Pathogenicity Comparison Between the Kikwit and Makona Ebola Virus Variants in Rhesus Macaques

Abstract

Enhanced virulence and/or transmission of West African Ebola virus (EBOV) variants, which are divergent from their Central African counterparts, are suspected to have contributed to the sizable toll of the recent Ebola virus disease (EVD) outbreak. This study evaluated the pathogenicity and shedding in rhesus macaques infected with 1 of 2 West African isolates (EBOV-C05 or EBOV-C07) or a Central African isolate (EBOV-K). All animals infected with EBOV-C05 or EBOV-C07 died of EVD, whereas 2 of 3 EBOV-Kinfected animals died. The viremia level was elevated 10-fold in EBOV-C05-infected animals, compared with EBOV-C07-or EBOV-K-infected animals. More-severe lung pathology was observed in 2 of 6 EBOV-C05/C07-infected macaques. This is the first detailed analysis of the recently circulating EBOV-C05/C07 in direct comparison to EBOV-K with 6 animals per group, and it showed that EBOV-C05 but not EBOV-C07 can replicate at higher levels and cause more tissue damage in some animals. Increased virus shedding from individuals who are especially susceptible to EBOV replication is possibly one of the many challenges facing the community of healthcare and policy-making responders since the beginning of the outbreak.

Recently Identified Mutations in the Ebola Virus-Makona Genome Do Not Alter Pathogenicity in Animal Models

“…However, we did not observe any difference in viral shedding from mucosal membranes, commonly used as an indirect measure for transmission (Gustin et al, 2013; Vetter et al, 2016), when macaques were infected with EBOV-Makona early or later 2014 isolates or with EBOV-Mayinga (Figure S6). This is in contrast to a previous study describing increased virus shedding associated with EBOV-Makona (C05 and C07) infection when compared to EBOV-Kikwit (Wong et al, 2016). Future studies are needed to address transmissibility of EBOV-Makona isolates, preferably utilizing an animal transmission model, which has not yet been established for EBOV.…”

“…This observation may be supported by the recent finding that polymorphism at 544 in GP, located in the internal fusion loop on GP2, decreased entry into monkey and certain human target cells mediated by the EBOV-Makona GP compared to the EBOV-Mayinga GP (Hoffmann et al, 2017). By contrast, increased virulence of EBOV-Makona isolates was found when compared to EBOV-Kikwit, the isolate derived from the 1995 outbreak in the Democratic Republic of Congo (Wong et al, 2016). Higher virulence could be an intrinsic biological feature of an isolate or the result of adaptation through passaging.…”

“…Higher virulence could be an intrinsic biological feature of an isolate or the result of adaptation through passaging. The influence of different passage numbers for EBOV-Mayinga (passage 5; this study) and EBOV-Kiwit (passage 3; Wong et al, 2016) on virulence needs to be clarified in the future, as a direct comparison between both isolates is missing to date. Nevertheless, differences among challenge strains should be carefully considered when interpreting biological phenotypes of EBOV isolates as well as for the choice of EBOV challenge strains for countermeasure efficacy studies.…”

“…We and others have studied certain biological aspects of EBOV-Makona in comparison with previous EBOV isolates (Mayinga 1976 and Kikwit 1995) (Dunham et al, 2015; Marzi et al, 2015; Wong et al, 2016). Despite controversial outcomes, no convincing finding has been published that EBOV-Makona bears unusual biological features explaining higher pathogenicity or increased transmissibility.…”

Clinical Evaluation of Ebola Virus Disease Therapeutics

“…Indeed, genomic variations among EBOV variants from different outbreaks have been observed [70, 75], and genomic alterations in EBOV Makona GP and L genes have been shown to enhance viral transcription and replication [77], as demonstrated in luciferase reporter assays in which mutant Makona GP and L polymerase were shown to induce stronger activities in human Huh-7 cells, as well as procure a growth advantage over wild-type Makona in both Huh-7 and monkey Vero-E6 cells [77]. Furthermore, it has been proposed that EBOV genomic alterations may be associated with elevated pathogenicity and viral shedding in NHPs because the West African isolates causing the recent outbreak induced higher mortality, higher viremia level and more severe tissue injury compared to other isolates [78] (see Outstanding Questions). Consequently, surveillance of EBOV genetic variations and their impact on the efficacy of relevant therapies will be an important consideration to ensure optimized and successful therapeutic regimens for EVD patients in the future.…”