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      Rift Valley Fever Vaccine Development, Progress and Constraints

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          Abstract

          The workshop Rift Valley Fever Vaccine Development, Progress and Constraints was organized by the Food and Agriculture Organization of the United Nations (FAO) and the Central Veterinary Institute of Wageningen University and Research Centre, under the umbrella of the Global Framework for the Progressive Control of Transboundary Animal Diseases, a joint initiative of FAO and the World Organisation for Animal Health. The workshop was supported by the Netherlands Ministry of Economic Affairs, Agriculture and Innovation, and by the US Centers for Disease Control and Prevention; other participants included the World Health Organization and the International Atomic Energy Agency. The meeting occurred January 19–21, 2011, at FAO headquarters in Rome, Italy, and was attended by 34 leading scientists in Rift Valley fever virus (RVFV) vaccine development, representatives of international organizations, and policy makers. Stakeholders from industry were represented by the International Federation for Animal Health. The main objective of the meeting was to gain consensus about desired characteristics of novel veterinary RVFV vaccines and to discuss how incentives can be established to ensure that these vaccines come to market. Historically, 2 vaccines have been available for control of RVFV in livestock. The first is based on the live-attenuated Smithburn virus ( 1 ). Although this vaccine is inexpensive and provides lasting immunity after 1 dose, its residual virulence renders it unsuitable for application in newborn and gestating livestock. A safe alternative is based on inactivated whole virus. For optimal immunity, however, this vaccine requires a booster and annual revaccination. Drawbacks of these classical vaccines explain the need for a new generation of RVFV vaccines. Workshop participants agreed that novel vaccines should be cost-effective and should provide swift and long duration of immunity after a single vaccination and that application should be safe regardless of the physiologic state of the animal. The possibility of needle-free delivery would be advantageous, especially when absence of virus circulation cannot be definitely established and reuse of needles represents a risk for further dissemination. Novel vaccines that enable differentiation between infected and vaccinated animals (DIVA) by use of an appropriate discriminatory assay would be beneficial. The live-attenuated candidate vaccines that were discussed during the meeting were the MP-12 vaccine ( 2 – 6 ), a recombinant RVFV that contains deletions in 2 of the 3 genome segments ( 7 ), and the clone 13 vaccine ( 8 – 10 ). Data presented during the workshop suggest that all 3 live-attenuated vaccine candidates are highly immunogenic and safe in ewes during the first trimester of gestation and that the MP-12 vaccine is immunogenic and a candidate for human vaccination. The clone 13 vaccine was recently registered and marketed in South Africa; the other live-attenuated vaccines could also come to market in the next decade. ELISAs based on nonstructural proteins could be used as DIVA assays to accompany these vaccines ( 11 ). Alternative vaccines discussed during the workshop are based on the structural glycoproteins Gn and Gc. These proteins are presented by vaccine vectors, produced in vivo from plasmid (DNA vaccines), or administered in the form of virus-like particles (VLPs). Apart from the high safety profile of these vaccines, an additional advantage is their potential application as DIVA vaccines that can be accompanied by commercially available nucleocapsid protein–based ELISAs. A challenge for these approaches is development of a cost-effective vaccine capable of providing protection after 1 dose. Vector vaccines discussed during the workshop are based on capripoxviruses, Newcastle disease virus (NDV), or modified vaccinia Ankara (MVA). It is hypothesized that multivalent capripoxvirus-based vector vaccines would be cost-effective, and their bivalent nature would make them attractive for inclusion in routine capripoxvirus immunization programs, thereby increasing immunity against RVFV. The experiments reported during the workshop suggest that capripoxvirus-vectored vaccines can provide protection against RVFV and capripoxviruses ( 12 , 13 ). An alternative approach is based on a vaccine strain of NDV ( 14 , 15 ). Mammals are not natural host species of NDV, and the efficacy of NDV-based vector vaccines is therefore unlikely to be compromised by preexisting immunity in the field. Vaccination with an NDV recombinant expressing the RVFV structural glycoproteins Gn and Gc has protected mice from lethal challenge, and 1 dose given to lambs resulted in a neutralizing antibody response ( 14 ). MVA is also being evaluated as a vector of RVFV antigens. A single vaccination of mice with an MVA vector expressing Gn and Gc (MVA-M4) provided complete protection (A. Brun, unpub. data). MVA-M4 is not only a promising vaccine candidate for livestock but, considering its safety profile, may also be evaluated as a vaccine for humans. Alternative vaccines with optimal safety profiles are alphavirus replicon–based vaccines (1 6), DNA vaccines ( 16 , 17 ), and VLP-based vaccines ( 18 , 19 ). Initial vaccination with an alphavirus replicon–based vaccine followed by a booster has been shown to protect mice, and promising DNA vaccines based on RVFV genes fused with genes encoding molecular adjuvants have shown promise in mouse trials ( 16 , 17 ). Progress has also been made in approaches that use VLPs. To improve the stability, quantity, and uniformity of VLPs, the Gag protein of Moloney murine leukemia virus was added to VLPs, referred to as chimeric VLPs. Adjuvanted chimeric VLPs protected rats after a single vaccination ( 18 ). In an alternative approach, VLPs that express the nucleocapsid gene from a packaged minigenome were produced and provided complete protection in mice after a single vaccination ( 19 ). These results, together with recently established improved production methods, suggest that VLP-based vaccines can soon become cost-effective alternatives for live vaccines. In conclusion, tremendous progress has been made in the development of novel vaccines for RVFV control. At the end of the workshop, participants drafted 11 recommendations to guide and facilitate the development of RVFV vaccines, norms and standards, and vaccine stockpiles for rapid deployment. These recommendations and other meeting documents are available at www.fao.org/ag/againfo/programmes/en/empres/RVF_2011.html.

