Vaccines

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Open AccessReview

Schistosome Vaccine Adjuvants in Preclinical and Clinical Research

by Rachel Stephenson, Hong You, Donald P. McManus and Istvan Toth

Vaccines 2014, 2(3), 654-685; https://doi.org/10.3390/vaccines2030654 - 2 Sep 2014

Cited by 24 | Viewed by 8339

There is currently no vaccine available for human use for any parasitic infections, including the helminth disease, schistosomiasis. Despite many researchers working towards this goal, one of the focuses has been on identifying new antigenic targets. The bar to achieve protective efficacy in [...] Read more.

There is currently no vaccine available for human use for any parasitic infections, including the helminth disease, schistosomiasis. Despite many researchers working towards this goal, one of the focuses has been on identifying new antigenic targets. The bar to achieve protective efficacy in humans was set at a consistent induction of 40% protection or better by the World Health Organisation (WHO), and although this is a modest goal, it is yet to be reached with the six most promising schistosomiasis vaccine candidates (Sm28GST, IrV5, Sm14, paramyosin, TPI, and Sm23). Adjuvant selection has a large impact on the effectiveness of the vaccine, and the use of adjuvants to aid in the stimulation of the immune system is a critical step and a major variable affecting vaccine development. In addition to a comprehensive understanding of the immune system, level of protection and the desired immune response required, there is also a need for a standardised and effective adjuvant formulation. This review summarises the status of adjuvants that have been or are being employed in schistosomiasis vaccine development focusing on immunisation outcomes at preclinical and clinical stages. Full article

(This article belongs to the Special Issue Peptide Vaccine)

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Open AccessReview

DNA Virus Vectors for Vaccine Production in Plants: Spotlight on Geminiviruses

by Kathleen L. Hefferon

Vaccines 2014, 2(3), 642-653; https://doi.org/10.3390/vaccines2030642 - 5 Aug 2014

Cited by 34 | Viewed by 10753

Abstract

Plants represent a safe, efficacious and inexpensive production platform by which to provide vaccines and other therapeutic proteins to the world’s poor. Plant virus expression vector technology has rapidly become one of the most popular methods to express pharmaceutical proteins in plants. This [...] Read more.

Plants represent a safe, efficacious and inexpensive production platform by which to provide vaccines and other therapeutic proteins to the world’s poor. Plant virus expression vector technology has rapidly become one of the most popular methods to express pharmaceutical proteins in plants. This review discusses several of the state-of-the-art plant expression systems based upon geminiviruses that have been engineered for vaccine production. An overview of the advantages of these small, single-stranded DNA viruses is provided and comparisons are made with other virus expression systems. Advances in the design of several different geminivirus vectors are presented in this review, and examples of vaccines and other biologics generated from each are described. Full article

(This article belongs to the Special Issue Vaccine Vector)

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Open AccessReview

Developments in Viral Vector-Based Vaccines

by Takehiro Ura, Kenji Okuda and Masaru Shimada

Vaccines 2014, 2(3), 624-641; https://doi.org/10.3390/vaccines2030624 - 29 Jul 2014

Cited by 349 | Viewed by 23770

Abstract

Viral vectors are promising tools for gene therapy and vaccines. Viral vector-based vaccines can enhance immunogenicity without an adjuvant and induce a robust cytotoxic T lymphocyte (CTL) response to eliminate virus-infected cells. During the last several decades, many types of viruses have been [...] Read more.

Viral vectors are promising tools for gene therapy and vaccines. Viral vector-based vaccines can enhance immunogenicity without an adjuvant and induce a robust cytotoxic T lymphocyte (CTL) response to eliminate virus-infected cells. During the last several decades, many types of viruses have been developed as vaccine vectors. Each has unique features and parental virus-related risks. In addition, genetically altered vectors have been developed to improve efficacy and safety, reduce administration dose, and enable large-scale manufacturing. To date, both successful and unsuccessful results have been reported in clinical trials. These trials provide important information on factors such as toxicity, administration dose tolerated, and optimized vaccination strategy. This review highlights major viral vectors that are the best candidates for clinical use. Full article

(This article belongs to the Special Issue Vaccine Vector)

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Open AccessArticle

Doubly Phosphorylated Peptide Vaccines to Protect Transgenic P301S Mice against Alzheimer’s Disease Like Tau Aggregation

by Monique Richter, Agneta Mewes, Manuela Fritsch, Ute Krügel, Ralf Hoffmann and David Singer

Vaccines 2014, 2(3), 601-623; https://doi.org/10.3390/vaccines2030601 - 29 Jul 2014

Cited by 11 | Viewed by 9510

Abstract

Intracellular neurofibrillary tangles and extracellular senile plaques are potential targets for active and passive immunotherapies. In this study we used the transgenic mouse model P301S for active immunizations with peptide vaccines composed of a double phosphorylated tau neoepitope (pSer202/pThr205, pThr212/pSer214, pThr231/pSer235) and an [...] Read more.

