title: Phase 1 clinical trial of apical membrane antigen 1: an asexual blood-stage vaccine for Plasmodium falciparum malaria.
abstract: Apical membrane antigen 1 (AMA1), a polymorphic merozoite surface protein, is a leading blood-stage malaria vaccine candidate. A phase 1 trial was conducted with 30 malaria-naive volunteers to assess the safety and immunogenicity of the AMA1-C1 malaria vaccine. AMA1-C1 contains an equal mixture of recombinant proteins based on sequences from the FVO and 3D7 clones of Plasmodium falciparum. The proteins were expressed in Pichia pastoris and adsorbed on Alhydrogel. Ten volunteers in each of three dose groups (5 mug, 20 mug, and 80 mug) were vaccinated in an open-label study at 0, 28, and 180 days. The vaccine was well tolerated, with pain at the injection site being the most commonly observed reaction. Anti-AMA1 immunoglobulin G (IgG) was detected by enzyme-linked immunosorbent assay (ELISA) in 15/28 (54%) volunteers after the second immunization and in 23/25 (92%) after the third immunization, with equal reactivity to both AMA1-FVO and AMA1-3D7 vaccine components. A significant dose-response relationship between antigen dose and antibody response by ELISA was observed, and the antibodies were predominantly of the IgG1 isotype. Confocal microscopic evaluation of sera from vaccinated volunteers demonstrated reactivity with P. falciparum schizonts in a pattern similar to native parasite AMA1. Antigen-specific in vitro inhibition of both FVO and 3D7 parasites was achieved with IgG purified from sera of vaccinees, demonstrating biological activity of the antibodies. To our knowledge, this is the first AMA1 vaccine candidate to elicit functional immune responses in malaria-naive humans, and our results support the further development of this vaccine.
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Center for Immunization Research, 624 N. Broadway, Room 217, Baltimore, MD 21205, USA. emalkin@niaid.nih.gov
authors.forename: Elissa M
authors.initials: EM
authors.lastname: Malkin
authors.forename: David J
authors.initials: DJ
authors.lastname: Diemert
authors.forename: Julie H
authors.initials: JH
authors.lastname: McArthur
authors.forename: John R
authors.initials: JR
authors.lastname: Perreault
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Miles
authors.forename: Birgitte K
authors.initials: BK
authors.lastname: Giersing
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Mullen
authors.forename: Andrew
authors.initials: A
authors.lastname: Orcutt
authors.forename: Olga
authors.initials: O
authors.lastname: Muratova
authors.forename: May
authors.initials: M
authors.lastname: Awkal
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Anthony
authors.initials: A
authors.lastname: Stowers
authors.forename: Carole A
authors.initials: CA
authors.lastname: Long
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mahanty
authors.forename: Louis H
authors.initials: LH
authors.lastname: Miller
authors.forename: Allan
authors.initials: A
authors.lastname: Saul
authors.forename: Anna P
authors.initials: AP
authors.lastname: Durbin
mesh_terms: D000328:Adult; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000953:Antigens, Protozoan / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D017780:Malaria Vaccines / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D018613:Microscopy, Confocal; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000254:growth & development / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D007074:Immunoglobulin G; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; D014614:Vaccines, Synthetic; C090077:apical membrane antigen I, Plasmodium