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Pilot dose escalation serology and body temperatures. (A) Results of total anti-RVFV ELISA testing of serum, (B) Rectal temperatures. Each vaccine dosage group contained 4 animals. One animal served as a sham-inoculated control. The error bars indicate standard deviations.
Source publication
Rift Valley fever virus (RVFV) is a mosquito-borne human and veterinary pathogen causing large outbreaks of severe disease throughout Africa and the Arabian Peninsula. Safe and effective vaccines are critically needed, especially those that can be used in a targeted one-health approach to prevent both livestock and human disease. We report here on...
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... nonpregnant animal safety and dose escalation study. No detectable febrile response, clinical illness, or inappetance was observed in any of the animals regardless of vaccine dose during the first 30 days p.v. (Fig. 2 and data not shown). No erythema or other signs of localized inflammation could be detected at the vaccination site during the first 72 h p.v. (data not shown), and no vaccination site tissue nodules or abscesses were detected at the end of the 30-day observation period. All sheep, regardless of dose, responded to the vaccination, with robust anti-RVFV ...
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... with robust anti-RVFV IgM responses detectable by 4 to 5 days p.v. and with a subsequent increase in IgG titers detectable by days 8 to 12. A dose-dependent response was observed, with ani- mals receiving the highest vaccine dose (1.0 10 5 PFU) mounting more rapid and higher-titer IgM/IgG responses than did animals given the lower doses (Fig. 2). IgG titers ranged from 100 to 400 in the vaccinates (Fig. 2). All vaccinated animals tested negative for RVFV by virus isolation and qRT- PCR regardless of the vaccine dose or time of sample collec- tion during the 30-day observation period (data not shown). No seroconversion or vaccine virus RNA was detected in the group-housed ...
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... to 5 days p.v. and with a subsequent increase in IgG titers detectable by days 8 to 12. A dose-dependent response was observed, with ani- mals receiving the highest vaccine dose (1.0 10 5 PFU) mounting more rapid and higher-titer IgM/IgG responses than did animals given the lower doses (Fig. 2). IgG titers ranged from 100 to 400 in the vaccinates (Fig. 2). All vaccinated animals tested negative for RVFV by virus isolation and qRT- PCR regardless of the vaccine dose or time of sample collec- tion during the 30-day observation period (data not shown). No seroconversion or vaccine virus RNA was detected in the group-housed sham-vaccinated control animal ( Fig. 2 and data not ...
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... from 100 to 400 in the vaccinates (Fig. 2). All vaccinated animals tested negative for RVFV by virus isolation and qRT- PCR regardless of the vaccine dose or time of sample collec- tion during the 30-day observation period (data not shown). No seroconversion or vaccine virus RNA was detected in the group-housed sham-vaccinated control animal ( Fig. 2 and data not ...
Citations
... The development of reliable challenge models for arbovirus diseases like RVFV is challenging because needle inoculation does not mimic natural infection via insect vectors [90]. The common model for RVFV is pregnant ewe because abortions are a hallmark among livestock [91]. However, pregnancy synchronization in ewes and the limited high biosecurity and biocontainment of animal spaces makes this model difficult to use. ...
The use of effective vaccines is among the most important strategies for the prevention and progressive control of transboundary infectious animal diseases. However, the use of vaccine is often impeded by the cost, a lack of cold chains and other factors. In resource-limited countries in Africa, one approach to improve coverage and reduce cost is to vaccinate against multiple diseases using combined vaccines. Therefore, the objective of this study was to evaluate a combined vaccine for the prevention and control of Lumpy Skin Disease (LSD), Contagious Bovine Pleuropneumonia (CBPP) and Rift Valley fever (RVF). The LSD and CBPP were formulated as a combined vaccine, and the RVF was formulated separately as live attenuated vaccines. These consisted of a Mycoplasma MmmSC T1/44 strain that was propagated in Hayflick-modified medium, RVF virus vaccine, C13T strain prepared in African green monkey cells (Vero), and the LSDV Neethling vaccine strain prepared in primary testis cells. The vaccines were tested for safety via the subcutaneous route in both young calves and pregnant heifers with no side effect, abortion or teratogenicity. The vaccination of calves induced seroconversions for all three vaccines starting from day 7 post-vaccination (PV), with rates of 50% for LSD, 70% for CBPP and 100% for RVF, or rates similar to those obtained with monovalent vaccines. The challenge of cattle vaccinated with the LSD/CBPP and the RVF vaccine afforded full protection against virulent strains of LSDV and RVFV. A satisfactory level of protection against a CBPP challenge was observed, with 50% of protection at 6 months and 81% at 13 months PV. A mass vaccination trial was performed in four regions of Burkina Faso that confirmed safety and specific antibody responses induced by the vaccines. The multivalent LSD/CBPP+RVF vaccine provides a novel and beneficial approach to the control of the three diseases through one intervention and, therefore, reduces the cost and improves vaccination coverage.
