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Rift Valley fever vaccines: current and future needs
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ScienceDirect Rift Valley fever vaccines: current and future needs Baptiste Dungu1, Baratang A Lubisi2 and Tetsuro Ikegami3,4,5 Rift Valley fever (RVF) is a zoonotic mosquito-borne bunyaviral disease associated with high abortion rates, neonatal deaths, and fetal malformations in ruminants, and mild to severe disease in humans. Outbreaks of RVF cause huge economic losses and public health impacts in endemic countries in Africa and the Arabian Peninsula. A proper vaccination strategy is important for preventing or minimizing outbreaks. Vaccination against RVF is not practiced in many countries, however, due to absence or irregular occurrences of outbreaks, despite serological evidence of RVF viral activity. Nonetheless, effective vaccination strategies, and functional national and international multi-disciplinary networks, remain crucial for ensuring availability of vaccines and supporting execution of vaccination in high risk areas for efficient response to RVF alerts and outbreaks. Addresses 1 MCI Sante Animale, Mohammedia, Morocco 2 Onderstepoort Veterinary Institute, Onderstepoort, Pretoria, South Africa 3 Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA 4 Sealy Center for Vaccine Development, The University of Texas Medical Branch, Galveston, TX, USA 5 Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch, Galveston, TX, USA Corresponding author: Ikegami, Tetsuro ([email protected])
Current Opinion in Virology 2018, 29:8–15 This review comes from a themed issue on Preventive and therapeutic vaccines Edited by Marc van Regenmortel and Martin Friede
https://doi.org/10.1016/j.coviro.2018.02.001 1879-6257/ã 2018 Published by Elsevier B.V.
Introduction Rift Valley fever (RVF), which is caused by the RVF phlebovirus (RVFV; genus Phlebovirus, family Phenuiviridae), is a mosquito-borne zoonotic disease that is highly pathogenic to both animals and humans [1,2]. The disease is characterized by high rates of abortions and mortalities in newborn sheep, cattle, and goats, as well as a transient febrile illness in humans with occasional complications that can progress to hemorrhagic fever, neurological disorders, or blindness in approximately 1–2% of patients [3]. Current Opinion in Virology 2018, 29:8–15
RVFV can be vertically transmitted via floodwater Aedes spp. mosquitoes, whereas other species of mosquitoes (e. g., Culex spp.) serve as amplifying vectors for RVFV by actively feeding on susceptible animals or humans [4,5]. Eggs of floodwater Aedes spp. that are infected with RVFV are present during inter-epizootic periods, and infected mosquitoes can hatch upon flooding [6]. RVF outbreaks could thus be associated with heavy rains or irrigation [7,8]. RVFV possesses a tripartite RNA genome, consisting of Large (L), Medium (M), and Small (S) segments [9]. The S-segment is an ambisense sequence, in which the negative- and positive-sense sequences encode N and NSs proteins, respectively. The L-segment encodes the L protein (RNA-dependent RNA polymerase), whereas the M-segment encodes at least two glycoprotein precursor proteins, which generate the 78 kDa protein, NSm protein, Gn protein, and Gc protein via cleavage by signal peptidases [10,11]. The Gn and Gc proteins are envelope glycoproteins that form capsomeres arranged on the surface of virions [12,13]. Although different RVFV strains have been isolated from ruminants, mosquitoes, humans, and bats in endemic countries, overall genetic diversity is at most 5% and 2% at the nucleotide and deduced amino acid levels, respectively [14–16]. The geographic distribution of RVF endemic areas has expanded since the first recorded outbreaks in Kenya in 1930–1931 (Figure 1a) [17]. Major RVF outbreaks have now been reported in Northern Africa (Egypt), Eastern Africa (Kenya, Tanzania, Somalia, and Sudan), Southern Africa (South Africa, Namibia, Zimbabwe, Zambia, and Mozambique), and Western Africa (Mauritania, Mali, Senegal, and Niger), as well as outside mainland Africa (Madagascar and The Comoros) and on the Arabian Peninsula (Saudi Arabia and Yemen) [1,18,19,20–22]. Approximately 18 000 to 200 000 human cases and 598 deaths were reported in Egypt in the 1977–1978 outbreak [23]. During a RVF outbreak in the Arabian Peninsula, 883 human cases and 124 deaths were reported in Saudi Arabia, and 1328 human cases and 166 deaths were reported in Yemen [24]. More recently, 1107 human cases and 351 deaths were reported in Kenya, Tanzania, and Somalia between 2006 and 2007, and 1174 cases and 241 deaths were reported in Sudan in 2008 [25]. A number of animal abortions and deaths have also been reported during RVF outbreaks [24]. The occurrence of new outbreaks in RVF-free regions and further geographical expansion of RVF endemicity is possible in the long term, due to the changing world climate and the presence of competent mosquito vectors www.sciencedirect.com
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Figure 1
(a)
RVF endemic countries
Sporadic RVF outbreaks RVF cases reported Evidence of RVFV circulation No reports or information
(b)
RVF vaccine implementation Smithburn vaccine (available) Clone 13 vaccine (field trial) Smithburn vaccine (available) Inactivated ZH501 strain vaccine (available) Smithburn vaccine (optional use) Clone 13T vaccine (available) Clone 13 vaccine (field trial) Clone 13T vaccine (registration) Clone 13T vaccine (field use) Smithburn vaccine (past use) Clone 13 vaccine (registration) Inactivated field strain vaccine (past use) Clone 13 vaccine (registration) Smithburn vaccine (available) Clone 13 vaccine (available) Inactivated field strain vaccine (available) Smithburn vaccine (past use) No implementation of RVF vaccines
Current Opinion in Virology
Countries in which Rift Valley fever (RVF) is endemic and RVF vaccines have been implemented. (a) The status of RVF in Africa and the Middle East. Countries with sporadic RVF outbreaks are shown in red, those with reported RVF disease case(s) in animals or humans are shown in purple, those with reported evidence of RVFV circulation are shown in blue, and those without specific evidence of RVFV circulation are shown in gray. (b) Current availability or past use of RVF vaccines are summarized using different colors, as indicated in the image.
