title: Progress with viral vectored malaria vaccines: A multi-stage approach involving "unnatural immunity".
abstract: Viral vectors used in heterologous prime-boost regimens are one of very few vaccination approaches that have yielded significant protection against controlled human malaria infections. Recently, protection induced by chimpanzee adenovirus priming and modified vaccinia Ankara boosting using the ME-TRAP insert has been correlated with the induction of potent CD8(+) T cell responses. This regimen has progressed to field studies where efficacy against infection has now been reported. The same vectors have been used pre-clinically to identify preferred protective antigens for use in vaccines against the pre-erythrocytic, blood-stage and mosquito stages of malaria and this work is reviewed here for the first time. Such antigen screening has led to the prioritization of the PfRH5 blood-stage antigen, which showed efficacy against heterologous strain challenge in non-human primates, and vectors encoding this antigen are in clinical trials. This, along with the high transmission-blocking activity of some sexual-stage antigens, illustrates well the capacity of such vectors to induce high titre protective antibodies in addition to potent T cell responses. All of the protective responses induced by these vectors exceed the levels of the same immune responses induced by natural exposure supporting the view that, for subunit vaccines to achieve even partial efficacy in humans, "unnatural immunity" comprising immune responses of very high magnitude will need to be induced.
authors.affiliation: The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: katie.ewer@ndm.ox.ac.uk.
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Ewer
authors.affiliation: The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK; Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852, USA.
authors.forename: Kailan
authors.initials: K
authors.lastname: Sierra-Davidson
authors.affiliation: The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Salman
authors.affiliation: The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Illingworth
authors.affiliation: The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Draper
authors.affiliation: The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Sumi
authors.initials: S
authors.lastname: Biswas
authors.affiliation: The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002986:Clinical Trials as Topic; D006801:Humans; D007117:Immunization, Secondary; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology*; D010963:Plasmodium falciparum / Q000235:genetics / Q000254:growth & development / Q000276:immunology; D015800:Protozoan Proteins / Q000276:immunology; D014611:Vaccination; D022223:Vaccines, Subunit / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics*
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D022223:Vaccines, Subunit; C041595:circumsporozoite protein, Protozoan; C069428:thrombospondin-related adhesive protein, protozoan
keywords: Clinical trials; Immunity; Malaria; Viral vectors