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Molecular characterization and clinical epidemiology of HCV in District Dir (Lower), Pakistan. Virusdisease 2018; 29:369-374. [PMID: 30159373 DOI: 10.1007/s13337-018-0457-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 05/04/2018] [Indexed: 10/16/2022] Open
Abstract
With about 200 million infections globally, Hepatitis C virus (HCV) infection is a major global health threat. The relative prevalence of hepatitis and HCV genotypes/subtypes varies among different geographic regions. Therefore, the present study was conducted to determine the prevalence of hepatitis C and HCV genotypes/subtypes in District Dir (Lower), Pakistan. Blood samples from HCV positive patients were genotyped through multiplex PCR using specific primers for HCV core region. A structured questionnaire was used to obtain information from the patients and data was statistically analyzed for different epidemiological parameters. The molecular evaluation results suggested the prevalence of genotype 3 in this study. The frequency of hepatitis C was found higher in males (P < 0.01). Present study suggests injections received at local clinics as a highly significant mode of HCV transmission to these patients (P < 0.002). These findings might be helpful for clinicians and related health care personnel to assess status of this important disease and highlight the need for more detailed evaluation of this devastating disease in order to frame better treatment strategies.
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Ikram A, Anjum S, Tahir M. In Silico Identification and Conservation Analysis of B-cell and T-Cell Epitopes of Hepatitis C Virus 3a Genotype Enveloped Glycoprotein 2 From Pakistan: A Step Towards Heterologous Vaccine Design. HEPATITIS MONTHLY 2014; 14:e9832. [PMID: 24976845 PMCID: PMC4071360 DOI: 10.5812/hepatmon.9832] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 07/22/2013] [Accepted: 10/17/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) is known for the eminent global disease burden responsible for encumbering public health. Development of an effective vaccine is the major need of the day; however, several obstacles loom ahead of this objective. One of the major barriers is that as a RNA virus, it mutates rapidly resulting in high sequence divergence and several viral isolates in the world. Theglycoprotein 2 (gpE2) is the primary component of HCV envelope with direct interaction with the host cell surface receptors; it is an indispensable target of neutralizing antibodies and hence, should be a fundamental component of vaccine design. OBJECTIVES This study focused on B-cells and T-cells epitopes prediction in HCV gpE2, particularly in 3a genotype, in Pakistan and identification of the conserved epitopes among various 3a isolates at global level, principally conserved across HCV major genotypes. MATERIALS AND METHODS Epitope finding was done by using online available bioinformatics tools including Immune Epitope Database (IEDB), ProPred-I, and ProPred. Conservation of these epitopes was found by aligning selected gpE2 sequences using MultAlin online software and conservancy analysis tool available at IEDB. RESULTS Many B-cell and T-cell epitopes predicted in gpE2 were found conserved among HCV 3a genotypes whereas few were conserved in other genotypes anticipating these epitopes as potential candidates of producing strong B-cell and T-cell response against HCV 3a and other genotypes. CONCLUSIONS HCV gpE2 is an ideal target for HCV vaccine. Prediction of epitope immunogenicity and characterization on the basis of peptide sequences will be significantly helpful for development of a heterologous vaccine against HCV variants.
