Human B-Cell Response Evolves During the Years After Ebola Infection

By Will Boggs MD

June 18, 2019

NEW YORK (Reuters Health) - The human B-cell response to Ebola virus evolves significantly during the three years after infection, according to detailed studies of four survivors of the 2014 West African outbreak.

"How to make long-lived antibody responses in people is a key question in vaccine development, so maybe there are lessons to be learned from Ebola infection," Dr. Carl W. Davis from Emory University, in Atlanta, told Reuters Health by email.

Ebola infection leads to extensive activation of B and T cells, and the robust B-cell responses eventually lead to the generation of highly potent protective antibodies. It's unclear what role these antibodies play in the initial control of infection and how these protective antibodies might change over time.

Dr. Davis and colleagues analyzed B-cell responses in four Ebola virus-infected patients during their three-year follow-up study, focusing primarily on antibodies to the Ebola virus surface glycoprotein (GP).

At discharge, all four patients had high GP-specific IgG antibody titers that persisted over two years, persistently elevated IgA levels and elevated GP-specific IgM titers that declined over time to background levels.

Ebola virus-specific IgG subclasses changed over time, with IgG1 persisting, IgG3 declining rapidly and IgG4 appearing late, the researchers report in Cell, online May 16.

The immunoglobulin repertoire evolved over time from mainly naive B cells during the peak of the blood antibody-secreting-cell response to hypermutated B cells during later follow-up.

Only a small subset of monoclonal antibodies that bound GP by ELISA recognized cell-surface GP, but this subset contained all neutralizing monoclonal antibodies.

Several monoclonal antibodies protected against Ebola in animals, including one monoclonal antibody that targeted an epitope under evolutionary selection during the 2014 outbreak.

"When we looked in detail at the individual monoclonal antibodies that made up the antibody response, we found similarities across the different patients," Dr. Davis said. "We normally think of a B cell response as very diverse and each antibody as almost one-of-a-kind. However, antibodies against certain regions on the Ebola glycoprotein - for example, the area near the receptor binding pocket - were derived from very similar genetic recombination events during B-cell development and evolved along similar paths. Since these antibodies protected animals against fatal Ebola-virus infection, we think they are the type of antibodies you would want to elicit with a vaccine."

"The antibodies in the patients continued to evolve and improve for over one year after the virus was cleared from the blood," he said. "For this to happen, it means the immune system was still being exposed to the virus. Although we know that Ebola virus can continue to persist in immune-privileged sites after the acute infection period, our study highlights the fact that viral antigens were continuing to stimulate the immune system."

"Interestingly, the patients started to develop what are known as IgG4 antibodies against the virus after 1-2 years," Dr. Davis said. "This IgG4 class of antibodies is seen in certain autoimmune diseases and in cases of chronic antigen exposure. So the switch to producing this type of antibody may represent an attempt by the immune system to limit the level of inflammation."

He added, "Our data on the IgG subclasses could lead to some interesting clinical follow-up studies in Ebola survivors. For example, one patient in this study developed uveitis after infection, and this same patient had persistence of the IgG3 class of antibodies that disappeared relatively rapidly in the other donors. It would be relatively straightforward to look at IgG subclasses in Ebola survivors and see if certain antibody patterns predict a higher chance of having complications after infection. Perhaps this could be useful for identifying patients who should receive more frequent follow-up care."


Cell 2019.