... The DDVax vaccine is a live-attenuated vaccine developed from the recombinant ZH501 strain, achieved by deleting both the NSs and the 78kD/NSm genes 111,112 . The NSs gene deletion reduces the vaccine's virulence in immunocompetent animals while robustly stimulating innate immune responses. ...
... The NSs gene deletion reduces the vaccine's virulence in immunocompetent animals while robustly stimulating innate immune responses. The vaccine's immunogenicity and protective efficacy against pathogenic RVFV challenge have been demonstrated in rats, pregnant ewes at 42 days of gestation, and common marmosets 67,111,112 . To assess vaccine safety, 20 vaccinated ewes at 42 days of gestation were monitored until they delivered neonates, and it was found that vaccination with DDVax did not lead to detectable viral RNA in the sera 112 . ...
... The vaccine's immunogenicity and protective efficacy against pathogenic RVFV challenge have been demonstrated in rats, pregnant ewes at 42 days of gestation, and common marmosets 67,111,112 . To assess vaccine safety, 20 vaccinated ewes at 42 days of gestation were monitored until they delivered neonates, and it was found that vaccination with DDVax did not lead to detectable viral RNA in the sera 112 . Each vaccinated ewe delivered at least one healthy lamb without any detectable viral RNA in the blood, brain, liver, and spleen. ...
Rift Valley fever (RVF) is a zoonotic viral disease transmitted by mosquitoes and causes abortion storms, fetal malformations, and newborn animal deaths in livestock ruminants. In humans, RVF can manifest as hemorrhagic fever, encephalitis, or retinitis. Outbreaks of RVF have been occurring in Africa since the early 20th century and continue to pose a threat to both humans and animals in various regions such as Africa, Madagascar, the Comoros, Saudi Arabia, and Yemen. The development of RVF vaccines is crucial in preventing mortality and morbidity and reducing the spread of the virus. While several veterinary vaccines have been licensed in endemic countries, there are currently no licensed RVF vaccines for human use. This review provides an overview of the existing RVF vaccines, as well as potential candidates for future studies on RVF vaccine development, including next-generation vaccines that show promise in combating the disease in both humans and animals.
... A liveattenuated MP12 RVFV strain has been developed as a vaccine; the vac cine has been shown to protect bovine and ovine dams against RVFV challenge and is safe and efficacious for use in neonatal calves and lambs (Morril et al. 1997). Another live attenuated RVFV vaccine lacking the NSs and NSm genes cannot be transmitted by mosquitoes (Bird et al. 2011;Crabtree et al. 2012). ...
... NSs was shown to promote the post-translational degradation of the TFIIH p62 subunit, which leads to cellular transcriptional cessation, including type I IFN genes [19], and to interfere with chromosome cohesion and segregation [20]. NSs is associated with the virulence of RVFV in various species, including mice, rats and ruminants [21][22][23][24][25]. Importantly, NSs is not needed for replication in interferon-incompetent cells in vitro but is essential for the virus to cause viremia and disease in interferon-competent animals [24]. ...
... Complete protection from high-dose virulent virus challenge was observed 28 days post-vaccination. Over the past 16 years since that initial study, DDvax has been proven safe, immunogenic, and effective in preventing virulent virus infection and disease following a single dose administration in a variety of animal species, including multiple rodent species, adult pregnant and non-pregnant livestock species, and two species of nonhuman primates (marmosets and rhesus macaques) [23,62,63] (and manuscripts in preparation). In each animal species tested, robust and rapid rises in neutralizing antibodies were observed from 14 to 21 days post-vaccination. ...
