Vesicular Stomatitis Virus Pseudotyped with Ebola Virus Glycoprotein Serves as a Protective, Noninfectious Vaccine against Ebola Virus Challenge in Mice

Abstract

The recent Ebola virus (EBOV) epidemic in West Africa demonstrates the potential for a significant public health burden caused by filoviral infections. No vaccine or antiviral is currently FDA approved. To expand the vaccine options potentially available, we assessed protection conferred by an EBOV vaccine composed of vesicular stomatitis virus pseudovirions that lack native G glycoprotein (VSVΔG) and bear EBOV glycoprotein (GP). These pseudovirions mediate a single round of infection. Both single-dose and prime/boost vaccination regimens protected mice against lethal challenge with mouse-adapted Ebola virus (ma-EBOV) in a dose-dependent manner. The prime/boost regimen provided significantly better protection than a single dose. As N-linked glycans are thought to shield conserved regions of the EBOV GP receptor-binding domain (RBD), thereby blocking epitopes within the RBD, we also tested whether VSVΔG bearing EBOV GPs that lack GP1 N-linked glycans provided effective immunity against challenge with ma-EBOV or a more distantly related virus, Sudan virus. Using a prime/boost strategy, high doses of GP/VSVΔG partially or fully denuded of N-linked glycans on GP1 protected mice against ma-EBOV challenge, but these mutants were no more effective than wild-type (WT) GP/VSVΔG and did not provide cross protection against Sudan virus. As reported for other EBOV vaccine platforms, the protection conferred correlated with the quantity of EBOV GP-specific Ig produced but not with the production of neutralizing antibodies. Our results show that EBOV GP/VSVΔG pseudovirions serve as a successful vaccination platform in a rodent model of Ebola virus disease and that GP1 N-glycan loss does not influence immunogenicity or vaccination success.IMPORTANCE The West African Ebola virus epidemic was the largest to date, with more than 28,000 people infected. No FDA-approved vaccines are yet available, but in a trial vaccination strategy in West Africa, recombinant, infectious VSV encoding the Ebola virus glycoprotein effectively prevented virus-associated disease. VSVΔG pseudovirion vaccines may prove as efficacious and have better safety, but they have not been tested to date. Thus, we tested the efficacy of VSVΔG pseudovirions bearing Ebola virus glycoprotein as a vaccine platform. We found that wild-type Ebola virus glycoprotein, in the context of this platform, provides robust protection of EBOV-challenged mice. Further, we found that removal of the heavy glycan shield surrounding conserved regions of the glycoprotein does not enhance vaccine efficacy.

Antibodies to the Glycoprotein GP2 Subunit Cross-React between Old and New World Arenaviruses

“…Recent reports have shown that neutralization is not an absolute requirement for a MAb to protect in vivo against influenza and Ebola viruses ( 21 – 25 ). Specifically, murine IgG2a and IgG2b MAbs have exhibited protection in the mouse model driven by effector functions.…”

Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection

“…More such antibodies could exist for Ebola virus, but may not have been pursued because initial antibody downselection is typically based on neutralization. In many EBOV vaccine studies, total antibody binding, rather than neutralization, is the best correlate of protection (Lennemann et al, 2017; Pushko et al, 2000; Schmaljohn and Lewis, 2016; Sullivan et al, 2009; Wong et al, 2012). Antibodies that recognize the IEF-linked, more accessible Tier 1 epitopes may even take precedence in polyclonal responses elicited by vaccination.…”

Can Ebola Virus Vaccines Have Universal Immune Correlates of protection?

“…These B cells may therefore possess unappreciated antibody-independent roles such as priming T cells, and only produce antibodies with T cell help following vaccination, which promote but are not predictive of survival. Protection by a replication-deficient vaccine based on VSV pseudotyped with EBOV GP was mediated by GP-specific binding antibodies (IgG and IgM) and not neutralizing antibodies [36]. Collectively, these studies raised the issue that EBOV vaccine platforms elicit distinct immune profiles and use different protection mechanisms [37] thus emphasizing that individual studies are required for each proposed vaccine platform to establish vaccine-specific mechanistic correlate(s) of protection.…”