-experienced adults in Burkina FasoNumber and Percentage Infected by GroupVaccine Efficacy Against Infection by Method
20. 38 % vaccine efficacy (VE) (p=0.02) during 6 months after the last dose of vaccine against Pf infection by thick blood smear (TBS) by proportional analysisThe highest VE against Pf infection by TBS ever recorded in a clinical trial of a malaria vaccine in Africa
21. Efficacy Against P. falciparum Infection by Thick Blood Smear6 months After Vaccination; Cohort 5 (n=80)PfSPZ Vaccine in malaria-experienced adults in Burkina FasoVaccine EfficacyProportional = 38% (p=0.02)Hazard ratio = 47% (p=0.06)
22. Participants experienced very little systemic reactogenicity and no local reactogenicity related to vaccinations (unblinded analysis to follow)Two doses of PfSPZ Vaccine was immunogenic and induced almost seven-fold increase in anti-PfCSP antibody compared to baseline in the highest dose groupCompares to a 3.5-fold increase from baseline in malaria-experienced Malian adults who received 5 doses of 2.7 x 105 SPZ, and who were protected against Pf infection in the subsequent malaria transmission seasonPfSPZ Vaccine induced significant anti-PfCSP antibodies in this populationConclusionsPfSPZ Vaccine in malaria-experienced adults in Burkina Faso
23. Three doses of PfSPZ Vaccine induced protection against Pf Vaccine efficacy: 38% by proportional analysis (primary analysis, p=0.02)PfSPZ Vaccine shows promise as a useful tool for preventing Pf infection and thereby in halting transmission and eliminating Pf from geographically defined areas. It will be critical to determine how the vaccine performs in children and infants. ConclusionsPfSPZ Vaccine in malaria-experienced adults in Burkina Faso
24. Immunogenicity studies in Cohort 5 participantsAnti-PfCSP antibody responsesAnti-PfSPZ antibodies (aIFA and aISI)Cellular immunology studiesProtection against infection by qPCR analysisCohort 5 participants will be followed through the 2018 malaria transmission seasonDuration of immune responseDuration of protection against infectionSieve Analysis comparing infections in protected versus non-protected by assembling field isolate genomesDNA and data from all efficacy trials in malaria-endemic areas will be needed to achieve adequate sample size to analyze strain specific efficacyFuture DirectionsPfSPZ Vaccine in malaria-experienced adults in Burkina Faso
25. AcknowledgementsCNRFP TeamSodiomon SirimaAlphonse OuédraogoAlfred TionoJ. M. KaboréIssa Nébie OuédraogoAmidou DiarraIssiaka SoulamaEdith BougoumaLydia DabréSafety MonitorTéné Marceline YaméogoDuke UniversityChris PloweThis project has been funded in whole or in part with Federal funds from the National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under U01 AI112367I.SanariaStephen HoffmanTom RichiePeter BillingsleyKim Lee SimEric JamesAnita ManojYonas AbebeNatasha KCTooba MurshedkarNIH DMIDGreg DeyeWalt JonesEffie NomicosSoju ChangBlossom SmithJoni LoveThe Emmes CorporationGail PotterJessie KennedyTejal GambhirUniversity of MarylandMelissa MyersJoana Carneiro da SilvaAmed OuattaraKirsten LykeMatthew AdamsKathleen StraussBiraj ShresthaSudhaunshu JoshiMiriam LauferAna R Da CostaTina Williams
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28. Dose escalation study of Sanaria’s irradiated sporozoite vaccine (PfSPZ Vaccine), followed by a randomized, double-blind, placebo-controlled phase 1 clinical trial to evaluate the safety and immunogenicity of PfSPZ Vaccine in malaria-experienced adults in Burkina Faso
29. Maximum Systemic Reactogenicity Cohorts 1-4PfSPZ Vaccine in malaria-experienced adults in Burkina Faso
30. Maximum Local Reactogenicity Cohorts 1-4PfSPZ Vaccine in malaria-experienced adults in Burkina Faso
31. Number and Percentage of Participants Experiencing Unsolicited Eventsa with 95% CI by Symptom and CohortPfSPZ Vaccine in malaria-experienced adults in Burkina Faso