Cross-Reactive and Potent Neutralizing Antibody Responses in Human Survivors of Natural Ebolavirus Infection

Abstract

Summary Recent studies have suggested that antibody-mediated protection against the Ebolaviruses may be achievable, but little is known about whether or not antibodies can confer cross-reactive protection against viruses belonging to diverse Ebolavirus species, such as Ebola virus (EBOV), Sudan virus (SUDV) and Bundibugyo virus (BDBV). We isolated a large panel of human monoclonal antibodies (mAbs) against BDBV glycoprotein (GP) using peripheral blood B cells from survivors of the 2007 BDBV outbreak in Uganda. We determined that a large proportion of mAbs with potent neutralizing activity against BDBV bind to the glycan cap and recognize diverse epitopes within this major antigenic site. We identified several glycan cap-specific mAbs that neutralized multiple ebolaviruses including SUDV, and a cross-reactive mAb that completely protected guinea pigs from the lethal challenge with heterologous EBOV. Our results provide a roadmap to develop a single antibody-based treatment effective against multiple Ebolavirus infections.

Chimeric Filoviruses for Identification and Characterization of Monoclonal Antibodies

“…We next tested the ability of MAbs isolated from filovirus survivors to bind to plaques formed by the constructed viruses. We tested the binding of MAbs BDBV43 or BDBV52 recently isolated from a survivor of BDBV infection (38) and MR78, MR235, or MR246 from a survivor of MARV infection (34) (Fig. 4A).…”

“…The antibody appeared to neutralize authentic EBOV less efficiently than VSV/EBOV-GP. Next, antibodies BDBV43 and BDBV52, isolated from a human survivor of BDBV infection (38) were tested. Again, authentic BDBV was less efficiently neutralized than VSV/BDBV-GP.…”

“…The data presented here suggest that surrogate systems such as chimeric VSV expressing filovirus GP may produce misleading results and therefore appear to be suboptimal for the reliable characterization of filovirus antibodies. The simultaneous circulation of multiple lineages of filoviruses in the same outbreak (46,47), along with the emergence of "new" filoviruses (5, 6), and improved methods for isolation of MAbs from survivors (34,38,48), along with the utility of their use in therapeutics, strongly support the need for improved efficient means of rapid screening and characterization of large panels of MAbs. Although a previous study demonstrated the possibility of the generation of viable ebolaviruses with some genes replaced with counterparts from a heterologous ebolavirus (49), the present study demonstrates that EBOV can easily tolerate exchange of GP not only from ebolaviruses but also from more distantly related marburgvirus and cuevavirus.…”

“…The importance of this mechanism in the context of human filovirus infections remains unclear. In a separate study we isolated BDBV52, an antibody from a survivor, which binds both recombinant GP and sGP but does not neutralize EBOV/ BDBV-GP (38). We hypothesized that this MAb can neutralize virus in the absence of sGP.…”

Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease

“…Recently, pan-Ebolavirus monoclonal antibodies with demonstrated in vitro activity have been identified (32)(33)(34), and these experimental candidates could be screened in ferrets in vivo. Other advantages with using ferrets as a potential animal model include better availability, smaller body sizes, less stringent housing requirements, and reduced costs.…”