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1.  The role of vaccines in the control of STDs: HPV vaccines. 
Genitourinary Medicine  1996;72(6):398-403.
Prophylactic vaccines for genital human papillomavirus (HPV) infection have been shown to be feasible in animal models, and suitable vaccine material based on virus-like particles can be produced in bulk at reasonable cost. Initiation of phase III clinical trials will follow definition of trial outcome measures through further epidemiological studies, and development of assays of host protective immunity. Vaccines could in principle eliminate HPV-related disease, as the human race is the only natural host for the relevant papillomaviruses (PVs). Therapeutic vaccines for genital HPV infection are also possible, but have not yet been demonstrated as feasible in practice because the choice of vaccine antigens is difficult, the method of their optimal delivery is uncertain, and the nature of the relevant antiviral immunity is unknown. PV species specificity will require trials to be conducted in man, which will slow definition of an ideal vaccine.
PMCID: PMC1195726  PMID: 9038634
2.  Regulatory T-cell vaccination independent of auto-antigen 
To date, efforts to treat autoimmune diseases have primarily focused on the disease symptoms rather than on the cause of the disease. In large part, this is attributed to not knowing the responsible auto-antigens (auto-Ags) for driving the self-reactivity coupled with the poor success of treating autoimmune diseases using oral tolerance methods. Nonetheless, if tolerogenic approaches or methods that stimulate regulatory T (Treg) cells can be devised, these could subdue autoimmune diseases. To forward such efforts, our approach with colonization factor antigen I (CFA/I) fimbriae is to establish bystander immunity to ultimately drive the development of auto-Ag-specific Treg cells. Using an attenuated Salmonella vaccine expressing CFA/I fimbriae, fimbriae-specific Treg cells were induced without compromising the vaccine's capacity to protect against travelers' diarrhea or salmonellosis. By adapting the vaccine's anti-inflammatory properties, it was found that it could also dampen experimental inflammatory diseases resembling multiple sclerosis (MS) and rheumatoid arthritis. Because of this bystander effect, disease-specific Treg cells are eventually induced to resolve disease. Interestingly, this same vaccine could elicit the required Treg cell subset for each disease. For MS-like disease, conventional CD25+ Treg cells are stimulated, but for arthritis CD39+ Treg cells are induced instead. This review article will examine the potential of treating autoimmune diseases without having previous knowledge of the auto-Ag using an innocuous antigen to stimulate Treg cells via the production of transforming growth factor-β and interleukin-10.
doi:10.1038/emm.2014.4
PMCID: PMC3972794  PMID: 24626168
autoimmunity; bacteria; fimbriae; mucosal immunity; regulatory T cells; vaccine
3.  Flagellin Fusion Proteins as Adjuvants or Vaccines Induce Specific Immune Responses  
Infection and Immunity  2004;72(5):2810-2816.
Vaccination is the most efficient prophylaxis against a variety of infectious diseases. New vaccination strategies rely on the incorporation of effective adjuvants, which stimulate the innate immune response and, in turn, activate the adaptive immune response. It is well established that flagellin induces inflammatory responses through the activation of antigen-presenting cells (APCs). In order to evaluate whether flagellin can serve as a carrier for the development of adjuvants or vaccines, we prepared a flagellin-enhanced green fluorescent protein (EGFP) fusion protein. Our results demonstrate that a flagellin-EGFP fusion protein is capable of stimulating APCs, resulting in the maturation of these cells and secretion of proinflammatory cytokines. Furthermore, APCs pulsed with the flagellin-EGFP fusion protein effectively process and present EGFP antigens. More importantly, animals immunized with the flagellin-EGFP fusion protein developed specific anti-EGFP T-cell responses. In contrast, recombinant EGFP was not able to stimulate APCs, nor did it induce a T-cell response. Thus, recombinant-flagellin fusion proteins may be suitable carriers as adjuvants or vaccines for the development of new vaccination strategies to induce and boost immune responses against infectious diseases and cancer.
doi:10.1128/IAI.72.5.2810-2816.2004
PMCID: PMC387897  PMID: 15102791
4.  The Janus Head of T Cell Aging – Autoimmunity and Immunodeficiency 
Immune aging is best known for its immune defects that increase susceptibility to infections and reduce adaptive immune responses to vaccination. In parallel, the aged immune system is prone to autoimmune responses and many autoimmune diseases increase in incidence with age or are even preferentially encountered in the elderly. Why an immune system that suboptimally responds to exogenous antigen fails to maintain tolerance to self-antigens appears to be perplexing. In this review, we will discuss age-associated deviations in the immune repertoire and the regulation of signaling pathways that may shed light on this conundrum.
