The Enigma of Concurrent Hepatitis B Surface Antigen (HBsAg) and Antibodies to HBsAg

Hepatitis B virus (HBV) infection continues to be a major health problem worldwide. The large-scale immunization programs for persons in high-risk groups, newborns, and adolescents have greatly reduced the incidence of new infection, but the ∼400 million HBV carriers with HBV surface antigen (HBsAg) in the blood remain a burden that will dwindle only within decades. Furthermore, an unknown disease potential is hidden in the carriers of " occult " HBV infection. In fact, the majority of people with " resolved " HBV infection (i.e., 40% of the world population) harbor the virus intrahepatically, but its replication is controlled by cyto-toxic T lymphocytes, and its spread is blocked by the host's neutralizing anti-bodies to HBsAg (anti-HBs). Anti-HBs are also the major protective component of vaccine-induced immunity. In view of their important protective role, occurrence of anti-HBs in HBsAg-positive patients with active chronic HBV infection is extremely puzzling. This phenomenon has been known since at least 1976 [1, 2]. Patients with chronic HBV infection may test persistently positive for HBsAg and anti-HBs without significant change in the infection status. This paradoxical pattern led to a seemingly obvious explanation: the subtype of the HBsAg and anti-HBs were heterologous. HBsAg subtype determinants were first described as allelic exclusive determinants d or y, in addition to the common HBsAg determinant a. Thus, HBsAg/ad was accompanied by anti-HBs/ y and vice versa [1–4]. These findings were later confirmed for the second pair of sub-type determinants, w and r, in patients in East Asia [5]. These studies from the 1970s and 1980s suggested that anti-HBs in HBV carriers had no significant protective or pathogenic effect and were usually associated with high replicative activity. It was speculated that the production of anti-HBs was not completely blocked in chronic HBV carriers, but B cells encoding high-affinity antibodies to the car-rier's own HBsAg would be somehow ineffective , whereas B cell clones encoding antibodies with low affinity to the ho-mologous HBsAg could expand and express their antibody [6]. These anti-HBs would not be bound to the carrier's own HBsAg but to HBsAg with slightly different antigenicity. The possibility that the heterotypic anti-HBs were induced by superinfection with a second HBV strain was dismissed by most studies. After the discovery of vaccine-induced HBsAg escape mutants in 1990, another explanation became likely and could be tested experimentally. Several studies employing PCR amplification and sequenc-ing of the gene for HBsAg (S gene) …