Human antibody repertoire after VSV-Ebola vaccination identifies novel targets and virus-neutralizing IgM antibodies

Abstract

Development of an effective vaccine against Ebola virus is of high priority. However, knowledge about potential correlates of protection and the durability of immune response after vaccination is limited. Here, we elucidate the human antibody repertoire after administration of vesicular stomatitis virus (VSV)-Ebola vaccine at 3 million, 20 million and 100 million plaque-forming units (PFU) and homologous VSV-Ebola vaccine boost in healthy adult volunteers. Whole genome-fragment phage display libraries, expressing linear and conformational epitopes of Ebola glycoprotein (GP), showed higher diversity of antibody epitopes in individuals vaccinated with 20 million PFU than in those vaccinated with 3 million or 100 million PFU. Surface plasmon resonance kinetics showed higher levels of GP-binding antibodies after a single vaccination with 20 million or 100 million PFU than with 3 million PFU, and these correlated strongly with neutralization titers. A second vaccination did not boost antibody or virus neutralization titers, which declined rapidly, and induced only minimal antibody affinity maturation. Isotype analysis revealed a predominant IgM response even after the second vaccination, which contributed substantially to virus neutralization in vitro. These findings may help identify new vaccine targets and aid development and evaluation of effective countermeasures against Ebola.

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

“…Antibodies that recognize the IEF-linked, more accessible Tier 1 epitopes may even take precedence in polyclonal responses elicited by vaccination. Indeed, GP1/Head and glycan cap mAbs were the most abundantly recognized epitopes by antibodies in vaccinee sera (Khurana et al, 2016) after the first dose of rVSV-based EBOV vaccine (Regules et al, 2015). The frequency of these antibodies persisted after the second vaccine dose, whereas that of HR2 and membrane-proximal antibodies decreased.…”

Comparison of the Efficacy of N9 Neuraminidase-Specific Monoclonal Antibodies against Influenza A(H7N9) Virus Infection

“…Samples of freshly prepared antibody (200 l) at 5-fold dilutions (starting concentrations of 50 g/ml for MAbs 1E8, 5H11, and 7F12 and of 10 g/ml for other MAbs) were injected at a flow rate of 50 l/min (120-s contact time) for association, and dissociation was performed over a 600-s interval (at a flow rate of 50 l/min). Responses from the protein surface were corrected for the response from a mock surface and for measurements from a separate, buffer-only injection as described before (27,28). Binding kinetics for the antibody-antigen interaction was calculated by a bivalent analyte model using Bio-Rad ProteOn manager software (version 3.0.1).…”

“…2 and 3C), they likely bind to different antigenic domains. In addition, they have different binding affinities to NA, as indicated by the equilibrium dissociation constants (K D s) ( Table 1) measured with surface plasmon resonance (SPR) (27,28). 10F4 and 2F6 have higher avidity for NA (K D values of 1.4 and 3.7 nM, respectively) than 1E8 and 11B2 (no binding was detected by SPR at the highest antibody concentration tested, 335 nM).…”

The vesicular stomatitis virus-based Ebola virus vaccine: From concept to clinical trials

“…In the two-dose regimen, the second dose was less reactogenic than the initial dose. 33 Serum sample analysis by Khurana et al . resulted in the identification of novel GP epitopes and, using a pseudo-particle assay in vitro , showed that IgM responses after vaccination are neutralizing, but a second dose administered 28 days after the first one did not significantly increase the antibody titer or repertoire.…”