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in the Mediterranean basin, Australia, Canada, Eastern and Western Europe, and the U.S. [26–30]. Any immediate risk of the incursion of RVF into RVF-free regions is uncertain, although there are trade embargos on ruminants and their products exported from Africa and the Arabian Peninsula due to animal health and zoosanitary concerns [31,32]. Nonetheless, the disease has been imported into Canada or China through infected persons, indicating a potential for transboundary RVFV spread via travelers [33,34]. Due to its devastating impact on local economies and public health via viral spread into animals and humans, and its potential for rapid transboundary spread, RVF is listed as a notifiable disease by the World Organization for Animal Health (OIE) [35]. RVFV itself is classified as a Category A Priority Pathogen by the National Institute of Allergy and Infectious Disease, and as an overlap select agent by the United States Department of Health and Human Services and Agriculture, due to its effect on human health and potential for use in bioterrorism [36]. Vaccination has been viewed and practiced as an effective means of controlling RVF in endemic countries, and the quest for improved formulations and vaccination strategies to build solid immunity and address the shortcomings of currently-available vaccines continues. This review aims to highlight the current and future role of RVF vaccines in the prevention and control of RVF.
Commercially-available RVF vaccines Vaccination is one of the most effective strategies for the prevention of viral diseases [37,38]. Several RVF vaccines have been developed and used for the immunization of livestock in some endemic countries (Figure 1b). The first RVF vaccine, the Smithburn vaccine, was developed in 1949 via serial intracerebral (i.c.) passages of the pathogenic Entebbe strain in mice. A neuroadapted strain was later established during serial passages (81 passages) in Uganda [39,40]. Additional i.c. passages of the Smithburn neurotropic strain were subsequently conducted in mice (102nd passage) in South Africa, leading to the creation of a master seed of the Smithburn vaccine [1,15,41]. More than one million lyophilized doses of vaccine containing 10% mouse brain extract were sold in South Africa and Kenya between 1951 and 1968, and six million doses in Zimbabwe between 1969 and 1970 [15]. In 1971, the modified live virus vaccine was developed via an amplification of Smithburn strain using BHK-21 cells, and distributed to several countries, including 22 million doses in Namibia and South Africa from 1974 to 1976; 4.2 million doses in South Africa, Israel, and Egypt in 1977; 3 million doses in Zimbabwe from 1978 to 1979 [41]; and approximately 10 million doses in Saudi Arabia in 2001 [42]. The Smithburn vaccine can induce a long-term protective immunity with a single dose in ruminants [43]. There is, Current Opinion in Virology 2018, 29:8–15
however, a potential risk of abortion or fetal malformation in pregnant animals, as well as possible genetic reassortment with pathogenic RVFV strains or reversion to virulence associated with the use of this vaccine, and its use is therefore recommended for non-pregnant animals within endemic countries before and after outbreaks [15,41,44–46]. Inactivated RVF vaccines have also been developed and registered in South Africa and Egypt (Figure 1b). These are the binary ethylenimine-inactivated RVF ZH501 and the formalin-inactivated RVF Menya (Menya/Sheep/258) strain-based vaccines produced by the Veterinary Serum and Vaccine Research Institute in Egypt [47], and the formalin-inactivated RVF vaccine derived from a field strain isolated from a cow at Onderstepoort Biological Product Ltd. (OBP) in South Africa, respectively [48,49]. The inactivated RVF vaccines are, in general, safe for both pregnant animals and use during RVF outbreaks, yet they require booster doses within three to four weeks following initial vaccination to induce protective immunity [44]. Since 2010, a novel live-attenuated RVF vaccine, the Clone 13 vaccine, has been registered in South Africa, Namibia, Botswana, Zambia, and Mozambique (Figure 1b). This vaccine was derived from a plaque clone of the 74HB59 strain from a human patient in the Central African Republic [50]. A 69% in-frame truncation of the NSs gene, which is a major virulence factor for RVFV, is responsible for the attenuation, whereas the L-segment and M-segment do not contribute to the attenuation phenotype [51,52]. Vaccination with a single dose of the Clone 13 vaccine can show protective efficacy in ruminants [53–55]. An overdose dose of Clone 13 vaccine (1 106 plaque forming units), however, showed viral invasion into the placenta and fetal malformations in ewes vaccinated at 50 days of gestation [56], indicating that overdose of this vaccine is not safe in pregnant animals. Nevertheless, the RVF Clone 13 vaccine is considered safe in pregnant animals and suitable for use during RVF outbreaks [44]. More than 28 million doses of Clone 13 vaccine have been used extensively in South Africa, including more than 10 million doses during the 2009–2010 outbreaks [44]. The Clone 13 vaccine has shown instability of infectious virus in liquid form at 22 C and a lyophilized form at 37 C [57], however, and appropriate storage is thus recommended to maintain its immunogenicity [57]. A second RVF Clone 13 vaccine, thermostable Clone 13 vaccine (Clone 13T vaccine), has been developed and registered in Morocco by MCI Sante Animale [57,58,59]. The Clone 13T vaccine was generated via a selection of viable virus populations at 56 C from the culture supernatants of Vero cells infected with the original Clone 13 strain, and then lyophilized in the presence of a www.sciencedirect.com
Rift Valley fever vaccines Dungu, Lubisi and Ikegami 11
stabilizer [58]. In addition to being registered in Morocco, this vaccine (RIFTOVAX-LR for large ruminants, RIFTOVAX-SR for small ruminants) has also been practically used in Senegal and Mali for RVF prevention (Figure 1b).
Vaccines conditionally licensed or currently under development In the U.S., a live-attenuated MP-12 vaccine, derived from an Egyptian ZH548 strain, was conditionally licensed for animal vaccination in 2013 [60,61,62]. The vaccine has been shown to be safe and efficacious in animals following single administration, to confer maternally-derived antibodies to unvaccinated offspring through colostrum, and has also proven safe and efficacious in humans [61]. The MP-12 vaccine is also an Investigational New Drug in the U.S., slated for further evaluation in human clinical trials. Intramuscular vaccination with the MP-12 vaccine could protect nonhuman primates from RVF via an aerosol challenge of a pathogenic RVFV strain [63], which supports the protection of vaccinees against RVF via an inhalation of RVFV. A formalin-inactivated RVF vaccine (TSI-GSD-200) derived from the Entebbe strain is also an Investigational New Drug in the U.S. This vaccine requires booster doses to maintain protective immunity [64–66], and is currently used to protect people whose vocations put them at high risk of contracting RVF [64]. By contrast to the MP-12 vaccine, the TSI-GSD-200 vaccine requires a larger dose, multiple initial inoculations followed by a booster after six months, and annual boosters, in addition to being expensive, difficult to produce, and in short supply [64,66–69]. Various strategies have been employed in endeavors to develop other new and improved RVF vaccines [70], including subunit vaccines, DNA vaccines, virus-like particles, virus replicon particles, virus-vectored vaccines, and genetically modified live-attenuated vaccines [71,72,73]. These vaccines have been tested in different animal models and possess different attributes. Commercialization following completion of all validation trials, mass scale production, and costs will depend on both the resources required to produce these vaccines and demand.
