Hepatitis C virus-like particles combined with novel adjuvant systems enhance virus-specific immune responses

Qiao, Ming; Murata, Kazumoto; Davis, Anthony R.; Jeong, Sook Hyang; Liang, T. Jake

doi:10.1053/jhep.2003.50000

Cited by 53 publications

(39 citation statements)

References 39 publications

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“…This observation is in contrast to the significant effect of this adjuvant in the mouse study (8)(9)(10). Although a minor enhancing effect of this adjuvant was observed in our previous baboon study (11), we believe this adjuvant in formulation with HCV-LPs is probably not useful in higher primates, including humans.…”

Section: Discussioncontrasting

confidence: 71%

“…In this study, we performed a proof-of-principle preclinical experiment to test the immunogenicity and efficacy of the HCV-LPs as a vaccine candidate in chimpanzees. We have previously shown the induction of broadly directed HCV-specific humoral and cellular immune response by HCV-LP immunization in mice and baboons (9)(10)(11), and this induced immunity provided protection in a surrogate vaccinia-HCV challenge model (9). We reason that HCV-LPs, as a particulate multivalent antigen, are a potent immunogen that can interact with the immune system for effective antigen presentation in class I and II pathways (15)(16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported the synthesis of HCV-like particles (HCV-LPs) by using a recombinant baculovirus containing the cDNA of HCV structural proteins, core, E1, and E2 (7). The HCV-LPs induced virus-specific humoral and cellular immune responses in BALB/c mice (8) and HLA-A 2.1 transgenic (AAD) mice (9,10). These HCV-LP-induced immune responses protected mice from challenge with recombinant HCV-vaccinia expressing HCV structural proteins (vvHCV.S) in a surrogate HCV-vaccinia challenge model (9).…”

Section: H Epatitis C Virus (Hcv) Is a Major Public Health Problemmentioning

confidence: 99%

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Immunization with hepatitis C virus-like particles results in control of hepatitis C virus infection in chimpanzees

Elmowalid

Qiao

Jeong

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

158

117

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Recombinant hepatitis C virus (HCV)-like particles (HCV-LPs) containing HCV structural proteins (core, E1, and E2) produced in insect cells resemble the putative HCV virions and are capable of inducing strong and broad humoral and cellular immune responses in mice and baboons. Here, we present evidence on the immunogenicity and induction of protective immunity by HCV-LPs in chimpanzees. Chimpanzees (two in each group), were immunized with HCV-LPs or HCV-LPs plus AS01B adjuvant. After immunizations, all animals developed an HCV-specific immune response including IFN-␥ ؉ , IL-2 ؉ , CD4 ؉ , and CD8 ؉ T cell and proliferative lymphocyte responses against core, E1, and E2. Upon challenge with an infectious HCV inoculum, one chimpanzee developed transient viremia with low HCV RNA titers (10 3 to 10 4 copies per ml) in the third and fourth weeks after the challenge. The three other chimpanzees became infected with higher levels of viremia (10 4 to 10 5 copies per ml), but their viral levels became unquantifiable (<10 3 copies per ml) 10 weeks after the challenge. After the HCV challenge, all four chimpanzees demonstrated a significant increase in peripheral and intrahepatic T cell and proliferative responses against the HCV structural proteins. These T cell responses coincided with the fall in HCV RNA levels. Four naïve chimpanzees were infected with the same HCV inoculum, and three developed persistent infection with higher viremia in the range of 10 5 to 10 6 copies per ml. Our study suggests that HCV-LP immunization induces HCV-specific cellular immune responses that can control HCV challenge in the chimpanzee model. envelope proteins ͉ prevention ͉ protective immunity ͉ vaccine ͉ viral clearance H epatitis C virus (HCV) is a major public health problem.Approximately 170 million people are infected by the virus worldwide (1, 2). HCV causes a high rate of chronic infection, which can lead to complications of chronic liver disease such as liver cirrhosis and hepatocellular carcinoma. The efficacy of therapy for chronically infected patients is less than satisfactory. Development of an effective vaccine may hold the key to controlling HCV infection. HCV displays high genetic and antigenic diversities, with at least six different genotypes and diverse quasispecies within infected individuals (1, 2). In addition to this inherent problem, the lack of convenient and robust tissue culture systems and small animal models further hampers the effort to develop an effective HCV vaccine (3). The use of recombinant HCV envelope proteins as a vaccine candidate has been met with variable success. High titers of anti-E1/E2 antibodies could be induced and possibly resulted in lower propensity to chronicity upon HCV challenge (3-5). Recently, a combined modality of plasmid DNA and adenoviral vector to deliver HCV structural and nonstructural antigens induced a strong HCV-specific cell-mediated immunity in chimpanzees and resulted in attenuated HCV infection after challenge (6). However, in this study, no obvious difference was observe...

