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• W1967627861 abstract "The induction of a robust neutralizing antibody (nAb) response is likely to be as essential as specific cell-mediated immunity (CMI) against multiple antigens for the development of effective preventive and therapeutic vaccines against hepatitis C virus (HCV) infection in humans. To date, no data on the immunogenicity of the replication-defective vaccinia virus (derived from the Tiantan strain) (rNTV)-based HCV vaccine in primates have been reported. This study describes in detail the immunogenicity of various vaccine candidates in rhesus macaques, including rNTV-based and replication-defective recombinant adenoviral (rAd)–based HCV vaccines, as well as HCV pseudotyped virus-like particles (HCVpp). Our data showed that rAd-HCV vaccine boosting induced robust CMI, while priming or boosting with HCVpp enhanced the antigen-specific nAb response after rAd-HCV vaccination; however, CMI was not enhanced. Vaccination includes rNTV-HCV priming induced robust antigen-specific antibody, particularly nAbs, and CMI responses. Furthermore, more robust and longer-lasting CMI and higher cytokine levels (both Th1 and Th2 types, especially IFN-γ) resulted from boosting with rAd-HCV. We conclude that the rNTV-based HCV vaccine induces robust nAbs and CMI when combined with a heterogeneous primer-booster strategy, which shows promise for development of a human HCV vaccine. The induction of a robust neutralizing antibody (nAb) response is likely to be as essential as specific cell-mediated immunity (CMI) against multiple antigens for the development of effective preventive and therapeutic vaccines against hepatitis C virus (HCV) infection in humans. To date, no data on the immunogenicity of the replication-defective vaccinia virus (derived from the Tiantan strain) (rNTV)-based HCV vaccine in primates have been reported. This study describes in detail the immunogenicity of various vaccine candidates in rhesus macaques, including rNTV-based and replication-defective recombinant adenoviral (rAd)–based HCV vaccines, as well as HCV pseudotyped virus-like particles (HCVpp). Our data showed that rAd-HCV vaccine boosting induced robust CMI, while priming or boosting with HCVpp enhanced the antigen-specific nAb response after rAd-HCV vaccination; however, CMI was not enhanced. Vaccination includes rNTV-HCV priming induced robust antigen-specific antibody, particularly nAbs, and CMI responses. Furthermore, more robust and longer-lasting CMI and higher cytokine levels (both Th1 and Th2 types, especially IFN-γ) resulted from boosting with rAd-HCV. We conclude that the rNTV-based HCV vaccine induces robust nAbs and CMI when combined with a heterogeneous primer-booster strategy, which shows promise for development of a human HCV vaccine. Approximately 150 million people worldwide are chronically infected with Hepatitis C virus (HCV), putting them at a higher risk of liver cirrhosis and liver cancer, and which is associated with the deaths of more than 350,000 people annually.1WHO Hepatitis C. 2012Google Scholar Although medications are improving rapidly, the development of effective vaccines for HCV, especially therapeutic ones, remains a top priority.2Barnes E Folgori A Capone S Swadling L Aston S Kurioka A et al.Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man.Sci Transl Med. 2012; 4: 115ra1Crossref PubMed Scopus (332) Google Scholar Fortunately, ∼25% of HCV-infected individuals spontaneously clear the virus during the acute stage of infection.2Barnes E Folgori A Capone S Swadling L Aston S Kurioka A et al.Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man.Sci Transl Med. 2012; 4: 115ra1Crossref PubMed Scopus (332) Google Scholar Researchers have identified several factors associated with viral clearance, which could facilitate development of an effective HCV vaccine.2Barnes E Folgori A Capone S Swadling L Aston S Kurioka A et al.Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man.Sci Transl Med. 2012; 4: 115ra1Crossref PubMed Scopus (332) Google Scholar Various studies have found that the induction and maintenance of strong helper and cytotoxic T-cell immune responses plays a pivotal role in viral clearance and defence against chronic HCV infection.2Barnes E Folgori A Capone S Swadling L Aston S Kurioka A et al.Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man.Sci Transl Med. 2012; 4: 115ra1Crossref PubMed Scopus (332) Google Scholar,3Lauer GM Immune responses to hepatitis C virus (HCV) infection and the prospects for an effective HCV vaccine or immunotherapies.J Infect Dis. 2013; 207 Suppl 1: S7-S12Crossref PubMed Scopus (47) Google Scholar An effective vaccine should induce multiple viral antigen-specific CD4+ and CD8+ T-cell responses, especially Th-1-type immune responses.4Micallef JM Kaldor JM Dore GJ Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies.J Viral Hepat. 2006; 13: 34-41Crossref PubMed Scopus (657) Google Scholar,5Cox AL Netski DM Mosbruger T Sherman SG Strathdee S Ompad D et al.Prospective evaluation of community-acquired acute-phase hepatitis C virus infection.Clin Infect Dis. 2005; 40: 951-958Crossref PubMed Scopus (165) Google Scholar,6Thimme R Oldach D Chang KM Steiger C Ray SC Chisari FV Determinants of viral clearance and persistence during acute hepatitis C virus infection.J Exp Med. 2001; 194: 1395-1406Crossref PubMed Scopus (1018) Google Scholar,7Stoll-Keller F Barth H Fafi-Kremer S Zeisel MB Baumert TF Development of hepatitis C virus vaccines: challenges and progress.Expert Rev Vaccines. 2009; 8: 333-345Crossref PubMed Scopus (81) Google Scholar At the same time, neutralizing antibody (nAb), induced by the candidate vaccine, should recognize and bind to a variety of genotypes of HCV at multiple sites to prevent infection.7Stoll-Keller F Barth H Fafi-Kremer S Zeisel MB Baumert TF Development of hepatitis C virus vaccines: challenges and progress.Expert Rev Vaccines. 2009; 8: 333-345Crossref PubMed Scopus (81) Google Scholar Also, the immune responses induced by immunogens are regulated by cytokines (e.g., IFN-γ, TNF-α, IL10), which then determine the outcome of HCV infection.8Amini M Poustchi H Hepatitis C virus spontaneous clearance: immunology and genetic variance.Viral Immunol. 2012; 25: 241-248Crossref PubMed Scopus (13) Google Scholar The integrated cytokine test, although cytokine production is majorly primarily by the genetic makeup of an individual, may assist in assessment of the efficacy of a candidate vaccine.2Barnes E Folgori A Capone S Swadling L Aston S Kurioka A et al.Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man.Sci Transl Med. 2012; 4: 115ra1Crossref PubMed Scopus (332) Google Scholar The antigen-presenting pathway is mediated and modulated by viral vectors,2Barnes E Folgori A Capone S Swadling L Aston S Kurioka A et al.Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man.Sci Transl Med. 2012; 4: 115ra1Crossref PubMed Scopus (332) Google Scholar,9Liu MA Immunologic basis of vaccine vectors.Immunity. 2010; 33: 504-515Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar which regulate the efficiency of antigen-presentation and the host immune response. After much research, several HCV vaccine candidates, including peptides, proteins, DNA, virus-like particles, and viral vector-based vaccines, have been developed.10Halliday J Klenerman P Barnes E Vaccination for hepatitis C virus: closing in on an evasive target.Expert Rev Vaccines. 2011; 10: 659-672Crossref PubMed Scopus (91) Google Scholar The immunogenic potential of these vaccines and combinations has been described in laboratory animals and humans.6Thimme R Oldach D Chang KM Steiger C Ray SC Chisari FV Determinants of viral clearance and persistence during acute hepatitis C virus infection.J Exp Med. 2001; 194: 1395-1406Crossref PubMed Scopus (1018) Google Scholar Previous studies revealed that most recombinant virus vectors, such as rAd and recombinant vaccinia virus (rVV), are advantageous in terms of their induction of the cellular immune response. Moreover, pseudotyped virus-like particles with HCV E1/E2 envelope proteins (HCVpp), derived from recombinant retroviral or lentiviral vectors, can induce high-titre antigen-specific antibodies and nAbs.11Garrone P Fluckiger AC Mangeot PE Gauthier E Dupeyrot-Lacas P Mancip J et al.A prime-boost strategy using virus-like particles pseudotyped for HCV proteins triggers broadly neutralizing antibodies in macaques.Sci