A Phase Ia Study to Assess the Safety and Immunogenicity of New Malaria Vaccine Candidates ChAd63 CS administered alone and with MVA CS Eoghan F. de Barra 1, Susanne H. Sheehy 2, Katie J. Ewer 2, Kerrie Hennigan 1, Ann Collins 1, Ian D. Poulton 2, Pooja Mange 2, Katharine A. Collins 2, Eleanor Berrie 3, Sarah Moyle 3, Alison M. Lawrie 2, Regitze Thoegersen 5, Egeruan Babatunde Imoukhuede 5, Odile Leroy 5, Alfredo Nicosia 4, Samuel J. McConkey 1, Adrian V. Hill 2 1. Dept of International Health and Tropical Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland, 2. Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, UK., Oxford, United Kingdom, 3. Clinical Biomanufacturing Facility, University of Oxford, UK., Oxford, United Kingdom, 4. Okairos, Pomezia, Rome, Italy, 5. European Vaccine Initiative, UniversitätsKlinikum Heidelberg, Germany Plasmodium falciparum malaria - Approximately 250 million cases and over 800,000 deaths worldwide in 2008, mostly in Africa. 1 - Resistance Anopheles mosquitoes to certain insecticides Malaria parasites to chemotherapeutic agents -Need for a new, effective intervention for the prevention or treatment of malaria. 2 A vaccine against malaria - Major goal of the Roll Back Malaria Partnership - Felt to be a key future strategy for reducing mortality from malaria and moving towards eradication. 3 Introduction: Inducing protective T-cell immunity against the malaria liver-stage parasite is a key target of malaria vaccine development. Circumsporozoite Protein (CS) expressed by sporozoites plays a key role in invasion into hepatocytes and has shown promise as antigen in other vaccine candidates. Prime boost vaccination utilising chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines expressing a range of antigens are in development and have shown to be consistently immunogenic, inducing extremely potent T cell responses. VACCINE Candidates – ChAd63 CS and MVA CS Novel CS antigen, omits the extreme C-terminus of the protein that encodes the GPI-anchor sequence and the N-terminal third of the protein N-terminal to the central B cell repeat Prime : ChAd63 CS (Chimpanzee adenovirus 63 expressing circumsporozoite protein) Boost: MVA CS (Modified vaccinia virus Ankara expressing circumsporozoite protein) Results Discussion These data indicate adequate safety of this novel viral vectored vaccine combination. The adverse events observed were of a nature seen with other vaccines utilizing the same vectors and were all self limiting. The vast majority were of minor severity. These data also establish a preferred dosing of ChAd63 CS for induction of potent T cell immune responses. The results of a phase II Controlled Human Malaria Infection study using this vaccine combination are also being presented at this meeting (Abstract LB- 361). Investigations of the detailed humoral and cellular immunology are ongoing. Adverse Events (AEs) All AEs graded possibly, probably or definitely related to vaccination are presented here. The highest grade of severity for each individual, for each AE has been used. No significant difference in AE type or grade has been observed between the two different doses of ChAd63 CS. References 1.WHO. World Malaria Report. World Health Organization White NJ. Antimalarial drug resistance. J Clin Invest 2004;113: Das P, Horton R. Malaria elimination: worthy, challenging, and just possible. Lancet 2010;376:1515. RCSI, 123 St. Stephen’s Green, Dublin 2, Ireland. Subject’s safety Overview: Serious adverse events (SAE) To date there have been no SAE. Suspected Unexpected Serious Adverse Reactions (SUSARs) To date there have been no SUSARs. Table 2: Overview of clinical trial groups: All vaccinations are intramuscular. Figure 4: ELISpot plate showing controls and Malaria peptide pools. One volunteer from group 1A at 90 days post ChAd63 CS and one volunteer from group 1B 1 week post MVA CS booster vaccine. Presentation no. LB-273 Immungenicity Both doses of ChAd63 CS were immunogenic, inducing high-level T cell responses. Mean peak responses at day 14 post vaccination were 351 and SFU/ million PBMC for doses of 5x10 9 vp and 5x10 10 respectively. Peak responses to MVA CS boosting were observed one week post vaccination, (day 63); 1655 SFU/million PBMC (ChAd63 CS dose 5x10 9 vp); 1327 SFU/million PBMC (ChAd63 CS dose 5x10 10 vp). The vaccine combination was safe and well tolerated at both doses of ChAd63 CS. Methods : We conducted a Phase Ia, non-randomized clinical trial in 24 healthy, malaria-naïve adults of the ChAd63 and MVA replication-deficient viral vectored vaccines both encoding the circumsporozoite Protein of P. falciparum. ChAd63-MVA CS was administered in a heterologous prime-boost regime 8 weeks apart. Two different doses of ChAd63 CS were assessed 5x10 9 Viral Particles (vp)and 5x10 10 vp following safety review. Serial assessments of immune response were performed using Enzyme-Linked Immunospot technique (ELISpot). Figure 3 : VAC038: Adverse events (AEs) deemed possibly, probably or definitely related to MVA CS 2 x 10 8 pfu. Figure 3a: Local AEs. Figure 3b: Systemic AEs. ‘Other systemic AE’ = upper respiratory tract inflammation. Figure 2: VAC038: Adverse events (AEs) deemed possibly, probably or definitely related to AdCh63 CS 5 x 10 9 vp and 5 x Figure 2a: Local AEs. ‘Other local AE’ = paraesthesia at injection site lasting 2 days. Figure 2b: Systemic AEs. ‘Other systemic AE’ = pruritus. ‘Lab’ = transient neutropenia Figure 2a Figure 2b Figure 3a Figure 3b Table 1: Overview of clinical trial design and objectives Acknowledgements: We wish to thank the Irish Aid for financial support through the European Vaccine Initiative and all the volunteers that participated in this study. Figure 5: ELISpot responses to CS peptides at day 14 and 63 post vaccination for both doses of ChAd63 CS. Figure 6: ELISpot responses to CS peptides thoughout the study for groups 1A, 1B, 2A and 2B. ClinicalTrials.gov Identifier: NCT Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3