研究者データベース

関屋 俊輝(セキヤ トシキ)
人獣共通感染症国際共同研究所 生物製剤研究開発部門
助教

基本情報

所属

  • 人獣共通感染症国際共同研究所 生物製剤研究開発部門

職名

  • 助教

学位

  • 博士(免疫学・微生物学)(メルボルン大学)

J-Global ID

研究分野

  • ライフサイエンス / 免疫学

研究活動情報

論文

  • Masanori Shiohara, Saori Suzuki, Shintaro Shichinohe, Hirohito Ishigaki, Misako Nakayama, Naoki Nomura, Masashi Shingai, Toshiki Sekiya, Marumi Ohno, Sayaka Iida, Naoko Kawai, Mamiko Kawahara, Junya Yamagishi, Kimihito Ito, Ryotarou Mitsumata, Tomio Ikeda, Kenji Motokawa, Tomoyoshi Sobue, Hiroshi Kida, Kazumasa Ogasawara, Yasushi Itoh
    Vaccine 40 30 4026 - 4037 2022年06月26日 [査読有り][通常論文]
     
    The All-Japan Influenza Vaccine Study Group has been developing a more effective vaccine than the current split vaccines for seasonal influenza virus infection. In the present study, the efficacy of formalin- and/or β-propiolactone-inactivated whole virus particle vaccines for seasonal influenza was compared to that of the current ether-treated split vaccines in a nonhuman primate model. The monovalent whole virus particle vaccines or split vaccines of influenza A virus (H1N1) and influenza B virus (Victoria lineage) were injected subcutaneously into naïve cynomolgus macaques twice. The whole virus particle vaccines induced higher titers of neutralizing antibodies against H1N1 influenza A virus and influenza B virus in the plasma of macaques than did the split vaccines. At challenge with H1N1 influenza A virus or influenza B virus, the virus titers in nasal swabs and the increases in body temperatures were lower in the macaques immunized with the whole virus particle vaccine than in those immunized with the split vaccine. Repertoire analyses of immunoglobulin heavy chain genes demonstrated that the number of B-lymphocyte subclones was increased in macaques after the 1st vaccination with the whole virus particle vaccine, but not with the split vaccine, indicating that the whole virus particle vaccine induced the activation of vaccine antigen-specific B-lymphocytes more vigorously than did the split vaccine at priming. Thus, the present findings suggest that the superior antibody induction ability of the whole virus particle vaccine as compared to the split vaccine is attributable to its stimulatory properties on the subclonal differentiation of antigen-specific B-lymphocytes.
  • Chimuka Handabile, Toshiki Sekiya, Naoki Nomura, Marumi Ohno, Tomomi Kawakita, Masashi Shingai, Hiroshi Kida
    Vaccines 10 5 2022年05月19日 
    Despite the use of vaccines, seasonal influenza remains a risk to public health. We previously proposed the inactivated whole virus particle vaccine (WPV) as an alternative to the widely used split vaccine (SV) for the control of seasonal and pandemic influenza based on the superior priming potency of WPV to that of SV. In this study, we further examined and compared the immunological potency of monovalent WPV and SV of A/California/7/2009 (X-179A) (H1N1) pdm09 (CA/09) to generate immune responses against heterologous viruses, A/Singapore/GP1908/2015 (IVR-180) (H1N1) pdm09 (SG/15), and A/duck/Hokkaido/Vac-3/2007 (H5N1) (DH/07) in mice. Following challenge with a lethal dose of heterologous SG/15, lower virus titer in the lungs and milder weight loss were observed in WPV-vaccinated mice than in SV-vaccinated ones. To investigate the factors responsible for the differences in the protective effect against SG/15, the sera of vaccinated mice were analyzed by hemagglutination-inhibition (HI) and neuraminidase-inhibition (NI) assays to evaluate the antibodies induced against viral hemagglutinin (HA) and neuraminidase (NA), respectively. While the two vaccines induced similar levels of HI antibodies against SG/15 after the second vaccination, only WPV-vaccinated mice induced significantly higher titers of NI antibodies against the strain. Furthermore, given the significant elevation of NI antibody titers against DH/07, an H5N1 avian influenza virus, WPV was also demonstrated to induce NA-inhibiting antibodies that recognize NA of divergent strains. This could be explained by the higher conservation of epitopes of NA among strains than for HA. Taking these findings together, NA-specific antibodies induced by WPV may have contributed to better protection from infection with heterologous influenza virus SG/15, compared with SV. The present results indicate that WPV is an effective vaccine for inducing antibodies against both HA and NA of heterologous viruses and may be a useful vaccine to conquer vaccine strain mismatch.
  • Yasutake Yanagihara, Sharon Y A M Villanueva, Naoki Nomura, Marumi Ohno, Toshiki Sekiya, Chimuka Handabile, Masashi Shingai, Hideaki Higashi, Shin-Ichi Yoshida, Toshiyuki Masuzawa, Nina G Gloriani, Mitsumasa Saito, Hiroshi Kida
    Microbiology spectrum 10 2 e0215721  2022年04月27日 
    Leptospirosis is a zoonotic disease caused by infection with pathogenic leptospires. Consistent with recent studies by other groups, leptospires were isolated from 89 out of 110 (80.9%) soil or water samples from varied locations in the Philippines in our surveillance study, indicating that leptospires might have a life cycle that does not involve animal hosts. However, despite previous work, it has not been confirmed whether leptospires multiply in the soil environment under various experimental conditions. Given the fact that the case number of leptospirosis is increased after flood, we hypothesized that waterlogged soil, which mimics the postflooding environment, could be a suitable condition for growing leptospires. To verify this hypothesis, pathogenic and saprophytic leptospires were seeded in the bottles containing 2.5 times as much water as soil, and bacterial counts in the bottles were measured over time. Pathogenic and saprophytic leptospires were found to increase their number in waterlogged soil but not in water or soil alone. In addition, leptospires were reisolated from soil in closed tubes for as long as 379 days. These results indicate that leptospires are in a resting state in the soil and are able to proliferate with increased water content in the environment. This notion is strongly supported by observations that the case number of leptospirosis is significantly higher in rainy seasons and increased after flood. Therefore, we reached the following conclusion: environmental soil is a potential reservoir of leptospires. IMPORTANCE Since research on Leptospira has focused on pathogenic leptospires, which are supposed to multiply only in animal hosts, the life cycle of saprophytic leptospires has long been a mystery. This study demonstrates that both pathogenic and saprophytic leptospires multiply in the waterlogged soil, which mimics the postflooding environment. The present results potentially explain why leptospirosis frequently occurs after floods. Therefore, environmental soil is a potential reservoir of leptospires and leptospirosis is considered an environment-borne as well as a zoonotic disease. This is a significant report to reveal that leptospires multiply under environmental conditions, and this finding leads us to reconsider the ecology of leptospires.
