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. Methodology/Principal Findings: After a preliminary safety evaluation of low dose AMA-1/AS01B (10 μg/0.5 mL) in 5 adults, 30 malaria-naïve adults were randomly allocated to receive full dose (50 μg/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 μg/mL (103-371 μg/mL), full dose AMA-1/AS01B 279 μg/mL (210-369 μg/ mL) and full dose AMA-1/AS02A 216 μg/mL (169-276 μg/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-γ) 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. Significance: 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.

Additional Metadata
Keywords ASO2A adjuvant, Plasmodium, Plasmodium falciparum, adolescent, adult, allele, animal, antibody detection, antibody response, apical membrane antigen 1, apical membrane antigen I, arthralgia, article, chloroquine, clinical trial, controlled clinical trial, controlled study, double blind procedure, drug combination, drug derivative, drug dose comparison, drug efficacy, drug eruption, drug fever, drug induced headache, drug megadose, drug safety, enzyme linked immunosorbent assay, fatigue, female, gamma interferon, genetics, human, immunogenicity, immunological adjuvant, immunology, injection site erythema, injection site pain, injection site swelling, lipid A, liposome, low drug dose, major clinical study, malaise, malaria falciparum, malaria vaccine, male, membrane protein, metabolism, middle aged, myalgia, nausea, papule, parasite antibody, parasite antigen, parasitemia, phase 1 clinical trial, phase 2 clinical trial, protozoal protein, pruritus, randomized controlled trial, saponin, skin inflammation, sporozoite
Persistent URL dx.doi.org/10.1371/journal.pone.0005254, hdl.handle.net/1765/16419
Citation
Spring, M.D., Cummings, J.F., Ockenhouse, C.F., Dutta, S., Reidler, R., Angov, E., … Heppner, D.G.. (2009). Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-l) administered in adjuvant system AS01B or AS02A. PLoS ONE, 4(4). doi:10.1371/journal.pone.0005254