Live-attenuated Rift Valley fever (RVF) vaccines transiently replicate in the vaccinated host, thereby effectively initiating an innate and adaptive immune response. Rift Valley fever virus (RVFV)-specific neutralizing antibodies are considered the main correlate of protection. Vaccination with classical live-attenuated RVF vaccines during gestation in livestock has been associated with fetal malformations, stillbirths, and fetal demise. Facilitated by an increased understanding of the RVFV infection and replication cycle and availability of reverse genetics systems, novel rationally-designed live-attenuated candidate RVF vaccines with improved safety profiles have been developed. Several of these experimental vaccines are currently advancing beyond the proof-of-concept phase and are being evaluated for application in both animals and humans. We here provide perspectives on some of these next-generation live-attenuated RVF vaccines and highlight the opportunities and challenges of these approaches to improve global health.
... Although the single deletion of NSs or NSm can attenuate the virulence phenotype of RVFV, the deletion of both the NSs and NSm proteins has the most significant attenuating effect (Crabtree et al, 2012). Several groups have developed a reverse genetics system to generate a recombinant virus that lacks both the NSs and NSm proteins (Bird et al, 2011;Brennan et al, 2011;Crabtree et al, 2012). This method potentially creates a safe and immunogenic live-attenuated vaccine (LAV) without the risk of reversion. ...
... This method potentially creates a safe and immunogenic live-attenuated vaccine (LAV) without the risk of reversion. A RVFV vaccine generated using this technique was previously determined to be safe and effective in pregnant and nonpregnant animals (Bird et al, 2011). ...
... The complete deletion of genes could possibly enable us to distinguish vaccinated from field-infected animals. This could potentially be achieved through the detection of the wt virus using an NSs or NSm antibody and through detection of the mutant virus using an anti-NSs or anti-NSm antibody as previously described (Bird et al, 2011). A CVV double deletion mutant virus would also have significant advantages similar to the double deletion mutant for SBV (Kraatz et al, 2015), including its potential inability to be transmitted by insect vectors. ...
Cache Valley virus (CVV) is a mosquito-borne bunyavirus that is enzootic throughout the new world. Although CVV is known as an important agricultural pathogen, primarily associated with embryonic lethality and abortions in ruminants, it has recently been recognized for its expansion as a zoonotic pathogen. With the increased emergence of bunyaviruses with human and veterinary importance, there have been significant efforts dedicated to the development of bunyavirus vaccines. In this study, the immunogenicity of a candidate live-attenuated vaccine (LAV) for CVV, which contains the deletion of the nonstructural small (NSs) and nonstructural medium (NSm) genes (2delCVV), was evaluated and compared with an autogenous candidate vaccine created through the inactivation of CVV using binary ethylenimine (BEI) with an aluminum hydroxide adjuvant (BEI-CVV) in sheep. Both 2delCVV and BEI-CVV produced a neutralizing antibody response that exceeds the correlate of protection, that is, plaque reduction neutralization test titer >10. However, on day 63 postinitial immunization, 2delCVV was more immunogenic than BEI-CVV. These results warrant further development of 2delCVV as a candidate LAV and demonstrate that the double deletion of the NSs and NSm genes can be applied to the development of vaccines and as a common attenuation strategy for orthobunyaviruses.
... The candidate vaccine used in this study was rationally designed through the deletion of virulence factors, NSs and NSm, which is based on previous work and because they have been shown to be virulence factors for wild-type RVFV (Bird et al, 2011;Ikegami et al, 2006;Won et al, 2007). There is also evidence of the NSs protein contributing to RVFV disease outcome in mice by modulating host cell features and defense mechanisms (Leger et al, 2020). ...
... While other RVFV candidate live attenuated vaccines have been developed through the deliberate deletion of NSs and NSm genes and demonstrated to be safe and immunogenic in mice and pregnant sheep (Bird et al, 2011;Bird et al, 2008), our work has important implications for the development of RVFV candidate live attenuated vaccines. While these vaccines were made using similar methods, the r2segMP12 strain with a two-segmented genome will have a reduced likelihood for reversion to the virulent phenotype. ...
