Ebolavirus: Comparison of Survivor Immunology and Animal Models in the Search for a Correlate of Protection

Abstract

Ebola viruses are enveloped, single-stranded RNA viruses belonging to the Filoviridae family and can cause Ebola virus disease (EVD), a serious haemorrhagic illness with up to 90% mortality. The disease was first detected in Zaire (currently the Democratic Republic of Congo) in 1976. Since its discovery, Ebola virus has caused sporadic outbreaks in Africa and was responsible for the largest 2013-2016 EVD epidemic in West Africa, which resulted in more than 28,600 cases and over 11,300 deaths. This epidemic strengthened international scientific efforts to contain the virus and develop therapeutics and vaccines. Immunology studies in animal models and survivors, as well as clinical trials have been crucial to understand Ebola virus pathogenesis and host immune responses, which has supported vaccine development. This review discusses the major findings that have emerged from animal models, studies in survivors and vaccine clinical trials and explains how these investigations have helped in the search for a correlate of protection.

Keywords: Ebolavirus; animal models; correlate of protection; survivors; vaccine.

Figure 1

(A) Structural proteins of EBOV. EBOV is composed of seven structural proteins: L-protein (L), Virion protein (VP) 40, VP24, VP30, VP35, Glycoprotein (GP), and Nucleoprotein (NP). GP is exposed on the viral envelope. It mediates host cell attachment and cell entry. The nucleocapsid is composed of NP, VP35, and VP24. NP binds the viral genome. The polymerase L and its cofactor VP35 drive genome replication and transcription. VP30 is a transcription factor which is also a component of the nucleocapsid. (B) Genomic structure of EBOV and genetic segments targeted for vaccines. Genes encoding for each structural protein are shown. Interestingly, the GP gene also encodes for soluble GP (sGP) and small soluble GP (ssGP). Licensed vaccines (rVSV-ZEBOV, Ad26.ZEBOV) and most candidate vaccines (ChAd3-EBO-Z, RNA and DNA vaccines) use GP as antigen because antibody responses following a natural infection mainly target GP. Other antigens such as NP or VP40 have been also evaluated in the licensed MVA-BN-Filo and some candidate peptide or virus-like particle (VLP)-based vaccines. Figure created with BioRender.com.

Figure 2

Pros and cons of animal models used in EBOV research compared to human studies. Studies in humans are invaluable to understand immunity. However, challenge experiments are only possible in animal models including non-human primates (NHPs), ferrets, Guinea pigs and mice. NHP is the gold standard as this model can be infected with WT EBOV and recapitulates EVD observed in humans. But this model is expensive and ethical and welfare concerns limit its broad use. It is the reason why other animal models have been developed even though they do not fully recapitulate human disease. Mouse models remain the most cost-effective and versatile model, but some adaptations are necessary to observe severe disease. Figure created with BioRender.

Figure 3

Preclinical and clinical studies in the search for correlates of protection. Studies of humoral and cellular responses in Evola virus disease (EVD) survivors and in vaccinated individuals is one strategy to establish correlates of protection. However, controlled challenge studies cannot be performed in humans. The second strategy to identify correlates of protection is the analysis of immune responses in challenge animal models, which allows to compare immunity in protected and not protected animals. Figure created with BioRender.