Safety and immunogenicity of a recombinant Plasmodium falciparum AMA1 malaria vaccine adjuvanted with Alhydrogel, Montanide ISA 720 or AS02.
BACKGROUND
Plasmodium falciparum Apical Membrane Antigen 1 (PfAMA1) is a candidate vaccine antigen expressed by merozoites and sporozoites. It plays a key role in red blood cell and hepatocyte invasion that can be blocked by antibodies.


RESULTS
We assessed the safety and immunogenicity of recombinant PfAMA1 in a dose-escalating, phase Ia trial. PfAMA1 FVO strain, produced in Pichia pastoris, was reconstituted at 10 microg and 50 microg doses with three different adjuvants, Alhydrogel, Montanide ISA720 and AS02 Adjuvant System. Six randomised groups of healthy male volunteers, 8-10 volunteers each, were scheduled to receive three immunisations at 4-week intervals. Safety and immunogenicity data were collected over one year. Transient pain was the predominant injection site reaction (80-100%). Induration occurred in the Montanide 50 microg group, resulting in a sterile abscess in two volunteers. Systemic adverse events occurred mainly in the AS02 groups lasting for 1-2 days. Erythema was observed in 22% of Montanide and 59% of AS02 group volunteers. After the second dose, six volunteers in the AS02 group and one in the Montanide group who reported grade 3 erythema (>50 mm) were withdrawn as they met the stopping criteria. All adverse events resolved. There were no vaccine-related serious adverse events. Humoral responses were highest in the AS02 groups. Antibodies showed activity in an in vitro growth inhibition assay up to 80%. Upon stimulation with the vaccine, peripheral mononuclear cells from all groups proliferated and secreted IFNgamma and IL-5 cytokines.


CONCLUSIONS
All formulations showed distinct reactogenicity profiles. All formulations with PfAMA1 were immunogenic and induced functional antibodies.


BACKGROUND
(Clinicaltrials.gov) NCT00730782.
Roestenberg
Meta
M
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. M.Roestenberg@mmb.umcn.nl
Remarque
Ed
E
de Jonge
Erik
E
Hermsen
Rob
R
Blythman
Hildur
H
Leroy
Odile
O
Imoukhuede
Egeruan
E
Jepsen
Soren
S
Ofori-Anyinam
Opokua
O
Faber
Bart
B
Kocken
Clemens H M
CH
Arnold
Miranda
M
Walraven
Vanessa
V
Teelen
Karina
K
Roeffen
Will
W
de Mast
Quirijn
Q
Ballou
W Ripley
WR
Cohen
Joe
J
Dubois
Marie Claude
MC
Ascarateil
Stéphane
S
van der Ven
Andre
A
Thomas
Alan
A
Sauerwein
Robert
R
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects; D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000536:Aluminum Hydroxide / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D016778:Malaria, Falciparum / Q000276:immunology* / Q000628:therapy*; D008297:Male; D008353:Mannitol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D008875:Middle Aged; D009829:Oleic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D010963:Plasmodium falciparum / Q000276:immunology; D016896:Treatment Outcome; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult
D000276:Adjuvants, Immunologic; D017780:Malaria Vaccines; D009829:Oleic Acids; D014614:Vaccines, Synthetic; C001681:mannide monooleate; D008353:Mannitol; D000536:Aluminum Hydroxide