Rationale for development of improved RVF vaccines and vaccination strategies RVF vaccines have contributed to the control of outbreaks in endemic countries, and regular vaccination has been recommended in several countries with sporadic or recurring outbreaks, such as South Africa, Kenya, Tanzania, Egypt, Sudan, and Saudi Arabia (Figure 1) [49,74]. Annual vaccinations are conducted in high risk areas in Saudi Arabia and South Africa, whereas bi-annual vaccinations are conducted in Egypt [75]. In Kenya and Tanzania, vaccination is conducted following warnings of imminent RVF outbreaks [75]. Vaccination calls have www.sciencedirect.com
not, however, been made in many other countries, such as Mauritania, Madagascar, or Niger, due to sporadic or no past occurrence of RVF outbreaks [44]. Despite the demonstrated safety and efficacy of commercially-available vaccines in preventing RVF in animals, concerns remain regarding their effectiveness in the prevention and control of outbreaks. In Egypt, the live-attenuated Smithburn vaccine has been intermittently applied before, during, and following outbreaks, and together with the use of contaminated needles, it was suspected to have contributed to the endemicity of the disease in the country [47]. Currently, an inactivated vaccine derived from the RVFV ZH501 strain is used for RVF control, yet recent studies have shown that seroconversion rates of immunized cattle are not as high as expected, as approximately 70% of cattle are considered vaccinated, but 15% exhibit seroconversion [48,76]. In Saudi Arabia, the herd immunity of sheep and goats, which are annually vaccinated with the Smithburn vaccine, ranged from 22.2% in the Jizan district to 39.3% in the Alarda districts in 2004, shortly after the 2000 outbreak vaccination campaigns [77]. A potential lack of a proper vaccination program has been indicated as one of the constraints in RVF eradication efforts in the country [77,78]. In South Africa, large RVF epidemics occurred in 1950– 1951, 1973–1976, and 2008–2011 [21]. A field survey of 150 farmers in six districts following the 2008–2011 RVF outbreaks indicated that 77% of farmers vaccinated all their animals, while 23% did not or only partially vaccinated [79]. Over 40 million doses of RVF vaccines were sold to control the 2008–2011 outbreaks in South Africa, yet a lack of protective efficacy of the Clone 13 vaccine was pointed out by farmers in the Eastern Cape Province [70]. Investigations nevertheless identified various irregularities, ranging from poor herd immunity prior to the outbreaks, contravention of the manufacturer’s instructions regarding cold chain, vaccination of pregnant and viremic animals, use of same needle on many animals, and vaccination with other unregistered formulations [79]. The Great Horn of Africa region’s biggest dilemma with periodic vaccination is the fact that RVF outbreaks occur at 10–20 year intervals; thus, it is not economically viable to run regular and periodic vaccination campaigns in countries such as Kenya and Tanzania. Furthermore, keeping vaccine stocks would also be fruitless, since the shelf life of RVF vaccines (e.g., Smithburn) is less than five years. Herd immunity at the onset of outbreaks is always very low as a result. In Eastern African countries such as Kenya and Tanzania, RVF outbreaks are often associated with heavy rains during the periodical El Nin˜o/ Southern Oscillation phenomenon [80–82]. Prediction of RVF outbreaks based on the climate-based model has led to an early warning system and recommendations for Current Opinion in Virology 2018, 29:8–15
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preparedness to minimize the risk of devastating RVF outbreaks in the affected regions, via the OIE, World Health Organization, and the Food and Agriculture Organization of the United Nations [83]. The Clone 13 vaccine is recommended for animal vaccinations by trained personnel in response to any outbreak of RVF in those countries, although vaccination during active RVFV circulation is not appropriate. Implementation of a similar forecasting system has not been applicable in Central and West Africa, where the occurrence of RVF outbreaks remains largely unpredictable. Vaccination programs for RVF have not yet been implemented in Western Africa, where the management of RVF outbreaks must rely on early detection and subsequent restriction of animal movement, and prevention of new infection through appropriate handling of potentially-infected animals or their products [84,85]. Control of mosquito activities could also be important for minimizing the transmission of RVFV during outbreaks [4,86]. In Niger, an epizootic of RVF occurred in 2016, and at least 28 persons died [19]. A serological study conducted in Niger in the 1980s showed that neutralizing antibodies were detectable in sheep, cattle, goats, and camels [87], indicating that transmission of RVFV between animals and mosquitoes had been occurring in the country. Further epidemiological analysis will be required to identify the mechanisms that trigger RVF outbreaks in Niger. Unless urgent risk for RVF outbreak is predicted, it will not be feasible to economically justify preventive vaccination of animals in endemic countries.
International collaborations will be important to facilitate the development of ideal RVF vaccines and vaccination strategies. Further extensive analysis of the effectiveness of RVF vaccination will identify pitfalls of vaccination strategies, which will lead to novel approaches for efficiently preventing the spread of RVFV during RVF outbreaks.
Conflict of interest BD supports RVF vaccine development as an independent consultant and an employee at the MCI, Sante Animale, Morocco. The views and conclusion contained in this document are those of authors and not necessarily represent opinions of specific employers.