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          Most cited references19

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          Genetic evidence for an interferon-antagonistic function of rift valley fever virus nonstructural protein NSs.

          Rift Valley fever virus (RVFV), a phlebovirus of the family Bunyaviridae, is a major public health threat in Egypt and sub-Saharan Africa. The viral and host cellular factors that contribute to RVFV virulence and pathogenicity are still poorly understood. All pathogenic RVFV strains direct the synthesis of a nonstructural phosphoprotein (NSs) that is encoded by the smallest (S) segment of the tripartite genome and has an undefined accessory function. In this report, we show that MP12 and clone 13, two attenuated RVFV strains with mutations in the NSs gene, were highly virulent in IFNAR(-/-) mice lacking the alpha/beta interferon (IFN-alpha/beta) receptor but remained attenuated in IFN-gamma receptor-deficient mice. Both attenuated strains proved to be excellent inducers of early IFN-alpha/beta production. In contrast, the virulent strain ZH548 failed to induce detectable amounts of IFN-alpha/beta and replicated extensively in both IFN-competent and IFN-deficient mice. Clone 13 has a defective NSs gene with a large in-frame deletion. This defect in the NSs gene results in expression of a truncated protein which is rapidly degraded. To investigate whether the presence of the wild-type NSs gene correlated with inhibition of IFN-alpha/beta production, we infected susceptible IFNAR(-/-) mice with S gene reassortant viruses. When the S segment of ZH548 was replaced by that of clone 13, the resulting reassortants became strong IFN inducers. When the defective S segment of clone 13 was exchanged with the wild-type S segment of ZH548, the reassortant virus lost the capacity to stimulate IFN-alpha/beta production. These results demonstrate that the ability of RVFV to inhibit IFN-alpha/beta production correlates with viral virulence and suggest that the accessory protein NSs is an IFN antagonist.
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            Characterization of clone 13, a naturally attenuated avirulent isolate of Rift Valley fever virus, which is altered in the small segment.

