Helder I Nakaya

Publications of Helder I Nakaya

• Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates.

  Authors: Marcin Kwissa, Helder I Nakaya, Herold Oluoch, Bali Pulendran

  Blood. 03/2012; 119(9):2044-55.

  TLR ligands (TLR-Ls) represent novel vaccine adjuvants, but their immunologic effects in humans remain poorly defined in vivo. In the present study, we analyzed the innate responses stimulated byTLR ligands (TLR-Ls) represent novel vaccine adjuvants, but their immunologic effects in humans remain poorly defined in vivo. In the present study, we analyzed the innate responses stimulated by different TLR-Ls in rhesus macaques. MPL (TLR4-L), R-848 (TLR7/8-L), or cytosine-phosphate-guanine oligodeoxynucleotide (TLR9-L) induced a rapid and robust expansion of blood neutrophils, with a concomitant reduction in PBMCs. Furthermore, all TLR-Ls induced rapid (3-8 hours) expansion of CD14(+) monocytes, but only TLR7/8-L and TLR9-L mobilized the CD14(+)CD16(+) and CD14(dim)CD16(++) monocytes, and only TLR7/8-L and TLR9-L induced activation of myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs), production of IP-10 and type-I IFN, and expression of type-I IFN-related and chemokine genes in the blood. In the draining lymph nodes (LNs), consistent with the effects in blood, all TLR-Ls induced expansion of CD14(+) monocytes, but only TLR7/8-L and TLR9-L expanded the activated CD14(+)CD16(+) cells. TLR4-L and TLR9-L differentially induced the expansion of mDCs and pDCs (1-3 days), but did not activate DCs. In contrast, TLR7/8-L did not induce DC expansion, but did activate mDCs. Finally, both TLR9-L and TLR7/8-L induced the expression of genes related to chemokines and type-I IFNs in LNs. Thus different TLR-Ls mediate distinct signatures of early innate responses both locally and systemically.

• Systems vaccinology: learning to compute the behavior of vaccine induced immunity.

  Authors: Helder I Nakaya, Shuzhao Li, Bali Pulendran

  Wiley interdisciplinary reviews. Systems biology and medicine. 03/2012; 4(2):193-205.

  The goal of systems biology is to access and integrate information about the parts (e.g., genes, proteins, cells) of a biological system with a view to computing and predicting the behavior of theThe goal of systems biology is to access and integrate information about the parts (e.g., genes, proteins, cells) of a biological system with a view to computing and predicting the behavior of the system. The past decade has witnessed technological revolutions in the capacity to make high throughput measurements about the behavior of genes, proteins, and cells. Such technologies are widely used in biological research and in medicine, such as toward prognosis and therapy response prediction in cancer patients. More recently, systems biology is being applied to vaccinology, with the goal of: (1) understanding the mechanisms by which vaccines stimulate protective immunity, and (2) predicting the immunogenicity or efficacy of vaccines. Here, we review the recent advances in this area, and highlight the biological and computational challenges posed. WIREs Syst Biol Med 2012, 4:193-205. doi: 10.1002/wsbm.163 For further resources related to this article, please visit the WIREs website.

• Systems vaccinology: its promise and challenge for HIV vaccine development.

  Authors: Helder I Nakaya, Bali Pulendran

  Current opinion in HIV and AIDS. 11/2011; 7(1):24-31.

  The use of systems biology approaches to understand and predict vaccine-induced immunity promises to revolutionize vaccinology. For centuries vaccines were developed empirically, with very littleThe use of systems biology approaches to understand and predict vaccine-induced immunity promises to revolutionize vaccinology. For centuries vaccines were developed empirically, with very little understanding of the mechanisms by which they mediate protective immunity. The so-called systems vaccinology approach employs high-throughput technologies (e.g. microarrays, RNA-seq and mass spectrometry-based proteomics and metabolomics) and computational modeling to describe the complex interactions between all the parts of immune system, with a view to elucidating new biological rules capable of predicting the behavior of the system. Systems biology successfully applied to yellow-fever and influenza vaccines has led to the discovery of signatures that predict vaccine immunogenicity, and promises to advance basic immunology research by providing novel mechanistic insights about immune regulation. However a major challenge of systems vaccinology concerns the analyses and interpretation of the large and noisy data sets generated by high-throughput techniques. Overcoming these issues, we envision that systems vaccinology will have a potential impact on vaccine development, including HIV vaccines. High-throughput technologies allow the investigation of vaccine-induced immune responses at system and molecular levels. These are currently being used to unravel new molecular insights about the immune system, and are on the verge of being integrated into clinical trials to enable rational vaccine design and development.