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Section: Discussioncontrasting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: H Epatitis C Virus (Hcv) Is a Major Public Health Problemmentioning

confidence: 99%

See 1 more Smart Citation

Immunization with hepatitis C virus-like particles results in control of hepatitis C virus infection in chimpanzees

Elmowalid

Qiao

Jeong

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

158

117

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“…New strategies to increase production of endogenous type 1 IFN production through administration of TLR9 or TLR7/8 ligands have been promising in early clinical trials and in experimental models. 39,[126][127][128][129] Activation of these pathways with exogenous ligands during HCV infection may have more complex biological and immune effects than simply induction of type I IFNs. Considering that TLR7/8 and TLR9 are both expressed in PDCs, activation of this cell type appears to have beneficial effects on antiviral immunity; however, TLR7/8 agonists can also impair monocyte-derived DC differentiation and maturation, thereby limiting their overall benefit.…”

Section: Innate Immunity As a Target In Hcv Therapymentioning

confidence: 99%

Altered innate immunity in chronic hepatitis C infection

2007

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H epatitis C virus (HCV) is a uniquely successful hepatitis virus in its ability to establish chronic infection in more than two-thirds of those who contract it. The inability of the innate and adaptive immune responses to control HCV invasion and replication contribute to development and persistence of chronic infection. Multiple components have been identified in this process, including pathways by which HCV subverts innate immune recognition and activation, delayed organization of an effective adaptive immune response, the tolerogenic liver environment, and the persistently high levels of viral antigens. We summarize recent findings on the interaction between HCV infection and innate immune responses. Hepatitis C Virus, Immune Responses and Hepatocytes-Brief OverviewA critical role for innate and adaptive immunity has been identified in HCV persistence and liver injury. During acute infection, type I interferon (IFN) is induced in the liver; however, HCV viral load does not decrease, suggesting that HCV interferes with antiviral mechanisms. Innate immune cells, including natural killer cells and dendritic cells shape innate immunity and determine adaptive immune activation. Vigorous, multi-epitopespecific, T helper 1-type and sustained CD4ϩ and CD8ϩ T cell responses were found in resolved acute HCV infections. [1][2][3][4] In contrast, in cases that progress to chronic infection, CD4ϩ T cell responses are weak, short-lived, and targeted to a narrow range of epitopes. 1

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“…Based on a previous report of the additive effects of lipid A and CpG adjuvants (29), these two peptides were mixed with combined MPL-AF plus CpG adjuvants and tested for their capacities to prime CTL responses. These two peptides were also compared for in vivo priming efficiency with an immunodominant H60 peptide (LT-FNYRNL) (30).…”

Section: Priming Capacities Of Hy Peptidesmentioning

confidence: 99%

Cysteine-Tailed Class I-Binding Peptides Bind to CpG Adjuvant and Enhance Primary CTL Responses

Wettstein¹,

Borson²,

Park

et al. 2005

The Journal of Immunology

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Immunostimulatory CpG motifs in synthetic oligonucleotides can be effective adjuvants for the priming of CTLs. We first observed that a single male-specific peptide (KCSRNRQYL) (HY2) was more efficient than another male-specific peptide (WMHHNMDLI) (HY1) at priming IFN-γ-secreting CTLs in vivo when combined with lipid A and CpG and that it also visibly precipitated CpG. The addition of the six N-terminal residues (KCSRNR) from HY2 to HY1 yielded a peptide, KCSRNR-HY1, that both precipitated CpG and primed increased numbers of HY1-specific CTLs. We refer to this type of peptide as a primotope that includes a class I binding peptide tailed with amino acids that increase priming. Ala residues were substituted for the Arg/Lys residues (ACSANA-HY1), and these substitutions did not reduce in vivo priming potential. However, the substitution of Ala for Cys (KASRNR-HY1) resulted in the complete loss of priming, demonstrating the importance of Cys for in vivo priming when mixed with CpG. This result suggested that increased priming was based in disulfide bonding between Cys residues and internal phosphorothioate groups of synthetic CpG. The addition of Cys-bearing primotopes to radiolabeled CpG with a single thioate group resulted in the appearance of a new band that was inhibited by 1) Cys > Ala substitution and 2) reduction and alkylation of CpG. These results reveal a novel mechanism for complexing class I binding peptides and CpG adjuvant for development of new peptide-adjuvant combinations for vaccines for cancer and infectious diseases.

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Hepatitis C virus-like particles combined with novel adjuvant systems enhance virus-specific immune responses

Cited by 53 publications

References 39 publications

Immunization with hepatitis C virus-like particles results in control of hepatitis C virus infection in chimpanzees

Immunization with hepatitis C virus-like particles results in control of hepatitis C virus infection in chimpanzees

Altered innate immunity in chronic hepatitis C infection

Cysteine-Tailed Class I-Binding Peptides Bind to CpG Adjuvant and Enhance Primary CTL Responses

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