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Affiliation(s)
- Aqsa Ikram
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Sadia Anjum
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
- Corresponding Author: Sadia Anjum, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan. Tel: +92-5190856152 Fax+92-5190856102, E-mail:
| | - Muhammad Tahir
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
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Wada T, Kohara M, Yasutomi Y. DNA vaccine expressing the non-structural proteins of hepatitis C virus diminishes the expression of HCV proteins in a mouse model. Vaccine 2013; 31:5968-74. [PMID: 24144476 DOI: 10.1016/j.vaccine.2013.10.037] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Revised: 09/03/2013] [Accepted: 10/08/2013] [Indexed: 12/20/2022]
Abstract
Most of the people infected with hepatitis C virus (HCV) develop chronic hepatitis, which in some cases progresses to cirrhosis and ultimately to hepatocellular carcinoma. Although various immunotherapies against the progressive disease status of HCV infection have been studied, a preventive or therapeutic vaccine against this pathogen is still not available. In this study, we constructed a DNA vaccine expressing an HCV structural protein (CN2), non-structural protein (N25) or the empty plasmid DNA as a control and evaluated their efficacy as a candidate HCV vaccine in C57BL/6 and novel genetically modified HCV infection model (HCV-Tg) mice. Strong cellular immune responses to several HCV structural and non-structural proteins, characterized by cytotoxicity and interferon-gamma (IFN-γ) production, were observed in CN2 or N25 DNA vaccine-immunized C57BL/6 mice but not in empty plasmid DNA-administered mice. The therapeutic effects of these DNA vaccines were also examined in HCV-Tg mice that conditionally express HCV proteins in their liver. Though a reduction in cellular immune responses was observed in HCV-Tg mice, there was a significant decrease in the expression of HCV protein in mice administered the N25 DNA vaccine but not in mice administered the empty plasmid DNA. Moreover, both CD8(+) and CD4(+) T cells were required for the decrease of HCV protein in the liver. We found that the N25 DNA vaccine improved pathological changes in the liver compared to the empty plasmid DNA. Thus, these DNA vaccines, especially that expressing the non-structural protein gene, may be an alternative approach for treatment of individuals chronically infected with HCV.
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Affiliation(s)
- Takeshi Wada
- Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, Ibaraki, Japan
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S. El-Hers M, A. El-Fada H, I.A. Saber W, M. El-Deeb A. Human Diseases Prosecution Among Viral Infection and Food Toxins:
A Review. INT J PHARMACOL 2013. [DOI: 10.3923/ijp.2013.390.404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Bailey J. An assessment of the use of chimpanzees in hepatitis C research past, present and future: 1. Validity of the chimpanzee model. Altern Lab Anim 2011; 38:387-418. [PMID: 21105756 DOI: 10.1177/026119291003800501] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The USA is the only significant user of chimpanzees in biomedical research in the world, since many countries have banned or limited the practice due to substantial ethical, economic and scientific concerns. Advocates of chimpanzee use cite hepatitis C research as a major reason for its necessity and continuation, in spite of supporting evidence that is scant and often anecdotal. This paper examines the scientific and ethical issues surrounding chimpanzee hepatitis C research, and concludes that claims of the necessity of chimpanzees in historical and future hepatitis C research are exaggerated and unjustifiable, respectively. The chimpanzee model has several major scientific, ethical, economic and practical caveats. It has made a relatively negligible contribution to knowledge of, and tangible progress against, the hepatitis C virus compared to non-chimpanzee research, and must be considered scientifically redundant, given the array of alternative methods of inquiry now available. The continuation of chimpanzee use in hepatitis C research adversely affects scientific progress, as well as chimpanzees and humans in need of treatment. Unfounded claims of its necessity should not discourage changes in public policy regarding the use of chimpanzees in US laboratories.
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Affiliation(s)
- Jarrod Bailey
- New England Anti-Vivisection Society, Boston, MA 02108-5100, USA.
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Park SH, Song MY, Nam HJ, Im SJ, Sung YC. Codelivery of IL-7 Augments Multigenic HCV DNA Vaccine-induced Antibody as well as Broad T Cell Responses in Cynomolgus Monkeys. Immune Netw 2010; 10:198-205. [PMID: 21286380 PMCID: PMC3026939 DOI: 10.4110/in.2010.10.6.198] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2010] [Revised: 11/09/2010] [Accepted: 11/12/2010] [Indexed: 01/10/2023] Open
Abstract
Background A crucial limitation of DNA vaccines is its weak immunogenicity, especially in terms of eliciting antibody responses in non-human primates or humans; therefore, it is essential to enhance immune responses to vaccination for the development of successful DNA vaccines for humans. Methods Here, we approached this issue by evaluating interleukin-7 (IL-7) as a genetic adjuvant in cynomolgus monkeys immunized with multigenic HCV DNA vaccine. Results Codelivery of human IL-7 (hIL-7)-encoding DNA appeared to increase DNA vaccine-induced antibody responses specific for HCV E2 protein, which plays a critical role in protecting from HCV infection. HCV-specific T cell responses were also significantly enhanced by codelivery of hIL-7 DNA. Interestingly, the augmentation of T cell responses by codelivery of hIL-7 DNA was shown to be due to the enhancement of both the breadth and magnitude of immune responses against dominant and subdominant epitopes. Conclusion Taken together, these findings suggest that the hIL-7-expressing plasmid serves as a promising vaccine adjuvant capable of eliciting enhanced vaccine-induced antibody and broad T cell responses.