• Phenotype, function, and gene expression profiles of programmed death-1(hi) CD8 T cells in healthy human adults.

  Authors: Jaikumar Duraiswamy, Chris C Ibegbu, David Masopust, Joseph D Miller, Koichi Araki, Gregory H Doho, Pramila Tata, Satish Gupta, Michael J Zilliox, Helder I Nakaya, Bali Pulendran, W Nicholas Haining, Gordon J Freeman, Rafi Ahmed

  Journal of immunology (Baltimore, Md. : 1950). 03/2011; 186(7):4200-12.

  T cell dysfunction is an important feature of many chronic viral infections. In particular, it was shown that programmed death-1 (PD-1) regulates T cell dysfunction during chronic lymphocyticT cell dysfunction is an important feature of many chronic viral infections. In particular, it was shown that programmed death-1 (PD-1) regulates T cell dysfunction during chronic lymphocytic choriomeningitis virus infection in mice, and PD-1(hi) cells exhibit an intense exhausted gene signature. These findings were extended to human chronic infections such as HIV, hepatitis C virus, and hepatitis B virus. However, it is not known if PD-1(hi) cells of healthy humans have the traits of exhausted cells. In this study, we provide a comprehensive description of phenotype, function, and gene expression profiles of PD-1(hi) versus PD-1(lo) CD8 T cells in the peripheral blood of healthy human adults as follows: 1) the percentage of naive and memory CD8 T cells varied widely in the peripheral blood cells of healthy humans, and PD-1 was expressed by the memory CD8 T cells; 2) PD-1(hi) CD8 T cells in healthy humans did not significantly correlate with the PD-1(hi) exhausted gene signature of HIV-specific human CD8 T cells or chronic lymphocytic choriomeningitis virus-specific CD8 T cells from mice; 3) PD-1 expression did not directly affect the ability of CD8 T cells to secrete cytokines in healthy adults; 4) PD-1 was expressed by the effector memory compared with terminally differentiated effector CD8 T cells; and 5) finally, an interesting inverse relationship between CD45RA and PD-1 expression was observed. In conclusion, our study shows that most PD-1(hi) CD8 T cells in healthy adult humans are effector memory cells rather than exhausted cells.

• Programming the magnitude and persistence of antibody responses with innate immunity.

  Authors: Sudhir Pai Kasturi, Ioanna Skountzou, Randy A Albrecht, Dimitrios Koutsonanos, Tang Hua, Helder I Nakaya, Rajesh Ravindran, Shelley Stewart, Munir Alam, Marcin Kwissa, Francois Villinger, Niren Murthy, John Steel, Joshy Jacob, Robert J Hogan, Adolfo García-Sastre, Richard Compans, Bali Pulendran

  Nature. 02/2011; 470(7335):543-7.

  Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendriticMany successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.

• Systems biology of vaccination for seasonal influenza in humans.

  Authors: Helder I Nakaya, Jens Wrammert, Eva K Lee, Luigi Racioppi, Stephanie Marie-Kunze, W Nicholas Haining, Anthony R Means, Sudhir P Kasturi, Nooruddin Khan, Gui-Mei Li, Megan McCausland, Vibhu Kanchan, Kenneth E Kokko, Shuzhao Li, Rivka Elbein, Aneesh K Mehta, Alan Aderem, Kanta Subbarao, Rafi Ahmed, Bali Pulendran

  Nature immunology. 01/2011; 12(8):786-95.