  • Marumi Ohno, Akemi Kakino, Toshiki Sekiya, Naoki Nomura, Masashi Shingai, Tatsuya Sawamura, Hiroshi Kida
    Scientific Reports 11 1 2021年12月 
    AbstractAlthough coagulation abnormalities, including microvascular thrombosis, are thought to contribute to tissue injury and single- or multiple-organ dysfunction in severe influenza, the detailed mechanisms have yet been clarified. This study evaluated influenza-associated abnormal blood coagulation utilizing a severe influenza mouse model. After infecting C57BL/6 male mice with intranasal applications of 500 plaque-forming units of influenza virus A/Puerto Rico/8/34 (H1N1; PR8), an elevated serum level of prothrombin fragment 1 + 2, an indicator for activated thrombin generation, was observed. Also, an increased gene expression of oxidized low-density lipoprotein (LDL) receptor-1 (Olr1), a key molecule in endothelial dysfunction in the progression of atherosclerosis, was detected in the aorta of infected mice. Body weight decrease, serum levels of cytokines and chemokines, viral load, and inflammation in the lungs of infected animals were similar between wild-type and Olr1 knockout (KO) mice. In contrast, the elevation of prothrombin fragment 1 + 2 levels in the sera and intravascular thrombosis in the lungs by PR8 virus infection were not induced in KO mice. Collectively, the results indicated that OLR1 is a critical host factor in intravascular thrombosis as a pathogeny of severe influenza. Thus, OLR1 is a promising novel therapeutic target for thrombosis during severe influenza.
  • Marumi Ohno, Michihito Sasaki, Yasuko Orba, Toshiki Sekiya, Md Abdul Masum, Osamu Ichii, Tatsuya Sawamura, Akemi Kakino, Yasuhiko Suzuki, Hiroshi Kida, Hirofumi Sawa, Masashi Shingai
    Viruses 13 11 2021年11月 
    Systemic symptoms have often been observed in patients with coronavirus disease 2019 (COVID-19) in addition to pneumonia, however, the details are still unclear due to the lack of an appropriate animal model. In this study, we investigated and compared blood coagulation abnormalities and tissue damage between male Syrian hamsters of 9 (young) and over 36 (aged) weeks old after intranasal infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite similar levels of viral replication and inflammatory responses in the lungs of both age groups, aged but not young hamsters showed significant prolongation of prothrombin time and prominent acute kidney damage. Moreover, aged hamsters demonstrated increased intravascular coagulation time-dependently in the lungs, suggesting that consumption of coagulation factors causes prothrombin time prolongation. Furthermore, proximal urinary tract damage and mesangial matrix expansion were observed in the kidneys of the aged hamsters at early and later disease stages, respectively. Given that the severity and mortality of COVID-19 are higher in elderly human patients, the effect of aging on pathogenesis needs to be understood and should be considered for the selection of animal models. We, thus, propose that the aged hamster is a good small animal model for COVID-19 research.
  • Masashi Shingai, Naoki Nomura, Toshiki Sekiya, Marumi Ohno, Daisuke Fujikura, Chimuka Handabile, Ryosuke Omori, Yuki Ohara, Tomohiro Nishimura, Masafumi Endo, Kazuhiko Kimachi, Ryotarou Mitsumata, Tomio Ikeda, Hiroki Kitayama, Hironori Hatanaka, Tomoyoshi Sobue, Fumihito Muro, Saori Suzuki, Cong Thanh Nguyen, Hirohito Ishigaki, Misako Nakayama, Yuya Mori, Yasushi Itoh, Marios Koutsakos, Brendon Y Chua, Katherine Kedzierska, Lorena E Brown, David C Jackson, Kazumasa Ogasawara, Yoichiro Kino, Hiroshi Kida
    Vaccine 39 29 3940 - 3951 2021年06月29日 
    Current detergent or ether-disrupted split vaccines (SVs) for influenza do not always induce adequate immune responses, especially in young children. This contrasts with the whole virus particle vaccines (WPVs) originally used against influenza that were immunogenic in both adults and children but were replaced by SV in the 1970s due to concerns with reactogenicity. In this study, we re-evaluated the immunogenicity of WPV and SV, prepared from the same batch of purified influenza virus, in cynomolgus macaques and confirmed that WPV is superior to SV in priming potency. In addition, we compared the ability of WPV and SV to induce innate immune responses, including the maturation of dendritic cells (DCs) in vitro. WPV stimulated greater production of inflammatory cytokines and type-I interferon in immune cells from mice and macaques compared to SV. Since these innate responses are likely triggered by the activation of pattern recognition receptors (PRRs) by viral RNA, the quantity and quality of viral RNA in each vaccine were assessed. Although the quantity of viral RNA was similar in the two vaccines, the amount of viral RNA of a length that can be recognized by PRRs was over 100-fold greater in WPV than in SV. More importantly, 1000-fold more viral RNA was delivered to DCs by WPV than by SV when exposed to preparations containing the same amount of HA protein. Furthermore, WPV induced up-regulation of the DC maturation marker CD86 on murine DCs, while SV did not. The present results suggest that the activation of antigen-presenting DCs, by PRR-recognizable viral RNA contained in WPV is responsible for the effective priming potency of WPV observed in naïve mice and macaques. WPV is thus recommended as an alternative option for seasonal influenza vaccines, especially for children.
  • Naoki Nomura, Keita Matsuno, Masashi Shingai, Marumi Ohno, Toshiki Sekiya, Ryosuke Omori, Yoshihiro Sakoda, Robert G Webster, Hiroshi Kida
    Virology 557 55 - 61 2021年05月 
    Genetic reassortment of influenza A viruses through cross-species transmission contributes to the generation of pandemic influenza viruses. To provide information on the ecology of influenza viruses, we have been conducting a global surveillance of zoonotic influenza and establishing an influenza virus library. Of 4580 influenza virus strains in the library, 3891 have been isolated from over 70 different bird species. The remaining 689 strains were isolated from humans, pigs, horses, seal, whale, and the environment. Phylogenetic analyses of the HA genes of the library isolates demonstrate that the library strains are distributed to all major known clusters of the H1, H2 and H3 subtypes of HA genes that are prevalent in humans. Since past pandemic influenza viruses are most likely genetic reassortants of zoonotic and seasonal influenza viruses, a vast collection of influenza A virus strains from various hosts should be useful for vaccine preparation and diagnosis for future pandemics.
  • Marios Koutsakos, Toshiki Sekiya, Brendon Y Chua, Thi Hoang Oanh Nguyen, Adam K Wheatley, Jennifer A Juno, Marumi Ohno, Naoki Nomura, Yuki Ohara, Tomohiro Nishimura, Masafumi Endo, Saori Suzuki, Hirohito Ishigaki, Misako Nakayama, Cong T Nguyen, Yasushi Itoh, Masashi Shingai, Kazumasa Ogasawara, Yoichiro Kino, Stephen J Kent, David C Jackson, Lorena E Brown, Hiroshi Kida, Katherine Kedzierska
    Immunology and cell biology 2020年08月01日 [査読有り][通常論文]
     