doi:10.3389/fimmu.2013.00131
PMCID: PMC3671290  PMID: 23761790
immunosenescence; autoimmunity; inflammation; pathogenesis; DNA damage response; T cell receptor signaling; rheumatoid arthritis; giant cell arteritis
5.  Targeted Delivery of VP1 Antigen of Foot-and-mouth Disease Virus to M Cells Enhances the Antigen-specific Systemic and Mucosal Immune Response 
Immune Network  2013;13(4):157-162.
Application of vaccine materials through oral mucosal route confers great economical advantage in animal farming industry due to much less vaccination cost compared with that of injection-based vaccination. In particular, oral administration of recombinant protein antigen against foot-and-mouth disease virus (FMDV) is an ideal strategy because it is safe from FMDV transmission during vaccine production and can induce antigen-specific immune response in mucosal compartments, where FMDV infection has been initiated, which is hardly achievable through parenteral immunization. Given that effective delivery of vaccine materials into immune inductive sites is prerequisite for effective oral mucosal vaccination, M cell-targeting strategy is crucial in successful vaccination since M cells are main gateway for luminal antigen influx into mucosal lymphoid tissue. Here, we applied previously identified M cell-targeting ligand Co1 to VP1 of FMDV in order to test the possible oral mucosal vaccination against FMDV infection. M cell-targeting ligand Co1-conjugated VP1 interacted efficiently with M cells of Peyer's patch. In addition, oral administration of ligand-conjugated VP1 enhanced the induction of VP1-specific IgG and IgA responses in systemic and mucosal compartments, respectively, in comparison with those from oral administration of VP1 alone. In addition, the enhanced VP1-specific immune response was found to be due to antigen-specific Th2-type cytokine production. Collectively, it is suggested that the M cell-targeting strategy could be applied to develop efficient oral mucosal vaccine against FMDV infection.
doi:10.4110/in.2013.13.4.157
PMCID: PMC3759713  PMID: 24009543
Foot-and-mouth disease virus; M cell; Mucosal immunity; Systemic immunity
6.  Mesenchymal stem cells as a novel vaccine platform 
Vaccines are the most efficient and cost-effective means of preventing infectious disease. However, traditional vaccine approaches have thus far failed to provide protection against human immunodeficiency virus (HIV), tuberculosis, malaria, and many other diseases. New approaches to vaccine development are needed to address some of these intractable problems. In this report, we review the literature identifying stimulatory effects of mesenchymal stem cells (MSC) on immune responses and explore the potential for MSC as a novel, universal vaccination platform. MSC are unique bone marrow-derived multipotent progenitor cells that are presently being exploited as gene therapy vectors for a variety of conditions, including cancer and autoimmune diseases. Although MSC are predominantly known for anti-inflammatory properties during allogeneic MSC transplant, there is evidence that MSC can actually promote adaptive immunity under certain settings. MSC have also demonstrated some success in anti-cancer therapeutic vaccines and anti-microbial prophylactic vaccines, as we report, for the first time, the ability of modified MSC to express and secrete a viral antigen that stimulates antigen-specific antibody production in vivo. We hypothesize that the unique properties of modified MSC may enable MSC to serve as an unconventional but innovative, vaccine platform. Such a platform would be capable of expressing hundreds of proteins, thereby generating a broad array of epitopes with correct post-translational processing, mimicking natural infection. By stimulating immunity to a combination of epitopes, it may be possible to develop prophylactic and even therapeutic vaccines to tackle major health problems including those of non-microbial and microbial origin, including cancer, or an infectious disease like HIV, where traditional vaccination approaches have failed.