Transl Med. 2011; 3: 94ra71Crossref PubMed Scopus (118) Google Scholar Heterologous prime-boost immunization seems to be a good strategy to enhance both humoral and cellular immune responses. The rAd-based vaccine was used as the priming vaccination, followed by boosting with HCVpp11Garrone P Fluckiger AC Mangeot PE Gauthier E Dupeyrot-Lacas P Mancip J et al.A prime-boost strategy using virus-like particles pseudotyped for HCV proteins triggers broadly neutralizing antibodies in macaques.Sci Transl Med. 2011; 3: 94ra71Crossref PubMed Scopus (118) Google Scholar,12Guan J Wen B Deng Y Zhang K Chen H Wu X et al.Effect of route of delivery on heterologous protection against HCV induced by an adenovirus vector carrying HCV structural genes.Virol J. 2011; 8: 506Crossref PubMed Scopus (12) Google Scholar and a combination of rAd- and DNA- or MVA-based vaccines proved efficacious in stimulating cell-mediated immunity (CMI). However, other heterologous prome-boost regimens, such as priming with HCVpp and boosting with rAd or rVV, may also have potential. The rVV, derived from the Tiantan strain (rVVT), has been widely used as a smallpox vaccine in China and proved to be less virulent than the pathogenic WR strain.13Fang Q Yang L Zhu W Liu L Wang H Yu W et al.Host range, growth property, and virulence of the smallpox vaccine: vaccinia virus Tian Tan strain.Virology. 2005; 335: 242-251Crossref PubMed Scopus (47) Google Scholar,14Zhao L Liu B Ren J Feng J Pang Z Gao J et al.Immunogenicity in mice and rhesus monkeys vaccinated with recombinant vaccinia virus expressing bivalent E7E6 fusion proteins from human papillomavirus types 16 and 18.Virol J. 2011; 8: 302Crossref PubMed Scopus (13) Google Scholar,15Ruan Li, ZJ, Lou Yuanmei, Lu Roujian (2006). Reproduction of defect type tiantan strain vaccinia virus. In: Inst. of Virosis Prevention & Control, CDPCC (ed). C12N7/01,C12N7/04 ed., vol. 1831122 CNGoogle Scholar Furthermore, by deleted the 26 genes associate with host range and virulence between the C and K digestion fragments of Hind III, we developed a recombinant, replication-defective vaccinia (Tiantan strain) viral vector (rNTV), which can well propagated in primary chick embryo fibroblasts but lack of replicative ability in primates and rabbits, and is therefore much safer than rVVT.15Ruan Li, ZJ, Lou Yuanmei, Lu Roujian (2006). Reproduction of defect type tiantan strain vaccinia virus. In: Inst. of Virosis Prevention & Control, CDPCC (ed). C12N7/01,C12N7/04 ed., vol. 1831122 CNGoogle Scholar To date, no data on the immunogenicity of the rNTV-based HCV vaccine in primates have been reported. HCV structural proteins might induce nAbs and activate T-cell responses that mediate viral clearance, and NS3 is essential for HCV clearance as it induces an early and sustained cell-mediated immune response.10Halliday J Klenerman P Barnes E Vaccination for hepatitis C virus: closing in on an evasive target.Expert Rev Vaccines. 2011; 10: 659-672Crossref PubMed Scopus (91) Google Scholar,16Dahari H Feinstone SM Major ME Meta-analysis of hepatitis C virus vaccine efficacy in chimpanzees indicates an importance for structural proteins.Gastroenterology. 2010; 139: 965-974Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar,17Lin Y Kwon T Polo J Zhu YF Coates S Crawford K et al.Induction of broad CD4+ and CD8+ T-cell responses and cross-neutralizing antibodies against hepatitis C virus by vaccination with Th1-adjuvanted polypeptides followed by defective alphaviral particles expressing envelope glycoproteins gpE1 and gpE2 and nonstructural proteins 3, 4, and 5.J Virol. 2008; 82: 7492-7503Crossref PubMed Scopus (49) Google Scholar Therefore, both structural proteins and the NS3 antigen are targets for HCV vaccine development.2Barnes E Folgori A Capone S Swadling L Aston S Kurioka A et al.Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man.Sci Transl Med. 2012; 4: 115ra1Crossref PubMed Scopus (332) Google Scholar Due to safety considerations, integration-deficient lentiviral vectors were used to capture HCV envelope proteins (E1, E2) and insert a relatively well conserved non-structural protein NS3 into the transfer genome as the target antigen.13Fang Q Yang L Zhu W Liu L Wang H Yu W et al.Host range, growth property, and virulence of the smallpox vaccine: vaccinia virus Tian Tan strain.Virology. 