title: Combining viral vectored and protein-in-adjuvant vaccines against the blood-stage malaria antigen AMA1: report on a phase 1a clinical trial.
abstract: The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase 1a clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines--chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising "mixed-modality" regimens were tested. All volunteers were primed with ChAd63, and then subsequently boosted with MVA and/or protein-in-adjuvant using either an 8- or 16-week prime-boost interval. We report on the safety of these regimens, as well as the T cell, B cell, and serum antibody responses. Notably, IgG antibody responses primed by ChAd63 were comparably boosted by AMA1 protein vaccine, irrespective of whether CPG 7909 was included in the Alhydrogel adjuvant. The ability to improve the potency of a relatively weak aluminium-based adjuvant in humans, by previously priming with an adenoviral vaccine vector encoding the same antigen, thus offers a novel vaccination strategy for difficult or neglected disease targets when access to more potent adjuvants is not possible.
authors.affiliation: The Jenner Institute Laboratories, University of Oxford, Oxford, UK; Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, UK. Electronic address: susanne.hodgson@ndm.ox.ac.uk.
authors.forename: Susanne H
authors.initials: SH
authors.lastname: Hodgson
authors.affiliation: The Jenner Institute Laboratories, University of Oxford, Oxford, UK.
authors.forename: Prateek
authors.initials: P
authors.lastname: Choudhary
authors.affiliation: The Jenner Institute Laboratories, University of Oxford, Oxford, UK.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Elias
authors.affiliation: The Jenner Institute Laboratories, University of Oxford, Oxford, UK.
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Milne
authors.affiliation: The Jenner Institute Laboratories, University of Oxford, Oxford, UK; Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Rampling
authors.affiliation: The Jenner Institute Laboratories, University of Oxford, Oxford, UK.
authors.forename: Sumi
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Poulton
authors.affiliation: Laboratory of Malaria and Vector Research, NIAID/NIH, Rockville, Maryland, USA.
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Miura
authors.affiliation: The Jenner Institute Laboratories, University of Oxford, Oxford, UK.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Douglas
authors.affiliation: The Jenner Institute Laboratories, University of Oxford, Oxford, UK.
authors.forename: Daniel Gw
authors.initials: DG
authors.lastname: Alanine
authors.affiliation: The Jenner Institute Laboratories, University of Oxford, Oxford, UK.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Illingworth
authors.affiliation: The Jenner Institute Laboratories, University of Oxford, Oxford, UK.
authors.forename: Simone C
authors.initials: SC
authors.lastname: de Cassan
authors.affiliation: Laboratory of Malaria and Vector Research, NIAID/NIH, Rockville, Maryland, USA.
authors.forename: Daming
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Okairòs, Rome, Italy; CEINGE, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Nicosia
authors.affiliation: Laboratory of Malaria and Vector Research, NIAID/NIH, Rockville, Maryland, USA.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Long
authors.affiliation: Clinical Biomanufacturing Facility, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Moyle
authors.affiliation: Clinical Biomanufacturing Facility, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Berrie
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Lawrie
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, NIAID/NIH, Rockville, Maryland, USA.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, NIAID/NIH, Rockville, Maryland, USA.
authors.forename: Ruth D
authors.initials: RD
authors.lastname: Ellis
authors.affiliation: The Jenner Institute Laboratories, University of Oxford, Oxford, UK.
authors.forename: Adrian V S
authors.initials: AVS
authors.lastname: Hill
authors.affiliation: The Jenner Institute Laboratories, University of Oxford, Oxford, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Draper
mesh_terms: D000261:Adenoviruses, Simian / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D000536:Aluminum Hydroxide / Q000008:administration & dosage; D000953:Antigens, Protozoan / Q000008:administration & dosage* / Q000276:immunology; D003131:Combined Modality Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007117:Immunization, Secondary; D017780:Malaria Vaccines / Q000008:administration & dosage*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D018155:Orthopoxvirus / Q000235:genetics; D010963:Plasmodium falciparum / Q000276:immunology*; D014611:Vaccination; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D009838:Oligodeoxyribonucleotides; C483020:ProMune; D000536:Aluminum Hydroxide