    Influenza remains a significant global public health burden, despite substantial annual vaccination efforts against circulating virus strains. As a result, novel vaccine approaches are needed to generate long-lasting and universal broadly cross-reactive immunity against distinct influenza virus strains and subtypes. Several new vaccine candidates are currently under development and/or in clinical trials. The successful development of new vaccines requires testing in animal models, other than mice, which capture the complexity of the human immune system. Importantly, following vaccination or challenge, the assessment of adaptive immunity at the antigen-specific level is particularly informative. In this study, using peripheral blood mononuclear cells (PBMCs) from cynomolgus macaques, we describe detection methods and in-depth analyses of influenza virus-specific B cells by recombinant hemagglutinin probes and flow cytometry, as well as the detection of influenza virus-specific CD8+ and CD4+ T cells by stimulation with live influenza A virus and intracellular cytokine staining. We highlight the potential of these assays to be used with PBMCs from other macaque species, including rhesus macaques, pigtail macaques and African green monkeys. We also demonstrate the use of a human cytometric bead array kit in detecting inflammatory cytokines and chemokines from cynomolgus macaques to assess cytokine/chemokine milieu. Overall, the detection of influenza virus-specific B and T cells, together with inflammatory responses, as described in our study, provides useful insights for evaluating novel influenza vaccines. Our data deciphering immune responses toward influenza viruses can be also adapted to understanding immunity to other infections or vaccination approaches in macaque models.
  • Marumi Ohno, Toshiki Sekiya, Naoki Nomura, Taku Ji Daito, Masashi Shingai, Hiroshi Kida
    Scientific reports 10 1 10879 - 10879 2020年07月02日 [査読有り][通常論文]
     
