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J Viral Hepat ; 19(9): 664-73, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22863271

ABSTRACT

Most hepatitis B virus (HBV) vaccines consist of viral small surface (S) protein subtype adw2 expressed in yeast cells. In spite of good efficacy, HBV-genotype and subtype differences, escape mutants and insufficient Th1 activation remain potential problems. To address these problems, we generated recombinant Semliki Forest virus (rSFV) vectors encoding S protein, subtype adw2 or ayw2, or a fragment of the large surface protein, amino acids 1-48 of the pre-S1 domain, fused to S (pre-S1.1-48/S). The antigen loop in S protein and the selected pre-S1 sequences are known targets of neutralizing antibodies. BALB/c mice were immunized intravenously with 10(7) rSFV particles and 10(8) rSFV particles 3 weeks later. Antibodies induced by rSFV encoding S proteins reacted preferentially with subtype determinants of yeast-derived S antigen but equally well with patient-derived S antigen. Immunization with rSFV encoding pre-S1.1-48/S resulted in formation of pre-S1- and S-specific immunoglobulin G (IgG), while immunization with the isogenic mutant without S start codon induced pre-S1 antibodies only. Neutralizing antibodies were determined by mixing with plasma-derived HBV/ayw2 and subsequent inoculation of susceptible primary hepatocyte cultures from Tupaia belangeri. S/adw2 antisera neutralized HBV/ayw2 as effectively as antisera raised with S/ayw2. The pre-S1 antibodies also completely neutralized HBV infectivity. The IgG1/IgG2a ratios ranged from 0.28 to 0.88 in the four immunized groups and were lowest for the pre-S1.1-48/S vector, indicating the strongest Th1 response. This vector type may induce subtype-independent and S-escape-resistant neutralizing antibodies against HBV.


Subject(s)
Antibodies, Neutralizing/blood , Drug Carriers , Genetic Vectors , Hepatitis B Antigens/immunology , Hepatitis B Surface Antigens/immunology , Hepatitis B Vaccines/immunology , Protein Precursors/immunology , Semliki forest virus/genetics , Animals , Cells, Cultured , Female , Hepatitis B Antibodies/blood , Hepatitis B Antigens/genetics , Hepatitis B Surface Antigens/genetics , Hepatitis B Vaccines/administration & dosage , Hepatitis B Vaccines/genetics , Hepatocytes/virology , Humans , Injections, Intravenous , Mice , Mice, Inbred BALB C , Neutralization Tests , Protein Precursors/genetics , Tupaia , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology
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