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Infection and Immunity, February 2004, p. 949-957, Vol. 72, No. 2
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.2.949-957.2004

CpG Oligodeoxynucleotide and Montanide ISA 51 Adjuvant Combination Enhanced the Protective Efficacy of a Subunit Malaria Vaccine

Sanjai Kumar,^1,2* Trevor R. Jones,¹ Miranda S. Oakley,¹ Hong Zheng,¹ Shanmuga P. Kuppusamy,¹ Alem Taye,¹ Arthur M. Krieg,³ Anthony W. Stowers,^4, David C. Kaslow,^4, and Stephen L. Hoffman^1,

Malaria Program, Naval Medical Research Center, Silver Spring, Maryland 20910,¹ Department of Microbiology and Immunology, Bloomberg School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205,² Coley Pharmaceutical Group, Wellesley, Massachusetts 02481, and Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242,³ Malaria Vaccine Development Unit, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892⁴

Received 2 September 2003/ Returned for modification 14 October 2003/ Accepted 16 November 2003

Unmethylated CpG dinucleotide motifs present in bacterial genomes or synthetic oligodeoxynucleotides (ODNs) serve as strong immunostimulatory agents in mice, monkeys and humans. We determined the adjuvant effect of murine CpG ODN 1826 on the immunogenicity and protective efficacy of the Saccharomyces cerevisiae-expressed 19-kDa C-terminal region of merozoite surface protein 1 (yMSP1₁₉) of the murine malaria parasite Plasmodium yoelii. We found that in C57BL/6 mice, following sporozoite challenge, the degree of protective immunity against malaria induced by yMSP1₁₉ in a formulation of Montanide ISA 51 (ISA) plus CpG ODN 1826 was similar or superior to that conferred by yMSP1₁₉ emulsified in complete Freund's adjuvant (CFA/incomplete Freund's adjuvant). In total, among mice immunized with yMSP1₁₉, 22 of 32 (68.7%) with ISA plus CpG 1826, 0 of 4 (0%) with CFA/incomplete Freund’s adjuvant, 0 of 4 (0%) with CpG 1826 mixed with ISA (no yMSP1₁₉), and 0 of 11 (0%) with CpG 1826 alone were completely protected against development of erythrocytic stage infection after sporozoite challenge. The adjuvant effect of CpG ODN 1826 was manifested as both significantly improved complete protection from malaria (defined as the absence of detectable erythrocytic form parasites) (P = 0.007, chi square) and reduced parasite burden in infected mice. In vivo depletions of interleukin-12 and gamma interferon cytokines and CD4⁺ and CD8⁺ T cells in vaccinated mice had no significant effect on immunity. On the other hand, immunoglobulin G (IgG) isotype levels appeared to correlate with protection. Inclusion of CpG ODN 1826 in the yMSP1₁₉ plus ISA vaccine contributed towards the induction of higher levels of IgG2a and IgG2b (Th1 type) antibodies, suggesting that CpG ODN 1826 caused a shift towards a Th1 type of immune response that could be responsible for the higher degree of protective immunity. Our results indicate that this potent adjuvant formulation should be further evaluated for use in clinical trials of recombinant malarial vaccine candidates.

Editor: W. A. Petri, Jr.

Present address: CSL Ltd., Melbourne, Australia.

Present address: Vical Inc., San Diego, Calif.

Present address: Sanaria Inc., Gaithersburg, Md.

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