Multiple epitopes of hepatitis B virus surface antigen targeted by human plasma‐derived immunoglobulins coincide with clinically observed escape mutations

Abstract

Hepatitis B immune globulin (HBIG) is a human plasma-derived immunoglobulin G concentrate that contains a high titer of neutralizing antibodies (anti-HBs) to the hepatitis B virus (HBV) surface antigen (HBsAg). HBIG is known to be highly effective in treating HBV infections, however, a more systematic characterization of the antibody binding sites on HBsAg and their correlation with emerging "escape" mutations in HBsAg was lacking. By using anti-HBs antibodies from HBIG lots to screen random peptide phage display libraries, we identified five clusters of peptides that corresponded to five distinct anti-HBs binding sites on the HBsAg. Three sites, Site II (C121-C124), Site III (M133-P135), and Site IV (T140-G145), were mapped within the "a" determinant, while the two other sites, Site I (Q101-M103) and Site V (I152-S154), were outside the "a" determinant. We then tested in binding assays HBsAg peptides containing clinically relevant mutations previously reported within these sites, such as Y134S, P142S, and G145R, and observed a significant reduction in anti-HBs binding activity to the mutated sites, suggesting a mechanism the virus may use to avoid HBIG-mediated neutralization. The current HBIG treatment could be improved by supplementing it with site-specific neutralizing monoclonal antibodies that target these mutations for control of HBV infections.

Vaccine escape challenges virus prevention: The example of two vaccine‐preventable oncogenic viruses

“…Hepatitis B immune globulin (HBIG), which is highly effective in treating HBV infection. 66 However, a recent study demonstrated that vaccinated and spontaneously recovered individuals develop broadly neutralizing antibodies (bNAbs), and bNAbs' combination with distinct epitopes suppresses escape mutations. 67 That evidence concludes that vaccine escape mutations are also induced by antibody monotherapy, resulting in resistance to both HBIG and neutralizing antibodies.…”

“…Vaccine escape mutants, including Y134S, P142S, and G145R, are also observed with a significant reduction in binding activity to Hepatitis B immune globulin (HBIG), which is highly effective in treating HBV infection 66 . However, a recent study demonstrated that vaccinated and spontaneously recovered individuals develop broadly neutralizing antibodies (bNAbs), and bNAbs' combination with distinct epitopes suppresses escape mutations 67 .…”

Uses and Challenges of Antiviral Polyclonal and Monoclonal Antibody Therapies

“…There are other considerations that also play a role in development or deployment of antibody therapies in an infectious disease setting. Although resistance to polyclonal antibodies has been reported 84 , polyclonal antiviral products are less likely to result in treatment-emergent resistance, or the formation of anti-drug antibodies, whereas both issues are a larger concern for mAb products. On the other hand, given the relative ease of engineering, development, and production of mAbs, they are well suited for rapid development, especially in an emerging infectious disease setting.…”

Uses and Challenges of Antiviral Polyclonal and Monoclonal Antibody Therapies

“…There are other considerations that also play a role in the development or deployment of antibody therapies in an infectious disease setting. Although resistance to polyclonal antibodies is reported [ 95 ], polyclonal antiviral products are less likely to result in treatment-emergent resistance or the formation of an antibody response to the treatment (anti-drug antibodies), whereas both issues are a larger concern for mAb products. On the other hand, given the relative ease of engineering, development, and production of mAbs, they are well suited for rapid development, especially in an emerging infectious disease setting.…”