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Infection and Immunity, December 2001, p. 7250-7253, Vol. 69, No. 12
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.12.7250-7253.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Codon Optimization of Gene Fragments Encoding Plasmodium falciparum Merzoite Proteins Enhances DNA Vaccine Protein Expression and Immunogenicity in Mice

David L. Narum,1 Sanjai Kumar,2 William O. Rogers,2 Steven R. Fuhrmann,1 Hong Liang,1 Miranda Oakley,2 Alem Taye,2 B. Kim Lee Sim,1 and Stephen L. Hoffman2,*

EntreMed, Inc., Rockville,1 and Malaria Program, Naval Medical Research Center, Silver Spring,2 Maryland

Received 29 May 2001/Returned for modification 7 July 2001/Accepted 30 August 2001

In contrast to conventional vaccines, DNA and other subunit vaccines exclusively utilize host cell molecules for transcription and translation of proteins. The adenine plus thymine content of Plasmodium falciparum gene sequences (~80%) is much greater than that of Homo sapiens (~59%); consequently, codon usage is markedly different. We hypothesized that modifying codon usage of P. falciparum genes encoded by DNA vaccines from that used by the parasite to those resembling mammalian codon usage would lead to increased P. falciparum protein expression in vitro in mouse cells and increased antibody responses in DNA-vaccinated mice. We synthesized gene fragments encoding the receptor-binding domain of the 175-kDa P. falciparum erythrocyte-binding protein (EBA-175 region II) and the 42-kDa C-terminal processed fragment of the P. falciparum merozoite surface protein 1 (MSP-142) using the most frequently occurring codon in mammals to code for each amino acid, and inserted the synthetic genes in DNA vaccine plasmids. In in vitro transient-expression assays, plasmids containing codon-optimized synthetic gene fragments (pS plasmids) showed greater than fourfold increased protein expression in mouse cells compared to those containing native gene fragments (pN plasmids). In mice immunized with 0.5, 5.0, or 50 µg of the DNA plasmids, the dose of DNA required to induce equivalent antibody titers was 10- to 100-fold lower for pS than for pN plasmids. These data demonstrate that optimizing codon usage in DNA vaccines can improve protein expression and consequently the immunogenicity of gene fragments in DNA vaccines for organisms whose codon usage differs substantially from that of mammals.

* Corresponding author. Present address: Celera Genomics, 45 West Gude Drive, Rockville, MD 20850-1232. Phone: (240) 453-3580. Fax: (240) 453-4580. E-mail: Stephen.Hoffman{at}Celera.com.

Infection and Immunity, December 2001, p. 7250-7253, Vol. 69, No. 12
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.12.7250-7253.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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