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Dive into the research topics where Nicolas Çuburu is active.

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Featured researches published by Nicolas Çuburu.


Proceedings of the National Academy of Sciences of the United States of America | 2008

Sublingual vaccination with influenza virus protects mice against lethal viral infection

Joo Hye Song; Huan H. Nguyen; Nicolas Çuburu; Taisuke Horimoto; Sung Youl Ko; Se Ho Park; Cecil Czerkinsky; Mi Na Kweon

We assessed whether the sublingual (s.l.) route would be an effective means of delivering vaccines against influenza virus in mice by using either formalin-inactivated or live influenza A/PR/8 virus (H1N1). Sublingual administration of inactivated influenza virus given on two occasions induced both systemic and mucosal antibody responses and conferred protection against a lethal intranasal (i.n.) challenge with influenza virus. Coadministration of a mucosal adjuvant (mCTA-LTB) enhanced these responses and resulted in complete protection against respiratory viral challenge. In addition, s.l. administration of formalin-inactivated A/PR/8 plus mCTA-LTB induced systemic expansion of IFN-γ-secreting T cells and virus-specific cytotoxic T lymphocyte responses. Importantly, a single s.l. administration of live A/PR/8 virus was not pathogenic and induced protection mediated by both acquired and innate immunity. Moreover, s.l. administration of live A/PR/8 virus conferred heterosubtypic protection against respiratory challenge with H3N2 virus. Unlike the i.n. route, the A/PR/8 virus, whether live or inactivated, did not migrate to or replicate in the CNS after s.l. administration. Based on these promising findings, we propose that the s.l. mucosal route offers an attractive alternative to mucosal routes for administering influenza vaccines.


Journal of Clinical Investigation | 2012

Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses

Nicolas Çuburu; Barney S. Graham; Christopher B. Buck; Rhonda C. Kines; Yuk-Ying S. Pang; Patricia M. Day; Douglas R. Lowy; John T. Schiller

The induction of persistent intraepithelial CD8+ T cell responses may be key to the development of vaccines against mucosally transmitted pathogens, particularly for sexually transmitted diseases. Here we investigated CD8+ T cell responses in the female mouse cervicovaginal mucosa after intravaginal immunization with human papillomavirus vectors (HPV pseudoviruses) that transiently expressed a model antigen, respiratory syncytial virus (RSV) M/M2, in cervicovaginal keratinocytes. An HPV intravaginal prime/boost with different HPV serotypes induced 10-fold more cervicovaginal antigen-specific CD8+ T cells than priming alone. Antigen-specific T cell numbers decreased only 2-fold after 6 months. Most genital antigen-specific CD8+ T cells were intra- or subepithelial, expressed αE-integrin CD103, produced IFN-γ and TNF-α, and displayed in vivo cytotoxicity. Using a sphingosine-1-phosphate analog (FTY720), we found that the primed CD8+ T cells proliferated in the cervicovaginal mucosa upon HPV intravaginal boost. Intravaginal HPV prime/boost reduced cervicovaginal viral titers 1,000-fold after intravaginal challenge with vaccinia virus expressing the CD8 epitope M2. In contrast, intramuscular prime/boost with an adenovirus type 5 vector induced a higher level of systemic CD8+ T cells but failed to induce intraepithelial CD103+CD8+ T cells or protect against recombinant vaccinia vaginal challenge. Thus, HPV vectors are attractive gene-delivery platforms for inducing durable intraepithelial cervicovaginal CD8+ T cell responses by promoting local proliferation and retention of primed antigen-specific CD8+ T cells.


Journal of Immunology | 2009

Sublingual Immunization with Nonreplicating Antigens Induces Antibody-Forming Cells and Cytotoxic T Cells in the Female Genital Tract Mucosa and Protects against Genital Papillomavirus Infection

Nicolas Çuburu; Mi-Na Kweon; Catherine Hervouet; Hye-Ran Cha; Yuk-Ying S. Pang; Jan Holmgren; Konrad Stadler; John T. Schiller; Fabienne Anjuère; Cecil Czerkinsky

We have recently reported that the sublingual (s.l.) mucosa is an efficient site for inducing systemic and mucosal immune responses. In this study, the potential of s.l. immunization to induce remote Ab responses and CD8+ cytotoxic responses in the female genital tract was examined in mice by using a nonreplicating Ag, OVA, and cholera toxin (CT) as an adjuvant. Sublingual administration of OVA and CT induced Ag-specific IgA and IgG Abs in blood and in cervicovaginal secretions. These responses were associated with large numbers of IgA Ab-secreting cells (ASCs) in the genital mucosa. Genital ASC responses were similar in magnitude and isotype distribution after s.l., intranasal, or vaginal immunization and were superior to those seen after intragastric immunization. Genital, but not blood or spleen, IgA ASC responses were inhibited by treatment with anti-CCL28 Abs, suggesting that the chemokine CCL28 plays a major role in the migration of IgA ASC progenitors to the reproductive tract mucosa. Furthermore, s.l. immunization with OVA induced OVA-specific effector CD8+ cytolytic T cells in the genital mucosa, and these responses required coadministration of the CT adjuvant. Furthermore, s.l. administration of human papillomavirus virus-like particles with or without the CT adjuvant conferred protection against genital challenge with human papillomavirus pseudovirions. Taken together, these findings underscore the potential of s.l. immunization as an efficient vaccination strategy for inducing genital immune responses and should impact on the development of vaccines against sexually transmitted diseases.