2005; 335: 242-251Crossref PubMed Scopus (47) Google Scholar,14Zhao L Liu B Ren J Feng J Pang Z Gao J et al.Immunogenicity in mice and rhesus monkeys vaccinated with recombinant vaccinia virus expressing bivalent E7E6 fusion proteins from human papillomavirus types 16 and 18.Virol J. 2011; 8: 302Crossref PubMed Scopus (13) Google Scholar,18Wanisch K Yáñez-Muñoz RJ Integration-deficient lentiviral vectors: a slow coming of age.Mol Ther. 2009; 17: 1316-1332Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar Recent studies have demonstrated the effectiveness of both recombinant viral vector–based vaccines and the prime-boost strategy in several clinical trials.2Barnes E Folgori A Capone S Swadling L Aston S Kurioka A et al.Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man.Sci Transl Med. 2012; 4: 115ra1Crossref PubMed Scopus (332) Google Scholar Research has begun to focus increasingly on replicating-deficient vaccinia virus Ankara (MVA)-based vaccines.2Barnes E Folgori A Capone S Swadling L Aston S Kurioka A et al.Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man.Sci Transl Med. 2012; 4: 115ra1Crossref PubMed Scopus (332) Google Scholar,19Youn JW Hu YW Tricoche N Pfahler W Shata MT Dreux M et al.Evidence for protection against chronic hepatitis C virus infection in chimpanzees by immunization with replicating recombinant vaccinia virus.J Virol. 2008; 82: 10896-10905Crossref PubMed Scopus (52) Google Scholar,20Habersetzer F Honnet G Bain C Maynard-Muet M Leroy V Zarski JP et al.A poxvirus vaccine is safe, induces T-cell responses, and decreases viral load in patients with chronic hepatitis C.Gastroenterology. 2011; 141: 890-899.e1Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Although not a natural host, the macaque has proven to be an important vaccination model for predicting successful human immune responses to multiple antigens because of the similarity of the macaque immune system to that of humans. Here, we compare a number of vaccination regimes in macaques using various HCV vaccine candidates; i.e., rAd-HCV, rNTV-HCV, and HCVpp. This report is to our knowledge the first to describe an optimized rNTV-based HCV vaccine regime that elicits robust CMI and cross-nAb responses in macaques when combined with rAd-HCV vaccine candidates. The construction and enrichment of the rAd-HCV, rNTV-HCV, and HCVpp vaccine candidates (Figure 1) were reported in our previous work, and their expression and infectivity were confirmed.12Guan J Wen B Deng Y Zhang K Chen H Wu X et al.Effect of route of delivery on heterologous protection against HCV induced by an adenovirus vector carrying HCV structural genes.Virol J. 2011; 8: 506Crossref PubMed Scopus (12) Google Scholar,21Deng Y Zhang K Tan W Wang Y Chen H Wu X et al.A recombinant DNA and vaccinia virus prime-boost regimen induces potent long-term T-cell responses to HCV in BALB/c mice.Vaccine. 2009; 27: 2085-2088Crossref PubMed Scopus (22) Google Scholar Eleven monkeys divided into three groups (Table 1) received I.M. immunizations with rAd-HCV, rNTV-HCV, or HCVpp vaccine candidates (Figure 1) via various prime-boost combinations according to the schedule outlined in Table 1. Each group was then evaluated in terms of immunogenicity (Figure 2).Table 1Schedule and dose of HCV vaccinationsGroupWeeks 0, 6Weeks 24, 30Week 36Monkey No.A—HCV pp,rAd-HCV060110671 (M)10 µg p24(CE1E2+C44P)06100141 (M)(1 × 1010+06070452 (F)1 × 1010)vp06060592 (F)B—rNTV-HCVrAd-HCV06050191 (M)(CE1E2+NS3)aOnly one immune with rNTV-HCV.