Acknowledgement TI was partly supported by the funding from the Sealy Center for Vaccine Development at the University of Texas Medical Branch at Galveston.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
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Summary There is a clear demand for RVF vaccines in several endemic countries with recurrent RVF outbreaks. Given the listed challenges, different approaches are urgently needed to improve herd or population immunity, especially during interepidemic periods. These approaches include: (1) improvement of vaccination strategies using currently-available highly-immunogenic vaccines (e.g., improvement of thermostability of vaccines, use of needleless vaccination); (2) use of nonviable vaccines instead of live-attenuated vaccines to reduce the concern of handling live viruses; (3) development of multivalent vaccines that protect against both RVF and other diseases widely and regularly vaccinated against, such as peste des petits ruminants, sheep and goat pox for small ruminants, or lumpy skin disease for cattle, although such vaccines have not yet been licensed to date; (4) establishment of a RVF vaccine or vaccine antigen stockpile at national or regional levels in countries without active RVFV circulation, which would permit the differentiation of vaccinated from infected animals (DIVA vaccine) [44]; and (5) improvement of early warning systems that may provide authorities with the lead time necessary to procure vaccines and conduct reactive vaccinations in time to ensure adequate herd immunity at the onset of outbreaks [88]. Current Opinion in Virology 2018, 29:8–15
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46. Botros B, Omar A, Elian K, Mohamed G, Soliman A, Salib A, Salman D, Saad M, Earhart K: Adverse response of nonindigenous cattle of European breeds to live attenuated Smithburn Rift Valley fever vaccine. J Med Virol 2006, 78:787791 http://dx.doi.org/10.1002/jmv.20624. 47. Kamal SA: Observations on rift valley fever virus and vaccines in Egypt. Virol J 2011, 8:532 http://dx.doi.org/10.1186/1743422X-8-532. 48. Barnard BJ, Botha MJ: An inactivated rift valley fever vaccine. J S Afr Vet Assoc 1977, 48:45-48. 49. Davies FG, Martin V: Prevention and control of Rift Valley fever. Recognizing Rift Valley fever. Food and Agriculture Organization of the United Nations; 2003:33-38. 50. Muller R, Saluzzo JF, Lopez N, Dreier T, Turell M, Smith J, Bouloy M: Characterization of clone 13, a naturally attenuated avirulent isolate of Rift Valley fever virus, which is altered in the small segment. Am J Trop Med Hyg 1995, 53:405-411. 51. Bouloy M, Janzen C, Vialat P, Khun H, Pavlovic J, Huerre M, Haller O: Genetic evidence for an interferon-antagonistic function of rift valley fever virus nonstructural protein NSs. J Virol 2001, 75:1371-1377 http://dx.doi.org/10.1128/ JVI.75.3.1371-1377.2001. 52. Ly HJ, Ikegami T: Rift Valley fever virus NSs protein functions and the similarity to other bunyavirus NSs proteins. Virol J 2016, 13:118 http://dx.doi.org/10.1186/s12985-016-0573810.1186. 53. von Teichman B, Engelbrecht A, Zulu G, Dungu B, Pardini A, Bouloy M: Safety and efficacy of Rift Valley fever Smithburn and Clone 13 vaccines in calves. Vaccine 2011, 29:5771-5777 http://dx.doi.org/10.1016/j.vaccine.2011.05.055. 54. Dungu B, Louw I, Lubisi A, Hunter P, von Teichman BF, Bouloy M: Evaluation of the efficacy and safety of the Rift Valley Fever Clone 13 vaccine in sheep. Vaccine 2010, 28:4581-4587 http:// dx.doi.org/10.1016/j.vaccine.2010.04.085. 55. Njenga MK, Njagi L, Thumbi SM, Kahariri S, Githinji J, Omondi E, Baden A, Murithi M, Paweska J, Ithondeka PM et al.: Randomized controlled field trial to assess the immunogenicity and safety of rift valley fever clone 13 vaccine in livestock. PLoS Negl Trop Dis 2015, 9:e0003550 http://dx.doi.org/10.1371/journal. pntd.0003550. 56. Makoschey B, van Kilsdonk E, Hubers WR, Vrijenhoek MP, Smit M, Wichgers Schreur PJ, Kortekaas J, Moulin V: Rift Valley fever vaccine virus clone 13 is able to cross the ovine placental barrier associated with foetal infections, malformations, and stillbirths. PLoS Negl Trop Dis 2016, 10:e0004550 http://dx.doi. org/10.1371/journal.pntd.0004550. This paper determined viral transmission of Rift Valley fever virus Clone 13 strain into fetus in pregnant cattles. 57. Daouam S, Fakri FZ, Ennaji MM, El Arkam A, Tadlaoui KO, Oura C, Elharrak M: Heat stability of the Rift Valley fever Clone 13 live vaccines. Trials Vaccinol 2014, 3:61-64. 58. Daouam S, Ghzal F, Arkam AE, Naouli Y, Jazouli M, Tadlaoui KO, Oura C, El Harrak M: Evaluation of the safety and efficacy of a live attenuated thermostable Rift Valley fever vaccine in sheep, goats and cattle. J Vaccines Vaccin 2015, 6:5. 59. Daouam S, Ghzal F, Naouli Y, Tadlaoui KO, Ennaji MM, Oura C, El Harrak M: Safety and immunogenecity of a live attenuated Rift Valley fever vaccine (CL13T) in camels. BMC Vet Res 2016, 12:154 http://dx.doi.org/10.1186/s12917-016-0775-810.1186. This study described a safety and immunogenicity of thermostable Clone 13 vaccine in camels. 60. Hills RE: Issuance of a Conditional License for Rift Valley Fever Vaccine, Modified Live Virus. Notice no. 13-12. Center for Veterinary Biologics; 2013. 61. Ikegami T: Rift Valley fever vaccines: an overview of the safety and efficacy of the live-attenuated MP-12 vaccine candidate. Exp Rev Vaccines 2017, 16:601-611 http://dx.doi.org/10.1080/ 14760584.2017.1321482. This review summarizes recent update of Rift Valley fever MP-12 vaccine studies. Current Opinion in Virology 2018, 29:8–15