doi:10.3389/fcimb.2012.00140
PMCID: PMC3499769  PMID: 23162801
MSC; vaccination; adaptive immunity; antibodies; antigen delivery
7.  Vaccination Without Auto-antigen Protects Against Collagen II-Induced Arthritis via Immune Deviation and Regulatory T Cells 1 
Anti-inflammation immunotherapy has been successfully applied for the treatment of autoimmune diseases. Mucosal vaccines against autoimmune disorders are beneficial by influencing the regulatory compartment of gut and systemic adaptive immune systems. A Salmonella vector expressing colonization factor antigen I (CFA/I), shown to behave as an anti-inflammatory vaccine, stimulates the production of CD4+ CD25+ T cells and regulatory cytokines. In this work, we queried whether Salmonella-CFA/I can protect DBA/1 mice from collagen-induced arthritis (CIA). The incidence of arthritis and cartilage loss in vaccinated DBA/1 mice was remarkably lower when compared to unprotected mice. Clinical findings were accompanied by the suppression of inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-27. Vaccination evoked a multi-tier response consisting of IL-4 producing Th2 cells, an increased production of TGF-β by CD4+ T cells, and suppression of collagen II (CII)-specific CD4+ T cell proliferation. To assess the contribution of Salmonella-CFA/I-primed CD4+ T cells, adoptive transfer studies with total CD4+, CD4+CD25−, or CD4+ CD25+ T cells were performed 15 days post-challenge. Mice receiving either subset showed reduced disease incidence and low clinical scores; however, mice receiving total CD4+ T cells showed delayed disease onset by 10 days with reduced clinical scores, reduced IL-17 and IL-27, but enhanced IL-4, IL-10, IL-13, and TGF-β. Inhibition of TGF-β or IL-4 compromised protective immunity. These data show that Salmonella-CFA/I vaccination of DBA/1 mice protects against CIA by stimulating TGF-β- and IL-4-producing regulatory CD4+ T cells.
PMCID: PMC2599931  PMID: 18684965
Th1/Th2 cells; tolerance; vaccination; mucosa
8.  Tolerogenic vaccines for Multiple Sclerosis 
Human Vaccines & Immunotherapeutics  2013;9(5):1032-1038.
Tolerogenic vaccines represent a new class of vaccine designed to re-establish immunological tolerance, restore immune homeostasis, and thereby reverse autoimmune disease. Tolerogenic vaccines induce long-term, antigen-specific, inhibitory memory that blocks pathogenic T cell responses via loss of effector T cells and gain of regulatory T cell function. Substantial advances have been realized in the generation of tolerogenic vaccines that inhibit experimental autoimmune encephalomyelitis in a preclinical setting, and these vaccines may be a prequel of the tolerogenic vaccines that may have therapeutic benefit in Multiple Sclerosis. The purpose here is to provide a snapshot of the current concepts and future prospects of tolerogenic vaccination for Multiple Sclerosis, along with the central challenges to clinical application.
doi:10.4161/hv.23685
PMCID: PMC3899137  PMID: 23357858
autoimmune disease; experimental autoimmune encephalomyelitis; immune; multiple sclerosis; myelin; neuroantigen; T lymphocytes; therapy; tolerance; vaccine
9.  Recent trends in vaccine delivery systems: A review 
Vaccines are the preparations given to patients to evoke immune responses leading to the production of antibodies (humoral) or cell-mediated responses that will combat infectious agents or noninfectious conditions such as malignancies. Alarming safety profile of live vaccines, weak immunogenicity of sub-unit vaccines and immunization, failure due to poor patient compliance to booster doses which should potentiate prime doses are few strong reasons, which necessitated the development of new generation of prophylactic and therapeutic vaccines to promote effective immunization. Attempts are being made to deliver vaccines through carriers as they control the spatial and temporal presentation of antigens to immune system thus leading to their sustained release and targeting. Hence, lower doses of weak immunogens can be effectively directed to stimulate immune responses and eliminate the need for the administration of prime and booster doses as a part of conventional vaccination regimen. This paper reviews carrier systems such as liposomes, microspheres, nanoparticles, dendrimers, micellar systems, ISCOMs, plant-derived viruses which are now being investigated and developed as vaccine delivery systems. This paper also describes various aspects of “needle-free technologies” used to administer the vaccine delivery systems through different routes into the human body.
doi:10.4103/2230-973X.82384
PMCID: PMC3465129  PMID: 23071924
Edible vaccines; microneedles; microparticulates; needle-free delivery; TLRs; vaccine delivery systems; vaccine
10.  Applications and challenges of multivalent recombinant vaccines 
The exceptional discoveries of antigen/gene delivery systems have allowed the development of novel prophylactic and therapeutic vaccine candidates. The vaccine candidates employ various antigen-delivery systems, particularly recombinant viral vectors. Recombinant viral vectors are experimental vaccines similar to DNA vaccines, but they use attenuated viruses or bacterium as a carrier “vector” to introduce microbial DNA to cells of the body. They closely mimic a natural infection and therefore can efficiently stimulate the immune system. Although such recombinant vectors may face extensive preclinical testing and will possibly have to meet stringent regulatory requirements, some of these vectors (e.g. measles virus vectors) may benefit from the profound industrial and clinical experience of the parent vaccine. Most notably, novel vaccines based on live attenuated viruses combine the induction of broad, strong and persistent immune responses with acceptable safety profiles. We assess certain technologies in light of their use against human immunodeficiency virus (HIV).
