Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909)

Abstract

NuThrax™ (Anthrax Vaccine Adsorbed with CPG 7909 Adjuvant) (AV7909) is in development. Samples obtained in a Phase Ib clinical trial were tested to confirm biomarkers of innate immunity and evaluate effects of CPG 7909 (PF-03512676) on adaptive immunity. Subjects received two intramuscular doses of commercial BioThrax® (Anthrax Vaccine Adsorbed, AVA), or two intramuscular doses of one of four formulations of AV7909. IP-10, IL-6, and C-reactive protein (CRP) levels were elevated 24 to 48 hours after administration of AV7909 formulations, returning to baseline by Day 7. AVA (no CPG 7909) resulted in elevated IL-6 and CRP, but not IP-10. Another marker of CpG, transiently decreased absolute lymphocyte counts (ALC), correlated with transiently increased IP-10. Cellular recall responses to anthrax Protective Antigen (PA) or PA peptides were assessed by IFN-gamma ELISpot assay performed on cryopreserved PBMCs obtained from subjects prior to immunization and 7 days following the second immunization (study day 21). One-half of subjects that received AV7909 with low-dose (0.25 mg/dose) CPG 7909 possessed positive Day 21 T cell responses to PA. In contrast, positive T cell responses occurred at an 11% average rate (1/9) for AVA-treated subjects. Differences in cellular responses due to dose level of CPG 7909 were not associated with differences in humoral anti-PA IgG responses, which were elevated for recipients of AV7909 compared to recipients of AVA. Serum markers at 24 or 48 hours (i.e. % ALC decrease, or increase in IL-6, IP-10, or CRP) correlated with the humoral (antibody) responses 1 month later, but did not correlate with cellular ELISpot responses. In summary, biomarkers of early responses to CPG 7909 were confirmed, and adding a CpG adjuvant to a vaccine administered twice resulted in increased T cell effects relative to vaccine alone. Changes in early biomarkers correlated with subsequent adaptive humoral immunity but not cellular immunity.

Unique Inflammatory Mediators and Specific IgE Levels Distinguish Local from Systemic Reactions after Anthrax Vaccine Adsorbed Vaccination

“…A recent study showed increased levels of CRP, but not of IP-10, in 17 individuals (not stratified by AEs) within 7 days after AVA administration (47). In the same study, individuals receiving an AVA formulation with CPG 7909 adjuvant had early increases in both CRP and IP-10.…”

Immunization with the Haemophilus ducreyi trimeric autotransporter adhesin DsrA with alum, CpG or imiquimod generates a persistent humoral immune response that recognizes the bacterial surface

“…CpG is a synthetic oligodeoxynucleotide containing unmethylated CpG motifs that binds TLR-9 and induce a Th1-dominated immune response [23, 28]. The vaccine adjuvant activity of CpG has been evaluated in a number of clinical trials using infectious disease vaccines such as anthrax [29–31] and malaria [32, 33] or when administered with experimental cancer vaccines [34, 35]. Recognized by TLR7–8, Imiquimod also induces Abs and a Th1-type immune response [23].…”

Correlation between anthrax lethal toxin neutralizing antibody levels and survival in guinea pigs and nonhuman primates vaccinated with the AV7909 anthrax vaccine candidate

“…Further investigation will be required to understand effect of CPG 7909 of antibody avidity memory B-cell populations. The potential contribution of early innate and T- cell mediated response to protective immunity has also been investigated in human subjects vaccinated with AV7909 (38). Biomarkers of early innate responses to CPG 7909 were confirmed, and adding a CpG adjuvant to a vaccine resulted in increased T cell effects relative to vaccine alone.…”