            The 74HB59 strain of Rift Valley fever (RVF) virus, isolated from a human case in the Central African Republic, was shown to be composed of a heterogeneous population of viruses when plaque-purified clones were analyzed for their reactivity with monoclonal antibodies (MAbs) directed against the nucleocapsid (N) protein or the nonstructural (NSs) protein. One of these clones, C13, was of particular interest in that it proved to be avirulent in mice and hamsters, and highly immunogenic. Although C13 showed normal reactivity with a large panel of MAbs directed at the glycoproteins, it failed to react with specific MAbs or polyclonal antibodies directed at the NSs protein and with a specific MAb recognizing the N protein of the Egyptian strains. Consequently, the small RNA segment, which encodes the N and NSs proteins in an ambisense strategy, was sequenced and compared with the existing sequence of the attenuated MP-12 RVF virus strain. We found that the NSs gene contained, in addition to two conservative coding changes, a large internal deletion of 549 nucleotides that removes 69% of the open reading frame but conserves in-frame the N and C termini of the predicted translation product. In addition, the sequence revealed that the N protein of C13 contained a single amino acid change. Clone C13 replicated normally in certain cell types in vitro and in Culex pipiens mosquitoes after intrathoracic inoculation, but established abortive infections in MRC-5 human fibroblasts.
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              Rift valley fever virus lacking the NSs and NSm genes is highly attenuated, confers protective immunity from virulent virus challenge, and allows for differential identification of infected and vaccinated animals.

              Rift Valley fever (RVF) virus is a mosquito-borne human and veterinary pathogen associated with large outbreaks of severe disease throughout Africa and more recently the Arabian peninsula. Infection of livestock can result in sweeping "abortion storms" and high mortality among young animals. Human infection results in self-limiting febrile disease that in approximately 1 to 2% of patients progresses to more serious complications including hepatitis, encephalitis, and retinitis or a hemorrhagic syndrome with high fatality. The virus S segment-encoded NSs and the M segment-encoded NSm proteins are important virulence factors. The development of safe, effective vaccines and tools to screen and evaluate antiviral compounds is critical for future control strategies. Here, we report the successful reverse genetics generation of multiple recombinant enhanced green fluorescent protein-tagged RVF viruses containing either the full-length, complete virus genome or precise deletions of the NSs gene alone or the NSs/NSm genes in combination, thus creating attenuating deletions on multiple virus genome segments. These viruses were highly attenuated, with no detectable viremia or clinical illness observed with high challenge dosages (1.0 x 10(4) PFU) in the rat lethal disease model. A single-dose immunization regimen induced robust anti-RVF virus immunoglobulin G antibodies (titer, approximately 1:6,400) by day 26 postvaccination. All vaccinated animals that were subsequently challenged with a high dose of virulent RVF virus survived infection and could be serologically differentiated from naïve, experimentally infected animals by the lack of NSs antibodies. These rationally designed marker RVF vaccine viruses will be useful tools for in vitro screening of therapeutic compounds and will provide a basis for further development of RVF virus marker vaccines for use in endemic regions or following the natural or intentional introduction of the virus into previously unaffected areas.
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                Author and article information

                Journal
                Emerg Infect Dis
                Emerging Infect. Dis
                EID
                Emerging Infectious Diseases
                Centers for Disease Control and Prevention
                1080-6040
                1080-6059
                September 2011
                : 17
                : 9
                : e1
                Affiliations
                [1]Author affiliations: Central Veterinary Institute of Wageningen University and Research Centre, Lelystad, the Netherlands (J. Kortekaas, R.J.M. Moormann);
                [2]Centers for Disease Control and Prevention, Atlanta, Georgia, USA (J. Zingeser);
                [3]Food and Agriculture Organization of the United Nations, Rome, Italy (J. Zingeser, P. de Leeuw, S. de La Rocque);
                [4]Centre International de Recherche Agronomique pour le Développement , Montpellier, France (S. de La Rocque);
                [5]International Atomic Energy Agency, Vienna, Austria (H. Unger)
                Author notes
                Address for correspondence: Jeroen Kortekaas, Central Veterinary Institute of Wageningen University and Research Centre–Virology, Edelhertweg 15, Lelystad, Flevoland 8219 PH, the Netherlands; email: jeroen.kortekaas@ 123456wur.nl
                Article
                11-0506
                10.3201/eid1709.110506
                3322093
                21888781
                74c2c255-47ea-402e-80b4-92146145f57a
                History
                Categories
                Online Conference Summary

                Infectious disease & Microbiology
                rift valley fever virus,workshop,recommendations,conference summary,viruses,vaccine

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