doi:10.4161/hv.23220
PMCID: PMC3891700  PMID: 23249651
vaccines; DNA; live attenuated viruses; HIV; measles; SIV; reverse genetics; recombinant vectors
11.  Physiological Role of Plasmacytoid Dendritic Cells and Their Potential Use in Cancer Immunity 
Dendritic cells (DCs) play a pivotal role in the control of innate and adaptive immune responses. They are a heterogeneous cell population, where plasmacytoid dendritic cells (pDCs) are a unique subset capable of secreting high levels of type I IFNs. It has been demonstrated that pDCs can coordinate events during the course of viral infection, atopy, autoimmune diseases, and cancer. Therefore, pDC, as a main source of type I IFN, is an attractive target for therapeutic manipulations of the immune system to elicit a powerful immune response against tumor antigens in combination with other therapies. The therapeutic vaccination with antigen-pulsed DCs has shown a limited efficacy to generate an effective long-lasting immune response against tumor cells. A rational manipulation and design of vaccines which could include DC subsets outside “Langerhans cell paradigm” might allow us to improve the therapeutic approaches for cancer patients.
doi:10.1155/2008/106321
PMCID: PMC2630490  PMID: 19190769
12.  Autoimmunity in the immune privileged eye: pathogenic and regulatory T cells 
Immunologic research  2008;42(1-3):41-50.
Experimental autoimmune uveitis (EAU) in animals serves as a model of human uveitis. EAU can be induced in mice by immunization with the retinal antigen inter-photoreceptor retinoid binding protein (IRBP) in complete Freund’s adjuvant (CFA) or by IRBP-pulsed mature dendritic cells, and can be driven either by a Th17 or a Th1 effector response, depending on the model. The direction of the response is affected by conditions present during the exposure to antigen, including the quality/quantity of innate receptor stimulation and/or type of APC. IL-17 and IFN-γ production by innate cells such as NKT may also affect the disease process. If exposure to antigen is via a hydrodynamic DNA vaccination with an IRBP-encoding plasmid, the response is directed to a regulatory phenotype, and disease is ameliorated or prevented. Our data shed light on effector and regulatory responses in autoimmune disease, provide balance to the Th1/Th17 paradigm and help to explain the clinical heterogeneity of human uveitis, which occurs in the face of responses to the same ocular antigen(s).
doi:10.1007/s12026-008-8031-3
PMCID: PMC2756228  PMID: 18629448
T lymphocytes; T regulatory cells; Th1; Th17; Uveitis; Autoimmune disease
13.  Designing the optimal vaccine: the importance of cytokines and dendritic cells 
Many vaccines existing today provide strong protection against a wide variety of infectious organisms, and these consist of either live attenuated or inactivated microorganisms. Most of these vaccines were developed empirically and there has not been a clear understanding of the immunological principles that contribute to this success. Recent advances in systems biology are being applied to the study of vaccines in order to determine which immunological parameters are the best predictors of success. New approaches to vaccine development include the identification of peptide epitopes and the manipulation of the immune response to generate the most appropriate response. Vaccines are being developed to prevent and/or treat such conditions as cancer and autoimmunity in addition to infectious diseases. Vaccines targeting this diverse group of diseases may need to elicit very different types of immune responses. Recent advances in our understanding of the functions of dendritic cells (DC) and cytokines in orchestrating qualitatively different immune responses has allowed the design of vaccines that can elicit immune responses appropriate for cancer, autoimmunity or infectious organisms. This review will focus on recent advances in the ways DC and cytokines can be used to develop the most appropriate and effective vaccines.
doi:10.2174/1875035401003010007
PMCID: PMC3149857  PMID: 21822455
Dendritic cells; cytokines; vaccine; immune response; T helper cells
14.  Cholera Toxin B Subunit Linked to Glutamic Acid Decarboxylase Suppresses Dendritic Cell Maturation and Function 
Vaccine  2011;29(46):8451-8458.