    Although the severity of influenza virus infections has been associated with host energy metabolism, the related mechanisms have not yet been clarified. Here we examined the effects of influenza virus infection on host energy metabolism in mice. After infecting mice with intranasal applications of 500 plaque-forming units of A/Puerto Rico/8/34 (H1N1; PR8) virus, the serum levels of most intermediates in the tricarboxylic acid (TCA) cycle and related metabolic pathways were significantly reduced. These data suggest that substrate supply to the TCA cycle is reduced under these conditions, rather than specific metabolic reactions being inhibited. Then, we focused on glucose and fatty acid metabolism that supply substrates to the TCA cycle. Akt phosphorylation following insulin injections was attenuated in the livers of PR8 virus-infected mice. Furthermore, glucose tolerance tests revealed that the PR8 virus-infected mice showed higher blood glucose levels than the vehicle-inoculated control mice. These results suggest that influenza virus infection impairs insulin signaling, which regulates glucose uptake. However, increases in the hepatic expressions of fatty acid-metabolizing enzymes suggest that fatty acids accumulate in liver cells of infected mice. Collectively, our data indicate that influenza virus infection dysregulates host energy metabolism. This line of investigation provides novel insights into the pathogenesis of influenza.
  • Toshiki Sekiya, Edin J Mifsud, Marumi Ohno, Naoki Nomura, Mayumi Sasada, Daisuke Fujikura, Takuji Daito, Masashi Shingai, Yuki Ohara, Tomohiro Nishimura, Masafumi Endo, Ryotarou Mitsumata, Tomio Ikeda, Hironori Hatanaka, Hiroki Kitayama, Kenji Motokawa, Tomoyoshi Sobue, Saori Suzuki, Yasushi Itoh, Lorena E Brown, Kazumasa Ogasawara, Yoichiro Kino, Hiroshi Kida
    Vaccine 37 15 2158 - 2166 2019年04月03日 [査読有り][通常論文]
     
