A Randomized, Controlled Trial Assessing the Immunogenicity of a Four- versus Three-Dose TBE Vaccination Schedule in Adults Aged 50+: Benefit Of an Optimized Schedule in Older TBE recipients (TBE-BOOST)

Background and Rationale: Tick-borne encephalitis (TBE) is a vaccine-preventable disease of the central nervous system, with disproportionately high incidence and severity in individuals aged 50+ years. Standard TBE vaccination consists of a 3-dose primary series followed by boosters every 10 years. However, effectiveness is significantly lower in those first vaccinated at age 50+, with higher rates of vaccine failure and shorter duration of protection. Evidence from observational and small clinical studies suggests that a 4-dose primary schedule may improve immune responses in this age group. In Switzerland, both 3- and 4-dose schedules are Swissmedic-approved, but the 4-dose schedule is rarely used. Objectives: We propose a randomized clinical trial to compare the immunogenicity of the 3- versus 4-dose TBE vaccination schedules in adults aged 50+ years. The aim is to determine whether the additional priming dose provides superior neutralizing antibody responses. The durability of immunity over the first year following completion of vaccination will also be assessed. Study Design and Methods: Adults aged 50+ years with no prior TBE vaccination will be recruited at the University of Zurich Travel Clinic and randomized 1:1 to receive either the standard 3-dose (Days 0, 30, 360) or 4-dose (Days 0, 7, 21, 360) schedule, both according to current Swissmedic labeling. Blood samples will be collected at Days 0, 60, 120, 360 (pre-dose), 400 (40 days after the final priming dose), and 720 (1 year after completion of the primary series). Primary endpoint: Neutralizing antibody (NT) geometric mean titers (GMT) at Day 400. Secondary endpoints: NT GMT at Day 720; proportion with NT =10 at Days 400 and 720; anti-TBEV IgG GMT at Days 400 and 720; and proportion with IgG >150 U/mL at Days 400 and 720. Exploratory endpoints: Early antibody kinetics at Days 60 and 120; conditional seropersistence (proportion with NT <10 at Day 720 among those with NT =10 at Day 400); and within-subject waning (change in log NT from Day 400 to Day 720). Safety, tolerability, adherence to timing windows, and completion rates will be monitored to inform feasibility, but are not formal endpoints. Significance: This trial, in conjunction with existing epidemiological data, will provide the strongest feasible evidence base to determine whether a 4-dose TBE schedule confers added benefit in older adults. If superiority is demonstrated, results could directly inform Swiss and European vaccination guidelines. Given that more than two million Swiss adults aged 50+ remain unvaccinated, optimizing priming schedules for this population could prevent dozens of TBE cases annually and reduce associated healthcare costs by millions of CHF.