Journal of Immunology | 2009

CCR7-CCL19/CCL21-Regulated Dendritic Cells Are Responsible for Effectiveness of Sublingual Vaccination

Joo-Hye Song; Jung‐Im Kim; Hyung-Joon Kwon; Doo-Hee Shim; Nirmala Parajuli; Nicolas Çuburu; Cecil Czerkinsky; Mi-Na Kweon

Our previous studies demonstrated the potential of the sublingual (s.l.) route for delivering vaccines capable of inducing mucosal as well as systemic immune responses. Those findings prompted us to attempt to identify possible inductive mechanism of s.l. vaccination for immune responses. Within 2 h after s.l. administration with cholera toxin (CT), significantly higher numbers of MHC class II+ cells accumulated in the s.l. mucosa. Of note, there were brisk expression levels of both CCL19 and CCL21 in cervical lymph nodes (CLN) 24 h after s.l. vaccination with CT. In reconstitution experiments using OVA-specific CD4+ or CD8+ T cells, s.l. vaccination elicited strong Ag-specific T cell proliferation mainly in CLN. Interestingly, Ag-specific T cell proliferation completely disappeared in CD11c-depleted and CCR7−/− mice but not in Langerin-depleted, macrophage-depleted, and CCR6−/− mice. Similar to CD4+ T cell responses, induction of Ag-specific IgG (systemic) and IgA (mucosal) Ab responses were significantly reduced in CD11c-depleted and CCR7−/− mice after s.l. vaccination with OVA plus CT. Although CD8α− dendritic cells ferried Ag from the s.l. mucosa, both migratory CD8α− and resident CD8α+ dendritic cells were essential to prime CD4+ T cells in the CLN. On the basis of these findings, we believe that CCR7 expressed CD8α−CD11c+ cells ferry Ag in the s.l. mucosa, migrate into the CLN, and share the Ag with resident CD8α+CD11c+ cells for the initiation of Ag-specific T and B cell responses following s.l. challenge. We propose that the s.l. mucosa is one of the effective mucosal inductive sites regulated by the CCR7-CCL19/CCL21 pathway.


Vaccine | 2010

Sublingual immunization with an HIV subunit vaccine induces antibodies and cytotoxic T cells in the mouse female genital tract.

Catherine Hervouet; Carmelo Luci; Nicolas Çuburu; Magali Cremel; Selma Bekri; Lene Vimeux; Concepción Marañón; Cecil Czerkinsky; Anne Hosmalin; Fabienne Anjuère

A vaccine against heterosexual transmission by human immunodeficiency virus (HIV) should generate cytotoxic and antibody responses in the female genital tract and in extra-genital organs. We report that sublingual immunization with HIV-1 gp41 and a reverse transcriptase polypeptide coupled to the cholera toxin B subunit (CTB) induced gp41-specific IgA antibodies and antibody-secreting cells, as well as reverse transcriptase-specific CD8 T cells in the genital mucosa, contrary to intradermal immunization. Conjugation of the reverse transcriptase peptide to CTB favored its cross-presentation by human dendritic cells to a T cell line from an HIV(+) patient. Sublingual vaccination could represent a promising vaccine strategy against heterosexual transmission of HIV-1.


Nature Protocols | 2013

Enzyme-linked immunospot assays for direct ex vivo measurement of vaccine-induced human humoral immune responses in blood

Giulietta Saletti; Nicolas Çuburu; Jae Seung Yang; Ayan Dey; Cecil Czerkinsky

The enzyme-linked immunospot (ELISPOT) assay was originally developed to enumerate antigen-specific antibody-secreting cells (ASCs), and has subsequently been adapted for various applications, including the detection cytokine-secreting cells. Owing to its exceptionally high sensitivity, the ELISPOT has proven to be especially useful for detecting discrete populations of active cells (e.g., antigen-specific cells). Because of its versatility, the ELISPOT assay is used for a wide range of applications, including clonal analyses of immune responses after vaccination or after immunotherapy. Here we describe standard protocols for the detection of human ASCs specific to virtually any vaccine antigen after enrichment of circulating plasmablasts. In addition, a protocol is described for the measurement of mucosal ASC responses after prior immunomagnetic enrichment of mucosally derived blood lymphocytes. The protocols described allow rapid (∼6–8 h) detection of specific ASCs in small (1–2 ml) samples of blood and can be performed in resource-poor settings.


