Suppression of flavivirus transmission from animal hosts to mosquitoes with a mosquito-delivered vaccine.

Zoonotic viruses circulate in the natural reservoir and sporadically spill over into human populations, resulting in endemics or pandemics. We previously found that the Chaoyang virus (CYV), an insect-specific flavivirus (ISF), is replication-defective in vertebrate cells. Here, we develope a proof-of-concept mosquito-delivered vaccine to control the Zika virus (ZIKV) within inaccessible wildlife hosts using CYV as the vector. The vaccine is constructed by replacing the pre-membrane and envelope (prME) proteins of CYV with those of ZIKV, assigned as CYV-ZIKV. CYV-ZIKV replicates efficiently in Aedes mosquitoes and disseminates to the saliva, with no venereal or transovarial transmission observed. To reduce the risk of CYV-ZIKV leaking into the environment, mosquitoes are X-ray irradiated to ensure 100% infertility, which does not affect the titer of CYV-ZIKV in the saliva. Immunization of mice via CYV-ZIKV-carrying mosquito bites elicites robust and persistent ZIKV-specific immune responses and confers complete protection against ZIKV challenge. Correspondingly, the immunized mice could no longer transmit the challenged ZIKV to naïve mosquitoes. Therefore, immunization with an ISF-vectored vaccine via mosquito bites is feasible to induce herd immunity in wildlife hosts of ZIKV. Our study provides a future avenue for developing a mosquito-delivered vaccine to eliminate zoonotic viruses in the sylvatic cycle.