    In contrast to current ether- or detergent-disrupted "split" vaccines (SVs) for influenza, inactivated whole influenza virus particle vaccines (WPVs) retain the original virus structure and components and as such may confer similar immunity to natural infection. In a collaboration between academia and industry, the potential of WPV as a new seasonal influenza vaccine was investigated. Each of the four seasonal influenza vaccine manufacturers in Japan prepared WPVs and SVs from the same batches of purified influenza virus. Both mice and monkeys vaccinated with the WPVs exhibited superior immune responses to those vaccinated with the corresponding SVs. Vaccination with A/California/07/2009 (H1N1) WPV enabled mice to survive a lethal challenge dose of homologous virus whereas those vaccinated with SV succumbed to infection within 6 days. Furthermore, mice vaccinated with WPV induced substantial numbers of multifunctional CD8+ T cells, important for control of antigenically drifted influenza virus strains. In addition, cytokines and chemokines were detected at early time points in the sera of mice vaccinated with WPV but not in those animals vaccinated with SV. These results indicate that WPVs induce enhanced innate and adaptive immune responses compared to equivalent doses of SVs. Notably, WPV at one fifth of the dose of SV was able to induce potent immunity with limited production of IL-6, one of the pyrogenic cytokines. We thus propose that WPVs with balanced immunogenicity and safety may set a new global standard for seasonal influenza vaccines.
  • Toshiki Sekiya, Junya Yamagishi, John Henry V. Gray, Paul G. Whitney, Axel Martinelli, Weiguang Zeng, Chinn Yi Wong, Chihiro Sugimoto, David C. Jackson, Brendon Y. Chua
    BIOMATERIALS 137 61 - 72 2017年08月 [査読有り][通常論文]
     
