Evaluation of the Efficacy, Potential for Vector Transmission, and Duration of Immunity of MP-12, an Attenuated Rift Valley Fever Virus Vaccine Candidate, in Sheep

Abstract

dRift Valley fever virus (RVFV) causes serious disease in ruminants and humans in Africa. In North America, there are susceptible ruminant hosts and competent mosquito vectors, yet there are no fully licensed animal vaccines for this arthropod-borne virus, should it be introduced. Studies in sheep and cattle have found the attenuated strain of RVFV, MP-12, to be both safe and efficacious based on early testing, and a 2-year conditional license for use in U.S. livestock has been issued. The purpose of this study was to further determine the vaccine's potential to infect mosquitoes, the duration of humoral immunity to 24 months postvaccination, and the ability to prevent disease and viremia from a virulent challenge. Vaccination experiments conducted in sheep found no evidence of a potential for vector transmission to 4 North American mosquito species. Neutralizing antibodies were elicited, with titers of >1:40 still present at 24 months postvaccination. Vaccinates were protected from clinical signs and detectable viremia after challenge with virulent virus, while control sheep had fever and high-titered viremia extending for 5 days. Antibodies to three viral proteins (nucleocapsid N, the N-terminal half of glycoprotein GN, and the nonstructural protein from the short segment NSs) were also detected to 24 months using competitive enzyme-linked immunosorbent assays. This study demonstrates that the MP-12 vaccine given as a single dose in sheep generates protective immunity to a virulent challenge with antibody duration of at least 2 years, with no evidence of a risk for vector transmission. R ift Valley fever virus (RVFV) is a vector-borne Phlebovirus (Bunyaviridae) that causes a noncontagious disease of wild and domestic ruminants and a zoonotic disease of humans. The virus has a tripartite RNA genome with large (L), medium (M), and small (S) segments (1). Rift Valley fever (RVF) is typically mild or unapparent in adult ruminants but causes abortion storms and high fatality rates in neonates. In humans, the disease may be undetected or exhibited by mild fever and flu-like symptoms; however, ocular disease, meningoencephalitis (2), and hemorrhagic fever syndromes are also possible, with case fatality rates ranging from 1% to 25% (3,4). Transmission between ruminants is by mosquitoes, while in humans, infection is often acquired by direct contact with tissues and fluids from infected animals (5).RVFV was first identified in 1930 in sub-Saharan Africa where it is endemic and causes periodic epizootics (6). It has shown the capability to expand into new regions by spreading into Egypt in 1977, causing an epidemic with high morbidity and mortality in livestock and humans, and to the Arabian Peninsula in 2000-2001 (7-9). Many mosquito species are competent vectors of the virus, including species present in North America (10-13), and stable flies and house flies are potential mechanical vectors (14). The range of competent vectors and susceptible ruminant hosts in the United States might contribute to the rapid spread a...

Rift Valley fever vaccines: an overview of the safety and efficacy of the live-attenuated MP-12 vaccine candidate

“…The MP-12 vaccine is an Investigational New Drug to be tested in humans, and its safety and immunogenicity have been tested in clinical trials, including healthy adults [33,34]. In 2013, the MP-12 vaccine was conditionally licensed to Zoetis Inc. for animal vaccination in the U.S. without specific descriptions in the issuance of a conditional license in terms of applied animal species, pregnancy, or age [35], and new vaccine master seed has been generated accordingly by additional amplification of TSI-GSD-223 in MRC-5 cells [27,36]. …”

“…This scenario is thought to be rare, however, as long as vaccination is conducted appropriately by excluding potentially viremic animals. Most vaccinated animals are not infected with the pathogenic RVFV strain, and mosquitoes cannot be infected with the vaccine strain by feeding on vaccinated animals with low viremia, such as ≤3.0 log 10 pfu/ml [27,52,53]. Field use of a live-attenuated vaccine will require special caution, however, to avoid vaccination of already infected animals [36], because MP-12 infection and dissemination rates of mosquito populations in endemic areas may not be the same as those found in mosquito colonies available in laboratories.…”

Attenuation and protective efficacy of Rift Valley fever phlebovirus rMP12-GM50 strain

“…Since MP-12 strain does not induce high titers of viremia in ruminants, it is considered unlikely that rMP12-GM50 strain can transmit from vaccinated animals to mosquitoes [51, 52]. If rMP12-GM50 strain and wild-type RVFV strains co-circulate in mosquitoes by any reasons, it is assumed that reassortant RVFV strains between two strains can be created.…”

Attenuation of pathogenic Rift Valley fever virus strain through the chimeric S-segment encoding sandfly fever phlebovirus NSs or a dominant-negative PKR

“…17,18 In the US, the live-attenuated MP-12 vaccine has been conditionally licensed for veterinary use. 19 The MP-12 vaccine is attenuated by a combination of mutations within the L-, M-and S-segments, and complete attenuation happens with the combination of all attenuated segments. 20 Moreover, each L-and M-segment encode 2 independent temperature-sensitive mutations, which limit MP-12 replication above 38 C. 21 A potential disadvantage of the MP-12 vaccine is a lack of a DIVA marker (Differentiation of Infected from Vaccinated Animals).…”