To B or Not to B: Mechanisms of Protection Conferred by rVSV-EBOV-GP and the Roles of Innate and Adaptive Immunity.

Amanda N Pinski,Ilhem Messaoudi

doi:10.3390/microorganisms8101473

Amanda N Pinski, Ilhem Messaoudi

Open Access

https://doi.org/10.3390/microorganisms8101473

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Journal: Microorganisms	Publication Date: Sep 25, 2020
Citations: 14	License type: CC BY 4.0

Affiliation: University of California, Irvine

Abstract

Zaire Ebola virus (EBOV) is a member of the Filoviridae family of negative sense, single-stranded RNA viruses. EBOV infection causes Ebola virus disease (EVD), characterized by coagulopathy, lymphopenia, and multi-organ failure, which can culminate in death. In 2019, the FDA approved the first vaccine against EBOV, a recombinant live-attenuated viral vector wherein the G protein of vesicular stomatitis virus is replaced with the glycoprotein (GP) of EBOV (rVSV-EBOV-GP, Ervebo® by Merck). This vaccine demonstrates high efficacy in nonhuman primates by providing prophylactic, rapid, and post-exposure protection. In humans, rVSV-EBOV-GP demonstrated 100% protection in several phase III clinical trials in over 10,000 individuals during the 2013–2016 West Africa epidemic. As of 2020, over 218,000 doses of rVSV-EBOV-GP have been administered to individuals with high risk of EBOV exposure. Despite licensure and robust preclinical studies, the mechanisms of rVSV-EBOV-GP-mediated protection are not fully understood. Such knowledge is crucial for understanding vaccine-mediated correlates of protection from EVD and to aid the further design and development of therapeutics against filoviruses. Here, we summarize the current literature regarding the host response to vaccination and EBOV exposure, and evidence regarding innate and adaptive immune mechanisms involved in rVSV-EBOV-GP-mediated protection, with a focus on the host transcriptional response. Current data strongly suggest a protective synergy between rapid innate and humoral immunity.

Highlights

Ebola virus, a member of the negative-sense, single stranded RNA virus family Filoviridae, is the causative agent of Ebola virus disease (EVD) [1,2]
Decline of CD4 T cells following infection is associated with fatal EVD in humans [108,109]. These findings suggest a critical integration of CD4 T cell responses and B cell-mediated immunity, which is further supported by the observation that CD4 T follicular helper (Tfh) cells are significantly induced in human rVSV-Ebola virus (EBOV)-GP vaccinees and their frequency correlates with levels of cytokines associated with B cell responses (e.g., IL-4, IL-6 TNF-alpha, IL-12) [110]
RVSV-EBOV-GP is effective both prophylactically and post-exposure to EBOV in nonhuman primates (NHPs) models, mechanisms of protection are inconclusive, but with most compelling data indicating a central role for humoral immunity complemented and enabled by innate immunity

Summary

Introduction

A member of the negative-sense, single stranded RNA virus family Filoviridae, is the causative agent of Ebola virus disease (EVD) [1,2]. The 2013-2016 West Africa outbreak which culminated in over 28,000 cases and 11,308 deaths was caused by the EBOV Makona strain, which despite sharing 97% sequence similarity with Mayinga and Kikwit, has a notably lower CFR of ~40% [28,29]. This epidemic (10 countries were involved) demonstrated the capacity for vast Ebola virus transmission and instituted a state of emergency that facilitated the development of prophylactics and therapeutics. Future applications may utilize the GP of different Ebola virus species, current efforts focus on protection against EBOV since it is the cause of multiple past and ongoing outbreaks [28,29] (Table 1)

Preclinical Studies in Nonhuman Primates

Clinical Studies to Market

Host Response to rVSV-EBOV-GP Vaccination

Correlates of rVSV-mediated Protection

Findings

10. Conclusions