    The lipopeptide R4Pam2Cys is an agonist for toll-like receptor-2 (TLR2), a key pathogen-associated molecular pattern receptor expressed on many antigen-presenting cells such as dendritic cells (DCs). Electrostatic association of R4Pam2Cys with soluble protein antigens significantly enhances their immunogenicity and there is evidence to suggest that reducing the size of suitably adjuvanted-antigen complexes in solution may further improve their immunostimulatory capabilities. In this study, we investigated how incorporation of polyethylene glycol (PEG) into R4Pam2Cys affects the size, activity and efficacy of formed antigen-lipopeptide complexes. The presence of PEG was shown to increase solubility with a concomitant reduction in the particle size of vaccine formulations that was dependent on the length of PEG used. When compared to non-PEGylated R4Pam2Cys, vaccination of animals with antigen-complexed PEGylated R4Pam2Cys resulted not only in improvements in antibody production but significantly higher antigen-specific CD8(+) T cell responses. Both lipopeptides exhibited similar in vitro capabilities to induce DC maturation, facilitate antigen uptake and presentation to T cells. Moreover, analyses of the transcriptomes obtained from DCs treated with either lipopeptide revealed a large number of commonly induced genes with similar transcript expression levels, suggesting that common signalling pathways and processes were engaged following activation by either lipopeptide. In vivo analysis however revealed that vaccination with antigen-complexed PEGylated R4Pam2Cys resulted in improved antigen presentation to T cells. These heightened responses were not attributed to prolonged antigen persistence but rather due to more rapid transportation of antigen from the injection site into the draining lymph nodes over a short period of time. Our results indicate that reducing the size of formed antigen-TLR2-agonist complexes by PEGylation does not compromise the activity of the agonist but in fact enhances its trafficking in vivo ultimately leading to improved humoral and cell-mediated immune responses. (C) 2017 Elsevier Ltd. All rights reserved.
  • Brendon Y. Chua, Chinn Yi Wong, Edin J. Mifsud, Kathryn M. Edenborough, Toshiki Sekiya, Amabel C. L. Tan, Francesca Mercuri, Steve Rockman, Weisan Chen, Stephen J. Turner, Peter C. Doherty, Anne Kelso, Lorena E. Brown, David C. Jackson
    MBIO 6 6 e01024 - 15 2015年11月 [査読有り][通常論文]
     
    The continual threat to global health posed by influenza has led to increased efforts to improve the effectiveness of influenza vaccines for use in epidemics and pandemics. We show in this study that formulation of a low dose of inactivated detergent-split influenza vaccine with a Toll-like receptor 2 (TLR2) agonist-based lipopeptide adjuvant (R(4)Pam(2)Cys) provides (i) immediate, antigen-independent immunity mediated by the innate immune system and (ii) significant enhancement of antigen-dependent immunity which exhibits an increased breadth of effector function. Intranasal administration of mice with vaccine formulated with R(4)Pam(2)Cys but not vaccine alone provides protection against both homologous and serologically distinct (heterologous) viral strains within a day of administration. Vaccination in the presence of R(4)Pam(2)Cys subsequently also induces high levels of systemic IgM, IgG1, and IgG2b antibodies and pulmonary IgA antibodies that inhibit hemagglutination (HA) and neuraminidase (NA) activities of homologous but not heterologous virus. Improved primary virus nucleoprotein (NP)-specific CD8(+) T cell responses are also induced by the use of R(4)Pam(2)Cys and are associated with robust recall responses to provide heterologous protection. These protective effects are demonstrated in wild-type and antibody-deficient animals but not in those depleted of CD8(+) T cells. Using a contact-dependent virus transmission model, we also found that heterologous virus transmission from vaccinated mice to naive mice is significantly reduced. These results demonstrate the potential of adding a TLR2 agonist to an existing seasonal influenza vaccine to improve its utility by inducing immediate short-term nonspecific antiviral protection and also antigen-specific responses to provide homologous and heterologous immunity. IMPORTANCE The innate and adaptive immune systems differ in mechanisms, specificities, and times at which they take effect. The innate immune system responds within hours of exposure to infectious agents, while adaptive immunity takes several days to become effective. Here we show, by using a simple lipopeptide-based TLR2 agonist, that an influenza detergent-split vaccine can be made to simultaneously stimulate and amplify both systems to provide immediate antiviral protection while giving the adaptive immune system time to implement long-term immunity. Both types of immunity induced by this approach protect against vaccine-matched as well as unrelated virus strains and potentially even against strains yet to be encountered. Conferring dual functionality to influenza vaccines is beneficial for improving community protection, particularly during periods between the onset of an outbreak and the time when a vaccine becomes available or in scenarios in which mass vaccination with a strain to which the population is immunologically naive is imperative.
  • Brendon Y. Chua, Toshiki Sekiya, Mohammad Al Kobaisi, Kirsty R. Short, David E. Mainwaring, David C. Jackson
    BIOMATERIALS 53 50 - 57 2015年06月 [査読有り][通常論文]
     
