Environmental Risk Assessment for rVSVΔG-ZEBOV-GP, a Genetically Modified Live Vaccine for Ebola Virus Disease

Abstract

rVSVΔG-ZEBOV-GP is a live, attenuated, recombinant vesicular stomatitis virus (rVSV)-based vaccine for the prevention of Ebola virus disease caused by Zaire ebolavirus. As a replication-competent genetically modified organism, rVSVΔG-ZEBOV-GP underwent various environmental evaluations prior to approval, the most in-depth being the environmental risk assessment (ERA) required by the European Medicines Agency. This ERA, as well as the underlying methodology used to arrive at a sound conclusion about the environmental risks of rVSVΔG-ZEBOV-GP, are described in this review. Clinical data from vaccinated adults demonstrated only infrequent, low-level shedding and transient, low-level viremia, indicating a low person-to-person infection risk. Animal data suggest that it is highly unlikely that vaccinated individuals would infect animals with recombinant virus vaccine or that rVSVΔG-ZEBOV-GP would spread within animal populations. Preclinical studies in various hematophagous insect vectors showed that these species were unable to transmit rVSVΔG-ZEBOV-GP. Pathogenicity risk in humans and animals was found to be low, based on clinical and preclinical data. The overall risk for non-vaccinated individuals and the environment is thus negligible and can be minimized further through defined mitigation strategies. This ERA and the experience gained are relevant to developing other rVSV-based vaccines, including candidates under investigation for prevention of COVID-19.

Keywords: ERA; ERVEBO®; GMO; Zaire ebolavirus; environmental impact; rVSV; recombinant vaccine; shedding; vesicular stomatitis virus; viremia.

Figure 1

Hypothesized viral life cycle for wild-type (a) Ebola virus and (b) vesicular stomatitis virus (VSV). Shown are the enzootic cycles (i.e., the predominant, long-term natural host reservoirs of the virus and transmission vectors) and epizootic cycles (i.e., spillover of the virus into other susceptible species and/or alternative transmission vectors). The main natural host reservoir of Ebola virus is thought to be certain species of Old World fruit bats, but the virus is capable of transmission to many other mammalian species [1,7,8,9,10]. The natural host reservoir of VSV is thought to be mainly small rodents, such as deer mice, with sandflies acting as transmission vectors; however, VSV is also capable of infecting many other animal species and can be transmitted via other insects [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32]. ^a Pool feeders, i.e., hematophagous arthropods that lacerate their host’s blood vessels and then consume the pooled blood. ^b Vessel feeders, i.e., hematophagous arthropods that consume blood by directly inserting their mouthparts into the lumen of their host’s capillary blood vessels.

Figure 1

Hypothesized viral life cycle for wild-type (a) Ebola virus and (b) vesicular stomatitis virus (VSV). Shown are the enzootic cycles (i.e., the predominant, long-term natural host reservoirs of the virus and transmission vectors) and epizootic cycles (i.e., spillover of the virus into other susceptible species and/or alternative transmission vectors). The main natural host reservoir of Ebola virus is thought to be certain species of Old World fruit bats, but the virus is capable of transmission to many other mammalian species [1,7,8,9,10]. The natural host reservoir of VSV is thought to be mainly small rodents, such as deer mice, with sandflies acting as transmission vectors; however, VSV is also capable of infecting many other animal species and can be transmitted via other insects [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32]. ^a Pool feeders, i.e., hematophagous arthropods that lacerate their host’s blood vessels and then consume the pooled blood. ^b Vessel feeders, i.e., hematophagous arthropods that consume blood by directly inserting their mouthparts into the lumen of their host’s capillary blood vessels.

Figure 2

Molecular structure of the chimeric rVSVΔG-ZEBOV-GP live, recombinant vaccine compared with wtVSV. L, large protein. M, matrix protein. N, nucleoprotein. P, phosphoprotein. VSV-G, vesicular stomatitis virus envelope glycoprotein. ZEBOV-GP, Ebola virus envelope glycoprotein.

Figure 3

Steps required to conduct an ERA for a GMO medicinal product under EMA regulations (left-hand column), illustrated by specific assessment examples from the ERA for rVSVΔG-ZEBOV-GP (right-hand column).

Figure 4

rVSVΔG-ZEBOV-GP shedding and excretion rates among participants in the V920-007 phase 1 clinical trial for whom corresponding data were available.

Figure 5

rVSVΔG-ZEBOV-GP viremia rates, over the first 3 days post-inoculation, among participants in the V920-004 phase 1 clinical trial.