(CE1E2+C44P)06060891 (M)(5× 107+(1 × 1010+06060632 (F)5 × 107) pfu1 × 1010)vp06050442 (F)CrAd-HCVHCV pp, 10 µg p24rNTV-HCV06110321 (M)(CE1E2 +C44P)(CE1E2+NS3)06050111 (M)(1 × 1010(5× 107+06080022 (F)+1 × 1010)vp5 × 107) pfu07050212(F)Macaques were immunized I. M. at each time point with the indicated vaccines, as described in the Materials and Methods. All monkeys were bled 2 and 4 weeks after each immunization.M, male monkey; F, female monkey.a Only one immune with rNTV-HCV. Open table in a new tab Macaques were immunized I. M. at each time point with the indicated vaccines, as described in the Materials and Methods. All monkeys were bled 2 and 4 weeks after each immunization. M, male monkey; F, female monkey. We first assessed the HCV-specific antibody response following administration of various vaccine regimens (Figure 3). Robust antibodies against E1, E2, and NS3 were induced among most of the monkeys in groups A and C, which were primed with both HCVpp and rNTV-HCV (Figure 3a–f). No significant enhancement of antibody against HCV target antigens was observed after boosting with HCVpp or rAd-HCV (Figure 3a–c). A single injection of rNTV produced a significantly higher E1 antibody titre than did a single injection of HCVpp or rAd-HCV (P = 0.042). In the rNTV-HCV priming group, the titre decreased slowly over the next 3 months, and HCV E1 (P = 0.004) and E2 (P = 0.035) antibody were also detected after heterologous boosting with rAd-HCV (Figure 3d–f). The titres of antibodies against E1 and E2 were low in the group primed with a single rAd-HCV, but anti-E1 antibody titre was enhanced after a second rAd-HCV injection (P = 0.03). Boosting with HCVpp increased the antibody titres against E1 and E2, which persisted up to week 34 in group C (Figure 3g–i). However, no increased production of antibodies against E1, E2, or NS3 was detected after further boosting with rNTV-HCV in group C (Figure 3g–i). The differences among the three groups were compared at each time point. There were no significant differences in levels of antibodies against E2 and NS3 among the three groups primed with HCVpp, rNTV-HCV, and rAd-HCV, although the anti-E1 antibody titre was higher in the group primed with rNTV-HCV (Figure 4a). In addition, the anti-E1 and -E2 responses in group B (rNTV-HCV priming and rAd-HCV boosting) were significantly higher than those in the other two groups (P < 0.023) at week 38 (Figure 4b).Figure 4E1 and E2 antibodies and cross-neutralizing antibodies titres at weeks 26 and 38. Serum samples were collected at weeks (a,c) +26 and (b,d) +38 from macaques. Differences among the three groups in hepatitis C virus (HCV) E1E2-specific antibody titres are shown in a and b. *P < 0.05, **P < 0.01 (one-way analysis of variance). (c,d) cross-neutralization of samples was tested at a dilution of 1:50 for their capacity to neutralize infection with HCVpp of various strains and genotypes. Huh-7 cells were infected with 100 TCID50 (median tissue culture infective dose). Neutralization of VSVGpp was performed in parallel as a control for specificity. Data are expressed as the means ± SD of the percentage of neutralization of HCVpp by sera tested in triplicate. P values from Student's t-tests comparing neutralization of HCVpp with that of control VSVGpp: *P < 0.05, **P < 0.01.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Next, we assessed the cross-neutralization ability of HCVpps pseudotyped with the E1 and E2 proteins of five genotypes: 1a (H77), 1b (Hebei), 2a (JFH1), 3a (S52), and 5a (SA13). Pseudoparticles with envelope protein G of VSV (VSVGpp) were used as the control. Serum samples were taken at weeks 26 (2 weeks after priming with HCVpp or rNTV-HCV) and 38 (2 weeks after boosting with rAd-HCV or rNTV-HCV). As shown in Figure 4c, at week 26, all three groups demonstrated significant neutralization of HCVpp derived from the 1b genotype,22Magiorkinis G Magiorkinis E Paraskevis D Ho SY Shapiro B Pybus OG et al.The global spread of hepatitis C virus 1a and 1b: a phylodynamic and phylogeographic analysis.PLoS Med. 2009; 6: e1000198Crossref PubMed Scopus (175) Google Scholar which was homologous to the immunogens. Furthermore, broad neutralizing ability of heterologous HCVpps (1a, 1b, 5a subtypes) was detected after a single vaccination with rNTV-HCV or HCVpp. The cross-neutralizing ability was further potentiated by boosting with rAd-HCV at week 38 (Figure 4d). However, a second rNTV booster did not enhance the neutralizing ability in group C (rAd-HCV prime and HCVpp boost). The antigen-specific T-cell responses induced by the three immune regimens were assessed by IFN-γ ELISPOT. Monkeys were bled 2 weeks after each vaccination, and peripheral blood mononuclear cells (PBMCs) isolated from whole blood were stimulated with overlapping peptides spanning the HCV target antigens. No CMI was detected in macaques primed with HCVpp at weeks 22 and 28. After boosting with rAd-HCV, three monkeys in the HCVpp priming group demonstrated positive immunity (median, 178; range: 27–541 SFU/million PBMCs), which was maintained up to week 50 (median, 78; range: 11–148 SFU/million PBMCs) (Figure 5a). In contrast, all four monkeys primed with rNTV-HCV showed strong CMI responses (median, 597; range: 311–1,210 SFU/million PBMCs) at week 22. The CMI response decreased markedly by week 32 in the group with rNTV-HCV priming, but marked enhancement resulted from rAd-HCV vaccination boosting at week 36 (median, 1,545; range: 818–2,210 SFU/million PBMCs). Furthermore, the CMI was maintained at a higher level in the group with rNTV-HCV prime/rAd-HCV boost compared with the other two groups at week 50, and was detectable up to week 74 (range: 121–496 SFU/million PBMCs) (Figure 5b). Before week 20, four monkeys were immunized with rAd twice, but only one monkey (06080022) demonstrated weak HCV-specific T-cell responses (range: 112–344 SFU/million PBMCs) (mainly to E2 peptides). The sample remained positive up to week 20. The rAd-primed group was then boosted with HCVpp at week 24, and although the response in 06080022 was not increased, other monkeys in the same group showed slight increases (median, 166; range: 110–232 SFU/million PBMCs). However, two boosts with HCVpps did not significantly reinforce the T-cell response. The rNTV boost at week 30 caused a marked increase in two out of four macaques in the rAd group (median, 324; range: 10–1,518 SFU/million PBMCs) (Figure 5c). In addition, specific T-cell responses were also assessed using four separate peptide pools spanning the four HCV vaccine targets (Core, E1, E2, NS3). The rNTV-HCV priming group exhibited significant enhancements in all four peptides, especially after boosting with rAd-HCV at week 36 (Figure 5d). In detail, priming with rNTV-HCV induced two monkeys in the group to be positive to E1, all positive to E2, and three positive to NS3; this was the only vaccine that was effective after a single administration. After boosting with rAd-HCV, all samples in group 2 became positive to the four peptides, with the exception of one monkey that was negative to NS3 and Core. This is a compelling advantage compared with the other two regimens. Boosting with rAd-HCV was also effective in the HCVpp-primed group. However, priming with rAd did not markedly enhance the CMI in group 1 (Figure 5d). The boost effect of rNTV-HCV was similarly disappointing in group 3 after boosting with HCVpp. Moreover, use of HCVpp as either the primer or booster antigen induced no detectable CMI. We also assessed the effect of the various regimens on cytokine production by PBMC. Freshly isolated PBMC were stimulated with the HCV peptide pools and the supernatants were harvested at 24 and 48 hours after stimulation, after which cytokine levels at week 38 were assessed. Commercial cytokine kits were used following the manufacturer's instructions and their respective standards. The assayed cytokines included those related to Th1 (TNF-α, IFN-γ, IL-2, and IL-12) and Th2 (IL-4, IL-5, IL-6, and IL-10) (Figure 6). Consistent with the ELISPOT results, the secreted concentrations of Th1 cytokines (IL-2, IL-12, TNF-α, and IFN-γ) in the PBMC of the group that received rNTV/rAd vaccination were higher than those of the other groups (Figure 6a). The rNTV-rAd group also showed enhancement of Th2 cytokines, which correlated with the strongest HCV-specific humoral immune response (Figure 6b). Although the rNTV-rAd group exhibited a higher IL-6 level than the other two groups, its rate of enhancement after peptide stimulation was significantly lower than that of the HCVpp/rAd-HCV group (Figure 6c). The rhesus macaque vaccination model is a useful tool in the evaluation of immune responses induced by HCV immunogens.15Ruan Li, ZJ, Lou Yuanmei, Lu Roujian (2006). Reproduction of defect type tiantan strain vaccinia virus. In: Inst. of Virosis Prevention & Control, CDPCC (ed). C12N7/01,C12N7/04 ed., vol. 1831122 CNGoogle Scholar We report herein for the first time the evaluation of immunogenicity in primates using a novel replication-defective rNTV-based HCV vaccine. We also performed