Dendritic cells are the largest population of antigen presenting cells in the body. One of their main functions is to regulate the delicate balance between immunity and tolerance responsible for maintenance of immunological homeostasis. Disruption of this delicate balance often results in chronic inflammation responsible for initiation of organ specific autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and type I diabetes. The cholera toxin B subunit (CTB) is a weak mucosal adjuvant known for its ability to stimulate immunity to antigenic proteins. However, conjugation of CTB to many autoantigens can induce immunological tolerance resulting in suppression of autoimmunity. In this study, we examined whether linkage of CTB to a 5 kDa C-terminal protein fragment of the major diabetes autoantigen glutamic acid decarboxylase (GAD35), can block dendritic cell (DC) functions such as biosynthesis of co-stimulatory factor proteins CD86, CD83, CD80 and CD40 and secretion of inflammatory cytokines. The results of human umbilical cord blood monocyte-derived DC - GAD35 autoantigen incubation experiments showed that inoculation of immature DCs (iDCs), with CTB-GAD35 protein dramatically suppressed levels of CD86, CD83, CD80 and CD40 co-stimulatory factor protein biosynthesis in comparison with GAD35 alone inoculated iDCs. Surprisingly, incubation of iDCs in the presence of the CTB-autoantigen and the strong immunostimulatory molecules PMA and Ionomycin revealed that CTB-GAD35 was capable of arresting PMA + Ionomycin induced DC maturation. Consistant with this finding, CTB-GAD35 mediated suppression of DC maturation was accompanied by a dramatic decrease in the secretion of the pro-inflammatory cytokines IL-12/23p40 and IL-6 and a significant increase in secretion of the immunosuppressive cytokine IL-10. Taken together, our experimental data suggest that linkage of the weak adjuvant CTB to the dominant type 1 diabetes autoantigen GAD strongly inhibits DC maturation through the down regulation of major co-stimulatory factors and inflammatory cytokine biosynthesis. These results emphasize the possibility that CTB-autoantigen fusion proteins enhance DC priming of naïve Th0 cell development in the direction of immunosuppressive T lymphocytes. The immunological phenomena observed here establish a basis for improvement of adjuvant augmented multi-component subunit vaccine strategies capable of complete suppression of organ-specific autoimmune diseases in vivo.
doi:10.1016/j.vaccine.2011.07.077
PMCID: PMC3551541  PMID: 21807047
adjuvant; autoimmunity; cholera toxin-B (CTB); dendritic cells; IDDM; juvenile diabetes
15.  DNA Vaccines: Developing New Strategies against Cancer 
Due to their rapid and widespread development, DNA vaccines have entered into a variety of human clinical trials for vaccines against various diseases including cancer. Evidence that DNA vaccines are well tolerated and have an excellent safety profile proved to be of advantage as many clinical trials combines the first phase with the second, saving both time and money. It is clear from the results obtained in clinical trials that such DNA vaccines require much improvement in antigen expression and delivery methods to make them sufficiently effective in the clinic. Similarly, it is clear that additional strategies are required to activate effective immunity against poorly immunogenic tumor antigens. Engineering vaccine design for manipulating antigen presentation and processing pathways is one of the most important aspects that can be easily handled in the DNA vaccine technology. Several approaches have been investigated including DNA vaccine engineering, co-delivery of immunomodulatory molecules, safe routes of administration, prime-boost regimen and strategies to break the immunosuppressive networks mechanisms adopted by malignant cells to prevent immune cell function. Combined or single strategies to enhance the efficacy and immunogenicity of DNA vaccines are applied in completed and ongoing clinical trials, where the safety and tolerability of the DNA platform are substantiated. In this review on DNA vaccines, salient aspects on this topic going from basic research to the clinic are evaluated. Some representative DNA cancer vaccine studies are also discussed.
doi:10.1155/2010/174378
PMCID: PMC2846346  PMID: 20368780
16.  Enhancement of Capsid Gene Expression: Preparing the Human Papillomavirus Type 16 Major Structural Gene L1 for DNA Vaccination Purposes 
Journal of Virology  2001;75(19):9201-9209.