Rift Valley fever virus (RVFV) is an emerging arbovirus that affects both ruminants and humans. RVFV causes severe and recurrent outbreaks in Africa and the Arabian Peninsula with a significant risk for emergence into new locations. Although there are a variety of RVFV veterinary vaccines for use in endemic areas, there is currently no licensed vaccine for human use; therefore, there is a need to develop and assess new vaccines. Herein, we report a live-attenuated recombinant vaccine candidate for RVFV, based on the previously described genomic reconfiguration of the conditionally licensed MP12 vaccine. There are two general strategies used to develop live-attenuated RVFV vaccines, one being serial passage of wild-type RVFV strains to select attenuated mutants such as Smithburn, Clone 13, and MP12 vaccine strains. The second strategy has utilized reverse genetics to attenuate RVFV strains by introducing deletions or insertions within the viral genome. The novel candidate vaccine characterized in this report contains a two-segmented genome that lacks the medium viral segment (M) and two virulence genes (nonstructural small and nonstructural medium). The vaccine candidate, named r2segMP12, was evaluated for the production of neutralizing antibodies to RVFV in outbred CD-1 mice. The immune response induced by the r2segMP12 vaccine candidate was directly compared to the immune response induced by the rMP12 parental strain vaccine. Our study demonstrated that a single immunization with the r2segMP12 vaccine candidate at 105 plaque-forming units elicited a higher neutralizing antibody response than the rMP12 vaccine at the same vaccination titer without the need for a booster.
... All (20/20) pregnant ewes vaccinated on day 42 when the risk of RVFV vaccine-related teratogenesis is highest, progressed to full-term delivery producing lambs without any congenital abnormalities. Of these, all (9/9) pregnant ewes that were challenged with virulent RVFV obtained sterilizing immunity and delivered healthy lambs [87]. In the common marmoset (Callithrix jacchus), a non-human primate (NHP) model, a single vaccine dose of this vaccine led to the development of robust antibody responses with no vaccine-induced adverse reactions, signs of RVFV infection, or infectious virus. ...
Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that causes high fetal and neonatal mortality in ruminants and a mild to fatal hemorrhagic fever in humans. There are no licensed RVF vaccines for human use while for livestock, commercially available vaccines are all either live attenuated or inactivated and have undesirable characteristics. The live attenuated RVF vaccines are associated with teratogenicity and residual virulence in ruminants while the inactivated ones require multiple immunisations to induce and maintain protective immunity. Additionally, nearly all licensed RVF vaccines lack the differentiating infected from vaccinated animals (DIVA) property making them inappropriate for use in RVF nonendemic countries. To address these limitations, novel DIVA-compatible RVF vaccines with better safety and efficacy than the licensed ones are being developed, aided fundamentally by a better understanding of the molecular biology of the RVF virus and advancements in recombinant DNA technology. For some of these candidate RVF vaccines, sterilizing immunity has been demonstrated in the discovery/feasibility phase with minimal adverse effects. This review highlights the progress made to date in RVF vaccine research and development and discusses the outstanding research gaps.
... Cell-adapted, formalininactivated RVFV vaccines were subsequently immunogenic in sheep 11 and saw agricultural use. More recently, a strain of RVFV generated by reverse genetics and lacking the virulence factors NSs and NSm has demonstrated immunogenicity and safety in a variety of animal model systems, including rodents, sheep, and non-human primates [12][13][14] . Multiple other RVFV vaccines have undergone preclinical studies, including a chimpanzee adenovirus vectored vaccine 15 , a 4-segmented RVFV vaccine 16 , and a capripoxvirus vectored vaccine 17 . ...
Rift Valley fever virus (RVFV) is a hemorrhagic fever virus with the potential for significant economic and public health impact. Vaccination with an attenuated strain, DelNSsRVFV, provides protection from an otherwise lethal RVFV challenge, but mechanistic determinants of protection are undefined. In this study, a murine model was used to assess the contributions of humoral and cellular immunity to DelNSsRVFV-mediated protection. Vaccinated mice depleted of T cells were protected against subsequent challenge, and passive transfer of immune serum from vaccinated animals to naïve animals was also protective, demonstrating that T cells were dispensable in the presence of humoral immunity and that humoral immunity alone was sufficient. Animals depleted of B cells and then vaccinated were protected against challenge. Total splenocytes, but not T cells alone, B cells alone, or B + T cells harvested from vaccinated animals and then transferred to naïve animals were sufficient to confer protection, suggesting that multiple cellular interactions were required for effective cellular immunity. Together, these data indicate that humoral immunity is sufficient to confer vaccine-mediated protection and suggests that cellular immunity plays a role in protection that requires the interaction of various cellular components.
