A Phase Ia Study to Assess the Safety and Immunogenicity of New Malaria Vaccine Candidates ChAd63 CS Administered Alone and with MVA CS

December A Phase Ia Study to Assess the Safety and Immunogenicity of New Malaria Vaccine Candidates ChAd63 CS Administered Alone and with MVA CS Editor: Thomas L. Richie 6 Sanaria. Inc 6 United States of America 6 Eoghan de Barra * 0 6 Susanne H. Hodgson 1 6 Katie J. Ewer 2 6 Carly M. Bliss 2 6 Kerrie Hennigan 0 6 Ann Collins 0 6 Eleanor Berrie 3 6 Alison M. Lawrie 1 6 Sarah C. Gilbert 2 6 Alfredo Nicosia 4 5 6 Samuel J. McConkey 0 6 Adrian V. S. Hill 2 6 0 Royal College of Surgeons in Ireland , Dublin, Ireland, 1 Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital , Oxford , United Kingdom, 2 The Jenner Institute, University of Oxford , Old Road Campus Research Building, Oxford , United Kingdom, 3 Clinical Biomanufacturing Facility, University of Oxford, Churchill Hospital , Oxford , United Kingdom, 4 Okairo`s AG , Rome , Italy, 5 CEINGE , Naples , Italy 6 Funding: The study was funded by a grant from the European Vaccine Initiative (EVI), http://www. euvaccine.eu/. Antibody assays were performed at WRAIR and were funded by the Malaria Vaccine Initiative. This work was also supported by the UK National Institute of Health Research through the Oxford Biomedical Research Centre (A91301 Adult Vaccine) and the Wellcome Trust (084113/Z/07/Z). SCG and AVSH are Jenner Investigators; AVSH is supported by a Wellcome Trust Principal Research Fellowship (45488/Z/05); and SHH holds a Wellcome Trust Research Training Fellowship (097940/Z/11/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript Background: Plasmodium falciparum (P. falciparum) malaria remains a significant cause of mortality and morbidity throughout the world. Development of an effective vaccine would be a key intervention to reduce the considerable social and economic impact of malaria. Methodology: We conducted a Phase Ia, non-randomized, clinical trial in 24 healthy, malaria-nave adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding the circumsporozoite protein (CS) of P. falciparum. Results: ChAd63-MVA CS administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to CS. With a priming ChAd63 CS dose of 56109 vp responses peaked at a mean of 1947 - Competing Interests: The authors have read the journals policy and have the following conflicts: AVSH and SCG are named inventors on patent filings related to immunisation with vectored malaria vaccines, specifically WO2008/122769. None of these products have been commercialized. AN was an employee of Okairos AG at the time of the study. Okairos AG has since been acquired by GSL Vaccines, which now owns patents and patent applications related to simian adenoviruses. None of the authors have had any consultancies relevant to this paper. This conflict of interest does not alter these authors adherence to all PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. SFC/million PBMC (median 1524) measured by ELIspot 7 days after the MVA boost and showed a mixed CD4+/CD8+ phenotype. With a higher priming dose of ChAd63 CS dose 561010 vp T cell responses did not increase (mean 1659 SFC/ million PBMC, median 1049). Serum IgG responses to CS were modest and peaked at day 14 post ChAd63 CS (median antibody concentration for all groups at day 14 of 1.3 mg/ml (range 011.9), but persisted throughout late follow-up (day 140 median antibody concentration groups 1B & 2B 0.9 mg/ml (range 04.7). Conclusions: ChAd63-MVA is a safe and highly immunogenic delivery platform for the CS antigen in humans which warrants efficacy testing. Trial Registration: ClinicalTrials.gov NCT01450280 Plasmodium falciparum (P. falciparum) malaria remains a cause of significant mortality and morbidity throughout the world [1]. Though one vaccine, RTS,S, has demonstrated promising results in Phase III trials, there remains a need to develop an alternative, more effective vaccine. For more than 40 years it has been known that it is possible to achieve high-level, sustained, protective immunity against the pre-erythrocytic stages of P. falciparum infection through immunization with the bites of .1000 infected, irradiated mosquitoes [25]. For many years the evidence suggested that antibodies against the major sporozoite surface antigen, the circumsporozoite protein (CS), were responsible for protection and this formed the basis of the design of the RTS,S vaccine [6]. However, based on data from murine adoptive transfer experiments and human trials it now seems that CD8+ T cells specific for parasite-derived peptide/class I MHC molecule complexes on the surface of infected hepatocytes are the primary immune effectors [714]. Thus the goal in malaria vaccine development is a vaccine that induces both humoral and cell-mediated immune responses resulting in memory T and B cells that are specific for epitopes derived from parasite proteins. Initially, it was thought that cytolysis of the infected hepatocyte by parasite-specific CD8+ T cells was the primary effector mechanism, but recent data suggest that the elimination of the infected hepatocytes is mediated by interferongamma (IFN-c) released by CD8+ T cells [15]. Researchers at the University of Oxford have been working for over 10 years to develop a 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 protein (TRAP) [16]. Multiple vectors for this antigen have been clinically tested including DNA, fowl pox (FP) and modified vaccinia virus Ankara (MVA), however T cell immunogenicity and clinical efficacy has been limited [1719]. More recently, heterologous prime boost with Chimpanzee adenovirus 63 (ChAd63) and MVA, both expressing ME-TRAP, has been shown to be the most immunogenic regimen to date, inducing more than 2400 IFNc producing T cells post boost [2022]. This heterologous prime-boost regime with the viral vectors ChAd63 and MVA has been shown to induce the highest T cell responses in humans of any vaccine platform, as well as strong antibody responses [2325]. Simian adenoviruses are not known to cause pathology or illness in humans and the prevalence of antibodies to chimpanzee origin adenoviruses is less than 5% in humans residing in the USA [26]. In Equatorial Africa prevalence is higher. A recent study in Kenya showed 4% of children to have high neutralising antibodies to ChAd63 [27]. The presence of pre-existing antibodies to adenoviral vectors has been an issue with human adenoviral vectors. However, data from the Phase IIb efficacy study of ChAd63-MVA ME-TRAP s (...truncated)