Recombinant Vesicular Stomatitis Virus Vector Mediates Postexposure Protection against Sudan Ebola Hemorrhagic Fever in Nonhuman Primates

Abstract

Recombinant vesicular stomatitis virus (VSV) vectors expressing homologous filoviral glycoproteins cancompletely protect rhesus monkeys against Marburg virus when administered after exposure and can partially protect macaques after challenge with Zaire ebolavirus. Here, we administered a VSV vector expressing the Sudan ebolavirus (SEBOV) glycoprotein to four rhesus macaques shortly after exposure to SEBOV. All four animals survived SEBOV challenge, while a control animal that received a nonspecific vector developed fulminant SEBOV hemorrhagic fever and succumbed. This is the first demonstration of complete postexposure protection against an Ebola virus in nonhuman primates and provides further evidence that postexposure vaccination may have utility in treating exposures to filoviruses.The filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), cause severe and often fatal infections in humans and nonhuman primates. While there is a single species of MARV, there are four recognized species of EBOV: Ivory Coast ebolavirus (also known as Cote d'Ivoire ebolavirus), Reston ebolavirus, Sudan ebolavirus (SEBOV), and Zaire ebolavirus (ZEBOV) (7,17). Until recently, nearly all EBOV outbreaks in humans have been caused by either SEBOV or ZEBOV. A possible fifth species of EBOV was associated with an outbreak in Uganda late in 2007, but little information is available regarding this new EBOV (1). Since 1976, there have been at least 10 outbreaks of ZEBOV, with case fatality rates approaching 90% (17). During the same period, there have been four outbreaks of SEBOV with mortality rates of approximately 50% (17).Remarkable progress has been made over the last few years in developing candidate preventive vaccines that can protect nonhuman primates against EBOV and MARV (2,3,14,15,[18][19][20][21]. Advances in development of postexposure treatments and therapies against the filoviruses have been much slower. Some degree of success has been achieved using strategies that mitigate the coagulation abnormalities that characterize filoviral infection (10,11,13). Several new postexposure treatment approaches based on small interfering RNA (12) and antisense oligomers (6, 22) have shown promising results in rodent models, but there have been no published reports of either treatment strategy being evaluated in the more stringent macaque models. Recently, we showed the first complete postexposure protection of nonhuman primates against a filovirus by administering a live-attenuated recombinant vesicular stomatitis virus (rVSV) vector expressing the MARV glycoprotein (GP) shortly after a high-dose MARV challenge (4). We subsequently demonstrated that an rVSV vector expressing the ZEBOV GP protected 50% of rhesus macaques when admin-* Corresponding author. Mailing address:

Post-exposure treatments for Ebola and Marburg virus infections

“…Subsequent studies by the same group showed that rVSV-EBOV (Mayinga strain) protected 50% of rhesus monkeys against EBOV (Kikwit strain) challenge 192 and that an rVSV-SUDV (Boniface strain) vaccine protected 100% of rhesus macaques against homologous SUDV challenge 193 .…”

Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease

“…In the recent past, experimental postexposure treatments for filovirus infections have included hyperimmune equine IgG (9), EBOV-specific human monoclonal IgG antibody (16), wholeblood transfusions from convalescent survivors (8), recombinant IFN (13), recombinant nematode anticoagulant protein C2 (19), recombinant human activated protein C (20,21), recombinant vesicular stomatitis virus vectors (22)(23)(24)(25), siRNAs (26), and phosphorodiamidate morpholino oligomers (27). A summary of these efforts is detailed in Table 2.…”

Ebola vaccines in clinical trial: The promising candidates

“…More important, 50% of cynomolgus macaques were survived if administrated with rVSV-EBOV 20 to 30 minutes after Ebola virus infection (Table 3). 13 Other preclinical studies also demonstrated a rapid and significant protection in NHPs. 12,14,[48][49][50][51][52] The first 3 open-label, uncontrolled, phase I clinical trials of rVSV-EBOV vaccine were conducted in Lambar en e, Kilifi, and Hamburg, respectively, which were designed to assess the safety, and immunogenicity of escalating doses ranging from 3 £ 10 5 to 2 £ 10 7 vp in early 2014 (NCT02283099, NCT02287480, NCT02296983) ( Table 1).…”

“…Results from pre-clinical trial studies indicated that both humoral and cellular immunity play an essential role in controlling and eliminating virus due to the spiking of Ebola virus envelope GP forms on the surface of mature virions. [12][13][14] The 2014 Ebola epidemic has significantly accelerated the development of Ebola vaccines, 46 clinical trials with Ebola vaccines were launched according to the registration on Clinicaltrial.gov and Pan African Clinical Trials Registry since then (Tables 1 and 2). 15 Different kinds of Ebola vaccines had been developed and evaluated, which can be roughly divided into 3 categories: non-replicative vector-based Ebola vaccines, replicative vector-based Ebola vaccines and others (Fig.…”