CIENCIASMEDICASNEWS: Ahead of Print - Use of Single-Injection Recombinant Vesicular Stomatitis Virus Vaccine to Protect Nonhuman Primates Against Lethal Nipah Virus Disease - Volume 25, Number 6—June 2019 - Emerging Infectious Diseases journal

Nipah virus (NiV) is a zoonotic pathogen that causes high case-fatality rates (CFRs) in humans. Two NiV strains have caused outbreaks: the Malaysia strain (NiVM), discovered in 1998–1999 in Malaysia and Singapore (≈40% CFR); and the Bangladesh strain (NiVB), discovered in Bangladesh and India in 2001 (≈80% CFR). Recently, NiVB in African green monkeys resulting in a more severe and lethal disease than NiVM. No NiV vaccines or treatments are licensed for human use. We assessed replication-restricted single-injection recombinant vesicular stomatitis vaccine NiV vaccine vectors expressing the NiV glycoproteins against NiVB challenge in African green monkeys. All vaccinated animals survived to the study endpoint without signs of NiV disease; all showed development of NiV F Ig, NiV G IgG, or both, as well as neutralizing antibody titers. These data show protective efficacy against a stringent and relevant NiVB model of human infection.

Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic zoonotic agents in the paramyxovirus genus Henipavirus. Human case-fatality rates (CFRs) for these viruses historically have ranged from 40% to >90% (1). NiV is categorized as a Biosafety Level 4 (BSL-4) pathogen because of the substantial illness and death it causes and the lack of approved vaccines and therapeutic drugs for human use. In 2015, the World Health Organization listed NiV as a priority pathogen because it is likely to cause severe outbreaks and, in early 2018, placed NiV on the Blueprint list of priority diseases (https://www.who.int/blueprint/priority-diseases). This WHO designation was bolstered because of a deadly NiV outbreak (CFR 89%) during spring 2018 in southwestern India, where NiV had not previously been reported (2).

Bats of the genus Pteropus are the primary reservoir in nature for NiV (3), but several other mammal species can be infected by NiV (4–7). Analysis of NiV genomes has identified 2 NiV strains responsible for outbreaks: Malaysia strain NiVM and Bangladesh strain (NiVB). NiVM caused the first identified outbreak of NiV during 1998–1999 in Malaysia and Singapore (≈270 persons infected; CFR ≈40%) (8,9) and perhaps was responsible for a 2014 outbreak in the Philippines (CFR ≈52%); however, this speculation is based on short genomic reads, so the NiV strain that caused this outbreak is not known (10). NiVB has caused repeated outbreaks in Bangladesh and northeastern India; outbreaks occurred almost every year during 2001–2015 (11–15). These NiVB outbreaks had higher CFRs, averaging ≈80% (14), and showed documented human-to-human transmission (11,16).

Eight experimental preventive candidate vaccines against henipaviruses have been evaluated in NiVM animal models: 1) canarypox and 2) vaccinia viruses encoding the NiVM fusion protein (F) or the NiVM attachment protein (G) that have shown protection against NiVM in hamsters and pigs (17,18); 3) a recombinant adeno-associated vaccine expressing the NiVM G protein that completely protected hamsters against homologous NiVM challenge (19); 4) recombinant vesicular stomatitis viruses (rVSVs) expressing the NiVM F protein or the NiVM G protein that had 100% efficacy in hamsters against NiVM (20); 5) rVSVs expressing the NiVB F protein or the NiVB G protein that completely protected ferrets from NiVM disease (21); 6) an rVSV expressing the Zaire ebolavirus (EBOV) glycoprotein (GP) and the NiVM G protein (rVSV-EBOV-GP-NiVG) that demonstrated efficacy in NiVM hamster (22) and African green monkey (Chlorocebus aethiops) (23) models; 7) a recombinant measles virus vector expressing the NiVM G protein that had efficacy in the NiVMAfrican green monkey model (24); and 8) a recombinant subunit vaccine based on the HeV G protein (sGHeV) that completely protected small animals against lethal HeV and NiVM infections (25–27) and was efficacious in the robust African green monkey model of HeV (28) and NiVMinfection (29). Of 8 vaccines, the sGHeV vaccine is furthest along in evaluation; it has received licensure as a veterinary vaccine for HeV in horses (Equivac HeV, Zoetis, https://www.zoetis.com) in Australia and is being considered as a human vaccine against NiV. When tested against NiV, these 8 vaccine vectors have been tested only against NiVM infection in animal models, and although the antigenicity of these vaccines should not be a concern given that HeV G is an immunogen against NiVM infection, there are new data on the NiVB African green monkey model to consider as far as dose/regimen of vaccines.

NiVB infection in African green monkeys is more pathogenic than NiVM infection (30). This difference resulted in significantly reduced efficacy of antibody therapy because of temporal differences in viral load. Specifically, the human monoclonal antibody m102.4 that had been shown to completely protect African green monkeys against lethal NiVM disease when treatment was delayed until day 5 after virus exposure provided no protection when African green monkeys were challenged with NiVB and treated beginning at day 5 after virus challenge (30,31). Considering these new data, the current vaccines against NiV need to be evaluated for possible differences in dose/regimen against the more pathogenic NiVB infection in the robust African green monkey model. To assess single-dose vaccine efficacy, we evaluated the rVSV vaccine vectors expressing either the NiVB F or NiVB G proteins 28 days after a single-dose vaccination in the NiVBAfrican green monkey model, which most faithfully recapitulates human disease (5,30).