Expression of the structural proteins L1 and L2 of the human papillomaviruses (HPV) is tightly regulated. As a consequence, attempts to express these prime-candidate genes for prophylactic vaccination against papillomavirus-associated diseases in mammalian cells by means of simple DNA transfections result in insufficient production of the viral antigens. Similarly, in vivo DNA vaccination using HPV L1 or L2 expression constructs produces only weak immune responses. In this study we demonstrate that transient expression of the HPV type 16 L1 and L2 proteins can be highly improved by changing the RNA coding sequence, resulting in the accumulation of significant amounts of virus-like particles in the nuclei of transfected cells. Data presented indicate that, in the case of L1, adaptation for codon usage accounts for the vast majority of the improvement in protein expression, whereas translation-independent posttranscriptional events contribute only to a minor degree. Finally, the adapted L1 genes demonstrate strongly increased immunogenicity in vivo compared to that of unmodified L1 genes.
doi:10.1128/JVI.75.19.9201-9209.2001
PMCID: PMC114488  PMID: 11533183
17.  Heat shock proteins and cancer vaccines: developments in the past decade and chaperoning in the decade to come 
Expert review of vaccines  2011;10(11):1553-1568.
Molecular chaperone–peptide complexes extracted from tumors (heat shock protein [HSP] vaccines) have been intensively studied in the preceding two decades, proving to be safe and effective in treating a number of malignant diseases. They offer personalized therapy and target a cross-section of antigens expressed in patients' tumors. Future advances may rely on understanding the molecular underpinnings of this approach to immunotherapy. One property common to HSP vaccines is the ability to stimulate antigen uptake by scavenger receptors on the antigen-presenting cell surface and trigger T-lymphocyte activation. HSPs can also induce signaling through Toll-Like receptors in a range of immune cells and this may mediate the effectiveness of vaccines.
doi:10.1586/erv.11.124
PMCID: PMC3243109  PMID: 22043955
antigen presentation; dendritic cell; heat shock protein; molecular chaperone; T lymphocyte; Toll-like receptor; vaccine
18.  Intrinsic adjuvanting of a novel single-cycle flavivirus vaccine in the absence of Type I Interferon receptor signaling 
Vaccine  2012;30(8):1465-1475.
Summary
Type I Interferons (IFNs) are critical for controlling pathogenic virus infections and can enhance immune responses. Hence their impact on the effectiveness of live-attenuated vaccines involves a balance between limiting viral antigen expression and enhancing the development of adaptive immune responses. We examined the influence of type I IFNs on these parameters following immunization with RepliVAX WN, a single-cycle flavivirus vaccine (SCFV) against West Nile virus (WNV) disease. RepliVAX WN-immunized mice produced IFN-α and displayed increased IFN-stimulated gene transcription in draining lymph nodes (LN). SCFV gene expression was over 100 fold-higher on days 1–3 post-infection in type I IFN receptor knockout mice (IFNAR−/−) compared to wild-type (wt) mice indicating a profound IFN-mediated suppression of SCFV gene expression in the wt animals. IFNAR−/− mice produced nearly equivalent levels of WNV-specific serum IgG and WNV-specific CD4+ T cell responses compared to wt mice. However, significantly higher numbers of WNV-specific CD8+ T cells were produced by IFNAR−/− mice and a significantly greater percentage of these T cells from IFNAR−/− mice produced only IFN-γ following antigen-specific re-stimulation. This altered cytokine expression was not associated with increased antigen load suggesting the loss of type I IFN receptor signaling was responsible for the altered quality of the CD8+ effector T cell response. Together, these results indicate that although type I IFN is not essential for the intrinsic adjuvanting of RepliVAX WN, it plays a role in shaping the cytokine secretion profiles of CD8+ effector T cells elicited by this SCFV.
doi:10.1016/j.vaccine.2011.12.103
PMCID: PMC3274573  PMID: 22226862
West Nile Virus; Single-cycle virus; CD8+ T cell; type I IFN
19.  Beyond empiricism: Informing vaccine development through innate immunity research 
Cell  2012;148(6):1284-1292.
Summary
While a great public heath success, vaccines provide suboptimal protection in some patient populations and are not available to protect against many infectious diseases. Insights from innate immunity research have led to a better understanding of how existing vaccines work and informed vaccine development. New adjuvants and delivery systems are being designed based upon their capacity to stimulate innate immune sensors and target antigens to dendritic cells, the cells responsible for initiating adaptive immune responses. Incorporating these adjuvants and delivery systems in vaccines can beneficially alter the quantitative and qualitative nature of the adaptive immune response resulting in enhanced protection.
doi:10.1016/j.cell.2012.02.012
PMCID: PMC3308125  PMID: 22424235
20.  Cellular Vaccine Approaches 
Cancer journal (Sudbury, Mass.)  2010;16(4):304-310.
