title: Phase Ia clinical evaluation of the safety and immunogenicity of the Plasmodium falciparum blood-stage antigen AMA1 in ChAd63 and MVA vaccine vectors.
abstract: 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.
  
  
  METHODS
  We conducted a Phase Ia, non-randomized clinical trial in 16 healthy, malaria-naïve 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). ChAd63-MVA AMA1 administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level 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 µg/mL and 41 µg/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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01095055.
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, United Kingdom. susanne.sheehy@ndm.ox.ac.uk
authors.forename: Susanne H
authors.initials: SH
authors.lastname: Sheehy
authors.forename: Christopher J A
authors.initials: CJ
authors.lastname: Duncan
authors.forename: Sean C
authors.initials: SC
authors.lastname: Elias
authors.forename: Sumi
authors.initials: S
authors.lastname: Biswas
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Collins
authors.forename: Geraldine A
authors.initials: GA
authors.lastname: O'Hara
authors.forename: Fenella D
authors.initials: FD
authors.lastname: Halstead
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Ewer
authors.forename: Tabitha
authors.initials: T
authors.lastname: Mahungu
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Spencer
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Miura
authors.forename: Ian D
authors.initials: ID
authors.lastname: Poulton
authors.forename: Matthew D J
authors.initials: MD
authors.lastname: Dicks
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Edwards
authors.forename: Eleanor
authors.initials: E
authors.lastname: Berrie
authors.forename: Sarah
authors.initials: S
authors.lastname: Moyle
authors.forename: Stefano
authors.initials: S
authors.lastname: Colloca
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cortese
authors.forename: Katherine
authors.initials: K
authors.lastname: Gantlett
authors.forename: Carole A
authors.initials: CA
authors.lastname: Long
authors.forename: Alison M
authors.initials: AM
authors.lastname: Lawrie
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gilbert
authors.forename: Tom
authors.initials: T
authors.lastname: Doherty
authors.forename: Alfredo
authors.initials: A
authors.lastname: Nicosia
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Draper
mesh_terms: D000261:Adenoviruses, Simian / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000913:Antibodies, Protozoan / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000276:immunology; D008018:Life Cycle Stages; D017780:Malaria Vaccines / Q000009:adverse effects* / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000254:growth & development / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics*; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D007371:Interferon-gamma