62. Caplen H, Peters CJ, Bishop DH: Mutagen-directed attenuation of Rift Valley fever virus as a method for vaccine development. J Gen Virol 1985, 66:2271-2277. 63. Morrill JC, Peters CJ: Protection of MP-12-vaccinated rhesus macaques against parenteral and aerosol challenge with virulent rift valley fever virus. J Infect Dis 2011, 204:229-236 http://dx.doi.org/10.1093/infdis/jir249. 64. Pittman PR, Liu CT, Cannon TL, Makuch RS, Mangiafico JA, Gibbs PH, Peters CJ: Immunogenicity of an inactivated Rift Valley fever vaccine in humans: a 12-year experience. Vaccine 1999, 18:181-189. 65. Rusnak JM, Gibbs P, Boudreau E, Clizbe DP, Pittman P: Immunogenicity and safety of an inactivated Rift Valley fever vaccine in a 19-year study. Vaccine 2011, 29:3222-3229 http:// dx.doi.org/10.1016/j.vaccine.2011.02.037. 66. Niklasson B, Peters CJ, Bengtsson E, Norrby E: Rift Valley fever virus vaccine trial: study of neutralizing antibody response in humans. Vaccine 1985, 3:123-127. 67. Frank-Peterside N: Response of laboratory staff to vaccination with an inactivated Rift Valley fever vaccine — TSI-GSD 200. Afr J Med Med Sci 2000, 29:89-92. 68. Kark JD, Aynor Y, Peters CJ: A rift Valley fever vaccine trial. I. Side effects and serologic response over a six-month followup. Am J Epidemiol 1982, 116:808-820. 69. Kark JD, Aynor Y, Peters CJ: A Rift Valley fever vaccine trial: 2. Serological response to booster doses with a comparison of intradermal versus subcutaneous injection. Vaccine 1985, 3:117-122. 70. FAO: The last hurdles towards Rift Valley Fever control. Report on the Ad hoc workshop on the Current State of Rift Valley Fever Vaccine And Diagnostics Development Rome; 5–7 March 2014. FAO Animal Production and Health Report, No. 9. Rome, Italy: 2015. 71. Faburay B, LaBeaud AD, McVey DS, Wilson WC, Richt JA: Current status of Rift Valley fever vaccine development. Vaccines 2017:5 http://dx.doi.org/10.3390/vaccines5030029. This review summarizes current status of different Rift Valley fever vaccine development. 72. Kortekaas J: One health approach to Rift Valley fever vaccine development. Antiviral Res 2014, 106:24-32 http://dx.doi.org/ 10.1016/j.antiviral.2014.03.008. 73. Indran SV, Ikegami T: Novel approaches to develop Rift Valley fever vaccines. Front Cell Infect Microbiol 2012, 2:131 http://dx. doi.org/10.3389/fcimb.2012.00131. 74. Geering WA, Davies FG, Martin V: Preparation of Rift Valley fever contingency plans. FAO Animal Health Manual No. 15. FAO of the United Nations; 2002. 75. Alhaj M: Safety and efficacy profile of commercial veterinary vaccines against Rift Valley fever: a review study. J Immunol Res 2016:7346294 http://dx.doi.org/10.1155/2016/7346294. This review describes commercially available Rift Valley fever vaccines available in Africa and the Arabian Peninsula. 76. Mroz C, Gwida M, El-Ashker M, Ziegler U, Homeier-Bachmann T, Eiden M, Groschup MH: Rift Valley fever virus infections in Egyptian cattle and their prevention. Transbound Emerg Dis 2017, 64:2049-2058 http://dx.doi.org/10.1111/tbed.12616. This study described seroconversion of cattle as a result of Rift Valley fever vaccination in Egypt. 77. Elfadil AA, Hasab-Allah KA, Dafa-Allah OM, Elmanea AA: The persistence of rift valley fever in the Jazan region of Saudi Arabia. Rev Sci Tech 2006, 25:1131-1136. 78. Sayed-Ahmed M, Nomier Y, Shoeib SM: Epidemic situation of Rift Valley fever in Egypt and Saudi Arabia. J Dairy Vet Anim Res 2015, 2:00034. 79. Mdlulwa Z, Ngwane CB: Evaluating the impact of 2010 Rift Valley fever outbreaks on sheep numbers in three provinces of South Africa. Afr J Agr Res 2017, 12:979-986. 80. Linthicum KJ, Anyamba A, Tucker CJ, Kelley PW, Myers MF, Peters CJ: Climate and satellite indicators to forecast Rift Valley fever epidemics in Kenya. Science 1999, 285:397-400. www.sciencedirect.com
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81. Anyamba A, Linthicum KJ, Small JL, Collins KM, Tucker CJ, Pak EW, Britch SC, Eastman JR, Pinzon JE, Russell KL: Climate teleconnections and recent patterns of human and animal disease outbreaks. PLoS Negl Trop Dis 2012, 6:e1465 http://dx. doi.org/10.1371/journal.pntd.0001465. 82. Anyamba A, Linthicum KJ, Small J, Britch SC, Pak E, de La Rocque S, Formenty P, Hightower AW, Breiman RF, Chretien JP et al.: Prediction, assessment of the Rift Valley fever activity in East and Southern Africa 2006–2008 and possible vector control strategies. Am J Trop Med Hyg 2010, 83:43-51 http://dx. doi.org/10.4269/ajtmh.2010.09-0289. 83. FAO, OIE, WHO: Africa — El Nin˜o and increased risk of Rift Valley fever — warning to countries . The Emergency Prevention System Watch; 2015. 84. Anyangu AS, Gould LH, Sharif SK, Nguku PM, Omolo JO, Mutonga D, Rao CY, Lederman ER, Schnabel D, Paweska JT et al.: Risk factors for severe Rift Valley fever infection in Kenya, 2007. Am J Trop Med Hyg 2010, 83:14-21 http://dx.doi.org/ 10.4269/ajtmh.2010.09-0293.
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85. Monaco F, Cosseddu GM, Doumbia B, Madani H, El Mellouli F, Jimenez-Clavero MA, Sghaier S, Marianneau P, Cetre-Sossah C, Polci A et al.: First external quality assessment of molecular and serological detection of Rift Valley fever in the Western Mediterranean Region. PLoS One 2015, 10:e0142129 http://dx.doi.org/10.1371/journal. pone.0142129. 86. Tchouassi DP, Okiro RO, Sang R, Cohnstaedt LW, McVey DS, Torto B: Mosquito host choices on livestock amplifiers of Rift Valley fever virus in Kenya. Parasit Vectors 2016, 9:184 http://dx. doi.org/10.1186/s13071-016-1473-x. 87. Mariner JC, Morrill J, Ksiazek TG: Antibodies to hemorrhagic fever viruses in domestic livestock in Niger: Rift Valley fever and Crimean-Congo hemorrhagic fever. Am J Trop Med Hyg 1995, 53:217-221. 88. Consultative Group for RVF Decision Support: Decision-support tool for prevention and control of Rift Valley fever epizootics in the Greater Horn of Africa. Am J Trop Med Hyg 2010, 83:75-85 http://dx.doi.org/10.4269/ajtmh.2010.83s2a03.
