Characterization of vaccine viremia, attenuation reversion, and safety: Combined results from the TAK-003 dengue...

Live-attenuated vaccines can replicate for a transient period post-vaccination and may be associated with symptoms resembling natural infection. The tetravalent dengue vaccine, TAK-003, has undergone extensive preclinical assessment to investigate vaccine RNAemia, viremia, genetic stability, and transmissibility. Here, we investigated the presence of vaccine RNAemia, attenuation loci reversions, and their association with viral-syndrome-like adverse events (AEs) in participants throughout the clinical development program. TAK-003 RNA positive serum samples were evaluated for viral replication and sequenced for reversions. Safety data (solicited AEs within 7/14 days; unsolicited AEs within 28 days) were assessed from a pooled phase 1/2 trial analysis. Participants who experienced febrile illness within 30 days post vaccination in the pivotal phase 3 DEN-301 trial and the phase 2 DEN-313 trial were tested for RNAemia and evaluated for AEs. TAK-003 RNAemia was detected in 441/805 (54.8%) of vaccinees (seronegative: 67.0%; seropositive: 33.0%) in the pooled analysis and in 39 participants with febrile illness from the DEN-301/DEN-313 trials (from 1022 febrile illnesses investigated). RNAemia peaked during the second week post-vaccination and mostly occurred after first dose. Although all four dengue virus (DENV) components were detected, RNAemia was most commonly due to DENV-2. 69 single locus reversions were detected; AEs reported in participants with reversions were generally non-serious, and not indicative of increased symptom severity. Pain at injection site (without RNAemia = 42.0%; RNAemia = 46.8%) and headache (without RNAemia = 36.6%; RNAemia = 37.6%) were the most frequently reported solicited AEs. Incidences of pain, erythema, rash, arthralgia, and fatigue were higher in participants with RNAemia. The incidence of unsolicited AEs was higher in participants with RNAemia (62.4%) than without (52.0%). In the DEN-301/DEN-313 analysis, participants with febrile illness showed a similar pattern of symptoms with and without RNAemia. The presence of RNAemia was associated with transient, mild-to-moderate symptoms, resembling natural infection, which were also observed in the absence of RNAemia.