Inverse relationship between innate and acquired immune responsiveness in mice initially dosed with cationic lipid DNA complexes (JVRS-100)

Hyporesponsiveness to excessive innate immune stimulation (i.e., lipopolysaccharide, lipoteichoic acid, and CpG oligonucleotides) has been studied extensively in vitro and documented in clinical treatment of sepsis patients with low inflammatory cytokine production, reduced leukocyte expression of HLA‐DR, and decreased antigen presentation. Closely spaced intravenous (IV) administration of JVRS‐100 has been shown to induce a short (7–10 day) refractory period for innate immune activation, with 50% of responsiveness restored after three days and 100% by 10–14 days. This refractory period was observed in interferon‐gamma and IFN‐gamma receptor knockout mice as well as mice pre‐dosed with IFN‐gamma or depleted of NK cells or plasmacytoid dendritic cells. In contrast to reduced capacity for antigen presentation (sepsis patients), IV administration of JVRS‐100, one day prior to vaccination with HKx31 heat‐inactivated influenza virus adjuvanted with JVRS‐100 significantly enhanced the influenza‐specific humoral immune response. Enhancement of the adaptive response to vaccination was greatest at the timepoints showing the maximum refractory period, suggesting an inverse relationship between cytokine production and immune activation. These findings may have implications for development of future vaccines, in which single or limited vaccination strategies are critical.