    In this study, we describe a biodegradable vaccine depot which persists in vivo for at least 4-months, provides synergistic adjuvant effects and also allows dose sparing of both antigen and adjuvant. A single administration results in immediate release of a priming dose of vaccine, by a process of syneresis, which is then followed by release of remaining vaccine which maintains robust antibody levels that last for more than a year. The platform technology comprises two aqueous components; one contains chitosan and hydroxyapatite, in which the vaccine is incorporated, and the other consists of a crosslinking agent, tripolyphosphate (TPP) and chondroitin sulphate. When co-injected into tissue, they spontaneously crosslink forming a firm yet compliant vaccine-containing depot. Whole body imaging of animals inoculated with the material show that the depot persists in situ for up to 19 weeks. Vaccination of mice with depot formulations containing ovalbumin (OVA) emulsified in Montanide ISA 61 adjuvant results in the induction of robust antibody responses using doses of adjuvant 40-fold less than those recommended by the manufacturer. Dose sparing effects were also apparent with antigen when delivered in the depot. Similar dose sparing effects were observed with Montanide ISA 50, complete and incomplete Freund's adjuvants but not with aluminium hydroxide nor Quil A. Antibody titres, induced by a single dose of antigen/adjuvant formulation incorporated in the depot, persisted at high levels for at least 55 weeks following a single dose of vaccine. (C) 2015 Elsevier Ltd. All rights reserved.
  • Brendon Y. Chua, Matthew R. Olson, Sammy Bedoui, Toshiki Sekiya, Chinn Y. Wong, Stephen J. Turner, David C. Jackson
    IMMUNOLOGY AND CELL BIOLOGY 92 4 377 - 383 2014年04月 [査読有り][通常論文]
     
    We have previously shown that the immunogenicity of protein antigens can be significantly enhanced if electrostatically associated with the Toll-like receptor-2 agonist-based lipopeptide R(4)Pam(2)Cys. The precise mechanisms and effectiveness of the cytotoxic T-lymphocyte (CTL)-mediated response facilitated by this agonist, however, have not been studied. Here we show that priming by dendritic cells (DCs) in the draining lymph nodes of animals vaccinated with antigen delivered using R(4)Pam(2)Cys results in significantly improved T-cell proliferation and induces their differentiation into polyfunctional effector CTLs characterised by granzyme B expression and the ability to secrete interferon-gamma, interleukin-2 and tumor necrosis factor-alpha 7 days after vaccination. After 30 days, frequencies of antigen-specific CD62(low)CD127(high) (effector memory), CD62(high)CD127(high) (central memory) and CD43(low)CD27(high) CD8(+) T cells, a phenotype associated with strong recall responses against respiratory infections, are also increased compared with responses obtained with antigens formulated in the adjuvants Alum (alhydrogel) and CFA (complete Freund's adjuvant). The phenotypic changes observed in these mice vaccinated using R(4)Pam(2)Cys further correlated with their ability to recall specific T cells into the lung to mediate the reduction of pulmonary viral titres following challenge with a chimeric influenza virus containing the K(b)OVA(257-264) epitope compared with animals vaccinated using Alum or CFA. The findings from this study not only demonstrate that better T-cell responses can be elicited using R(4)Pam(2)Cys compared with classically utilised adjuvants but also highlight the potential effectiveness of this lipopeptide-based adjuvant particularly against viral infections that require resolution through cell-mediated immunity.
  • Brendon Y. Chua, Douglas Johnson, Amabel Tan, Linda Earnest-Silveira, Toshiki Sekiya, Ruth Chin, Joseph Torresi, David C. Jackson
    PLOS ONE 7 10 e47492  2012年10月 [査読有り][通常論文]
     
