CPG 7909, an Immunostimulatory TLR9 Agonist Oligodeoxynucleotide, as Adjuvant to Engerix-B� HBV Vaccine in Healthy Adults: A Double-Blind Phase I/II Study

Abstract

Oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG ODN) act as potent Th1-like immune enhancers with many antigens in animal models. We have extended these observations to the first clinical evaluation of the safety, tolerability and immunogenicity of CPG 7909 when added to a commercial HBV vaccine. In a randomized, double-blind phase I dose escalation study, healthy volunteers aged 18-35 years were vaccinated at 0, 4 and 24 weeks by intramuscular injection with Engerix-B (GlaxoSmithKline). The regular adult dose of 20 microg recombinant hepatitis B surface antigen (HBsAg) adsorbed to alum was administered mixed with saline (control) or with CPG 7909 at one of three doses (0.125, 0.5 or 1.0 mg). HBsAg-specific antibody responses (anti-HBs) appeared significantly sooner and were significantly higher at all timepoints up to and including 24 weeks in CPG 7909 recipients compared to control subjects (p< or = 0.001). Strikingly, most CpG 7909-vaccinated subjects developed protective levels of anti-HBs IgG within just two weeks of the priming vaccine dose. A trend towards higher rates of positive cytotoxic T cell lymphocyte responses was noted in the two higher dose groups of CPG 7909 compared to controls. The most frequently reported adverse events were injection site reactions, flu-like symptoms and headache. While these were more frequent in CPG 7909 groups than in the control group (p<0.0001), most were reported to be of mild to moderate intensity regardless of group. In summary, CPG 7909 as an adjuvant to Engerix-B was well-tolerated and enhanced vaccine immunogenicity. CPG 7909 may allow the development of a two-dose prophylactic HBV vaccine.

T cell responses to hepatitis B surface antigen are detectable in non-vaccinated individuals

“…Currently, early studies using immunostimulatory CpG oligodeoxynucleotides (CpG ODN) suggest a breakthrough in hepatitis B prevention. Not only do vaccines develop considerably higher titers after three vaccinations with this new combination vaccine, but most of them already mount protective titers after the first vaccination compared to none of the controls immunized with HBsAg alone [37] . It will be interesting to study whether the seroconversion after HBV-CpG ODN vaccination is also accompanied by the induction of T cell responses as shown here and whether previous non-responders will now mount comparable T cell responses as a result of vaccination.…”

Potential adjuvantic properties of innate immune stimuli

“…The majority of individuals receiving CPG 7909 also developed protective levels of anti-HBs IgG within just 2 weeks of the priming vaccine dose, compared with none of the subjects receiving the commercial vaccine alone. 221 The use of CpG ODN also increased the proportion of antigen-specific high-avidity antibodies, indicating augmentation of the late-affinity maturation in the activated plasmocytes. 222 It is pertinent to note in this context that CpG oligodeoxynucleotides are distinguished in their ability to expand the long-lived memory B cell populations.…”

Non‐clinical safety evaluation of repeated intramuscular administration of the AS15 immunostimulant combined with various antigens in rabbits and cynomolgus monkeys

“…Furthermore, no signs of systemic toxicity were observed after single or repeated administrations of the malaria candidate vaccines formulated with AS01 or AS02 Adjuvant Systems in rabbits (Segal et al ., 2015). CpG ODNs have been tested as adjuvants in a number of non‐clinical and phase I–III clinical trials testing vaccines against infectious diseases (Cooper et al ., 2004a,2004b; Klinman et al ., 2006; Mullen et al ., 2008) and cancer (Brody et al ., 2010; Pilon‐Thomas et al ., 2006; Speiser et al ., 2005; Valmori et al ., 2007). In previous studies in non‐human primates or in humans, no significant toxicities were reported after injections of CpG 7909 even at high doses (Krieg et al ., 2004; Stewart et al ., 2008).…”