Induction of anti-human immunodeficiency virus (HIV) neutralizing antibodies in rabbits immunized with recombinant HIV--hepatitis B surface antigen particles.

Michel, Marie‐Louise; Mancini, Maryline; Sobczak, Eliane; Favier, Véronique; Guétard, Denise; Bahraoui, Elmostafa; Tiollais, Pierre

doi:10.1073/pnas.85.21.7957

Cited by 60 publications

(36 citation statements)

References 26 publications

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“…It has also been used as a carrier for the presentation of foreign epitopes like tetanus toxoid (4), the glycoprotein D of herpes simplex virus (49), capsid protein of poliovirus (9,11,12), antigens derived from the malaria parasite (29,50), HCV (31), and human immunodeficiency virus (33). The external hydrophilic loop is a preferred site of insertion, and the BamHI restriction site (corresponding to aa 112 and 113) within the HBsAg gene has been used to insert DNA fragments of various lengths (10).…”

Section: Discussionmentioning

confidence: 99%

Antigenicity and Immunogenicity of Novel Chimeric Hepatitis B Surface Antigen Particles with Exposed Hepatitis C Virus Epitopes

Netter

Macnaughton

Woo

et al. 2001

J Virol

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The small envelope protein of hepatitis B virus (HBsAg-S) can self-assemble into highly organized virus like particles (VLPs) and induce an effective immune response. In this study, a restriction enzyme site was engineered into the cDNA of HBsAg-S at a position corresponding to the exposed site within the hydrophilic a determinant region (amino acid [aa] 127-128) to create a novel HBsAg vaccine vector allowing surface orientation of the inserted sequence. We inserted sequences of various lengths from hypervariable region 1 (HVR1) of the hepatitis C virus (HCV) E2 protein containing immunodominant epitopes and demonstrated secretion of the recombinant HBsAg VLPs from transfected mammalian cells. A number of different recombinant proteins were synthesized, and HBsAg VLPs containing inserts up to 36 aa were secreted with an efficiency similar to that of wild-type HBsAg. The HVR1 region exposed on the particles retained an antigenic structure similar to that recognized immunologically during natural infection. VLPs containing epitopes from either HCV-1a or -1b strains were produced that induced strain-specific antibody responses in immunized mice. Injection of a combination of these VLPs induced antibodies against both HVR1 epitopes that resulted in higher titers than were achieved by vaccination with the individual VLPs, suggesting a synergistic effect. This may lead to the development of recombinant particles which are able to induce a broad anti-HCV immune response against the HCV quasispecies or other quasispecies-like infectious agents.Hepatitis C virus (HCV) is now recognized as the major cause of non-A, non-B hepatitis. It has been estimated that about 170 million people worldwide are infected with HCV, of whom 70 to 80% will develop chronic liver disease, leading to cirrhosis in 10 to 20% and liver cancer (hepatocellular carcinoma) in 1 to 5% of chronically infected individuals (6). The linear, single-stranded, positive-sense HCV RNA genome of ca. 9.5 kb contains a single open reading frame (ORF) encoding a polyprotein which is cleaved into the individual mature viral proteins by host-and virus-specific proteinases. Three structural proteins have been identified, the core protein and two envelope proteins, E1 and E2.It has been reported that cellular and humoral immune responses play a pivotal role in the host defense mechanism against HCV (8, 36). Most HCV carriers have circulating antibodies to the virus envelope proteins and to a region located in the extreme amino terminus of E2, hypervariable region 1 (HVR1), which has been reported to contain neutralizing Bcell epitopes and a T-cell epitope (16,17,44). HVR1 probably represents the major site of HCV genetic drift, with amino acid substitutions leading to escape from recognition by existing anti-HVR1 antibodies. Due to the variability within the HVR1 region, it has been proposed that these mutations are responsible for the persistence of HCV infection through neutralizing antibody escape mutants (25,46,52). Qualitative antibody changes accompany HVR1 epi...