Proceedings of the National Academy of Sciences of the United States of America | 2008

From the Cover: Sublingual vaccination with influenza virus protects mice against lethal viral infection

Joo-Hye Song; Huan H. Nguyen; Nicolas Çuburu; Taisuke Horimoto; Sung-Youl Ko; Se-Ho Park; Cecil Czerkinsky; Mi-Na Kweon

We assessed whether the sublingual (s.l.) route would be an effective means of delivering vaccines against influenza virus in mice by using either formalin-inactivated or live influenza A/PR/8 virus (H1N1). Sublingual administration of inactivated influenza virus given on two occasions induced both systemic and mucosal antibody responses and conferred protection against a lethal intranasal (i.n.) challenge with influenza virus. Coadministration of a mucosal adjuvant (mCTA-LTB) enhanced these responses and resulted in complete protection against respiratory viral challenge. In addition, s.l. administration of formalin-inactivated A/PR/8 plus mCTA-LTB induced systemic expansion of IFN-γ-secreting T cells and virus-specific cytotoxic T lymphocyte responses. Importantly, a single s.l. administration of live A/PR/8 virus was not pathogenic and induced protection mediated by both acquired and innate immunity. Moreover, s.l. administration of live A/PR/8 virus conferred heterosubtypic protection against respiratory challenge with H3N2 virus. Unlike the i.n. route, the A/PR/8 virus, whether live or inactivated, did not migrate to or replicate in the CNS after s.l. administration. Based on these promising findings, we propose that the s.l. mucosal route offers an attractive alternative to mucosal routes for administering influenza vaccines.


Human Vaccines & Immunotherapeutics | 2016

Moving forward with human papillomavirus immunotherapies

Nicolas Çuburu; John T. Schiller

ABSTRACT Persistent human papillomavirus (HPV) is the primary etiologic agent of cervical cancer and causes a significant number of vulvar, penile, anal and oropharyngeal cancers. The development of highly effective HPV therapeutic vaccines is a reasonable goal given the recent advances in basic and applied immunology. A number of vaccine strategies designed to induce systemic T cell responses have been tested in clinical trials against high grade cervical or vulvar high grade neoplasia and cancers, but with limited success. In line with the emerging trend to focus more on the epithelial context of HPV infection and premalignant disease, it might be advantageous to develop vaccination strategies that promote trafficking of HPV-specific T cells into lesions and overcome the local immunosuppressive environment. The development of more biologically relevant animal models would improve the preclinical evaluation of therapeutic vaccine candidates. Finally, persistent infection and low grade lesions may prove to be easier targets for therapeutic vaccines, and these vaccines would likely be commercially viable in high income countries and valuable components in screen and treat programs in low resource settings.


Journal of Virology | 2016

Erratum for Pastrana et al., BK Polyomavirus Genotypes Represent Distinct Serotypes with Distinct Entry Tropism

Diana V. Pastrana; Upasana Ray; Thomas G. Magaldi; Rachel M. Schowalter; Nicolas Çuburu; Christopher B. Buck

Volume 87, no. 18, p. [10105–10113][1], 2013. Page 10109, [Fig. 4A][2]: For BKV-IVb1 (3rd line), amino acid 73, “K” should read “E.” For BKV-IVb1, amino acid 77, “E” should read “N.” [Fig. 4A][2] should appear as shown below. ![Figure][3] [1]: /lookup/doi/10.1128/JVI.


Proceedings of the National Academy of Sciences of the United States of America | 2008

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Joo-Hye Song; Huan H. Nguyen; Nicolas Çuburu; Taisuke Horimoto; Sung-Youl Ko; Se-Ho Park; Cecil Czerkinsky; Mi-Na Kweon

We assessed whether the sublingual (s.l.) route would be an effective means of delivering vaccines against influenza virus in mice by using either formalin-inactivated or live influenza A/PR/8 virus (H1N1). Sublingual administration of inactivated influenza virus given on two occasions induced both systemic and mucosal antibody responses and conferred protection against a lethal intranasal (i.n.) challenge with influenza virus. Coadministration of a mucosal adjuvant (mCTA-LTB) enhanced these responses and resulted in complete protection against respiratory viral challenge. In addition, s.l. administration of formalin-inactivated A/PR/8 plus mCTA-LTB induced systemic expansion of IFN-γ-secreting T cells and virus-specific cytotoxic T lymphocyte responses. Importantly, a single s.l. administration of live A/PR/8 virus was not pathogenic and induced protection mediated by both acquired and innate immunity. Moreover, s.l. administration of live A/PR/8 virus conferred heterosubtypic protection against respiratory challenge with H3N2 virus. Unlike the i.n. route, the A/PR/8 virus, whether live or inactivated, did not migrate to or replicate in the CNS after s.l. administration. Based on these promising findings, we propose that the s.l. mucosal route offers an attractive alternative to mucosal routes for administering influenza vaccines.

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Mi-Na Kweon

International Vaccine Institute

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John T. Schiller

National Institutes of Health

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Huan H. Nguyen

International Vaccine Institute

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Sung-Youl Ko

Seoul National University

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Christopher B. Buck

National Institutes of Health

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Rhonda C. Kines

National Institutes of Health

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Yuk-Ying S. Pang

National Institutes of Health

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