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Infection and Immunity, June 2005, p. 3677-3685, Vol. 73, No. 6
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.6.3677-3685.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phase 1 Clinical Trial of Apical Membrane Antigen 1: an Asexual Blood-Stage Vaccine for Plasmodium falciparum Malaria

Elissa M. Malkin,1* David J. Diemert,1 Julie H. McArthur,2 John R. Perreault,2 Aaron P. Miles,1 Birgitte K. Giersing,1,{dagger} Gregory E. Mullen,1 Andrew Orcutt,1 Olga Muratova,1 May Awkal,1 Hong Zhou,1 Jin Wang,1 Anthony Stowers,1,{ddagger} Carole A. Long,1 Siddhartha Mahanty,1 Louis H. Miller,1 Allan Saul,1 and Anna P. Durbin2*

Malaria Vaccine Development Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland,1 Center for Immunization Research, Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland2

Received 21 December 2004/ Returned for modification 2 February 2005/ Accepted 8 February 2005

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-naïve 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 µg, 20 µg, and 80 µg) 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-naïve humans, and our results support the further development of this vaccine.

* Corresponding author. Mailing address for Anna Durbin: Johns Hopkins University Bloomberg School of Public Health, Center for Immunization Research, 624 N. Broadway, Room 217, Baltimore, MD 21205. Phone: (410) 614-4736. Fax: (410) 502-6898. E-mail: adurbin{at}jhsph.edu. Mailing address for Elissa Malkin: Malaria Vaccine Development Branch, 5640 Fishers Lane, Twinbrook 1, Rockville, MD 20852. Phone: (301)443-2064. Fax: (301) 480-1962. E-mail: emalkin{at}niaid.nih.gov.

Editor: W. A. Petri, Jr.

{dagger} Current address: Malaria Vaccine Initiative, Rockville, Md.

{ddagger} Current address: CSL, Ltd., Victoria, Australia.

Infection and Immunity, June 2005, p. 3677-3685, Vol. 73, No. 6
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.6.3677-3685.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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