Current Opinion in Virology 2018, 29:8–15
ScienceDirect Rift Valley fever vaccines: current and future needs Baptiste Dungu1, Baratang A Lubisi2 and Tetsuro Ikegami3,4,5 Rift Valley fever (RVF) is a zoonotic mosquito-borne bunyaviral disease associated with high abortion rates, neonatal deaths, and fetal malformations in ruminants, and mild to severe disease in humans. Outbreaks of RVF cause huge economic losses and public health impacts in endemic countries in Africa and the Arabian Peninsula. A proper vaccination strategy is important for preventing or minimizing outbreaks. Vaccination against RVF is not practiced in many countries, however, due to absence or irregular occurrences of outbreaks, despite serological evidence of RVF viral activity. Nonetheless, effective vaccination strategies, and functional national and international multi-disciplinary networks, remain crucial for ensuring availability of vaccines and supporting execution of vaccination in high risk areas for efficient response to RVF alerts and outbreaks. Addresses 1 MCI Sante Animale, Mohammedia, Morocco 2 Onderstepoort Veterinary Institute, Onderstepoort, Pretoria, South Africa 3 Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA 4 Sealy Center for Vaccine Development, The University of Texas Medical Branch, Galveston, TX, USA 5 Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch, Galveston, TX, USA Corresponding author: Ikegami, Tetsuro ([email protected])
Current Opinion in Virology 2018, 29:8–15 This review comes from a themed issue on Preventive and therapeutic vaccines Edited by Marc van Regenmortel and Martin Friede
https://doi.org/10.1016/j.coviro.2018.02.001 1879-6257/ã 2018 Published by Elsevier B.V.
Introduction Rift Valley fever (RVF), which is caused by the RVF phlebovirus (RVFV; genus Phlebovirus, family Phenuiviridae), is a mosquito-borne zoonotic disease that is highly pathogenic to both animals and humans [1,2]. The disease is characterized by high rates of abortions and mortalities in newborn sheep, cattle, and goats, as well as a transient febrile illness in humans with occasional complications that can progress to hemorrhagic fever, neurological disorders, or blindness in approximately 1–2% of patients [3]. Current Opinion in Virology 2018, 29:8–15
RVFV can be vertically transmitted via floodwater Aedes spp. mosquitoes, whereas other species of mosquitoes (e. g., Culex spp.) serve as amplifying vectors for RVFV by actively feeding on susceptible animals or humans [4,5]. Eggs of floodwater Aedes spp. that are infected with RVFV are present during inter-epizootic periods, and infected mosquitoes can hatch upon flooding [6]. RVF outbreaks could thus be associated with heavy rains or irrigation [7,8]. RVFV possesses a tripartite RNA genome, consisting of Large (L), Medium (M), and Small (S) segments [9]. The S-segment is an ambisense sequence, in which the negative- and positive-sense sequences encode N and NSs proteins, respectively. The L-segment encodes the L protein (RNA-dependent RNA polymerase), whereas the M-segment encodes at least two glycoprotein precursor proteins, which generate the 78 kDa protein, NSm protein, Gn protein, and Gc protein via cleavage by signal peptidases [10,11]. The Gn and Gc proteins are envelope glycoproteins that form capsomeres arranged on the surface of virions [12,13]. Although different RVFV strains have been isolated from ruminants, mosquitoes, humans, and bats in endemic countries, overall genetic diversity is at most 5% and 2% at the nucleotide and deduced amino acid levels, respectively [14–16]. The geographic distribution of RVF endemic areas has expanded since the first recorded outbreaks in Kenya in 1930–1931 (Figure 1a) [17]. Major RVF outbreaks have now been reported in Northern Africa (Egypt), Eastern Africa (Kenya, Tanzania, Somalia, and Sudan), Southern Africa (South Africa, Namibia, Zimbabwe, Zambia, and Mozambique), and Western Africa (Mauritania, Mali, Senegal, and Niger), as well as outside mainland Africa (Madagascar and The Comoros) and on the Arabian Peninsula (Saudi Arabia and Yemen) [1,18,19,20–22]. Approximately 18 000 to 200 000 human cases and 598 deaths were reported in Egypt in the 1977–1978 outbreak [23]. During a RVF outbreak in the Arabian Peninsula, 883 human cases and 124 deaths were reported in Saudi Arabia, and 1328 human cases and 166 deaths were reported in Yemen [24]. More recently, 1107 human cases and 351 deaths were reported in Kenya, Tanzania, and Somalia between 2006 and 2007, and 1174 cases and 241 deaths were reported in Sudan in 2008 [25]. A number of animal abortions and deaths have also been reported during RVF outbreaks [24]. The occurrence of new outbreaks in RVF-free regions and further geographical expansion of RVF endemicity is possible in the long term, due to the changing world climate and the presence of competent mosquito vectors www.sciencedirect.com
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Figure 1
(a)
RVF endemic countries
Sporadic RVF outbreaks RVF cases reported Evidence of RVFV circulation No reports or information
(b)
RVF vaccine implementation Smithburn vaccine (available) Clone 13 vaccine (field trial) Smithburn vaccine (available) Inactivated ZH501 strain vaccine (available) Smithburn vaccine (optional use) Clone 13T vaccine (available) Clone 13 vaccine (field trial) Clone 13T vaccine (registration) Clone 13T vaccine (field use) Smithburn vaccine (past use) Clone 13 vaccine (registration) Inactivated field strain vaccine (past use) Clone 13 vaccine (registration) Smithburn vaccine (available) Clone 13 vaccine (available) Inactivated field strain vaccine (available) Smithburn vaccine (past use) No implementation of RVF vaccines
Current Opinion in Virology
Countries in which Rift Valley fever (RVF) is endemic and RVF vaccines have been implemented. (a) The status of RVF in Africa and the Middle East. Countries with sporadic RVF outbreaks are shown in red, those with reported RVF disease case(s) in animals or humans are shown in purple, those with reported evidence of RVFV circulation are shown in blue, and those without specific evidence of RVFV circulation are shown in gray. (b) Current availability or past use of RVF vaccines are summarized using different colors, as indicated in the image.
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Current Opinion in Virology 2018, 29:8–15
10 Preventive and therapeutic vaccines
in the Mediterranean basin, Australia, Canada, Eastern and Western Europe, and the U.S. [26–30]. Any immediate risk of the incursion of RVF into RVF-free regions is uncertain, although there are trade embargos on ruminants and their products exported from Africa and the Arabian Peninsula due to animal health and zoosanitary concerns [31,32]. Nonetheless, the disease has been imported into Canada or China through infected persons, indicating a potential for transboundary RVFV spread via travelers [33,34]. Due to its devastating impact on local economies and public health via viral spread into animals and humans, and its potential for rapid transboundary spread, RVF is listed as a notifiable disease by the World Organization for Animal Health (OIE) [35]. RVFV itself is classified as a Category A Priority Pathogen by the National Institute of Allergy and Infectious Disease, and as an overlap select agent by the United States Department of Health and Human Services and Agriculture, due to its effect on human health and potential for use in bioterrorism [36]. Vaccination has been viewed and practiced as an effective means of controlling RVF in endemic countries, and the quest for improved formulations and vaccination strategies to build solid immunity and address the shortcomings of currently-available vaccines continues. This review aims to highlight the current and future role of RVF vaccines in the prevention and control of RVF.