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Affiliation(s)
- Su-Hyung Park
- Division of Molecular and Life Science, Integrative Bioscience and Biotechnology, WCU, Pohang University of Science and Technology (POSTECH), Pohang 790-784, Korea
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Seo SH, Jin HT, Park SH, Youn JI, Sung YC. Optimal induction of HPV DNA vaccine-induced CD8+ T cell responses and therapeutic antitumor effect by antigen engineering and electroporation. Vaccine 2009; 27:5906-12. [PMID: 19651174 DOI: 10.1016/j.vaccine.2009.07.033] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2009] [Revised: 07/08/2009] [Accepted: 07/14/2009] [Indexed: 12/23/2022]
Abstract
Since human papillomavirus (HPV) E6 and E7 are promising tumor antigens, we engineered E6 and E7 antigens to generate an optimal HPV DNA vaccine by codon optimization (Co), fusion of E6 and E7, addition of a tissue plasminogen activator (tpa) signal sequence, addition of CD40 ligand (CD40L) or Fms-like tyrosine kinase-3 ligand (Flt3L). The resulting constructs were investigated in terms of their antitumor activity as well as induction of HPV-specific CD8(+) T cell responses. When E6(Co) and E7(Co) were fused (E67(Co)), CD8(+) T cell responses specific for E6 or E7 antigen decreased, but the preventive antitumor effect rather improved, demonstrating the importance of broad immunity. Interestingly, Flt3L-fused HPV DNA vaccine exhibited stronger E6- and E7-specific CD8(+) T cell responses as well as therapeutic antitumor effect than that of CD40L linked HPV DNA vaccine. Finally, the optimal construct, tFE67(Co), was generated by including tpa signal sequence, Flt3L, fusion of E6 and E7, and codon optimization, which induces 23 and 25 times stronger E6- and E7-specific CD8(+) T cell responses than those of initial E67 fusion construct. In particular, inclusion of electroporation in intramuscular immunization of tFE67(Co) further enhances HPV-specific CD8(+) T cell responses, leading to complete tumor regression in a therapeutic setting. Thus, our results provide valuable insight on effective HPV DNA vaccine design and suggest that tFE67(Co) delivered with electroporation may be a promising therapeutic HPV DNA vaccine against cervical cancer.
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Affiliation(s)
- Sang Hwan Seo
- Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
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Evidence for protection against chronic hepatitis C virus infection in chimpanzees by immunization with replicating recombinant vaccinia virus. J Virol 2008; 82:10896-905. [PMID: 18753204 DOI: 10.1128/jvi.01179-08] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Given the failures of nonreplicating vaccines against chronic hepatitis C virus (HCV) infection, we hypothesized that a replicating viral vector may provide protective immunity. Four chimpanzees were immunized transdermally twice with recombinant vaccinia viruses (rVV) expressing HCV genes. After challenge with 24 50% chimpanzee infective doses of homologous HCV, the two control animals that had received only the parental VV developed chronic HCV infection. All four immunized animals resolved HCV infection. The difference in the rate of chronicity between the immunized and the control animals was close to statistical significance (P = 0.067). Immunized animals developed vigorous gamma interferon enzyme-linked immunospot responses and moderate proliferative responses. To investigate cross-genotype protection, the immunized recovered chimpanzees were challenged with a pool of six major HCV genotypes. During the acute phase after the multigenotype challenge, all animals had high-titer viremia in which genotype 4 dominated (87%), followed by genotype 5 (13%). However, after fluctuating low-level viremia, the viremia finally turned negative or persisted at very low levels. This study suggests the potential efficacy of replicating recombinant vaccinia virus-based immunization against chronic HCV infection.
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Park SH, Lee SR, Hyun BH, Kim BM, Sung YC. Codelivery of PEG-IFN-α inhibits HCV DNA vaccine-induced T cell responses but not humoral responses in African green monkeys. Vaccine 2008; 26:3978-83. [DOI: 10.1016/j.vaccine.2008.05.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2007] [Revised: 04/17/2008] [Accepted: 05/09/2008] [Indexed: 11/28/2022]
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Abstract
AIM: To develop hepatitis C virus (HCV) vaccine using HBcAg as the immuno-carrier to express HCV T epitope and to investigate its immunogenicity in mice.
