LNP-CpG: deploy the self-adjuvant role of mRNA vaccines

Abstract

With the rapid advancement of mRNA vaccines, lipid nanoparticles (LNPs) have emerged as pivotal carriers and adjuvants for non-mRNA vaccine modalities, driven by their superior nucleic acid delivery efficiency and intrinsic self-adjuvanting properties. In this study, we systematically evaluated various formulation strategies combining LNPs and the CpG adjuvant within a varicella-zoster virus glycoprotein E (VZV-gE) subunit vaccine framework. We demonstrated that uniform nanoparticles formed by LNP-encapsulated CpG (LNP-CpG), when simply admixed with the gE antigen, elicited superior immunogenicity compared to alternative encapsulation configurations. Intramuscular administration of a two-dose (LNP-CpG)+gE regimen significantly augmented both humoral and cellular immune responses in mice, markedly outperforming the commercial vaccine Shingrix (administered at a 1/10 human dose). Crucially, the identical regimen induced robust, comparable immune profiles to a full human dose of Shingrix in rhesus macaques. Furthermore, LNP-CpG displayed broad-spectrum utility across diverse vaccine platforms, demonstrating efficacy against both respiratory (RSV) and neurotropic (HSV) pathogens, compatibility with multiple modalities, including subunit (VZV-gE, RSV-Pre-F), live-attenuated (LA-HSV), and inactivated (i-HSV) vaccines; and versatile implementation in a combined VZV+RSV formulation. Collectively, our findings position LNP-CpG as a versatile, safe, highly efficacious adjuvant platform with substantial clinical translational potential, offering a compelling paradigm for next-generation vaccine development.