Systems biology applied to vaccine and immunotherapy development

Molecular Biology and Viral Oncology, Dept of Experimental Oncology, Istituto Nazionale Tumori Fond Pascale, Via Mariano Semmola 142, 80131 Napoli, Italy.
BMC Systems Biology (Impact Factor: 2.44). 09/2011; 5(1):146. DOI: 10.1186/1752-0509-5-146
Source: PubMed


Immunotherapies, including vaccines, represent a potent tool to prevent or contain disease with high morbidity or mortality such as infections and cancer. However, despite their widespread use, we still have a limited understanding of the mechanisms underlying the induction of protective immune responses.
Immunity is made of a multifaceted set of integrated responses involving a dynamic interaction of thousands of molecules; among those is a growing appreciation for the role the innate immunity (i.e. pathogen recognition receptors - PRRs) plays in determining the nature and duration (immune memory) of adaptive T and B cell immunity. The complex network of interactions between immune manipulation of the host (immunotherapy) on one side and innate and adaptive responses on the other might be fully understood only employing the global level of investigation provided by systems biology.
In this framework, the advancement of high-throughput technologies, together with the extensive identification of new genes, proteins and other biomolecules in the "omics" era, facilitate large-scale biological measurements. Moreover, recent development of new computational tools enables the comprehensive and quantitative analysis of the interactions between all of the components of immunity over time.
Here, we review recent progress in using systems biology to study and evaluate immunotherapy and vaccine strategies for infectious and neoplastic diseases. Multi-parametric data provide novel and often unsuspected mechanistic insights while enabling the identification of common immune signatures relevant to human investigation such as the prediction of immune responsiveness that could lead to the improvement of the design of future immunotherapy trials. Thus, the paradigm switch from "empirical" to "knowledge-based" conduct of medicine and immunotherapy in particular, leading to patient-tailored treatment.

