Serologic Cross-Reactivity of Human IgM and IgG Antibodies to Five Species of Ebola Virus

Abstract

Five species of Ebola virus (EBOV) have been identified, with nucleotide differences of 30–45% between species. Four of these species have been shown to cause Ebola hemorrhagic fever (EHF) in humans and a fifth species (Reston ebolavirus) is capable of causing a similar disease in non-human primates. While examining potential serologic cross-reactivity between EBOV species is important for diagnostic assays as well as putative vaccines, the nature of cross-reactive antibodies following EBOV infection has not been thoroughly characterized. In order to examine cross-reactivity of human serologic responses to EBOV, we developed antigen preparations for all five EBOV species, and compared serologic responses by IgM capture and IgG enzyme-linked immunosorbent assay (ELISA) in groups of convalescent diagnostic sera from outbreaks in Kikwit, Democratic Republic of Congo (n = 24), Gulu, Uganda (n = 20), Bundibugyo, Uganda (n = 33), and the Philippines (n = 18), which represent outbreaks due to four different EBOV species. For groups of samples from Kikwit, Gulu, and Bundibugyo, some limited IgM cross-reactivity was noted between heterologous sera-antigen pairs, however, IgM responses were largely stronger against autologous antigen. In some instances IgG responses were higher to autologous antigen than heterologous antigen, however, in contrast to IgM responses, we observed strong cross-reactive IgG antibody responses to heterologous antigens among all sets of samples. Finally, we examined autologous IgM and IgG antibody levels, relative to time following EHF onset, and observed early peaking and declining IgM antibody levels (by 80 days) and early development and persistence of IgG antibodies among all samples, implying a consistent pattern of antibody kinetics, regardless of EBOV species. Our findings demonstrate limited cross-reactivity of IgM antibodies to EBOV, however, the stronger tendency for cross-reactive IgG antibody responses can largely circumvent limitations in the utility of heterologous antigen for diagnostic assays and may assist in the development of antibody-mediated vaccines to EBOV. Ebola virus (EBOV) is a highly pathogenic virus, capable of causing Ebola hemorrhagic fever in humans and non-human primates. Five species of EBOV have been identified. To examine whether infection with one EBOV species results in antibodies that cross-react with other EBOV species, we selected groups of human diagnostic samples from four outbreaks, which were each due to a different EBOV species, and compared IgM and IgG responses by ELISA to each of the five EBOV species. For samples from an individual outbreak, we found limited IgM reactivity to species of EBOV other than the virus species the individual was infected with. In contrast, for all groups of outbreak samples we observed strong cross-reactive IgG antibodies to all EBOV species. Our study demonstrates that IgG antibody responses tend to be more cross-reactive than IgM antibody responses in people infected with EBOV, a finding that has implications for the development of diagnostic assays and vaccines to EBOV.