Evaluation of the Efficacy of ChAd63-MVA Vectored Vaccines Expressing Circumsporozoite Protein and ME-TRAP Against Controlled Human Malaria Infection in Malaria-Naive Individuals

JID Evaluation of the Efficacy of ChAd63-MVA Vectored Vaccines Expressing Circumsporozoite Protein and ME-TRAP Against Controlled Human Malaria Infection in Malaria-Naive Individuals Susanne H. Hodgson Katie J. Ewer Carly M. Bliss Nick J. Edwards Thomas Rampling Nicholas A. Anagnostou Eoghan de Barra 3 Tom Havelock 5 Georgina Bowyer Ian D. Poulton Simone de Cassan Rhea Longley Joseph J. Illingworth Alexander D. Douglas Pooja B. Mange Katharine A. Collins Rachel Roberts Stephen Gerry 1 Eleanor Berrie 0 Sarah Moyle 0 Stefano Colloca Riccardo Cortese 2 Robert E. Sinden 4 Sarah C. Gilbert Philip Bejon 7 Alison M. Lawrie Alfredo Nicosia 6 Saul N. Faust 5 Adrian V. S. Hill 0 Clinical Biomanufacturing Facility, University of Oxford 1 Centre for Statistics in Medicine 2 Okairos , Basel , Switzerland 3 Royal College of Surgeons in Ireland , Dublin , Ireland 4 Division of Cell and Molecular Biology, Imperial College London , United Kingdom 5 NIHR Wellcome Trust Clinical Research Facility, University of Southampton and University Hospital Southampton NHS Foundation Trust 6 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II , Italy 7 Centre for Geographical Medical Research (Coast), Kenya Medical Research Institute-Wellcome Trust , Kilifi Background. Circumsporozoite protein (CS) is the antigenic target for RTS,S, the most advanced malaria vaccine to date. Heterologous prime-boost with the viral vectors simian adenovirus 63 (ChAd63)-modified vaccinia virus Ankara (MVA) is the most potent inducer of T-cells in humans, demonstrating significant efficacy when expressing the preerythrocytic antigen insert multiple epitope-thrombospondin-related adhesion protein (ME-TRAP). We hypothesized that ChAd63-MVA containing CS may result in a significant clinical protective efficacy. Methods. We conducted an open-label, 2-site, partially randomized Plasmodium falciparum sporozoite controlled human malaria infection (CHMI) study to compare the clinical efficacy of ChAd63-MVA CS with ChAd63-MVA ME-TRAP. Results. One of 15 vaccinees (7%) receiving ChAd63-MVA CS and 2 of 15 (13%) receiving ChAd63-MVA METRAP achieved sterile protection after CHMI. Three of 15 vaccinees (20%) receiving ChAd63-MVA CS and 5 of 15 (33%) receiving ChAd63-MVA ME-TRAP demonstrated a delay in time to treatment, compared with unvaccinated controls. In quantitative polymerase chain reaction analyses, ChAd63-MVA CS was estimated to reduce the liver parasite burden by 69%-79%, compared with 79%-84% for ChAd63-MVA ME-TRAP. Conclusions. ChAd63-MVA CS does reduce the liver parasite burden, but ChAd63-MVA ME-TRAP remains the most promising antigenic insert for a vectored liver-stage vaccine. Detailed analyses of parasite kinetics may allow detection of smaller but biologically important differences in vaccine efficacy that can influence future vaccine development. Clinical Trials Registration. NCT01623557. - The worldwide burden of P. falciparum malaria remains a major public health concern [1], with approximately 207 million cases and 627 000 deaths worldwide in 2012 [2]. The preerythrocytic P. falciparum vaccine RTS,S, formed from fusion of the circumsporozoite protein (CS) to the surface-antigen of hepatitis B virus, is the most advanced malaria vaccine in development. However, it confers only limited, relatively shortlived protection in African infants [35]. Analysis of the immunological correlates of immunity induced by RTS,S suggests that high levels of antibodies against CS on the sporozoite correlate with protection, with a possible minor contribution from low levels of induced CD4+ T cells [68]. While these clinical results are the most effective to date in a field setting, there remains a need to improve on this limited clinical efficacy [9, 10], either through modifications to RTS,S or by developing vaccine strategies that combine numerous antigens or vaccine platforms. Increasingly, data from animal models and vectored immunizations demonstrate a correlation between CD8+ T cells and immunity to liver-stage parasites, even in the absence of antibodies [1117]. Clinical vaccine development had been hampered by the limited ability of traditional subunit vaccine strategies, namely adjuvanted protein constructs, to induce high enough numbers of antigen-specific CD8+ T cells that may confer protection [18]. However, more recently, adenoviral-vectored malaria vaccines administered in heterologous prime-boost regimens with a modified vaccinia virus Ankara (MVA) boost have been capable of inducing good humoral and T-cell responses that include high levels of CD8+ T cells [1721]. These CD8+ T-cell responses have been associated with clinical efficacy [17]. Given concerns regarding the effect of preexisting immunity on the immunological potency of human adenoviruses, simian adenoviruses (ChAd) are being developed as alternative, potent vectors [22]. Indeed, prime-boost vaccination with ChAd63 and MVA expressing the leading preerythrocytic antigen, ME-TRAP, is clinically the most potent inducer of CD8+ T cells in humans and the most effective malaria vaccine besides RTS,S, demonstrating efficacy, defined as sterile protection or delay, in 8 of 14 malaria-naive volunteers (57%) following sporozoite challenge [17]. Given that CS is expressed during both the sporozoite and liver stages of P. falciparum infection and therefore is possibly susceptible to both humoral and cell-mediated immunity at both stages, we assess here the efficacy of ChAd63-MVA expressing CS. If effective, this vaccine could then be combined with ChAd63-MVA expressing ME-TRAP or RTS,S, to improve clinical efficacy. Following a phase 1a study of ChAd63-MVA CS in malaria-naive volunteers, in which the regimen was shown to be safe and immunogenic (de Barra et al, submitted), we performed a study of controlled human infection with Plasmodium sporozoites (also known as controlled human malaria infection [CHMI]) [23], using the standard challenge model involving infectious bites from 5 mosquitoes, to compare the efficacy of ChAd63-MVA CS with that of ChAd63-MVA ME-TRAP. Participants The study was conducted at the Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford (Oxford, United Kingdom), and at the National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility, part of the University of Southampton and University Hospital Southampton National Health Service (NHS) Foundation Trust (Southampton, United Kingdom). The challenge procedure was performed as previously described [24], using 5 infectious bites from P. falciparum strain 3D7infected Anopheles stephensi mosquitoes. This took place at the Alexander Fleming Building, Imperial College (London, United Kingdom), and mosquitoes were supplied by the Department of Entomology, Walter Reed Army Institute of Research (WRAIR; Washington, DC). Healthy, malaria-naive men and non-pregnant women aged 1845 years were invited to part (...truncated)