Safety study of Rift Valley Fever human vaccine candidate (DDVax) in mosquitoes

Abstract

Rift Valley fever virus (RVFV) is a mosquito-borne pathogen with significant human and veterinary health consequences that periodically emerges in epizootics. RVFV causes fetal loss and death in ruminants and in humans can lead to liver and renal disease, delayed-onset encephalitis, retinitis, and in some cases severe haemorrhagic fever. A live attenuated vaccine candidate (DDVax), was developed by the deletion of the virulence factors NSs and NSm from a clinical isolate, ZH501, and has proven safe and immunogenic in rodents, pregnant sheep and non-human primates. Deletion of NSm also severely restricted mosquito midgut infection and inhibited vector-borne transmission. To demonstrate environmental safety, this study investigated the replication, dissemination and transmission efficiency of DDVax in mosquitoes following oral exposure compared to RVFV strains MP-12 and ZH501. Infection and dissemination profiles were also measured in mosquitoes 7 days after they fed on goats inoculated with DDvax or MP-12. We hypothesized that DDVax would infect mosquitoes at significantly lower rates than other RVFV strains and, due to lack of NSm, be transmission incompetent. Exposure of Ae. aegypti and Cx. tarsalis to 8 log 10 plaque forming units (PFU)/ml DDVax by artificial bloodmeal resulted in significantly reduced DDVax infection rates in mosquito bodies compared to controls. Plaque assays indicated negligible transmission of infectious DDVax in Cx. tarsalis saliva (1/140 sampled) and none in Ae. aegypti saliva (0/120). Serum from goats inoculated with DDVax or MP-12 did not harbour detectable infectious virus by plaque assay at 1, 2 or 3 days post-inoculation.Infectious virus was, however, recovered from Aedes and Culex bodies that fed on goats vaccinated with MP-12 (13.8% and 4.6%, respectively), but strikingly, DDvaxpositive mosquito bodies were greatly reduced (4%, and 0%, respectively). Furthermore, DDVax did not disseminate to legs/wings in any of the goat-fed mosquitoes. Collectively, these results are consistent with a beneficial environmental safety profile.

Replication Kinetics of a Candidate Live-Attenuated Vaccine for Cache Valley Virus in Aedes albopictus

“…More recently, a human vaccine candidate for RVFV lacking the NSm gene was unable to infect, replicate, or be transmitted by multiple mosquito species (Campbell et al, 2022 ). Therefore, the NSs and NSm genes appear to be required for the efficient replication of bunyaviruses in mosquitoes.…”

Artificial Feeding Systems for Vector-Borne Disease Studies

“…Drug and Vaccine Development: Artificial feeding methods have emerged as a promising frontier in the development of drugs and vaccines against VBDs. This innovative approach provides a controlled platform for evaluating the efficacy of pharmaceutical compounds and vaccine candidates within a vector–host–pathogen context [ 183 , 184 , 185 ]. Live attenuated vaccine candidates such as DDVax are administered to mosquito vectors using artificial feeding systems, mimicking their natural feeding behaviors [ 185 ].…”

Perspectives of Next-Generation Live-Attenuated Rift Valley Fever Vaccines for Animal and Human Use

“…As part of the safety assessments of DDvax and these other gene deletion RVF viruses, initial mosquito transmission experiments revealed that the NSm gene (and/or P78) confers critical mosquito mid-gut barrier evasion mechanisms that, when deleted, provide an additional environmental containment safety factor. Across several studies, the DDvax research team has definitively demonstrated that DDvax cannot be efficiently transmitted by multiple mosquito vectors due to the specific deletion of the NSm gene region [ 26 , 29 , 64 ]. These results, when taken together, indicated that DDvax might provide in a single dose rapid, safe, and robust protection from RVFV infection with an excellent environmental safety profile that would potentially enable use in both routine and emergency outbreak response-related vaccination campaigns.…”