METHODS: We constructed the plasmid pTrc-coreNheI using gene engineering technique, constructed the pcDNA3.1-coreNheI-GFP plasmid with GFP as the reporter gene, and transfected them into Hela cells. The expression of GFP was observed under confocal microscopy and the feasibility of using HBcAg as an immuno-carrier vaccine was studied. pTrc-core gene with a synthetic T epitope antigen gene of HCV (35-44aa) was fused and expressed in the plasmid pTrc-core-HCV (T). For the fusion of the HBcAg-T protein, sucrose, density gradient centrifugation was used, and its molecular weight and purity were analyzed by SDS-PAGE. Then balb/c mice were immunized by the plasmid with the HBcAg (expressed by pTrc-core) protein as control. The tumor regression potential was investigated in mice and evaluated at appropriate time. After three times of immunization, the peripheral blood and spleen of vaccinated mice were collected. HBcAb was detected by ELISA, and nonspecific T lymphocyte proliferation and response of splenocytes were respectively examined by MTT assay. T cell subset of blood and spleen were detected by FACS.
RESULTS: GFP was successfully expressed. Tumor regression trial showed that no tumor formation was found in the group receiving immunization, while tumor xenograft progression was not changed in the control group. Strong nonspecific lymphocyte proliferation response was induced. FACS also showed that the ratio of CD8+ T cells in the experimental group was higher than the controls, but the serum HBcAb in experimental group was similar to the control.
CONCLUSION: HBcAg can be used as an immuno-carrier of vaccine, the fusion of HBcAg-T protein could induce stronger cellular immune responses and it might be a candidate for therapeutic vaccines specific for HCV.
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Affiliation(s)
- Jia-Yu Chen
- Medical School of Taizhou University, Taizhou 318000, Zhejiang Province, China.
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Li YP, Kang HN, Babiuk LA, Liu Q. Elicitation of strong immune responses by a DNA vaccine expressing a secreted form of hepatitis C virus envelope protein E2 in murine and porcine animal models. World J Gastroenterol 2006; 12:7126-35. [PMID: 17131474 PMCID: PMC4087773 DOI: 10.3748/wjg.v12.i44.7126] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To characterize the immunogenicity of a hepatitis C virus (HCV) E2 DNA vaccine alone or with a protein vaccine boost in murine and porcine animal models.
METHODS: A DNA vaccine expressing a secreted form of HCV E2 protein was constructed and used to vaccinate mice and piglets with or without boosting with a recombinant E2 protein vaccine formulated with CpG ODN and 10% Emulsigen. The immunogenicity of HCV E2 vaccines was analyzed by ELISA for antibody responses, MTT assay for lymphocyte proliferation, ELISPOT for the number of interferon-γ secreting cells, and cytotoxic T lymphocyte assays.
RESULTS: Intradermal injection of E2 DNA vaccine induced strong Th1-like immune responses in mice. In piglets, E2 DNA vaccine elicited moderate and more balanced immune responses. A DNA vaccine prime and protein boost vaccination strategy induced significantly higher E2-specific antibody levels and shifted the immune response towards Th2-like ones in piglets.
CONCLUSION: A DNA vaccine expressing a secreted form of HCV E2 protein elicited E2-specific immune responses in mice and piglets. Recombinant E2 protein vaccination following DNA immunization significantly increased the antibody response in piglets. These HCV E2 vaccines may represent promising hepatitis C vaccine candidates for further investigations.
