Longitudinal Analysis of the Human B Cell Response to Ebola Virus Infection

Abstract

Summary Ebola virus (EBOV) remains a public health threat. We performed a longitudinal study of B cell responses to EBOV in four survivors of the 2014 West African outbreak. Infection induced lasting EBOV-specific IgG antibodies, but their subclass composition changed over time, with IgG1 persisting, IgG3 rapidly declining, and IgG4 appearing late. Striking changes occurred in the immunoglobulin repertoire, with massive recruitment of naïve B cells that subsequently underwent hypermutation. We characterized a large panel of EBOV glycoprotein-specific monoclonal antibodies (mAbs). Only a small subset of mAbs that bound glycoprotein by ELISA recognized cell-surface glycoprotein. However, this subset contained all neutralizing mAbs. Several mAbs protected against EBOV disease in animals, including one mAb that targeted an epitope under evolutionary selection during the 2014 outbreak. Convergent antibody evolution was seen across multiple donors, particularly among VH3–13 neutralizing antibodies specific for the GP1 core. Our study provides a benchmark for assessing vaccine-induced immunity.

Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV

“…Re-occurring antibodies that share the same V genes have occasionally been reported in response to infections with viruses such as HIV-1, Zika and West Nile virus [45][46][47] . For EVD, a longitudinal analysis of four survivors revealed a preference for IGHV3-13 in EBOV-neutralizing antibodies 48 . This gene is also utilized by mAb114 23 and by antibodies that were elicited upon DNA/Ad5 encoded EBOV GP immunization of macaques 49 .…”

“…EBOV-neutralizing activity has been demonstrated to be a critical factor for antibody-mediated protection 26,27,36,53 . Although little was known about the time of development of neutralizing antibodies, a recent longitudinal analysis of EVD survivors demonstrated a prolonged antibody maturation process and an increase in neutralizing activity, even many months after acute infection 48 . In another study, rVSV-ZEBOV vaccination was documented to induce an early IgM serum response and suggested a predominant role for IgM antibodies for neutralization and potentially for early protection 54 .…”

Rapid isolation of potent SARS-CoV-2 neutralizing antibodies and protection in a small animal model

“…Such low SHM may be associated with the isolation of the nAbs relatively soon after infection, and perhaps before affinity-maturation has progressed. Low SHM has also been described for potent nAbs to Ebola virus, respiratory syncytial virus (RSV), Middle East Respiratory Syndrome coronavirus (MERS-CoV) and yellow fever virus [11][12][13][14] and may indicate that the human naïve repertoire is often sufficiently diverse to respond effectively to many pathogens with little mutation. Of course, nAb efficacy and titer may increase over time as described for other viruses and it will be interesting to see if even more potent nAbs to SARS-CoV-2 evolve in our donors in the future.…”

Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization

“…ExpiCHO (hamster, female origin) and FreeStyle 293F (human, female origin) cell lines were purchased from ThermoFisher Scientific and cultured according to the manufacturer's protocol. The Jurkat-EBOV GP (variant Makona) (Davis et al, 2019), Jurkat-BDBV GP (strain Uganda), Jurkat-SUDV GP (strain Gulu) cell lines stably transduced to display respective GP on the surface (Davis and Ahmed, unpublished) were a kind gift from Carl Davis (Emory University, Atlanta, GA). An NIH 3T3 engineered fibroblast line (mouse, male origin) constitutively expressing cell-surface human CD154 (CD40 ligand), secreted human B cell activating factor (BAFF) and human IL-21 was kindly provided by Dr. Deepta Bhattacharya (Washington University in St. Louis, MO).…”