KA101 outperforms other clinical adjuvants in inducing balanced Th1/Th2 immunity and robust B cell responses to varicella-zoster virus glycoprotein E.

Reactivation of latent varicella-zoster virus (VZV) causes herpes zoster, which can further progress to persistent postherpetic neuralgia in a subset of patients. Rational adjuvant selection is critical for the development of recombinant VZV glycoprotein E (gE) subunit vaccines. In this study, we systematically evaluated the immunomodulatory properties of six adjuvants formulated with recombinant VZV gE in a mouse model. Multi-dimensional analyses, including innate and adaptive immunity, transcriptomics, and B-cell receptor (BCR) repertoire profiling, revealed that distinct adjuvants shape adaptive immune responses through divergent innate immune activation patterns. Traditional aluminum hydroxide and MF59 mainly induced Th2-biased humoral immunity but showed limited cellular immune activation. As TLR agonists, Poly(I:C) displayed a Th2-skewed profile with partial Th1 tendencies and exhibited oligoclonal B-cell expansion, whereas CpG 1018 potently promoted Th1 polarization and cytotoxic T-cell responses. Lipid nanoparticle (LNP) formulations drove chemokine-dependent inflammatory recruitment and facilitated dendritic cell maturation and humoral immune programming. Notably, KA101, a liposomal adjuvant containing MPL and QS-21, exhibited unique synergistic effects by inducing early IFN-γ production and simultaneously eliciting robust cellular immunity and high-titer neutralizing antibodies. Moreover, KA101 enhanced germinal center reactions, diversified the B-cell repertoire, and supported the establishment of long-term immune memory. Collectively, these findings provide mechanistic insights into adjuvant-antigen interactions and establish a rational framework for developing next-generation herpes zoster subunit vaccines with potent cellular and humoral immunogenicity and durable immune memory.