INTRODUCTION: Pathological accumulation of tau (pTau) contributes to various tauopathies, including Alzheimers disease (AD), and correlates with cognitive decline. A rapid surge in tau-targeted approaches via anti-sense oligonucleotides, active/passive immunotherapies suggests that targeting p-Tau is a viable strategy against tauopathies. METHOD: We describe a multi-species validation of our previously described Qß virus-like particle (VLP)-based vaccine technology targeting phosphorylated tau on threonine 181 (pT181-Qß). RESULTS: Two vaccine doses of pT181-Qß, without any adjuvants, elicited robust antibody responses in two different mouse models of tauopathy (PS19 and hTau) and rhesus macaques. In mouse models, vaccination reduced AT180+ hyperphosphorylated, Sarkosyl insoluble, Gallyas silver positive tau, inflammasomes/neuroinflammation, and improved recognition memory and motor function without inducing adverse T-cell activation. Anti-pT181 antibodies are reactive to pTau in human AD brains, engage pT181+ tau in human brain lysates, and are central nervous system bioavailable. DISCUSSION: Our results suggest the translational utility of pT181-Qß against tauopathies. HIGHLIGHTS: Icosahedral display of phosphorylated tau at threonine 181 (pT181) Qß virus-like particle surface (pT181-Qß vaccine) induces a robust immune response in mice and in non-human primates (NHPs) pT181-Qß vaccination reduces pathological tau (pTau) and brain atrophy, and improves memory and motor function in PS19 and hTau mice. pT181-Qß vaccination-induced immunoglobulin Gs (IgGs) are safe, Th2 skewed (anti-inflammatory), specific to pTau in human AD brain, and efficiently engage pT181 in NHPs and human brain lysate. pT181+ tau in human plasma correlates with the neurofilament light in subjects with mild cognitive impairment (MCI)-suggesting the presence of pT181-Qß vaccine target in the early disease state.