  Here we have used a systems biology approach to study innate and adaptive responses to vaccination against influenza in humans during three consecutive influenza seasons. We studied healthy adultsHere we have used a systems biology approach to study innate and adaptive responses to vaccination against influenza in humans during three consecutive influenza seasons. We studied healthy adults vaccinated with trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV). TIV induced higher antibody titers and more plasmablasts than LAIV did. In subjects vaccinated with TIV, early molecular signatures correlated with and could be used to accurately predict later antibody titers in two independent trials. Notably, expression of the kinase CaMKIV at day 3 was inversely correlated with later antibody titers. Vaccination of CaMKIV-deficient mice with TIV induced enhanced antigen-specific antibody titers, which demonstrated an unappreciated role for CaMKIV in the regulation of antibody responses. Thus, systems approaches can be used to predict immunogenicity and provide new mechanistic insights about vaccines.

• Systems vaccinology.

  Authors: Bali Pulendran, Shuzhao Li, Helder I Nakaya

  Immunity. 10/2010; 33(4):516-29.

  Vaccination is one of the greatest triumphs of modern medicine, yet we remain largely ignorant of the mechanisms by which successful vaccines stimulate protective immunity. Two recent advances areVaccination is one of the greatest triumphs of modern medicine, yet we remain largely ignorant of the mechanisms by which successful vaccines stimulate protective immunity. Two recent advances are beginning to illuminate such mechanisms: realization of the pivotal role of the innate immune system in sensing microbes and stimulating adaptive immunity, and advances in systems biology. Recent studies have used systems biology approaches to obtain a global picture of the immune responses to vaccination in humans. This has enabled the identification of early innate signatures that predict the immunogenicity of vaccines, and identification of potentially novel mechanisms of immune regulation. Here, we review these advances and critically examine the potential opportunities and challenges posed by systems biology in vaccine development.

• The T helper type 2 response to cysteine proteases requires dendritic cell-basophil cooperation via ROS-mediated signaling.

  Authors: Hua Tang, Weiping Cao, Sudhir Pai Kasturi, Rajesh Ravindran, Helder I Nakaya, Kousik Kundu, Niren Murthy, Thomas B Kepler, Bernard Malissen, Bali Pulendran

  Nature immunology. 07/2010; 11(7):608-17.

  The mechanisms that initiate T helper type 2 (T(H)2) responses are poorly understood. Here we demonstrate that cysteine protease-induced T(H)2 responses occur via 'cooperation' between migratoryThe mechanisms that initiate T helper type 2 (T(H)2) responses are poorly understood. Here we demonstrate that cysteine protease-induced T(H)2 responses occur via 'cooperation' between migratory dermal dendritic cells (DCs) and basophils positive for interleukin 4 (IL-4). Subcutaneous immunization with papain plus antigen induced reactive oxygen species (ROS) in lymph node DCs and in dermal DCs and epithelial cells of the skin. ROS orchestrated T(H)2 responses by inducing oxidized lipids that triggered the induction of thymic stromal lymphopoietin (TSLP) by epithelial cells mediated by Toll-like receptor 4 (TLR4) and the adaptor protein TRIF; by suppressing production of the T(H)1-inducing molecules IL-12 and CD70 in lymph node DCs; and by inducing the DC-derived chemokine CCL7, which mediated recruitment of IL-4(+) basophils to the lymph node. Thus, the T(H)2 response to cysteine proteases requires DC-basophil cooperation via ROS-mediated signaling.

• Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans.

  Authors: Troy D Querec, Rama S Akondy, Eva K Lee, Weiping Cao, Helder I Nakaya, Dirk Teuwen, Ali Pirani, Kim Gernert, Jiusheng Deng, Bruz Marzolf, Kathleen Kennedy, Haiyan Wu, Soumaya Bennouna, Herold Oluoch, Joseph Miller, Ricardo Z Vencio, Mark Mulligan, Alan Aderem, Rafi Ahmed, Bali Pulendran

  Nature immunology. 12/2008;

  A major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene 'signatures' that predicted immune responses inA major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene 'signatures' that predicted immune responses in humans vaccinated with yellow fever vaccine YF-17D. Vaccination induced genes that regulate virus innate sensing and type I interferon production. Computational analyses identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4-an orchestrator of the integrated stress response-that correlated with and predicted YF-17D CD8(+) T cell responses with up to 90% accuracy in an independent, blinded trial. A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy.