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Yellow fever virus (YFV) is a mosquito-borne flavivirus, endemic in 47 countries in Africa and South America, which causes febrile symptoms that can evolve in 15% of the patients to serious hemorrhagic conditions, liver injury, and multiorgan failure. Although a highly effective vaccine (YF-17D vaccine) is available, to date, no antiviral drugs have been approved for the prevention and treatment of YFV infections.This review article focuses on the description of viral targets that have been considered within YFV and flavivirus drug discovery studies and on the most relevant candidates reported so far that elicit broad-spectrum inhibition against relevant strains and mutants of YFV.Considering the growing interest on (re)emerging vector-borne viral infections, it is expected that flavivirus drug discovery will quickly deliver potential candidates for clinical evaluation. Due to similarity among flaviviral targets, several candidates identified against different flaviviruses have shown broad-spectrum activity, thus exhibiting anti-YFV activity, as well. In this regard, it would be desirable to routinely include the assessment of antiviral activity against different YFV strains. On the other hand, the development of host targeting agents are still at an initial stage and deserve further focused efforts.

Dengue virus (DENV), the causative agent of dengue disease, is among the most important mosquito-borne pathogens worldwide. DENV is composed of four closely related serotypes and belongs to the Flaviviridae family alongside other important arthropod-borne viral pathogens such as Zika virus (ZIKV), West Nile virus (WNV) and Yellow Fever virus (YFV). After infection, the antibody response is mostly directed to the viral E glycoprotein which is composed of three structural domains named DI, DII and DIII that share variable degrees of homology among different viruses. Recent evidence supports a close serological interaction between ZIKV and DENV. The possibility of worse clinical outcomes as a consequence of antibody-dependent enhancement of infection (ADE) due to cross-reactive antibodies with poor neutralisation activity is a matter of concern. We tested polyclonal sera from groups of female Balb/C mice vaccinated with DNA constructs expressing DI/DII, DIII or the whole sE from different DENV serotypes and compared their activity in terms of cross-reactivity, neutralisation of virus infection and ADE. Our results indicate that the polyclonal antibody responses against the whole sE protein are highly cross-reactive with strong ADE and poor neutralisation activities due to DI/DII immunodominance. Conversely, anti-DIII polyclonal antibodies are type-specific, with no ADE towards ZIKV, WNV and YFV, and strong neutralisation activity restricted only to DENV.