Human vaccine candidate (DDVax) development against Rift Valley Fever: dissemination safety studies in mosquitoes

Rift Valley fever virus (RVFV) is a mosquito-borne pathogen with significant human and veterinary health consequences that periodically emerges in epizootics. RVF 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 hemorrhagic 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 feeding on goats inoculated with DDvax or MP-12. Hypothesis: DDVax should infect mosquitoes at significantly lower rates than other RVF strains and, due to lack of NSm, be transmission incompetent. Exposure of Ae. aegypti and Cx. tarsalis to 6-8 log 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 harbor detectable infectious virus by plaque assay at 1, 2, or 3 days-post-inoculation; infectious virus was, however, recovered from mosquito bodies that fed on goats vaccinated with MP-12 (13.8% and 4.6%, respectively), but strikingly, DDvax positive 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 .

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Safety and efficacy of ChAdOx1 RVF vaccine against Rift Valley fever in pregnant sheep and goats

npj Vaccines ◽

10.1038/s41541-019-0138-0 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 4

Author(s):

Anna Stedman ◽

Daniel Wright ◽

Paul J. Wichgers Schreur ◽

Madeleine H. A. Clark ◽

Adrian V. S. Hill ◽

...

Keyword(s):

Rift Valley ◽

Rift Valley Fever ◽

Rift Valley Fever Virus ◽

Febrile Illness ◽

Neutralizing Antibody ◽

High Titre ◽

Valley Fever ◽

Sheep And Goats ◽

Pregnant Sheep ◽

Human Use

Abstract Rift Valley fever virus (RVFV) is a zoonotic mosquito-borne virus that was first discovered in Kenya in 1930 and has since spread to become endemic in much of Africa and the Arabian Peninsula. Rift Valley fever (RVF) causes recurrent outbreaks of febrile illness associated with high levels of mortality and poor outcomes during pregnancy—including foetal malformations, spontaneous abortion and stillbirths—in livestock, and associated with miscarriage in humans. No vaccines are available for human use and those licensed for veterinary use have potential drawbacks, including residual virulence that may contraindicate their use in pregnancy. To address this gap, we previously developed a simian adenovirus vectored vaccine, ChAdOx1 RVF, that encodes RVFV envelope glycoproteins. ChAdOx1 RVF is fully protective against RVF in non-pregnant livestock and is also under development for human use. Here, we now demonstrate that when administered to pregnant sheep and goats, ChAdOx1 RVF is safe, elicits high titre RVFV neutralizing antibody, and provides protection against viraemia and foetal loss, although this protection is not as robust for the goats. In addition, we provide a description of RVFV challenge in pregnant goats and contrast this to the pathology observed in pregnant sheep. Together, our data further support the ongoing development of ChAdOx1 RVF vaccine for use in livestock and humans.

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Inactivation of infectious virus and serological detection of virus antigen in Rift Valley fever virus-exposed mosquitoes fixed with paraformaldehyde

Journal of Virological Methods ◽

10.1016/j.jviromet.2013.01.014 ◽

2013 ◽

Vol 189 (1) ◽

pp. 184-188 ◽

Cited By ~ 5

Author(s):

Rebekah Kading ◽

Mary Crabtree ◽

Barry Miller

Keyword(s):

Rift Valley ◽

Rift Valley Fever ◽

Infectious Virus ◽

Rift Valley Fever Virus ◽

Virus Antigen ◽

Fever Virus ◽

Serological Detection ◽

Valley Fever

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Efficacy of a recombinant Rift Valley fever virus MP-12 with NSm deletion as a vaccine candidate in sheep

Vaccine ◽

10.1016/j.vaccine.2013.12.064 ◽

2014 ◽

Vol 32 (20) ◽

pp. 2345-2349 ◽

Cited By ~ 19

Author(s):

Hana M. Weingartl ◽

Charles K. Nfon ◽

Shunzhen Zhang ◽

Peter Marszal ◽

William C. Wilson ◽

...

Keyword(s):

Rift Valley ◽

Rift Valley Fever ◽

Vaccine Candidate ◽

Rift Valley Fever Virus ◽

Fever Virus ◽

Valley Fever

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

Transboundary and Emerging Diseases ◽

10.1111/tbed.14415 ◽

2021 ◽

Author(s):

Corey L. Campbell ◽

Trey K. Snell ◽

Susi Bennett ◽

John H. Wyckoff ◽

Darragh Heaslip ◽

...

Keyword(s):

Rift Valley ◽

Rift Valley Fever ◽

Vaccine Candidate ◽

Safety Study ◽

Valley Fever ◽

Human Vaccine

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Safety and Immunogenicity of Rift Valley Fever MP-12 and a Novel arMP-12?NSm21/384 Recombinant Vaccine Candidate in Native Breed of Black Head Sheep (Ovis aries) from Tanzania

Journal of Vaccines & Vaccination ◽

10.4172/2157-7560.1000394 ◽

2018 ◽

Vol 09 (04) ◽

Author(s):

Adamson EK ◽

Nyundo S ◽

Rowland J ◽

Palermo PM ◽

Matiko MK ◽

...

Keyword(s):

Rift Valley ◽

Rift Valley Fever ◽

Vaccine Candidate ◽

Recombinant Vaccine ◽

Ovis Aries ◽

Valley Fever ◽

Native Breed ◽

Black Head

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Rift Valley Fever Virus-induced Encephalomyelitis and Hepatitis in Calves

Veterinary Pathology ◽

10.1177/030098589202900602 ◽

1992 ◽

Vol 29 (6) ◽

pp. 495-502 ◽

Cited By ~ 32

Author(s):

M. K. Rippy ◽

M. J. Topper ◽

C. A. Mebus ◽

J. C. Morrill

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Rift Valley ◽

Rift Valley Fever ◽

Positive Staining ◽

Post Inoculation ◽

Valley Fever ◽

Viral Antigens ◽

The Central Nervous System ◽

The Brain

Three calves (Nos. 1, 2 = 7 days old; No. 3 = 21 days old) were inoculated subcutaneously with virulent Rift Valley fever (RVF) virus. All calves became viremic and clinically ill, but the two 7-day-old calves were moribund and were euthanatized subsequently on post-inoculation day (PID) 3. Highest viral titers were measured in the serum, with lesser concentrations in the brain, heart, spleen, and liver of these animals. Viral antigens were detected by immunohistochemical analysis only in the livers, where positive staining was localized in coalescing foci of hepatocellular necrosis. The 21-day-old calf appeared to recover after viremia and pyrexia but became lethargic and ataxic and was euthanatized on PID 9. The calf was no longer viremic, and RVF virus was isolated only from the brain. Microscopic examination of the central nervous system revealed diffuse perivascular infiltrates of lymphocytes and macrophages, multifocal meningitis, and focal areas of neuronal necrosis and aggregates of macrophages, lymphocytes, and neutrophils throughout all regions of the brain and cervical spinal cord. There was positive immunohistochemical staining for viral antigens within the cytoplasm of neurons and glial cells throughout the central nervous system. Thus, RVF virus can cause encephalomyelitis in calves, and the specific virologic diagnosis can be made by immunohistochemical localization of viral antigens in formalin-fixed tissues.

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