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Available from: Maria Lina Tornesello, Oct 02, 2015
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    • "A major challenge in vaccinology is to predict vaccine efficacy [31-33]. Here, we used a multiparametric systems biology approach to identify gene signatures predictive of an immune response, using an experimental platform based on PBMCs from 6 HCV-positive subjects stimulated ex vivo with the IGKV3-20 light-chain protein, as candidate idiotype vaccine. "
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    ABSTRACT: We have previously shown that a candidate idiotype vaccine, based on the IGKV3-20 light chain protein, is able to induce activation of circulating antigen presenting cells (APCs) in both HCV-positive and HCV-negative subjects, with production of Th2-type cytokines. In addition, such a candidate idiotype vaccine induces an early gene expression pattern, characterized by the strong induction of an innate immune response, and a late pattern, characterized by a prevalent B cell response. Nonetheless, some HCV-positive individuals showed a complete lack of maturation of circulating APCs with low levels of cytokine production, strongly suggesting the possible identification of selective impairments in immune response in individual subjects. Peripheral blood mononuclear cells (PBMCs) were stimulated ex vivo with IGKV3-20 for 24 h and 6 days. Analysis of the global gene expression profile as well as the cytokine pattern was performed for individual subjects. The gene expression profile showed a strong agreement with the cytokine pattern. Indeed, the expression pattern of immune-related genes is highly predictive of the individual immunological phenotype. The overall results represent a proof of concept, indicating the efficacy of such an ex vivo screening platform for predicting individual's responsiveness to an antigen as well as guiding optimization of vaccine design. Larger cohort study will be needed to validate results observed in the study.
    Journal of Translational Medicine 01/2014; 12(1):11. DOI:10.1186/1479-5876-12-11 · 3.93 Impact Factor
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    • "In fact, a significant proportion of the human cancer vaccine trials to date are targeted against embryonic antigens such as carcinoembryonic antigen (Greiner et al., 2002) cancer/testes antigen (Chiriva- Internati, 2011; Mirandola et al., 2011) and α-fetoprotein etc (Toyoda et al., 2011). Unfortunately, targeting one antigen alone is unlikely to generate effective antitumor immune responses to mediate tumor rejection because of rapid appearance of escape mutants and the general inefficiency of monovalent cancer vaccines (Buonaguro et al., 2011; Durrant et al., 2011). Interestingly, it was found that cancer stem cells (CSCs) and embryonic stem cells (ESCs) shared similar cell surface markers and antigens not presented by adult tissues, which played a part in metastasis, angiogenesis and increased chemoradiotherapy resistance in cancer (Field et al., 2010; Kee et al., 2012; Lopez et al., 2012), so immune response against ESCs RESEARCH ARTICLE "
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    ABSTRACT: Objective: To investigate the therapeutic potential of human embryonic stem cells (hESCs) as a vaccine to induce an immune response and provide antitumor protection in a rat model. Methods: Cross-reactivity of antigens between hESCs and tumour cells was screened by immunohistochemistry. Fischer 344 rats were divided into 7 groups, with 6 rats in each, immunized with: Group 1, hESC; Group 2, pre-inactivated mitotic NuTu-19; Group 3 PBS; Group 4, hESC; Group 5, pre-inactivated mitotic NuTu-19; Group 6, PBS; Group 7, hESC only. At 1 (Groups 1-3) or 4 weeks (Groups 4-6) after the last vaccination, each rat was challenged intraperitoneally with NuTu-19. Tumor growth and animal survival were closely monitored. Rats immunized with H9 and NuTu- 19 were tested by Western blot analysis of rat orbital venous blood for cytokines produced by Th1 and Th2 cells. Results: hESCs presented tumour antigens, markers, and genes related to tumour growth, metastasis, and signal pathway interactions. The vaccine administered to rats in Group 1 led to significant antitumor responses and enhanced tumor rejection in rats with intraperitoneal inoculation of NuTu-19 cells compared to control groups. In contrast, rats in Group 4 did not display any elevation of antitumour responses. Western blot analysis found cross-reactivity among antibodies generated between H9 and NuTu-19. However, the cytokines did not show significant differences, and no side effects were detected. Conclusion: hESC-based vaccination is a promising modality for immunotherapy of ovarian cancer.
    Asian Pacific journal of cancer prevention: APJCP 09/2012; 13(9):4295-300. DOI:10.7314/APJCP.2012.13.9.4295 · 2.51 Impact Factor
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    • "However, these classical approaches have not been successful for some important and highly variable or multi-strain pathogens such as DENV, enteroviruses, HIV, and hepatitis C virus. For vaccination to become a reality for such diseases or improving current vaccines like influenza and foot and mouth disease virus, new vaccine approaches need to be developed taking into account the unique epitope hierarchy in each pathogen and tailoring immunogens to elicit an appropriate protective immune response [52-55]. Increasing the induction of broadly cross-reactive yet protective immune responses for HIV, influenza, and hepatitis C virus, or reducing pathogenic cross-reactive responses for example, in DENV may become possible with these and other similar approaches. "
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    ABSTRACT: Dengue viruses (DENV) are the most important arboviruses of humans and cause significant disease. Infection with DENV elicits antibody responses to the envelope glycoprotein, predominantly against immunodominant, cross-reactive, weakly-neutralizing epitopes. These weakly-neutralizing antibodies are implicated in enhancing infection via Fcγ receptor bearing cells and can lead to increased viral loads that are associated with severe disease. Here we describe results from the development and testing of cross-reactivity reduced DENV-2 DNA vaccine candidates that contain substitutions in immunodominant B cell epitopes of the fusion peptide and domain III of the envelope protein. Cross-reactivity reduced and wild-type vaccine candidates were similarly immunogenic in outbred mice and elicited high levels of neutralizing antibody, however mice immunized with cross-reactivity reduced vaccines produced significantly reduced levels of immunodominant cross-reactive antibodies. Sera from mice immunized with wild-type, fusion peptide-, or domain III- substitution containing vaccines enhanced heterologous DENV infection in vitro, unlike sera from mice immunized with a vaccine containing a combination of both fusion peptide and domain III substitutions. Passive transfer of immune sera from mice immunized with fusion peptide and domain III substitutions also reduced the development of severe DENV disease in AG129 mice when compared to mice receiving wild type immune sera. Reducing cross-reactivity in the envelope glycoprotein of DENV may be an approach to improve the quality of the anti-DENV immune response.
    Virology Journal 06/2012; 9(1):115. DOI:10.1186/1743-422X-9-115 · 2.18 Impact Factor
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