Experimental Rift Valley fever in rhesus macaques

Abstract

Rift Valley fever (RVF) is a major cause of human morbidity and mortality in endemic areas of sub-Saharan Africa and has the potential to cause epidemic disease in receptive areas world-wide. In this study, a RVF viral isolate from the 1977 Egyptian epidemic (ZH-501) inoculated intravenously into rhesus macaques caused a benign viremic infection in most, but resulted in the hemorrhagic fever syndrome in 20 per cent (3 of 15). Serious disease of this type has not previously been observed in nonhuman primates inoculated with RVF virus and may be a consequence of the viral strain used or the route of inoculation. Severe disease was accompanied by extensive liver necrosis, disseminated intravascular coagulation, and microangiopathic hemolytic anemia. We also attempted to prevent RVF by passive transfer of serum from vaccinated rhesus monkeys (plaque-reduction neutralization test titer 1:2,560). As little as 0.025 ml/kg prevented the development of viremia in naive rhesus monkeys after subcutaneous inoculation of virus. The monkey model should be helpful in understanding the pathogenesis and prevention of human RVF.

Rift Valley Fever Virus Clearance and Protection from Neurologic Disease Are Dependent on CD4 + T Cell and Virus-Specific Antibody Responses

“…Indeed, several of the most promising replication-competent vaccine candidates lack NSs and are associated with an early systemic antiviral response (20) followed by a strong neutralizing antibody response correlating with protection from subsequent challenge with wild-type RVFV (18,(20)(21)(22)(23). These vaccine studies corroborate results from early passive transfer studies with nonhuman primates (24) and mice (25) that indicated protection from RVFV challenge is antibody mediated. However, little is known about how the host immune response influences clinical outcome during primary RVFV infection.…”

Pathologic Studies on Suspect Animal and Human Cases of Rift Valley Fever from an Outbreak in Eastern Africa, 2006–2007

“…16 Autopsy samples from rhesus monkeys experimentally infected with RVFV displayed severe liver necrosis as the major microscopic finding. 17,18 Van der Lugt and others 19 studied the distribution of RVF viral antigens by immunoperoxidase in liver, spleen, lymph node, lung, and kidney of eight experimentally infected new-born lambs and four new-born lambs that died of RVF. Viral antigens were most prominent in the liver and were detected in the cytoplasm of hepatocytes at early stage of infection.…”

An alphavirus replicon-derived candidate vaccine against Rift Valley fever virus

“…The RVFV Gn and Gc glycoproteins are the major targets of protective immunity [17][18][19], therefore, the RVFV M segment, which encodes the Gn and Gc glycoproteins, as well as the non-structural protein nsM, was introduced behind the 26S promoter of the SIN-based replicons, as outlined in Figure 1. Correct orientation of the RVFV M segment was confirmed by restriction digest and by sequencing the full-length replicon/RVFV M segment constructs.…”

“…The M segment RNA encodes a non-structural protein NSm of unknown function, plus a polyprotein precursor of the Gn and Gc glycoproteins which form the envelope peplomers that mediate binding and entry of virus into permissive cells [15,16]. The glycoproteins induce production of neutralizing antibody and protective immunity against infection with RVFV [17][18][19].…”