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Clin. Vaccine Immunol. doi:10.1128/CVI.00420-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Activation of Innate Immunity in Healthy Macaca mulatta by Single Subcutaneous Dose of cGMP CpG 7909; Safety, IP-10 Kinetics and Comparison to Human Responses

Walter Reed Army Institute of Research, Silver Spring, Maryland, USA; Coley Pharmaceutical Group, Wellesley, Massachusetts, USA; Defense Advanced Research Projects Agency, Arlington, Virginia, USA

^* To whom correspondence should be addressed. Email: ann.stewart{at}wrp-ksm.org.

	Abstract

Background: Following demonstration that mouse-optimized CpG oligodeoxynucleotides stimulated innate immune protection against intracellular pathogens, we tested the ability of CpG 7909, a primate-optimized TLR9 agonist, to stimulate rhesus macaques to produce interferon-inducible protein-10 (IP-10), a biomarker of immune activation. This study was performed prior to a similar trial in humans, in order to facilitate the development of CpG 7909 as an immunomodulator for biodefense.

Methods: A single, subcutaneous dose of clinical grade CpG 7909 was given to 4 groups of healthy adult rhesus macaques [0 mg (n=5), 0.75 mg (n=9), 1.5 mg (n=9) or 3.0 mg (n=9)]. Directed physical examination findings, clinical laboratory values, and serum IP-10 concentrations were collected at scheduled intervals for 28 days.

Results: All three dose levels of CpG 7909 were safe and not associated with significant clinical or laboratory abnormality. Time to peak serum IP-10 concentration was 1.0 days at the 0.75 mg dose, and 0.5 days for the 1.5 and 3.0 mg doses. A dose-dependent response was observed for the magnitude and duration of IP-10 concentrations, which remained significantly above baseline for 3 days in the 3.0 mg and 1.5 mg dose groups, but above baseline for only 2 days in the 0.75 mg dose group. There were no non-responders to CpG 7909. These rhesus macaque safety and IP-10 response data closely parallel a subsequent Phase 1 human study of subcutaneously administered CpG 7909.

Conclusion: A single dose of clinical grade CpG 7909 induced a rapid, sustained IP-10 response, a biomarker for activation of the innate immune system. Given the similar susceptibility of humans and rhesus macaque to infectious diseases, the rhesus macaque appears to be a suitable model to evaluate the potential of CpG 7909-mediated innate immune activation to protect humans against pathogens.