Phase Ia Clinical Evaluation of the Safety and Immunogenicity of the Plasmodium falciparum Blood-Stage Antigen AMA1 in ChAd63 and MVA Vaccine Vectors

et al. (2012) Phase Ia Clinical Evaluation of the Safety and Immunogenicity of the Plasmodium falciparum Blood-Stage Antigen AMA1 in ChAd63 and MVA Vaccine Vectors. PLoS ONE 7(2): e31208. doi:10.1371/journal.pone.0031208 Phase Ia Clinical Evaluation of the Safety and Immunogenicity of the Plasmodium falciparum Blood- Stage Antigen AMA1 in ChAd63 and MVA Vaccine Vectors Susanne H. Sheehy 0 1 Christopher J. A. Duncan 0 1 Sean C. Elias 0 1 Sumi Biswas 0 1 Katharine A. Collins 0 1 Geraldine A. O'Hara 0 1 Fenella D. Halstead 0 1 Katie J. Ewer 0 1 Tabitha Mahungu 0 1 Alexandra J. Spencer 0 1 Kazutoyo Miura 0 1 Ian D. Poulton 0 1 Matthew D. J. Dicks 0 1 Nick J. Edwards 0 1 Eleanor Berrie 0 1 Sarah Moyle 0 1 Stefano Colloca 0 1 Riccardo Cortese 0 1 Katherine Gantlett 0 1 Carole A. Long 0 1 Alison M. Lawrie 0 1 Sarah C. 0 1 Gilbert 0 1 Tom Doherty 0 1 Alfredo Nicosia 0 1 Adrian V. S. Hill 0 1 Simon J. Draper 0 1 Denise L. Doolan, Queensland Institute of Medical Research, Australia 0 Funding: This work was supported by the European Malaria Vaccine Development Association (EMVDA), a European Commission FP6-funded consortium (http:// www.emvda.org/) [LSHP-CT-2007-037506]; the UK National Institute of Health Research through the Oxford Biomedical Research Centre (http://www.oxfordbrc. org/) [A91301 Adult Vaccine]; and the Wellcome Trust (http://www.wellcome.ac.uk/) [084113/Z/07/Z]. The GIA work was supported by the PATH Malaria Vaccine Initiative (MVI; http://www.malariavaccine.org/) and the Intramural Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov/Pages/default.aspx). CJAD holds a Wellcome Trust Research Training Fellowship [RTEI0]; SCG, AVSH and SJD are Jenner Investigators; AVSH was supported by a Wellcome Trust Principal Research Fellowship [45488/Z/05]; and SJD is a UK Medical Research Council Career Development Fellow [G1000527]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript 1 1 Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital , Oxford , United Kingdom , 2 The Jenner Institute, University of Oxford , Oxford , United Kingdom , 3 University College London Clinical Research Facility, University College Hospital , London , United Kingdom , 4 Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases/National Institutes of Health , Rockville, Maryland , United States of America, 5 Clinical Biomanufacturing Facility, University of Oxford, Churchill Hospital , Oxford , United Kingdom , 6 Okairo` s AG, Rome, Italy, 7 CEINGE, Naples , Italy Background: Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question. Methodology: We conducted a Phase Ia, non-randomized clinical trial in 16 healthy, malaria-nave adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding two alleles (3D7 and FVO) of the P. falciparum blood-stage malaria antigen; apical membrane antigen 1 (AMA1). ChAd63MVA AMA1 administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing highlevel T cell responses to both alleles 3D7 (median 2036 SFU/million PBMC) and FVO (median 1539 SFU/million PBMC), with a mixed CD4+/CD8+ phenotype, as well as substantial AMA1-specific serum IgG responses (medians of 49 mg/mL and 41 mg/ mL for 3D7 and FVO AMA1 respectively) that demonstrated growth inhibitory activity in vitro. Conclusions: ChAd63-MVA is a safe and highly immunogenic delivery platform for both alleles of the AMA1 antigen in humans which warrants further efficacy testing. ChAd63-MVA is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where strong cellular and humoral immune responses are required for protection. Trial Registration: ClinicalTrials.gov NCT01095055 - Competing Interests: AJS, MDJD, SCG, AVSH and SJD are named inventors on US 12/595 574 and UK PCT/GB2008/01262, US 12/595 351 and UK PCT/GB2008/ 01271 novel adenovirus patent applications covering malaria vectored vaccines and immunization regimes. This does not alter our adherence to all the PLoS ONE policies on sharing data and materials. 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 our adherence to all the PLoS ONE policies on sharing data and materials. An effective vaccine against the blood-stage of Plasmodium falciparum infection could significantly contribute to any future strategy for reducing malaria morbidity and mortality, limiting transmission and aiding disease eradication [1]. Although antidisease and anti-parasitic immunity is naturally acquired against blood-stage infection following repeated exposure [2], replicating such immunity by vaccination has proved extremely difficult [3]. There have been recent reports of efficacy observed in retrospective/post-hoc analyses from Phase Ib safety and immunogenicity trials of a blood-stage vaccine [4] or one with a bloodstage component [5]. More encouragingly, significant strainspecific efficacy was also recently reported in a pre-specified secondary analysis of a Phase IIb trial of a mono-valent 3D7 strain apical membrane antigen 1 (AMA1) protein vaccine [6]. Of note, this vaccine also showed an encouraging signal in a prior Phase IIa controlled human malaria infection study [7]. However, despite these extensive efforts to date, no candidate blood-stage vaccine has been developed that has demonstrated statistically significant efficacy with regard to clinical outcome in a pre-specified primary endpoint analysis in a Phase IIa/b clinical trial designed to assess vaccine efficacy [3,8]. The majority of such blood-stage vaccine candidates have traditionally focused on recombinant protein-inadjuvant formulations with the aim of inducing growth inhibitory antibody responses against merozoite antigens involved in the erythrocyte invasion process [3]. However, increasing evidence suggests that T cells can also play an important contributory role in the mediation (...truncated)