Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-1) administered in adjuvant system AS01B or AS02A.
BACKGROUND
This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A Adjuvant Systems.


RESULTS
After a preliminary safety evaluation of low dose AMA-1/AS01B (10 microg/0.5 mL) in 5 adults, 30 malaria-naïve adults were randomly allocated to receive full dose (50 microg/0.5 mL) of AMA-1/AS01B (n = 15) or AMA-1/AS02A (n = 15), followed by a malaria challenge. All vaccinations were administered intramuscularly on a 0-, 1-, 2-month schedule. All volunteers experienced transient injection site erythema, swelling and pain. Two weeks post-third vaccination, anti-AMA-1 Geometric Mean Antibody Concentrations (GMCs) with 95% Confidence Intervals (CIs) were high: low dose AMA-1/AS01B 196 microg/mL (103-371 microg/mL), full dose AMA-1/AS01B 279 microg/mL (210-369 microg/mL) and full dose AMA-1/AS02A 216 microg/mL (169-276 microg/mL) with no significant difference among the 3 groups. The three vaccine formulations elicited equivalent functional antibody responses, as measured by growth inhibition assay (GIA), against homologous but not against heterologous (FVO) parasites as well as demonstrable interferon-gamma (IFN-gamma) responses. To assess efficacy, volunteers were challenged with P. falciparum-infected mosquitoes, and all became parasitemic, with no significant difference in the prepatent period by either light microscopy or quantitative polymerase chain reaction (qPCR). However, a small but significant reduction of parasitemia in the AMA-1/AS02A group was seen with a statistical model employing qPCR measurements.


CONCLUSIONS
All three vaccine formulations were found to be safe and highly immunogenic. These immune responses did not translate into significant vaccine efficacy in malaria-naïve adults employing a primary sporozoite challenge model, but encouragingly, estimation of parasite growth rates from qPCR data may suggest a partial biological effect of the vaccine. Further evaluation of the immunogenicity and efficacy of the AMA-1/AS02A formulation is ongoing in a malaria-experienced pediatric population in Mali.


BACKGROUND
www.clinicaltrials.gov NCT00385047.
Spring
Michele D
MD
United States Military Malaria Vaccine Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America. michele.spring@us.army.mil
Cummings
James F
JF
Ockenhouse
Christian F
CF
Dutta
Sheetij
S
Reidler
Randall
R
Angov
Evelina
E
Bergmann-Leitner
Elke
E
Stewart
V Ann
VA
Bittner
Stacey
S
Juompan
Laure
L
Kortepeter
Mark G
MG
Nielsen
Robin
R
Krzych
Urszula
U
Tierney
Ev
E
Ware
Lisa A
LA
Dowler
Megan
M
Hermsen
Cornelus C
CC
Sauerwein
Robert W
RW
de Vlas
Sake J
SJ
Ofori-Anyinam
Opokua
O
Lanar
David E
DE
Williams
Jack L
JL
Kester
Kent E
KE
Tucker
Kathryn
K
Shi
Meng
M
Malkin
Elissa
E
Long
Carole
C
Diggs
Carter L
CL
Soisson
Lorraine
L
Dubois
Marie-Claude
MC
Ballou
W Ripley
WR
Cohen
Joe
J
Heppner
D Gray
DG
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D000953:Antigens, Protozoan / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D004311:Double-Blind Method; D004338:Drug Combinations; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008565:Membrane Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000276:immunology / Q000378:metabolism; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D012503:Saponins / Q000008:administration & dosage* / Q000494:pharmacology
C501939:ASO2A adjuvant; D000276:Adjuvants, Immunologic; D000953:Antigens, Protozoan; D004338:Drug Combinations; D008050:Lipid A; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; D012503:Saponins; C090077:apical membrane antigen I, Plasmodium