Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses

Abstract

Vaccines and therapies are urgently needed to address public health needs stemming from emerging pathogens and biological threat agents such as the filoviruses Ebola virus (EBOV) and Marburg virus (MARV). Ebola virus (EBOV) and Marburg virus (MARV) of the virus familyFiloviridae are emerging and reemerging pathogens that cause hemorrhagic fever with high mortality rates in humans and nonhuman primates 1-3 . The public health concern about filoviruses has increased in recent years as a result of increased awareness and frequency of cases in central Africa as evidenced by the current outbreak of MARV in Angola 4 and also because filoviruses are considered to be potential agents of bioterrorism 5 . Currently, there are no EBOV or MARV vaccines or therapies approved for human use. Recently, we generated live attenuated recombinant vesicular stomatitis viruses (rVSV) expressing the transmembrane glycoprotein of Zaire ebolavirus (ZEBOV; VSV ∴∆G/ZEBOVGP) and MARV (VSV∆G/MARVGP) 6 . Our study evaluated the utility of these rVSV vectors as candidate vaccines for EBOV and MARV using the cynomolgus macaque model.Filovirus vaccine research has been extensively reviewed in the past and has primarily focused on EBOV 7,8 . The first EBOV vaccine to protect nonhuman primates was a DNA prime-adenovirus boost approach using both the glycoprotein and nucleoprotein as target antigens 9 . This approach required several months for immunity to develop, which limited the utility of this strategy. More recently, an accelerated vaccine was described. A single immunization of nonhuman primates with 2 × 10 12 particles of an equal mixture of human adenovirus 5 vectors carrying either the gene encoding ZEBOV glycoprotein or the gene encoding ZEBOV nucleoprotein resulted in complete protection against ZEBOV 10 . Despite the intriguing success of the adenovirus vaccine, preexisting immunity rates of between 40 and 60% have been reported to adenovirus in the human population and this may eventually limit the utility of this approach [11][12][13] .A smaller number of efforts have focused on developing vaccines against MARV. Alphavirus replicons expressing MARV proteins protected cynomolgus monkeys from homologous MARV challenge 14 . Subsequent studies evaluating this platform as a vaccine for EBOV were less encouraging, as the EBOV counterpart of this alphavirus replicon platform was unable to protect any animal against lethal EBOV challenge under similar test conditions 7 . The ideal vaccine would protect humans from infection from all four EBOV species (ZEBOV, Sudan ebolavirus (SEBOV), Reston ebolavirus, Ivory Coast ebolavirus) and MARV. Although the adenovirusbased vaccine platform has completely protected nonhuman primates against ZEBOV 9,10 , and the platform based on alphavirus replicons protected monkeys against MARV 14 , no platform has demonstrably protected nonhuman primates against both of these viruses.Vaccines based on live attenuated rVSV have been highly effective in animal models and are particularly attractive because they can ...

How Ebola and Marburg viruses battle the immune system

“…Nucleoprotein alone provided incomplete protection in monkeys infected with MARV, whereas viral glycoprotein by itself (or admixed with nucleoprotein) prevented illness and death in six out of six infected animals 4 . Similarly, the first successes in protecting non-human primates against ZEBOV were with a vaccine containing glycoprotein; subsequent studies showed glycoprotein by itself to be sufficient 64,65 , and there are no published data to indicate that there are any other proteins capable of protecting non-human primates against ZEBOV in the absence of glycoprotein.…”

“…It has been confounding to some researchers that neutralization of filoviruses by antibodies -as measured by a reduction in viral infectivity after admixture with antibodies -has proved to be a completely unreliable in vitro predictor of antibody or vaccine effectiveness 4,64,70,76 . Others researchers point to a rich history of antibodies shown to protect in ways other than what is popularly understood as neutralization 77 .…”

“…A recent report with a recombinant adenovirus that expresses the ZEBOV glycoprotein, in which the minimal protective dose of 10 10 particles is described as a 'low dose' , affirms that protection is dependent on the vaccine dose 65 , and might explain why repliconbased vaccines given at much lower doses have not been uniformly successful 67 and DNA vaccines have been only partially effective 79 . Live vesicular stomatitis virus (VSV) 64 or parainfluenza virus 80,81 recombinants, which show considerable promise in protecting non-human primates from filoviral infection, presumably generate high amounts of viral glycoprotein antigen in vivo. Herein resides a most familiar challenge of vaccine licensure: the achievement of a suitable balance between vaccine potency and vaccine safety.…”

The vesicular stomatitis virus-based Ebola virus vaccine: From concept to clinical trials

“…When challenged intramuscularly with a lethal dose of 1,000 PFU of EBOV 28 days after vaccination, animals were completely protected, with no disease signs and no challenge virus viremia detectable. 10 Vaccination with VSV-EBOV also protected cynomolgus macaques from lethal challenge via the aerosol route. 11 …”

“…10 , 13 Importantly, it was shown that vaccination of cynomolgus macaques with a VSV-EBOV vaccine expressing the GP from the EBOV-Kikwit strain, isolated during the 1995 EBOV outbreak in Kikwit, Democratic Republic of the Congo, 21 that was subsequently used in clinical trials resulted in complete protection from lethal challenge with the EBOV-Makona strain isolated during the West African EBOV epidemic. 20 Thus, the currently available VSV-EBOV vaccine will likely be protective in future EBOV outbreaks.…”