Commercially-available RVF vaccines Vaccination is one of the most effective strategies for the prevention of viral diseases [37,38]. Several RVF vaccines have been developed and used for the immunization of livestock in some endemic countries (Figure 1b). The first RVF vaccine, the Smithburn vaccine, was developed in 1949 via serial intracerebral (i.c.) passages of the pathogenic Entebbe strain in mice. A neuroadapted strain was later established during serial passages (81 passages) in Uganda [39,40]. Additional i.c. passages of the Smithburn neurotropic strain were subsequently conducted in mice (102nd passage) in South Africa, leading to the creation of a master seed of the Smithburn vaccine [1,15,41]. More than one million lyophilized doses of vaccine containing 10% mouse brain extract were sold in South Africa and Kenya between 1951 and 1968, and six million doses in Zimbabwe between 1969 and 1970 [15]. In 1971, the modified live virus vaccine was developed via an amplification of Smithburn strain using BHK-21 cells, and distributed to several countries, including 22 million doses in Namibia and South Africa from 1974 to 1976; 4.2 million doses in South Africa, Israel, and Egypt in 1977; 3 million doses in Zimbabwe from 1978 to 1979 [41]; and approximately 10 million doses in Saudi Arabia in 2001 [42]. The Smithburn vaccine can induce a long-term protective immunity with a single dose in ruminants [43]. There is, Current Opinion in Virology 2018, 29:8–15
however, a potential risk of abortion or fetal malformation in pregnant animals, as well as possible genetic reassortment with pathogenic RVFV strains or reversion to virulence associated with the use of this vaccine, and its use is therefore recommended for non-pregnant animals within endemic countries before and after outbreaks [15,41,44–46]. Inactivated RVF vaccines have also been developed and registered in South Africa and Egypt (Figure 1b). These are the binary ethylenimine-inactivated RVF ZH501 and the formalin-inactivated RVF Menya (Menya/Sheep/258) strain-based vaccines produced by the Veterinary Serum and Vaccine Research Institute in Egypt [47], and the formalin-inactivated RVF vaccine derived from a field strain isolated from a cow at Onderstepoort Biological Product Ltd. (OBP) in South Africa, respectively [48,49]. The inactivated RVF vaccines are, in general, safe for both pregnant animals and use during RVF outbreaks, yet they require booster doses within three to four weeks following initial vaccination to induce protective immunity [44]. Since 2010, a novel live-attenuated RVF vaccine, the Clone 13 vaccine, has been registered in South Africa, Namibia, Botswana, Zambia, and Mozambique (Figure 1b). This vaccine was derived from a plaque clone of the 74HB59 strain from a human patient in the Central African Republic [50]. A 69% in-frame truncation of the NSs gene, which is a major virulence factor for RVFV, is responsible for the attenuation, whereas the L-segment and M-segment do not contribute to the attenuation phenotype [51,52]. Vaccination with a single dose of the Clone 13 vaccine can show protective efficacy in ruminants [53–55]. An overdose dose of Clone 13 vaccine (1 106 plaque forming units), however, showed viral invasion into the placenta and fetal malformations in ewes vaccinated at 50 days of gestation [56], indicating that overdose of this vaccine is not safe in pregnant animals. Nevertheless, the RVF Clone 13 vaccine is considered safe in pregnant animals and suitable for use during RVF outbreaks [44]. More than 28 million doses of Clone 13 vaccine have been used extensively in South Africa, including more than 10 million doses during the 2009–2010 outbreaks [44]. The Clone 13 vaccine has shown instability of infectious virus in liquid form at 22 C and a lyophilized form at 37 C [57], however, and appropriate storage is thus recommended to maintain its immunogenicity [57]. A second RVF Clone 13 vaccine, thermostable Clone 13 vaccine (Clone 13T vaccine), has been developed and registered in Morocco by MCI Sante Animale [57,58,59]. The Clone 13T vaccine was generated via a selection of viable virus populations at 56 C from the culture supernatants of Vero cells infected with the original Clone 13 strain, and then lyophilized in the presence of a www.sciencedirect.com
Rift Valley fever vaccines Dungu, Lubisi and Ikegami 11
stabilizer [58]. In addition to being registered in Morocco, this vaccine (RIFTOVAX-LR for large ruminants, RIFTOVAX-SR for small ruminants) has also been practically used in Senegal and Mali for RVF prevention (Figure 1b).
Vaccines conditionally licensed or currently under development In the U.S., a live-attenuated MP-12 vaccine, derived from an Egyptian ZH548 strain, was conditionally licensed for animal vaccination in 2013 [60,61,62]. The vaccine has been shown to be safe and efficacious in animals following single administration, to confer maternally-derived antibodies to unvaccinated offspring through colostrum, and has also proven safe and efficacious in humans [61]. The MP-12 vaccine is also an Investigational New Drug in the U.S., slated for further evaluation in human clinical trials. Intramuscular vaccination with the MP-12 vaccine could protect nonhuman primates from RVF via an aerosol challenge of a pathogenic RVFV strain [63], which supports the protection of vaccinees against RVF via an inhalation of RVFV. A formalin-inactivated RVF vaccine (TSI-GSD-200) derived from the Entebbe strain is also an Investigational New Drug in the U.S. This vaccine requires booster doses to maintain protective immunity [64–66], and is currently used to protect people whose vocations put them at high risk of contracting RVF [64]. By contrast to the MP-12 vaccine, the TSI-GSD-200 vaccine requires a larger dose, multiple initial inoculations followed by a booster after six months, and annual boosters, in addition to being expensive, difficult to produce, and in short supply [64,66–69]. Various strategies have been employed in endeavors to develop other new and improved RVF vaccines [70], including subunit vaccines, DNA vaccines, virus-like particles, virus replicon particles, virus-vectored vaccines, and genetically modified live-attenuated vaccines [71,72,73]. These vaccines have been tested in different animal models and possess different attributes. Commercialization following completion of all validation trials, mass scale production, and costs will depend on both the resources required to produce these vaccines and demand.
