Assessment of Humoral Immune Responses to Blood-Stage Malaria Antigens following ChAd63-MVA Immunization, Controlled Human Malaria Infection and Natural Exposure

Controlled Human Malaria Infection and Natural Exposure. PLoS ONE 9(9): e107903. doi:10.1371/journal.pone.0107903 Assessment of Humoral Immune Responses to Blood- Stage Malaria Antigens following ChAd63-MVA Immunization, Controlled Human Malaria Infection and Natural Exposure Sumi Biswas 0 Prateek Choudhary 0 Sean C. Elias 0 Kazutoyo Miura 0 Kathryn H. Milne 0 Simone C. de Cassan 0 Katharine A. Collins 0 Fenella D. Halstead 0 Carly M. Bliss 0 Katie J. Ewer 0 Faith H. Osier 0 Susanne H. Hodgson 0 Christopher J. A. Duncan 0 Geraldine A. O'Hara 0 Carole A. Long 0 Adrian V. S. Hill 0 Simon J. Draper 0 Denise L. Doolan, Queensland Institute of Medical Research, Australia 0 1 The Jenner Institute, University of Oxford , Oxford , United Kingdom , 2 Laboratory of Malaria and Vector Research, NIAID/NIH, Rockville, Maryland, United States of America, 3 KEMRI Centre for Geographic Medicine Research, Kilifi, Kenya, 4 Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital , Oxford , United Kingdom The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite - MSP1 and AMA1. These antigens were delivered to healthy malaria-nave adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors - ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases targets, these data should help to guide further immuno-monitoring studies of vaccine-induced human antibody responses. - Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by the UK Medical Research Council (MRC; http://www.mrc.ac.uk) [grant number G0700735]; the EMVDA (European Malaria Vaccine Development Association; http://www.emvda.org), a European Commission FP6-funded consortium [LSHP-CT-2007-037506]; the UK National Institute of Health Research through the Oxford Biomedical Research Centre (http://oxfordbrc.nihr.ac.uk/); the Wellcome Trust (http://www.wellcome.ac.uk) [084113/Z/07/Z]; and by EVIMalaR (http://www.evimalar.org) funded by the European Communitys Seventh Framework Programme (FP7/2007-2013) [Grant agreement No. 242095]. The GIA work was supported by the PATH Malaria Vaccine Initiative (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). SHH holds a Wellcome Trust Research Training Fellowship (097940/Z/11/Z). AVSH and SJD are Jenner Investigators (http://www.jenner.ac.uk). SB is a NDM Leadership Fellow (http://www.ndm.ox.ac.uk) and Junior Research Fellow of St Catherines College, Oxford University (http://www.stcatz.ox.ac.uk). SJD is a UK MRC Career Development Fellow [G1000527] and Lister Institute Research Prize Fellow (http://www.lister-institute.org.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: SCdC, KAC, AVSH and SJD are named inventors on patent applications covering malaria vaccines and immunization regimes (Adenoviral vectors encoding a pathogen or tumour antigen, WO/2008/122811; Viral vector immunogenic compositions, GB1016471.3). This does not alter the authors adherence to PLoS ONE policies on sharing data and materials. . These authors contributed equally to this work. Plasmodium falciparum is the preeminent cause of human malaria disease and a leading example of a parasite with a complex multi-host multi-stage lifecycle where a number of steps in the infectious process have been shown to be antibodysusceptible. These include the invasion of liver cells by sporozoites delivered from the mosquito bite; the invasion of red blood cells (RBC) by merozoites; clearance of infected RBC; and sexual-stage development within the blood meal inside the mosquito midgut [1]. However, despite tremendous efforts, the development of a highly effective subunit vaccine against infection, disease or transmission has proved an elusive goal, and P. falciparum continues to exert a huge burden on global public health in terms of morbidity and mortality [2], as well as financially in terms of maintaining effective control and intervention measures [3]. Such difficulties, with regard to subunit vaccine development have arisen through a variety of reasons, including factors relating to the complex biology of the parasites lifecycle coupled with an incomplete understanding of protective immune effector mechanisms that function in vivo in humans [4]. One leading strategy for many years has sought to develop an effective antibody-inducing vaccine against the blood-stage merozoite, seeking to neutralize RBC invasion [5]. For a number of decades, merozoite surface protein 1 (MSP1) [6] and apical membrane antigen 1 (AMA1) [7] have been assessed as leading subunit vaccine candidate antigens both are expressed by the invasive blood-stage merozoite, with evidence they are also present at the late liver-stage [8] or sporozoite stage [9] of the parasite lifecycle. These antigens, most often delivered as antibodyinducing recombinant protein formulated in adjuvant, (...truncated)