Background

AV-1980R/A is recombinant protein-based tau vaccine designed to elicit antibodies to pathologic tau. It fuses three copies of a tau2-18 peptide to 12 T-cell activating antigens. This MultiTep vaccine platform includes a synthetic pan-T cell antigen, as well as antigens derived from Tetanus toxin, hepatitis B, and influenza virus. The foreign antigens function to boost antibody responses to the tau peptide by activating memory and helper T cells, while avoiding stimulation of potentially harmful autoreactive T cells. This is important in older people, who tend to mount weaker responses to vaccines. The vaccine is formulated with the adjuvant AdvaxCpG55.2.

This vaccine targets a different tau epitope than did previous, failed N-terminal directed tau antibodies (Nov 2022 conference news). The tau2-18 peptide includes tau’s so-called phosphatase activation domain, which is hidden in normally folded tau, and becomes exposed once tau starts to aggregate (Combs et al., 2016; Combs and Kanaan, 2017).

In preclinical work, AV-1980R/A induced high antibody titers in mice (Davtyan et al., 2016). Antibodies from vaccinated PS19 tau transgenic mice recognized neurofibrillary tangles and plaque-associated dystrophic neurites in AD brain sections, and nondenatured tau from AD brain (Hovakimyan et al., 2019). Vaccination prevented age-related motor and cognitive deficits in the PS19 mice, and significantly reduced insoluble and phosphorylated tau species in brain. In the Tg4510 tau mouse model, immunization induced strong antibody responses, and detectable IgG in brain. These animals had improvement in short-term memory, but not in other behavioral tasks. Antibodies reduced pSer396 tau, but not other phosphorylated species, in brain (Joly-Amado et al., 2020). In nonhuman primates, the vaccine elicited antibodies that recognized pathological tau tangles and tau-positive neurites in sections from AD brain without staining sections from non-AD brain, supporting human trials (Hovakimyan et al., 2022).

A DNA version of AV-1980 produced high titer antibodies, with no evidence of autoreactive T cell responses in THY-Tau22 mice (Davtyan et al., 2017). Vaccination reduced brain total tau and some forms of phosphorylated tau in the mice. 

The MultiTEP platform is being used to develop other vaccines for neurodegenerative diseases. The Aβ vaccine AV-1959D is currently in Phase 1. Vaccines to α-synuclein, and a dual Aβ/tau vaccine are also being developed (Kim et al., 2022; Davtyan et al., 2019).

Findings

A Phase 1 study is planned to begin in July 2025. It will enroll 48 participants with preclinical AD who are amyloid-positive and without cognitive impairment. Three cohorts are to receive 20, 60, or 180 μg, or placebo, by intramuscular injection four times over 36 weeks. Primary outcomes are safety, tolerability, and adverse events. Secondary outcomes will assess anti-tau antibodies in blood, T helper response, and possible activation of autoreactive T cells. Exploratory outcomes are changes in AD-related brain and plasma biomarkers including Aβ42, Aβ40, Aβ42/40, p-tau217, p-tau181, p-tau231, t-tau, NfL, GFAP, and tau MK-6240 PET; and immune response profile by immunoglobulin isotypes, cytokines, and other measures.

This trial is not listed in registries yet.