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Affiliation(s)
- Yi-Ping Li
- Vaccine and Infectious Disease Organization, University of Saskatchewan, 120 Veterinary Road, Saskatoon, Saskatchewan, S7N 5E3, Canada
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Gudmundsdotter L, Sjödin A, Boström AC, Hejdeman B, Theve-Palm R, Alaeus A, Lidman K, Wahren B. Therapeutic immunization for HIV. ACTA ACUST UNITED AC 2006; 28:221-30. [PMID: 17031650 DOI: 10.1007/s00281-006-0029-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2005] [Accepted: 12/23/2005] [Indexed: 10/24/2022]
Abstract
Vaccines have entered into human clinical trials against infectious diseases and as therapies against cancer. The HIV virus establishes a latent infection at a very early stage and the T cell memory of the infected patient is rapidly destroyed. However, results of immunotherapy after DNA and protein immunization show that vaccine-induced immune responses might be present for a long period of time. Patients subjected to therapeutic immunization appear to do well, and to have a small immunological advantage, which, however, will have to be improved. The vaccine therapy should start early, while adequate reservoirs of appropriate T helper cells are available and still inducible. The DNA vaccines induce a relatively long-lived immunological memory, and gene-based immunization is effective in inducing cytotoxic CD8(+) T cells and CD4+ helper cells. Protein vaccines, on the other hand, primarily give T cell help. It thus appears that DNA and protein approaches to HIV immunization complement each other. A surprisingly broad reactivity to peptides from different subtypes of HIV was identified in individuals infected with several subtypes of HIV.
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Leroux-Roels G. Development of prophylactic and therapeutic vaccines against hepatitis C virus. Expert Rev Vaccines 2006; 4:351-71. [PMID: 16026249 DOI: 10.1586/14760584.4.3.351] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The hepatitis C virus was discovered 15 years ago as the agent responsible for most cases of transfusion-associated hepatitis non-A, non-B. At present, 180 million people worldwide are estimated to be infected with the virus, producing severe and progressive liver disease in millions and representing the most common reason for liver transplantation in adults. Although the spread of the virus can be halted by the application of primary prevention strategies, such as routine testing of blood donations, inactivation of blood products and systematic use of disposable needles and syringes, the development of a prophylactic vaccine could facilitate the control of this infection and protect those at high risk of being infected with hepatitis C virus. As the present therapy of chronic hepatitis C virus infections, consisting of a combined administration of pegylated interferon-alpha and ribavirin, is only successful in 50% of patients infected with genotype 1, and is costly and associated with serious side effects, there is an urgent need for better tolerated and more effective treatment modalities, and a therapeutic vaccine may be the solution. This review first provides an overview of the present knowledge regarding the interaction between the virus and immune system of the infected host, with special attention given to the possible mechanisms responsible for chronic evolution of the infection. The numerous candidate vaccines that have been developed in the past 10 years are discussed, including the studies in which their immunogenicity has been examined in rodents and chimpanzees. Finally, the only studies of therapeutic vaccines performed in humans to date are considered.
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Affiliation(s)
- Geert Leroux-Roels
- Centre for Vaccinology, Ghent University and Hospital, De Pintelaan 185, B-900 Ghent, Belgium.
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Youn JW, Park SH, Lavillette D, Cosset FL, Yang SH, Lee CG, Jin HT, Kim CM, Shata MTM, Lee DH, Pfahler W, Prince AM, Sung YC. Sustained E2 antibody response correlates with reduced peak viremia after hepatitis C virus infection in the chimpanzee. Hepatology 2005; 42:1429-36. [PMID: 16317673 DOI: 10.1002/hep.20934] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Immune correlates of protection against hepatitis C virus (HCV) infection are not well understood. Here we investigated 2 naive and 6 immunized chimpanzees before and after intravenous challenge, 12 weeks after the last immunization, with 100 50% chimpanzee infectious doses (CID(50)) of heterologous genotype 1b HCV. Vaccination with recombinant DNA and adenovirus vaccines expressing HCV core, E1E2, and NS3-5 genes induced long-term HCV-specific antibody and T-cell responses and reduced peak viral load about 100 times compared with controls (5.91 +/- 0.38 vs. 3.81 +/- 0.71 logs, respectively). There was a statistically significant inverse correlation between peak viral loads and envelope glycoprotein 2 (E2)-specific antibody responses at the time of challenge. Interestingly, one vaccinee that had sterilizing immunity against slightly heterologous virus generated the highest level of E2-specific total and neutralizing antibody responses as well as strong NS3/NS5-specific T-cell proliferative responses. The other four vaccinees with low levels of E2-specific antibody had about 44-fold reduced peak viral loads but eventually developed persistent infections. In conclusion, vaccine-induced E2-specific antibody plays an important role in prevention from nonhomologous virus infection and may provide new insight into the development of an effective HCV vaccine.
