Safety and Immunogenicity of Heterologous Prime-Boost Immunisation with Plasmodium falciparum Malaria Candidate Vaccines, ChAd63 ME-TRAP and MVA ME-TRAP, in Healthy Gambian and Kenyan Adults

in Healthy Gambian and Kenyan Adults. PLoS ONE 8(3): e57726. doi:10.1371/journal.pone.0057726 Safety and Immunogenicity of Heterologous Prime-Boost Immunisation with Plasmodium falciparum Malaria Candidate Vaccines, ChAd63 ME-TRAP and MVA ME- TRAP, in Healthy Gambian and Kenyan Adults Caroline Ogwang 0 1 2 3 4 Muhammed Afolabi 0 1 2 3 4 Domtila Kimani 0 1 2 3 4 Ya Jankey Jagne 0 1 2 3 4 Susanne H. Sheehy 0 1 2 3 4 Carly M. Bliss 0 1 2 3 4 Christopher J. A. Duncan 0 1 2 3 4 Katharine A. Collins 0 1 2 3 4 Miguel A. Garcia Knight 0 1 2 3 4 Eva Kimani 0 1 2 3 4 Nicholas A. Anagnostou 0 1 2 3 4 Eleanor Berrie 0 1 2 3 4 Sarah Moyle 0 1 2 3 4 Sarah C. Gilbert 0 1 2 3 4 Alexandra J. Spencer 0 1 2 3 4 Peninah Soipei 0 1 2 3 4 Jenny Mueller 0 1 2 3 4 Joseph Okebe 0 1 2 3 4 Stefano Colloca 0 1 2 3 4 Riccardo Cortese 0 1 2 3 4 Nicola K. Viebig 0 1 2 3 4 Rachel Roberts 0 1 2 3 4 Katherine Gantlett 0 1 2 3 4 Alison M. Lawrie 0 1 2 3 4 Alfredo Nicosia 0 1 2 3 4 Egeruan B. Imoukhuede 0 1 2 3 4 Philip Bejon 0 1 2 3 4 Britta C. Urban 0 1 2 3 4 Katie L. Flanagan 0 1 2 3 4 Katie J. Ewer 0 1 2 3 4 Roma Chilengi 0 1 2 3 4 Adrian V. S. Hill 0 1 2 3 4 Kalifa Bojang 0 1 2 3 4 Aric Gregson, University of California Los Angeles, United States of America 0 Road Campus Research Building, Oxford, United Kingdom, 5 Clinical Biomanufacturing Facility, University of Oxford, Churchill Hospital , Oxford , United Kingdom , 6 Okairo` s 1 Clinical Vaccinology and Tropical Medicine, The Jenner Institute, Churchill Hospital , Oxford , United Kingdom , 4 The Jenner Institute Laboratories, University of Oxford , Old 2 1 Kenya Medical Research Institute, Centre for Geographical Medical Research (Coast) , Kilifi, Kenya, 2 Medical Research Council Unit , Fajara , The Gambia, 3 Centre for 3 Federico II Naples , Naples , Italy , 10 Liverpool School of Tropical Medicine , Liverpool , United Kingdom 4 AG , Rome, Italy, 7 CEINGE, Naples, Italy, 8 European Vaccine Initiative, Heidelberg, Germany , 9 Department of Molecular Medicine and Medical Biotechnology, University Background: Heterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified vaccinia Virus Ankara (MVA) vectored vaccines is a strategy recently shown to be capable of inducing strong cell mediated responses against several antigens from the malaria parasite. ChAd63-MVA expressing the Plasmodium falciparum pre-erythrocytic antigen ME-TRAP (multiple epitope string with thrombospondin-related adhesion protein) is a leading malaria vaccine candidate, capable of inducing sterile protection in malaria nave adults following controlled human malaria infection Methodology: We conducted two Phase Ib dose escalation clinical trials assessing the safety and immunogenicity of ChAd63-MVA ME-TRAP in 46 healthy malaria exposed adults in two African countries with similar malaria transmission Results: ChAd63-MVA ME-TRAP was shown to be safe and immunogenic, inducing high-level T cell responses (median Conclusions: ChAd63-MVA ME-TRAP is a safe and highly immunogenic vaccine regimen in adults with prior exposure to malaria. Further clinical trials to assess safety and immunogenicity in children and infants and protective efficacy in the field are now warranted. ClinicalTrials.gov NCT01379430 Trial Registration: Pactr.org PACTR2010020001771828 Pactr.org PACTR201008000221638 ClinicalTrials.gov NCT01373879 - Funding: This work was performed by the Malaria Vectored Vaccines Consortium (MVVC), a four year integrated project funded by the European and Developing Countries Clinical Trials Partnership (EDCTP). The work was also supported by the UK National Institute of Health Research through the Oxford Biomedical Research Centre (http://www.oxfordbrc.org/) [A91301 Adult Vaccine], the Wellcome Trust (http://www.wellcome.ac.uk/) [084113/Z/07/Z] and the Medical Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: AH is a named inventor on the following patent applications on malaria vectored vaccines and immunization regimes (WO2008/122769, Adenoviral vector encoding malaria antigen; and WO 2008/122811 Novel adenovirus vectors). Authors from Okairo` s are employees of and/or shareholders in Okairo` s, which is developing vectored vaccines for malaria and other diseases. This does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. . These authors contributed equally to this work. Malaria caused by Plasmodium falciparum remains a leading cause of childhood morbidity and mortality, predominantly in Africa, in spite of the implementation of extensive control measures [1,2]. An effective vaccine remains a key objective if disease transmission and severity is to be substantially reduced [3]. The most advanced malaria vaccine in development, the protein-adjuvant vaccine RTS,S/AS01 targeting the pre-erythrocytic stage of infection [4], is currently in phase III clinical trials and has been shown to confer partial protection over the 12 months following immunization [5,6]. Whilst notable as the most efficacious malaria vaccine to date there remains a considerable need to improve on its limited clinical efficacy [7], either through modifications to the RTS,S vaccine or by developing vaccine strategies that combine multiple antigens or vaccine types [8]. Analysis of the immunological correlates of immunity induced by the RTS,S vaccine in both phase IIa sporozoite challenge studies [9,10] and a trial in Mozambique [11] provide evidence that very high levels of antibodies to circumsporozoite protein (CS) correlate with protection in humans [12]. However, this correlation is relatively weak. It is unlikely that there is a component of direct T cell mediated protection induced by the vaccine as the magnitude of the CD4+ T cell response measured after vaccination is modest (approximately 150 SFU /million PBMCs on ELIspot) and no CD8+ T cells are induced [13]. Increasing data from animal models, fieldwork and inoculation of volunteers with irradiated sporozoites support an important role for CD8+ T cells in mediating pre-erythrocytic immunity, even in the absence of antibodies [14]. Whilst pre-clinical studies demonstrate a clear correlation between CD8+ T cells and protection [1519], clinical vaccine studies have been hampered by the limited ability of existing subunit vaccine strategies, namely adjuvanted protein constructs, to induce high enough numbers of antigen specific CD8+ T cells to confer protection [20]. The Jenner Institute has been working to develop a T cell inducing pre-erythrocytic P. falciparum malaria vaccine using the sporozoite and liver stage antigen ME-TRAP. This antigen contains a fusion protein of multiple epitopes (ME; a string of 20 epitopes, mainly CD8+ T cell epitopes from pre-erythrocytic antigens) and the P. falciparum pre-erythrocytic antigen, thrombospondin-related adhesion protei (...truncated)