TLR9 and STING agonists adjuvanted varicella-zoster virus glycoprotein E induced a potent and durable nasal vaccine response

Herpes zoster is caused by the reactivation of latent varicella-zoster virus (VZV), primarily affecting middle-aged and older individuals and often accompanied by severe pain and other complications. Vaccination is an effective preventive measure against this disease. In the present study, we evaluated the adjuvant activity of Toll-like receptor (TLR)9 and TLR7 agonists in combination with stimulator of interferon genes (STING) agonists for a VZV-glycoprotein E (gE)-based vaccine. Among the tested combinations, the CpG-2722 (TLR9 agonist) and 2'3'-c-di-AM(PS)2 (STING agonist) pairing exhibited potent immunostimulatory activity in immune cells and superior adjuvant activity for VZV-gE vaccines in a mouse models. Shingrix, a licensed herpes zoster vaccine, is administered intramuscularly. The CpG-2722/2'3'-c-di-AM(PS)2 combination adjuvanted VZV vaccine, administered intramuscularly, effectively induced higher gE-specific IgG responses than that induced by the Shingrix and imiquimod/2'3'-c-di-AM(PS)2 adjuvant vaccine. Notably, intranasal administration of the CpG-2722/2'3'-c-di-AM(PS)2 adjuvanted VZV vaccine to mice elicited a robust antigen-specific IgA response, which was barely detectable in intramuscularly administered vaccines. Two doses of the intranasal immunization, administered at a two-week interval, provided long-lasting protection, as antigen-specific IgG levels remained elevated for months without booster immunization. Further investigation into the functional mechanism revealed that CpG-2722 combined with 2'3'-c-di-AM(PS)2 induced a strong antigen-dependent T helper 1 (Th1) cytokine response, consistent with the antigen-independent cytokine-inducing properties of this adjuvant combination. This study demonstrates that the TLR9 and STING agonists formulated adjuvant induces a potent and long-lasting immune response, highlighting its potential as a promising adjuvant candidate for nasal VZV vaccines.