    Although many studies provide strong evidence supporting the development of HCV virus-like particle (VLP)-based vaccines, the fact that heterologous viral vectors and/or multiple dosing regimes are required to induce protective immunity indicates that it is necessary to improve their immunogenicity. In this study, we have evaluated the use of an anionic self-adjuvanting lipopeptide containing the TLR2 agonist Pam(2)Cys (E(8)Pam(2)Cys) to enhance the immunogenicity of VLPs containing the HCV structural proteins (core, E1 and E2) of genotype 1a. While co-formulation of this lipopeptide with VLPs only resulted in marginal improvements in dendritic cell (DC) uptake, its ability to concomitantly induce DC maturation at very small doses is a feature not observed using VLPs alone or in the presence of an aluminium hydroxide-based adjuvant (Alum). Dramatically improved VLP and E2-specific antibody responses were observed in VLP+E(8)Pam(2)Cys vaccinated mice where up to 3 doses of non-adjuvanted or traditionally alum-adjuvanted VLPs was required to match the antibody titres obtained with a single dose of VLPs formulated with this lipopeptide. This result also correlated with significantly higher numbers of specific antibody secreting cells that was detected in the spleens of VLP+E(8)Pam(2)Cys vaccinated mice and greater ability of sera from these mice to neutralise the binding and uptake of VLPs by Huh7 cells. Moreover, vaccination of HLA-A2 transgenic mice with this formulation also induced better VLP-specific IFN-gamma-mediated responses compared to non-adjuvanted VLPs but comparable levels to that achieved when coadministered with complete freund's adjuvant. These results suggest overall that the immunogenicity of HCV VLPs can be significantly improved by the addition of this novel adjuvant by targeting their delivery to DCs and could therefore constitute a viable vaccine strategy for the treatment of HCV.

その他活動・業績

  • Toshiki Sekiya, Marumi Ohno, Naoki Nomura, Chimuka Handabile, Masashi Shingai, David C. Jackson, Lorena E. Brown, Hiroshi Kida Viruses 13 (6) 2021年06月 
    Despite seasonal influenza vaccines having been routinely used for many decades, influenza A virus continues to pose a global threat to humans, causing high morbidity and mortality each year. The effectiveness of the vaccine is largely dependent on how well matched the vaccine strains are with the circulating influenza virus strains. Furthermore, low vaccine efficacy in naïve populations such as young children, or in the elderly, who possess weakened immune systems, indicates that influenza vaccines need to be more personalized to provide broader community protection. Advances in both vaccine technologies and our understanding of influenza virus infection and immunity have led to the design of a variety of alternate vaccine strategies to extend population protection against influenza, some of which are now in use. In this review, we summarize the progress in the field of influenza vaccines, including the advantages and disadvantages of different strategies, and discuss future prospects. We also highlight some of the challenges to be faced in the ongoing effort to control influenza through vaccination.
  • Brendon Y Chua, Toshiki Sekiya, David C Jackson Viral immunology 31 (2) 150 -158 2018年03月 [査読有り][通常論文]
     
    Empirically derived vaccines have in the past relied on the isolation and growth of disease-causing microorganisms that are then inactivated or attenuated before being administered. This is often done without prior knowledge of the mechanisms involved in conferring protective immunity. Recent advances in scientific technologies and in our knowledge of how protective immune responses are induced enable us to rationally design novel and safer vaccination strategies. Such advances have accelerated the development of inactivated whole-organism- and subunit-based vaccines. In this review, we discuss ideal attributes and criteria that need to be considered for the development of vaccines and some existing vaccine platforms. We focus on inactivated vaccines against influenza virus and ways by which vaccine efficacy can be improved with the use of adjuvants and Toll-like receptor-2 signaling.


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