the first in-depth analysis of the specific immunity induced in macaques following various prime-boost combinations of rNTV-HCV/rAd-HCV/HCVpp. Recombinant adenoviral-based or MVA-based vaccines against HCV and other persistent pathogens (HIV-1, TB, and HBV) have shown promise in preclinical and clinical studies.3Lauer GM Immune responses to hepatitis C virus (HCV) infection and the prospects for an effective HCV vaccine or immunotherapies.J Infect Dis. 2013; 207 Suppl 1: S7-S12Crossref PubMed Scopus (47) Google Scholar,23Fattori E Zampaglione I Arcuri M Meola A Ercole BB Cirillo A et al.Efficient immunization of rhesus macaques with an HCV candidate vaccine by heterologous priming-boosting with novel adenoviral vectors based on different serotypes.Gene Ther. 2006; 13: 1088-1096Crossref PubMed Scopus (38) Google Scholar,24Barouch DH Novel adenovirus vector-based vaccines for HIV-1.Curr Opin HIV AIDS. 2010; 5: 386-390Crossref PubMed Scopus (96) Google Scholar,25Pantaleo G Esteban M Jacobs B Tartaglia J Poxvirus vector-based HIV vaccines.Curr Opin HIV AIDS. 2010; 5: 391-396Crossref PubMed Scopus (67) Google Scholar Recently, several viral vaccine candidates have shown great promise in preclinical and clinical trials, transiently reducing viral loads in some chronically infected subjects. Among these, viral vector (especially rAd or rMVA-based) vaccine candidates and heterogeneous prime-boost vaccination may represent the most promising strategy for development of an HCV vaccine.2Barnes E Folgori A Capone S Swadling L Aston S Kurioka A et al.Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man.Sci Transl Med. 2012; 4: 115ra1Crossref PubMed Scopus (332) Google Scholar,10Halliday J Klenerman P Barnes E Vaccination for hepatitis C virus: closing in on an evasive target.Expert Rev Vaccines. 2011; 10: 659-672Crossref PubMed Scopus (91) Google Scholar,17Lin Y Kwon T Polo J Zhu YF Coates S Crawford K et al.Induction of broad CD4+ and CD8+ T-cell responses and cross-neutralizing antibodies against hepatitis C virus by vaccination with Th1-adjuvanted polypeptides followed by defective alphaviral particles expressing envelope glycoproteins gpE1 and gpE2 and nonstructural proteins 3, 4, and 5.J Virol. 2008; 82: 7492-7503Crossref PubMed Scopus (49) Google Scholar,23Fattori E Zampaglione I Arcuri M Meola A Ercole BB Cirillo A et al.Efficient immunization of rhesus macaques with an HCV candidate vaccine by heterologous priming-boosting with novel adenoviral vectors based on different serotypes.Gene Ther. 2006; 13: 1088-1096Crossref PubMed Scopus (38) Google Scholar The distinguished safety record of rTTV, coupled with its ability to induce robust and persistent CMI in humans, make this live-attenuated vaccine an attractive vector candidate for HCV vaccines.17Lin Y Kwon T Polo J Zhu YF Coates S Crawford K et al.Induction of broad CD4+ and CD8+ T-cell responses and cross-neutralizing antibodies against hepatitis C virus by vaccination with Th1-adjuvanted polypeptides followed by defective alphaviral particles expressing envelope glycoproteins gpE1 and gpE2 and nonstructural proteins 3, 4, and 5.J Virol. 2008; 82: 7492-7503Crossref PubMed Scopus (49) Google Scholar Given the concerns surrounding the pre-existing immunity and potential risks of rAd5- and rTTV-based vaccines in humans, it remains encouraging that comparable immunogenicity can be achieved in primates using replication-defective rNTV-based vaccine candidates and a heterologous prime-boost regimen.26Robert-Guroff M Replicating and non-replicating viral vectors for vaccine development.Curr Opin Biotechnol. 2007; 18: 546-556Crossref PubMed Scopus (187) Google Scholar rNTV is a novel viral vector vaccine based on the Tiantan strain of vaccinia virus, which is a highly attenuated strain used widely as a safe viral vector to deliver antigens.15Ruan Li, ZJ, Lou Yuanmei," @default.
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• W1967627861 date "2013-09-01" @default.
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• W1967627861 title "The Novel Replication-defective Vaccinia Virus (Tiantan Strain)–based Hepatitis C Virus Vaccine Induces Robust Immunity in Macaques" @default.
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