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Section: Discussionmentioning

confidence: 99%

Antigenicity and Immunogenicity of Novel Chimeric Hepatitis B Surface Antigen Particles with Exposed Hepatitis C Virus Epitopes

Netter

Macnaughton

Woo

et al. 2001

J Virol

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“…The enhanced immunogenic character of particulate HBsAg has previously lent support for its use as a carrier for foreign epitopes (Valenzuela et al, 1985;Delpeyroux et al, 1986;Rutgers et al, 1988;Michel et al, 1988;von Brunn et al, 1991). The heterologous sequences were predominantly fused to the N terminus of the S protein (with or without preS2 sequences), as this site proved to be rather permissive for insertions (Valenzuela et al, 1985;Rutgers et al, 1988;Michel et al, 1988).…”

Section: Assembly and Secretion Of Modified Env Proteinsmentioning

confidence: 99%

“…The heterologous sequences were predominantly fused to the N terminus of the S protein (with or without preS2 sequences), as this site proved to be rather permissive for insertions (Valenzuela et al, 1985;Rutgers et al, 1988;Michel et al, 1988). Upon synthesis in transfected cells, insertions of up to 84 residues in the preS2 region were compatible with assembly and release of the modified HBsAg particles (Michel et al, 1988). Conversely, insertions within the S encoding region were only poorly tolerated and have been shown to be size-limited to about 20 residues (Delpeyroux et al, 1987;Bruss & Ganem, 1991).…”

Section: Assembly and Secretion Of Modified Env Proteinsmentioning

confidence: 99%

“…Because of its intrinsic adjuvant potential, particulate HBsAg has been developed as a carrier for the presentation of various foreign antigens, e.g. epitopes of herpes simplex virus type 1 glycoprotein D (Valenzuela et al, 1985), neutralization epitopes of the capsid protein VP1 of poliovirus (Delpeyroux et al, 1986), malarial parasite antigen (Rutgers et al, 1988;von Brunn et al, 1991) or selected human immunodeficiency virus type 1 determinants (Michel et al, 1988). In this respect, particulate HBsAg should also be useful for the preparation of multivalent hepatitis B immunogens containing additional protective epitopes of the HBV envelope.…”

Section: Introductionmentioning

confidence: 99%

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Properties of modified hepatitis B virus surface antigen particles carrying preS epitopes

Prange

Werr

Birkner

et al. 1995

Journal of General Virology

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The current hepatitis B virus (HBV) vaccines contain the small (S) and middle (M) viral envelope proteins in particulate form but lack the large (L) protein. Although these particles elicit protective immunity to HBV, inclusion of the immunogenic preS1 region of the L protein may enhance their efficacy. To present preS1-derived epitopes on secretable subviral particles we rearranged the HBV envelope ORF by fusing part or all of the preS 1 region to either the N or C terminus of the S protein. Fusion of the first 42 residues of preS1 to either site allowed efficient secretion of the modified particles and rendered the linked sequence accessible at the surface of the particle. Conversely, fusion of preS1 sequences to the C terminus of the M protein completely blocked secretion. This block to secretion could be rescued by provision ofa heterologous N-terminal signal sequence. All these particles displayed preS1, preS2 and S protein antigenicity. In mice, each construct elicited high titres ofpreS 1-specific antibodies which recognized the authentic L protein. Particles composed of the modified M protein also induced a preS2-specific response. Unexpectedly, however, neither particle elicited S protein-specific antibodies. Nonetheless, the genetic approach employed here represents a strategy to incorporate preSl-derived epitopes both in high density and in highly immunogenic form into their authentic carrier matrix.

