Abstract
BACKGROUND: Induction of CD8 (+) T-cells using viral vectors is a promising strategy in developing effective vaccines against pre-erythrocytic malaria. A recent comparative assessment of candidate antigens using this approach in a mouse model had identified Liver Stage Antigen 1 (LSA1) and Liver Stage Associated Protein 2 (LSAP2) as more protective than TRAP and CSP antigens, which have been the dominant focus of clinical testing. We proposed that combining these within a novel dual antigenic insert (LS2), encoded alongside an orthologous immunogenic domain from invariant chain in ChAdOx1, and the F11 promoter in MVA, could translate to protective clinical efficacy against malaria. METHODS: We conducted a non-randomised, open-label, dose escalation phase I/IIa study in UK adults, vaccinating a small lead-in group with ChAdOx1 LS2 5x10 (9) vp (group 1; n = 3) and subsequently a heterologous prime-boost group with ChAdOx1 LS2 2.5x10 (10) vp and MVA LS2 2x10 (8) pfu (group 2; n = 10). Group 2 volunteers and 6 unvaccinated controls underwent Controlled Human Malaria Infection (CHMI) delivered by mosquito bite and standardized follow-up. RESULTS: Vaccination with ChAdOx1 LS2 (both low and full doses) and MVA LS2 were generally well tolerated with solicited symptoms observed similar to previous vectored vaccines and no Severe Adverse Events (SAEs). Immunogenicity of the prime-boost schedule as measured by IFN-γ ELISpot was high showing median response of 4473 SFC/10 (6) PBMC at the pre-challenge timepoint, covering a broad range of potential determinants. All vaccinated volunteers became infected with malaria during CHMI with a median time to diagnosis of 13 days compared to 13.25 days in controls. CONCLUSIONS: Though this study further indicates ChAd/MVA as a safe, highly effective platform for driving CD8 (+) responses specific to liver-stage malaria antigens, the promise of LSA1 and LSAP2 as potential candidates shown preclinically has not translated to protection from infection in humans.Clinical Trial Registration ClinicalTrials.gov (Ref: NCT03203421), date of registration, 3 (rd) July 2017.