Antiviral sugar baits to reduce arbovirus transmission: a proof-of-concept study

Dengue virus (DENV) and chikungunya virus (CHIKV) remain major global health threats, yet approved antiviral therapies are lacking. Antiviral sugar baits (AVSBs) represent a novel transmission-blocking strategy that exploits the natural sugar-feeding behaviour of mosquitoes to deliver antiviral compounds directly to the mosquito vector. In this study, we evaluated the antiviral efficacy of AVSBs containing JNJ-A07, {beta}-D-N4-hydroxycytidine (NHC), molnupiravir (MPV), and 4'-fluorouridine (4'FlU) in Aedes aegypti mosquitoes. An ex vivo mosquito gut model was used to select antiviral concentrations and to assess the ability of 4'FlU to reach the mosquito midgut following sugar feeding. AVSBs were subsequently evaluated for their effects on mosquito attractiveness, longevity, fecundity, and fertility, as well as their ability to suppress DENV and CHIKV infection in vivo. 4'FlU potently inhibited CHIKV replication in ex vivo mosquito guts and retained antiviral activity following sugar-bait administration. None of the antiviral compounds affected mosquito attraction to the bait, while only modest and compound-specific effects on mosquito fitness were observed. AVSBs containing JNJ-A07 significantly reduced DENV infection and dissemination, whereas 4'FlU-containing AVSBs significantly reduced CHIKV infection and viral loads. In contrast, NHC- and MPV-containing AVSBs did not exhibit antiviral activity in vivo. Collectively, these findings provide proof-of-concept for AVSBs as a novel strategy to reduce arbovirus transmission by targeting viral replication within the mosquito vector, suggesting that AVSBs could complement existing arbovirus control measures.