Therapeutic cancer vaccines aim to generate immunologic targeting of cancer cells through the induction of effective cellular and antibody-mediated responses specific for antigens selectively expressed by the tumor. Exploiting the adaptive immune system as a targeted tool against cancer is appealing in its capacity for exact specificity and avoidance of unintended tissue damage seen by other conventional agents such as chemotherapy. There are a multitude of challenges to designing effective vaccine strategies. The components of a vaccine strategy start with the challenges of selecting immunogenic, tumor-specific antigen targets, choosing a platform with which to deliver the antigens, and enhancing the immunostimulatory context in which the vaccines are delivered. Although understanding the components of effective T-cell activation is essential, successful effector T cells can only be produced if there is also an understanding of the natural processes that tumors exploit to down-modulate active immune responses. These processes are normally used to down-regulate excessive tissue-destructive immune responses against infectious agents once the infecting agent is cleared or to prevent autoimmunity. Advances in molecular and cellular technologies continue to provide insights into the regulation of immune responses both to infectious agents and to cancer that may be manipulated to tip the balance in favor of tumor regression over immune tolerance. This review focuses primarily on cellular vaccines. For the purpose of this review, cellular vaccines are defined as vaccines that use whole cells or cell lysates either as the source of antigens or the platform in which to deliver the antigens. Dendritic cell (DC)-based vaccines focus on ex vivo antigen delivery to DCs. Other platforms such as GVAX (tumor cells genetically engineered to produce granulocyte-macrophage colony-stimulating factor) aim to deliver tumor antigens in vivo in an immune stimulatory context to endogenous DCs. Because data continue to emerge regarding the importance of the maturation status of DCs and the importance of the particular subset of DCs being targeted, these insights will be integrated into vaccine strategies that are likely to produce more effective vaccines.
doi:10.1097/PPO.0b013e3181eb33d7
PMCID: PMC3086689  PMID: 20693840
cancer vaccine; cellular; dendritic cell; T cell
21.  IMMUNIZATION OF GUINEA PIGS AGAINST LYMPHOCYTIC CHORIOMENINGITIS WITH FORMOLIZED TISSUE VACCINES 
Guinea pigs can be immunized against lymphocytic choriomeningitis by 2 or 3 injections with formolized vaccines prepared from a variety of infected guinea pig tissues. Vaccines prepared from the consolidated areas of diseased lungs gave the best results. The immunity produced was partial in the majority of the cases, in that the vaccinated animals as a rule showed fever after the test of immunity and virus was present in the circulation during the febrile period. Vaccines prepared from infected mouse tissue had no, or very little, immunizing power for guinea pigs, even when prior to formolization they contained at least as much virus as guinea pig tissue vaccines. This failure to immunize appears to be due to the interference by heterologous antigens, since the immunity induced by homologous vaccines was often inhibited when formolized normal mouse tissue suspensions treated in the same manner as the guinea pig tissue vaccines were added to the latter before inoculation. The inhibitory effect of the heterologous tissue was less marked when it was not mixed with the vaccine but injected simultaneously on the opposite side of the body. The immunizing power of homologous vaccines did not parallel their virus content prior to formolization. A high degree of immunity, characterized by protective antibodies in the serum, was produced in some guinea pigs by prolonged treatment with large doses of homologous vaccine, while sera of guinea pigs vaccinated in the ordinary manner contained no detectable neutralizing antibodies. It is possible, therefore, that the immunity produced by inactive virus differs only quantitatively from that induced by an infection.
PMCID: PMC2133657  PMID: 19870778
22.  Vaccine delivery using nanoparticles 
Vaccination has had a major impact on the control of infectious diseases. However, there are still many infectious diseases for which the development of an effective vaccine has been elusive. In many cases the failure to devise vaccines is a consequence of the inability of vaccine candidates to evoke appropriate immune responses. This is especially true where cellular immunity is required for protective immunity and this problem is compounded by the move toward devising sub-unit vaccines. Over the past decade nanoscale size (<1000 nm) materials such as virus-like particles, liposomes, ISCOMs, polymeric, and non-degradable nanospheres have received attention as potential delivery vehicles for vaccine antigens which can both stabilize vaccine antigens and act as adjuvants. Importantly, some of these nanoparticles (NPs) are able to enter antigen-presenting cells by different pathways, thereby modulating the immune response to the antigen. This may be critical for the induction of protective Th1-type immune responses to intracellular pathogens. Their properties also make them suitable for the delivery of antigens at mucosal surfaces and for intradermal administration. In this review we compare the utilities of different NP systems for the delivery of sub-unit vaccines and evaluate the potential of these delivery systems for the development of new vaccines against a range of pathogens.
doi:10.3389/fcimb.2013.00013
PMCID: PMC3607064  PMID: 23532930
nanoparticle; vaccine; adjuvant; antigen-presenting cell; immunity
23.  Using Multivalent Adenoviral Vectors for HIV Vaccination 
PLoS ONE  2013;8(3):e60347.