Rationale for development of improved RVF vaccines and vaccination strategies RVF vaccines have contributed to the control of outbreaks in endemic countries, and regular vaccination has been recommended in several countries with sporadic or recurring outbreaks, such as South Africa, Kenya, Tanzania, Egypt, Sudan, and Saudi Arabia (Figure 1) [49,74]. Annual vaccinations are conducted in high risk areas in Saudi Arabia and South Africa, whereas bi-annual vaccinations are conducted in Egypt [75]. In Kenya and Tanzania, vaccination is conducted following warnings of imminent RVF outbreaks [75]. Vaccination calls have www.sciencedirect.com
not, however, been made in many other countries, such as Mauritania, Madagascar, or Niger, due to sporadic or no past occurrence of RVF outbreaks [44]. Despite the demonstrated safety and efficacy of commercially-available vaccines in preventing RVF in animals, concerns remain regarding their effectiveness in the prevention and control of outbreaks. In Egypt, the live-attenuated Smithburn vaccine has been intermittently applied before, during, and following outbreaks, and together with the use of contaminated needles, it was suspected to have contributed to the endemicity of the disease in the country [47]. Currently, an inactivated vaccine derived from the RVFV ZH501 strain is used for RVF control, yet recent studies have shown that seroconversion rates of immunized cattle are not as high as expected, as approximately 70% of cattle are considered vaccinated, but 15% exhibit seroconversion [48,76]. In Saudi Arabia, the herd immunity of sheep and goats, which are annually vaccinated with the Smithburn vaccine, ranged from 22.2% in the Jizan district to 39.3% in the Alarda districts in 2004, shortly after the 2000 outbreak vaccination campaigns [77]. A potential lack of a proper vaccination program has been indicated as one of the constraints in RVF eradication efforts in the country [77,78]. In South Africa, large RVF epidemics occurred in 1950– 1951, 1973–1976, and 2008–2011 [21]. A field survey of 150 farmers in six districts following the 2008–2011 RVF outbreaks indicated that 77% of farmers vaccinated all their animals, while 23% did not or only partially vaccinated [79]. Over 40 million doses of RVF vaccines were sold to control the 2008–2011 outbreaks in South Africa, yet a lack of protective efficacy of the Clone 13 vaccine was pointed out by farmers in the Eastern Cape Province [70]. Investigations nevertheless identified various irregularities, ranging from poor herd immunity prior to the outbreaks, contravention of the manufacturer’s instructions regarding cold chain, vaccination of pregnant and viremic animals, use of same needle on many animals, and vaccination with other unregistered formulations [79]. The Great Horn of Africa region’s biggest dilemma with periodic vaccination is the fact that RVF outbreaks occur at 10–20 year intervals; thus, it is not economically viable to run regular and periodic vaccination campaigns in countries such as Kenya and Tanzania. Furthermore, keeping vaccine stocks would also be fruitless, since the shelf life of RVF vaccines (e.g., Smithburn) is less than five years. Herd immunity at the onset of outbreaks is always very low as a result. In Eastern African countries such as Kenya and Tanzania, RVF outbreaks are often associated with heavy rains during the periodical El Nin˜o/ Southern Oscillation phenomenon [80–82]. Prediction of RVF outbreaks based on the climate-based model has led to an early warning system and recommendations for Current Opinion in Virology 2018, 29:8–15
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preparedness to minimize the risk of devastating RVF outbreaks in the affected regions, via the OIE, World Health Organization, and the Food and Agriculture Organization of the United Nations [83]. The Clone 13 vaccine is recommended for animal vaccinations by trained personnel in response to any outbreak of RVF in those countries, although vaccination during active RVFV circulation is not appropriate. Implementation of a similar forecasting system has not been applicable in Central and West Africa, where the occurrence of RVF outbreaks remains largely unpredictable. Vaccination programs for RVF have not yet been implemented in Western Africa, where the management of RVF outbreaks must rely on early detection and subsequent restriction of animal movement, and prevention of new infection through appropriate handling of potentially-infected animals or their products [84,85]. Control of mosquito activities could also be important for minimizing the transmission of RVFV during outbreaks [4,86]. In Niger, an epizootic of RVF occurred in 2016, and at least 28 persons died [19]. A serological study conducted in Niger in the 1980s showed that neutralizing antibodies were detectable in sheep, cattle, goats, and camels [87], indicating that transmission of RVFV between animals and mosquitoes had been occurring in the country. Further epidemiological analysis will be required to identify the mechanisms that trigger RVF outbreaks in Niger. Unless urgent risk for RVF outbreak is predicted, it will not be feasible to economically justify preventive vaccination of animals in endemic countries.
International collaborations will be important to facilitate the development of ideal RVF vaccines and vaccination strategies. Further extensive analysis of the effectiveness of RVF vaccination will identify pitfalls of vaccination strategies, which will lead to novel approaches for efficiently preventing the spread of RVFV during RVF outbreaks.
Conflict of interest BD supports RVF vaccine development as an independent consultant and an employee at the MCI, Sante Animale, Morocco. The views and conclusion contained in this document are those of authors and not necessarily represent opinions of specific employers.
Acknowledgement TI was partly supported by the funding from the Sealy Center for Vaccine Development at the University of Texas Medical Branch at Galveston.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
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Summary There is a clear demand for RVF vaccines in several endemic countries with recurrent RVF outbreaks. Given the listed challenges, different approaches are urgently needed to improve herd or population immunity, especially during interepidemic periods. These approaches include: (1) improvement of vaccination strategies using currently-available highly-immunogenic vaccines (e.g., improvement of thermostability of vaccines, use of needleless vaccination); (2) use of nonviable vaccines instead of live-attenuated vaccines to reduce the concern of handling live viruses; (3) development of multivalent vaccines that protect against both RVF and other diseases widely and regularly vaccinated against, such as peste des petits ruminants, sheep and goat pox for small ruminants, or lumpy skin disease for cattle, although such vaccines have not yet been licensed to date; (4) establishment of a RVF vaccine or vaccine antigen stockpile at national or regional levels in countries without active RVFV circulation, which would permit the differentiation of vaccinated from infected animals (DIVA vaccine) [44]; and (5) improvement of early warning systems that may provide authorities with the lead time necessary to procure vaccines and conduct reactive vaccinations in time to ensure adequate herd immunity at the onset of outbreaks [88]. Current Opinion in Virology 2018, 29:8–15
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