Randomized study of teriflunomide effects on immune responses to neoantigen and recall antigens

Abstract

Objective: To evaluate immune responses to neoantigen and recall antigens in healthy subjects treated with teriflunomide.

Methods: This was a randomized, double-blind, placebo-controlled study. Subjects received oral teriflunomide (70 mg once daily for 5 days followed by 14 mg once daily for 25 days) or placebo for 30 days. Antibody responses were evaluated following rabies vaccination (neoantigen) applied at days 5, 12, and 31 of the treatment period. Occurrence of delayed-type hypersensitivity (DTH) to Candida albicans, Trichophyton, and tuberculin (recall antigens) was assessed before and at the end of treatment to investigate cellular memory response. Safety and pharmacokinetics were evaluated.

Results: Forty-six randomized subjects were treated (teriflunomide, n = 23; placebo, n = 23) and completed the rabies vaccination. Geometric mean titers for rabies antibodies were lower with teriflunomide at days 31 and 38 than with placebo. However, all subjects achieved sufficient seroprotection following rabies vaccination (titers well above the 0.5 IU/mL threshold). Overall, the DTH response to recall antigens in the teriflunomide group did not notably differ from responses in the placebo group.

Conclusions: Following vaccination, geometric mean titers for rabies antibodies were lower with teriflunomide than with placebo. However, teriflunomide did not limit the ability to achieve seroprotective titers against this neoantigen. Evaluation of DTH showed that teriflunomide had no adverse impact on the cellular memory response to recall antigens.

Classification of evidence: This study provides Class II evidence that in normal subjects treated with teriflunomide, antibody titer responses to rabies vaccination are lower than with placebo but sufficient for seroprotection.

Figure 1. Study design

A screening period of 2–21 days was followed by an active treatment period of 30 days with teriflunomide 14 mg or placebo. The study was complete 12–17 days after the accelerated drug elimination phase. DTH = delayed-type hypersensitivity.

Figure 2. Subject disposition

Figure 3. Immune response to neoantigen: Geometric mean titers of antirabies antibody levels over time

At days 31 and 38, all subjects achieved antibody titers above the 0.5 IU/mL threshold for seroprotection. Error bars show SD for each data point.

Figure 4. Number of subjects with positive DTH response to recall antigens before and at the end of treatment

A positive delayed-type hypersensitivity (DTH) reaction was defined as a diameter of induration ≥2 mm measured 48 hours after intradermal administration of the antigen. Three subjects (2 receiving teriflunomide, 1 receiving placebo) had positive DTH for at least one antigen at baseline but discontinued prematurely from the study and did not have DTH testing at the end of treatment. These subjects are not included. C. albicans = Candida albicans; PPD = tuberculin purified protein derivatives.