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“…HBsAg(S) VLPs have been used as carriers of viral envelop epitopes (8,29,30) and as antigens of the malaria parasite (41). The external hydrophilic loop of HBsAg(S) near its major B cell epitope, the "a" determinant, was a preferred site for insertion of foreign antigens.…”

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confidence: 99%

Low-Dose Adenovirus Vaccine Encoding Chimeric Hepatitis B Virus Surface Antigen-Human Papillomavirus Type 16 E7 Proteins Induces Enhanced E7-Specific Antibody and Cytotoxic T-Cell Responses

Báez-Astúa

Herraez-Hernandez

Garbi

et al. 2005

J Virol

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Induction of effective immune responses may help prevent cancer progression. Tumor-specific antigens, such as those of human papillomaviruses involved in cervical cancer, are targets with limited intrinsic immunogenicity. Here we show that immunization with low doses (10 6 infectious units/dose) of a recombinant human adenovirus type 5 encoding a fusion of the E7 oncoprotein of human papillomavirus type 16 to the carboxyl terminus of the surface antigen of hepatitis B virus (HBsAg) induces remarkable E7-specific humoral and cellular immune responses. The HBsAg/E7 fusion protein assembled efficiently into virus-like particles, which stimulated antibody responses against both carrier and foreign antigens, and evoked antigen-specific kill of an indicator cell population in vivo. Antibody and T-cell responses were significantly higher than those induced by a control adenovirus vector expressing wild-type E7. Such responses were not affected by preexisting immunity against either HBsAg or adenovirus. These data demonstrate that the presence of E7 on HBsAg particles does not interfere with particle secretion, as it occurs with bigger proteins fused to the C terminus of HBsAg, and results in enhancement of CD8 ؉ -mediated T-cell responses to E7. Thus, fusion to HBsAg is a convenient strategy for developing cervical cancer therapeutic vaccines, since it enhances the immunogenicity of E7 while turning it into an innocuous secreted fusion protein.Tumor cells of certain types of cancer express proteins, designated as tumor-specific antigens (TSAs), which are not present in nontumor cells. In neoplasias caused by oncoviruses, such as cervical cancers associated with human papillomavirus type 16 (HPV-16) and liver cancers caused by the hepatitis B and C viruses, the viral proteins represent TSAs. A natural mechanism for elimination of chronically infected or transformed cells is activation of cytotoxic T lymphocytes (CTLs) specific for the viral proteins. However, such proteins, are in general weak immunogens and do not induce adequate activation of antigen-specific T cells.The E6 and E7 products of HPV-16 induce transformation by blocking p53 and retinoblastoma (Rb)-mediated cell cycle control pathways, respectively, and by activating cyclins E and A (44). These proteins are constitutively expressed, albeit at low levels, in preneoplastic as well as cancer tissues and, therefore, represent persistent TSAs. Several lines of evidence suggest that E7 may be an effective immunological target for vaccines against oncogenic HPVs. Cell-mediated immunity to E7 has been demonstrated in HPV-mediated intraepithelial lesions of the uterine cervix (2, 31). Cytolytic T cells to HPV-16 E7 have been found in the blood of women with HPV-16-positive cervical neoplasia (20), and lymphoproliferative responses to E7 were found to inversely correlate with viral load (21). In addition, most cervical intraepithelial lesions caused by HPV regress spontaneously, and the phenomenon is accompanied by macrophage and CD4 ϩ

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Induction of anti-human immunodeficiency virus (HIV) neutralizing antibodies in rabbits immunized with recombinant HIV--hepatitis B surface antigen particles.

Cited by 60 publications

References 26 publications

Antigenicity and Immunogenicity of Novel Chimeric Hepatitis B Surface Antigen Particles with Exposed Hepatitis C Virus Epitopes

Antigenicity and Immunogenicity of Novel Chimeric Hepatitis B Surface Antigen Particles with Exposed Hepatitis C Virus Epitopes

Properties of modified hepatitis B virus surface antigen particles carrying preS epitopes

Low-Dose Adenovirus Vaccine Encoding Chimeric Hepatitis B Virus Surface Antigen-Human Papillomavirus Type 16 E7 Proteins Induces Enhanced E7-Specific Antibody and Cytotoxic T-Cell Responses

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