... For Rift Valley fever virus (RVFV), a mosquito-transmitted phlebovirus from the Bunyavirales order, DIVA-capable vaccine candidates have previously been developed and insights in these experimental data were used as a basis to develop similar SBV-specific vaccines. On one hand, RVFV mutant viruses lacking non-structural proteins NSs and NSm were shown to replicate efficiently in cell culture and, besides being DIVA-compatible, they protected rats and sheep from viremia after experimental RVFV infection [24,25]. On the other hand, a RVFV subunit vaccine based on the viral glycoproteins Gn and Gc conferred sterile protection of sheep against virulent virus challenge [26]. ...
Background
Subsequent to its first detection in 2011, the insect-transmitted bunyavirus Schmallenberg virus (SBV; genus Orthobunyavirus) caused a large-scale epizootic of fetal malformation in the European ruminant population. By now, SBV established an enzootic status in Central Europe with regular wave-like re-emergence, which has prompted intensive research efforts in order to elucidate the pathogenesis and to develop countermeasures. Since different orthobunyaviruses share a very similar structural organization, SBV has become an important model virus to study orthobunyaviruses in general and for the development of vaccines. In this review article, we summarize which vaccine formulations have been tested to prevent SBV infections in livestock animals.
Main
In a first step, inactivated SBV candidate vaccines were developed, which efficiently protected against an experimental SBV infection. Due to the inability to differentiate infected from vaccinated animals (= DIVA capability), a series of further approaches ranging from modified live, live-vectored, subunit and DNA-mediated vaccine delivery to multimeric antigen-presentation on scaffold particles was developed and evaluated. In short, it was repeatedly demonstrated that the N-terminal half of the glycoprotein Gc, composed of the Gc head and the head-stalk, is highly immunogenic, with a superior immunogenicity of the complete head-stalk domain compared to the Gc head only. Furthermore, in all Gc protein-based vaccine candidates, immunized animals can be readily discriminated from animals infected with the field virus by the absence of antibodies against the viral N-protein.
Conclusions
Using SBV as a model virus, several vaccination-challenge studies in target species underscored the superior performance of antigenic domains compared to linear epitopes regarding their immunogenicity. In addition, it could be shown that holistic approaches combining immunization-challenge infection studies with structural analyses provide essential knowledge required for an improved vaccine design.
... A number of novel vaccines in development are based on the immunogenic glycoproteins delivered as subunit or by different platforms [reviewed in (Faburay et al., 2017;Ikegami, 2019)]. Although some of these approaches are providing promising results (Wilson et al., 2021), live attenuated vaccines remain as the strongest immune inductors in terms of duration and breadth of the immune response after a single dose inoculation, and their improvement in terms of safety has been the subject of intense RVF research in the past decade (Bird et al., 2011;Kalveram et al., 2011;Kortekaas et al., 2011;Wichgers-Schreur et al., 2020). The availability of RVFV reverse genetics systems allows designing novel rational attenuation strategies obviously conditioned by the previous identification and understanding of such attenuating determinants (Tercero and Makino, 2020). ...
Rift Valley fever (RVF) is an arboviral zoonotic disease affecting many African countries with the potential to spread to other geographical areas. RVF affects sheep, goats, cattle and camels, causing a high rate of abortions and death of newborn lambs. Also, humans can be infected, developing a usually self-limiting disease that can turn into a more severe illness in a low percentage of cases. Although different veterinary vaccines are available in endemic areas in Africa, to date no human vaccine has been licensed. In previous works, we described the selection and characterization of a favipiravir-mutagenized RVFV variant, termed 40Fp8, with potential as a RVF vaccine candidate due to the strong attenuation shown in immunocompromised animal models. Compared to the parental South African 56/74 viral strain, 40Fp8 displayed 7 amino acid substitutions in the L-protein, three of them located in the central region corresponding to the catalytic core of the RNA-dependent RNA polymerase (RdRp). In this work, by means of a reverse genetics system, we have analyzed the effect on virulence of these amino acid changes, alone or combined, both in vitro and in vivo. We found that the simultaneous introduction of two changes (G924S and A1303T) in the heterologous ZH548-RVFV Egyptian strain conferred attenuated phenotypes to the rescued viruses as shown in infected mice without affecting virus immunogenicity. Our results suggest that both changes induce resistance to favipiravir likely associated to some fitness cost that could be the basis for the observed attenuation in vivo. Conversely, the third change, I1050V, appears to be a compensatory mutation increasing viral fitness. Altogether, these results provide relevant information for the safety improvement of novel live attenuated RVFV vaccines.
