Markedly prolonged incubation period of hepatitis B in a chimpanzee passively immunized with a human monoclonal antibody to the a determinant of hepatitis B surface antigen.

Abstract

The protective efficacy of a human monoclonal antibody directed against the a determinant of hepatitis B virus (HBV) surface antigen was studied in a chimpanzee. A single high dose of 5 mg/kg (body weight) of monoclonal antibody SDZ OST 577 was intravenously administered to a chimpanzee, followed by intravenous challenge with 103-5 chimpanzee infectious doses of a wild-type HBV, the MS-2 strain (ayw subtype). The passively acquired antibody to HBV surface antigen could be detected for 40 weeks. Serum HBV DNA tested by a "nested" polymerase chain reaction assay was negative through the 36th week after virus challenge but became positive by the 38th week. The chimpanzee subsequently developed acute hepatitis B -1 year after challenge. The nucleotide sequence of the a determinant of the surface gene of the replicated virus was identical with that of the inoculated wild-type virus. Thus, a human monoclonal antibody directed against the a determinant ofHBV surface antigen delayed but did not prevent experimental infection of HBV and hepatitis in the chimpanzee. Our results indicate an incomplete ability of this antibody to protect against HBV infection in vivo after a single infusion.

Licensed recombinant hepatitis B vaccines protect chimpanzees against infection with the prototype surface gene mutant of hepatitis B virus

“…The samples were tested for the presence of HBV DNA by PCR using conditions that have been described 32,37,38 with a nested primer set designed for the amplification of the gene encoding the a determinant of the HBV S protein. The nucleotide sequence of the primers was as follows: the outer sense primer was 5Ј-GAGAATTCAGAGTCTAGACTCGTG-GTGGACTT-3Ј, the outer antisense primer was 5Ј-TGAG-GATCCTACGAACCACTGAACAAATGGCAC-3Ј, the inner sense primer was 5Ј-CGCGAATTCTAGACTCGTGGTGGACTTCTCTCA-3Ј, and the inner antisense primer was 5Ј-CTAGGATCCACTGAA-CAAATGGCACTAGTAA-3Ј.…”

“…The sensitivity of the PCR assay was monitored with 10 0.5 CID 50 of the MS-2 strain of HBV. 37 Direct nucleotide sequencing of the amplified DNA was performed by the dideoxy chain termination method as described previously. 32,37,38 Quantification and Subtyping of Anti-HBs Standard Assays.…”

“…37 Direct nucleotide sequencing of the amplified DNA was performed by the dideoxy chain termination method as described previously. 32,37,38 Quantification and Subtyping of Anti-HBs Standard Assays. Serum samples collected from the 4 vaccinated chimpanzees at 3 weeks after the second vaccine dose and immediately before virus challenge were analyzed for anti-HBs titer and anti-HBs/a, d, and y subtype activities.…”

In vivo hepatitis B virus-neutralizing activity of an anti-HBsAg humanized antibody in chimpanzees

“…For the prevention or post-exposure prophylaxis of HBV infection, human mAbs specific to the common a determinant of the S protein have been developed and their HBV-neutralizing activities were demonstrated in chimpanzees or humans (Ogata et al, 1993;Heijtink et al, 1999;Eren et al, 2000;Galun et al, 2002). However, mostly their HBV-neutralizing activities were demonstrated against only ayw subtype.…”

“…The common a determinant of the S protein was shown to elicit virus-neutralizing and protective antibodies (Bhatnager et al, 1982;Dreesman et al, 1982;Heermann et al, 1987). In addition, a single mAb specific to the common a determinant of the S protein was demonstrated to have virus-neutralizing activity in chimpanzees or humans (Ogata et al, 1993;Heijtink et al, 1999;Eren et al, 2000;Galun et al, 2002). However, since the escape mutants of the common a determinant have arisen (Fujii et al, 1992;McMahon et al, 1992;Kohno et al, 1996;Terrault et al, 1998), development of more new anti-HBV neutralizing antibodies would be beneficial in the immunoprophylaxis of HBV infection.…”