Adenoviral vectors have been used for a variety of vaccine applications including cancer and infectious diseases. Traditionally, Ad-based vaccines are designed to express antigens through transgene expression of a given antigen. For effective vaccine development it is often necessary to express or present multiple antigens to the immune system to elicit an optimal vaccine as observed preclinically with mosaic/polyvalent HIV vaccines or malaria vaccines. Due to the wide flexibility of Ad vectors they are an ideal platform for expressing large amounts of antigen and/or polyvalent mosaic antigens. Ad vectors that display antigens on their capsid surface can elicit a robust humoral immune response, the “antigen capsid-incorporation” strategy. The adenoviral hexon protein has been utilized to display peptides in the majority of vaccine strategies involving capsid incorporation. Based on our abilities to manipulate hexon HVR2 and HVR5, we sought to manipulate HVR1 in the context of HIV antigen display for the first time ever. More importantly, peptide incorporation within HVR1 was utilized in combination with other HVRs, thus creating multivalent vectors. To date this is the first report where dual antigens are displayed within one Ad hexon particle. These vectors utilize HVR1 as an incorporation site for a seven amino acid region of the HIV glycoprotein 41, in combination with six Histidine incorporation within HVR2 or HVR5. Our study illustrates that these multivalent antigen vectors are viable and can present HIV antigen as well as His6 within one Ad virion particle. Furthermore, mouse immunizations with these vectors demonstrate that these vectors can elicit a HIV and His6 epitope-specific humoral immune response.
doi:10.1371/journal.pone.0060347
PMCID: PMC3610663  PMID: 23555957
24.  Prime–boost approaches to tuberculosis vaccine development 
Expert review of vaccines  2012;11(10):1221-1233.
Four individuals die from active TB disease each minute, while at least 2 billion are latently infected and at risk for disease reactivation. BCG, the only licensed TB vaccine, is effective in preventing childhood forms of TB; however its poor efficacy in adults, emerging drug-resistant TB strains and tedious chemotherapy regimes, warrant the development of novel prophylactic measures. Designing safe and effective vaccines against TB will require novel approaches on several levels, including the administration of rationally selected mycobacterial antigens in efficient delivery vehicles via optimal immunization routes. Given the primary site of disease manifestation in the lungs, development of mucosal immunization strategies to generate protective immune responses both locally, and in the circulation, may be important for effective TB prophylaxis. This review focuses on prime–boost immunization strategies currently under investigation and highlights the potential of mucosal delivery and rational vaccine design based on systems biology.
doi:10.1586/erv.12.94
PMCID: PMC3572762  PMID: 23176655
BCG; lung immunity; mucosal delivery; prime boost; recombinant viral vectors; systems biology; tuberculosis; T cell; vaccine
25.  J‐LEAPS peptide and LEAPS dendritic cell vaccines 
Microbial biotechnology  2012;5(2):203-213.
Summary
The J‐LEAPS vaccines contain a peptide from β‐2‐microglobulin covalently attached to disease‐related peptides of 8–30 amino acids which contain a T cell epitope. The J‐LEAPS vaccines can initiate a protective Th1 immune response or modulate an ongoing Th17 autoimmune response to the peptide. J‐LEAPS vaccines activate and direct the nature of the subsequent immune response by promoting the maturation of precursor cells into a unique type of dendritic cell that produces interleukin 12, but not IL‐1 or tumour necrosis factor, and presents the antigenic peptide to T cells. Adoptive transfer of JgD‐LEAPS dendritic cells, matured with an anti‐HSV‐1 vaccine, promoted antigen‐specific Th1 protection against lethal challenge with the virus. J‐LEAPS peptide immunogens and J‐LEAPS dendritic cell vaccines have potential applications for antimicrobial prevention and therapy, treatment of autoimmune diseases, and for cancer immunotherapy.
doi:10.1111/j.1751-7915.2011.00278.x
PMCID: PMC3815780  PMID: 21895992

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