Phase 1/2a Study of the Malaria Vaccine Candidate Apical Membrane Antigen-1 (AMA-1) Administered in Adjuvant System AS01B or AS02A

• Published in: PloS one Vol. 4; no. 4; p. e5254
• Main Authors: Spring, Michele D., Cummings, James F., Ockenhouse, Christian F., Dutta, Sheetij, Reidler, Randall, Angov, Evelina, Bergmann-Leitner, Elke, Stewart, V. Ann, Bittner, Stacey, Juompan, Laure, Kortepeter, Mark G., Nielsen, Robin, Krzych, Urszula, Tierney, Ev, Ware, Lisa A., Dowler, Megan, Hermsen, Cornelus C., Sauerwein, Robert W., de Vlas, Sake J., Ofori-Anyinam, Opokua, Lanar, David E., Williams, Jack L., Kester, Kent E., Tucker, Kathryn, Shi, Meng, Malkin, Elissa, Long, Carole, Diggs, Carter L., Soisson, Lorraine, Dubois, Marie-Claude, Ballou, W. Ripley, Cohen, Joe, Heppner, D. Gray
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.04.2009; Public Library of Science (PLoS)
• Subjects: Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - pharmacology; Adolescent; Adult; Adults; Alleles; Analysis; Animals; Antigens; Antigens, Protozoan - administration & dosage; Antigens, Protozoan - genetics; Antigens, Protozoan - immunology; Appropriate technology; Aquatic insects; Biological effects; Biological response modifiers; Confidence intervals; Double-Blind Method; Drug Combinations; Effectiveness; Enzyme-Linked Immunosorbent Assay; Enzymes; Erythema; Evaluation; Formulations; Goats; Growth rate; Health care; Homology; Humans; Immune response; Immunogenicity; Immunology; Infectious Diseases; Interferon; Light microscopy; Lipid A - administration & dosage; Lipid A - analogs & derivatives; Lipid A - pharmacology; Lymphocytes; Malaria; Malaria vaccine; Malaria Vaccines - administration & dosage; Malaria Vaccines - adverse effects; Malaria Vaccines - immunology; Malaria, Falciparum - prevention & control; Mathematical models; Medical research; Medical societies; Medicine, Experimental; Membrane proteins; Membrane Proteins - administration & dosage; Membrane Proteins - genetics; Membrane Proteins - immunology; Microbiology; Middle Aged; Mosquitoes; Pain; Parasitemia; Parasites; Peptides; Plasmodium falciparum; Plasmodium falciparum - immunology; Plasmodium falciparum - metabolism; Polymerase chain reaction; Population (statistical); Proteins; Protozoan Proteins - administration & dosage; Protozoan Proteins - genetics; Protozoan Proteins - immunology; Safety; Saponins - administration & dosage; Saponins - pharmacology; Statistical analysis; Statistical models; Studies; Vaccination; Vaccine efficacy; Vaccines; Vector-borne diseases; γ-Interferon; United States > US; Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005254

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. 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. 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. www.clinicaltrials.gov NCT00385047.