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Preclinical and clinical experience with dupilumab on the correlates of live attenuated vaccines

Wechsler, M;Souza-Machado, A;Xu, C;Mao, X;Kapoor, U;Khokhar, F;O’Malley, J;Petro, C;Casullo, V;Mannent, L;Rowe, P;Jacob-Nara, J;Ruddy, M;Laws, E;Purcell, L;Hardin, M;

Background The safety and tolerability of live attenuated vaccines in patients administered dupilumab for moderate-to-severe asthma have not been previously evaluated. During the LIBERTY ASTHMA TRAVERSE open-label extension study (ClinicalTrials.gov identifier NCT02134028), a yellow fever outbreak in Brazil required administration of a live attenuated vaccine to at-risk individuals. Objective Our aim was to evaluate immune response to a live attenuated vaccine in the context of IL-4 receptor blockade (REGN1103, a dupilumab surrogate) in mice and in dupilumab-treated patients with moderate-to-severe asthma who participated in TRAVERSE. Methods In the preclinical study, mice were coadministered REGN1103/isotype control and live attenuated influenza vaccine/control, followed by influenza virus challenge. During TRAVERSE, 37 patients discontinued dupilumab treatment and were administered 17D live attenuated yellow fever vaccine (YFV). Safety and tolerability data, dupilumab serum concentrations, and plaque reduction neutralization titers before and after vaccination were collected. Results In the preclinical study, there was no impact of REGN1103 on vaccine efficacy in mice. In TRAVERSE, all 37 patients who received YFV achieved seroprotection despite most having therapeutic levels of dupilumab, with the magnitude of response appearing unrelated to prevaccination dupilumab concentrations. No instances of vaccine-related adverse events or vaccine hypersensitivity were reported in 36 patients; 1 patient reported nonserious body ache, malaise, and dizziness 7 days after vaccination but recovered fully. Conclusion The preclinical model suggested that dupilumab does not affect the efficacy of live attenuated influenza vaccine. The live attenuated YFV did not raise safety concerns and appeared to be well tolerated in patients with asthma who recently discontinued dupilumab treatment, and dupilumab concentrations had no apparent impact on immunologic response to the vaccine.