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Affiliation(s)
- Jin-Won Youn
- National Research Laboratory of DNA Medicine, Division of Molecular and Life Science, POSTECH Biotech Center, Pohang University of Science and Technology, Republic of Korea
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Kim MS, Sin JI. Both antigen optimization and lysosomal targeting are required for enhanced anti-tumour protective immunity in a human papillomavirus E7-expressing animal tumour model. Immunology 2005; 116:255-66. [PMID: 16162274 PMCID: PMC1817814 DOI: 10.1111/j.1365-2567.2005.02219.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
DNA immunization is a new approach for cancer immune therapy. In this study, we constructed human papillomavirus (HPV) 16 E7 expression vector cassettes and then compared the abilities of these constructs to induce antitumour protection. Lysosome-targeted E7 antigens, and to a lesser degree signal sequence-conjugated and transmembrane region sequence-conjugated E7 antigens in a DNA form, displayed tumour protection significantly higher than wild-type E7 antigens. This enhanced tumour protection was mediated by CD8+ cytotoxic T lymphocytes (CTL), as determined by in vivo T-cell depletion and in vitro interferon-gamma (IFN-gamma) production. Subsequent co-injection with interleukin-12-expressing cDNA showed insignificantly enhanced antitumour protection. However, E7 codon optimization plus lysosomal targeting resulted in a dramatic enhancement in antitumour protection both prophylactically and therapeutically through augmentation of the E7-specific CTL population, compared to either one of them alone. However, wild-type or codonoptimized E7 antigens without intracellular targeting displayed no protection against tumour challenge. Thus, these data suggest that antigen codon optimization plus lysosomal targeting strategy could be important in crafting more efficacious E7 DNA vaccines for tumour protection.
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Affiliation(s)
- Mi Suk Kim
- Department of Obstetrics and Gynaecology, School of Medicine, Catholic Universit of Daegu, Namgu, Daegu, Korea
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16
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Suh YS, Park KS, Sauermann U, Franz M, Norley S, Wilfingseder D, Stoiber H, Fagrouch Z, Heeney J, Hunsmann G, Stahl-Hennig C, Sung YC. Reduction of viral loads by multigenic DNA priming and adenovirus boosting in the SIVmac-macaque model. Vaccine 2005; 24:1811-20. [PMID: 16274888 DOI: 10.1016/j.vaccine.2005.10.026] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2005] [Revised: 09/27/2005] [Accepted: 10/10/2005] [Indexed: 10/25/2022]
Abstract
In this study, we investigated the ability of a multigenic SIV DNA prime/replication-defective adenovirus serotype 5 (rAd/SIV) boost regimen to induce SIV-specific immune responses and protection against intrarectal challenge with SIVmac251 in rhesus macaques. Four rhesus macaques were immunized intramuscularly three times at 8-week intervals with SIV DNA vaccine and boosted once with rAd/SIV vaccine Four control macaques received the same amount of mock plasmid DNA and mock adenovirus vector. While the SIV DNA vaccine included plasmids expressing a mutated human IL-12 gene (IL-12N222L) as well as SIVmac239 structural and regulatory genes, the rAd/SIV vaccine contained rAd vectors expressing SIVmac239 genes only. Immunization with SIV DNA vaccine alone induced SIV-specific IFN-gamma ELISPOT responses in only two of four vaccinated macaques, whereas all animals developed SIV-specific T-cell responses and Env- and Tat-specific antibody responses following the rAd/SIV vaccine boost. Upon intrarectal challenge with pathogenic SIVmac251, strong anamnestic Env-specific binding and neutralizing antibody responses were detected in the vaccinated macaques. Overall, the immunized macaques had lower peak and set-point viral loads than control macaques, suggesting that the induced immune responses play a role in the control of viremia. In addition, the loss of CD4+ T cells was delayed in the vaccinated macaques after challenge. These results indicate that the multigenic DNA prime-adenovirus boost immunization may be a promising approach in developing an effective AIDS vaccine.
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Affiliation(s)
- You S Suh
- Department of Virology and Immunology, German Primate Center, Göttingen, Germany
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Affiliation(s)
- Peter Karayiannis
- Department of Medicine A, Faculty of Medicine, Division of Medicine, St Mary's Campus, Imperial College, London W2 1NY, UK.
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