Intracellular neurofibrillary tangles and extracellular senile plaques are potential targets for active and passive immunotherapies. In this study we used the transgenic mouse model P301S for active immunizations with peptide vaccines composed of a double phosphorylated tau neoepitope (pSer202/pThr205, pThr212/pSer214, pThr231/pSer235) and an immunomodulatory T cell epitope from the tetanus toxin or tuberculosis antigen Ag85B. Importantly, the designed vaccine combining Alzheimer’s disease (AD) specific B cell epitopes with foreign (bacterial) T cell epitopes induced fast immune responses with high IgG₁ titers after prophylactic immunization that subsequently decreased over the observation period. The effectiveness of the immunization was surveyed by evaluating the animal behavior, as well as the pathology in the brain by biochemical and histochemical techniques. Immunized mice clearly lived longer with reduced paralysis than placebo-treated mice. Additionally, they performed significantly better in rotarod and beam walk tests at the age of 20 weeks, indicating that the disease development was slowed down. Forty-eight weeks old vaccinated mice passed the beam walk test significantly better than control animals, which together with the increased survival rates undoubtedly prove the treatment effect. In conclusion, the data provide strong evidence that active immune therapies can reduce toxic effects of deposits formed in AD. Full article

(This article belongs to the Special Issue Peptide Vaccine)

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Open AccessArticle

Gene Expression Driven by a Strong Viral Promoter in MVA Increases Vaccination Efficiency by Enhancing Antibody Responses and Unmasking CD8⁺ T Cell Epitopes

by Pablo D. Becker, Miriam Nörder, Sebastian Weissmann, Ronny Ljapoci, Volker Erfle, Ingo Drexler and Carlos A. Guzmán

Vaccines 2014, 2(3), 581-600; https://doi.org/10.3390/vaccines2030581 - 22 Jul 2014

Cited by 9 | Viewed by 7490

Abstract

Viral vectors are promising tools for vaccination strategies and immunotherapies. However, CD8⁺ T cell responses against pathogen-derived epitopes are usually limited to dominant epitopes and antibody responses to recombinant encoded antigens (Ags) are mostly weak. We have previously demonstrated that the timing [...] Read more.

Viral vectors are promising tools for vaccination strategies and immunotherapies. However, CD8⁺ T cell responses against pathogen-derived epitopes are usually limited to dominant epitopes and antibody responses to recombinant encoded antigens (Ags) are mostly weak. We have previously demonstrated that the timing of viral Ag expression in infected professional Ag-presenting cells strongly shapes the epitope immunodominance hierarchy. T cells recognizing determinants derived from late viral proteins have a clear disadvantage to proliferate during secondary responses. In this work we evaluate the effect of overexpressing the recombinant Ag using the modified vaccinia virus early/late promoter H5 (mPH5). Although the Ag-expression from the natural promoter 7.5 (P7.5) and the mPH5 seemed similar, detailed analysis showed that mPH5 not only induces higher expression levels than P7.5 during early phase of infection, but also Ag turnover is enhanced. The strong overexpression during the early phase leads to broader CD8 T cell responses, while preserving the priming efficiency of stable Ags. Moreover, the increase in Ag-secretion favors the induction of strong antibody responses. Our findings provide the rationale to develop new strategies for fine-tuning the responses elicited by recombinant modified vaccinia virus Ankara by using selected promoters to improve the performance of this viral vector. Full article

(This article belongs to the Special Issue Vaccine Vector)

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Open AccessArticle

Immunotherapy with an HIV-DNA Vaccine in Children and Adults

by Paolo Palma, Lindvi Gudmundsdotter, Andrea Finocchi, Lars E. Eriksson, Nadia Mora, Veronica Santilli, Angela Aquilani, Emma C. Manno, Paola Zangari, Maria Luisa Romiti, Carla Montesano, Alba Grifoni, Andreas Brave, Karl Ljungberg, Pontus Blomberg, Stefania Bernardi, Eric Sandström, Bo Hejdeman, Paolo Rossi and Britta Wahren

Vaccines 2014, 2(3), 563-580; https://doi.org/10.3390/vaccines2030563 - 17 Jul 2014

Cited by 11 | Viewed by 8830

Abstract

Therapeutic HIV immunization is intended to induce new HIV-specific cellular immune responses and to reduce viral load, possibly permitting extended periods without antiretroviral drugs. A multigene, multi-subtype A, B, C HIV-DNA vaccine (HIVIS) has been used in clinical trials in both children and [...] Read more.

Therapeutic HIV immunization is intended to induce new HIV-specific cellular immune responses and to reduce viral load, possibly permitting extended periods without antiretroviral drugs. A multigene, multi-subtype A, B, C HIV-DNA vaccine (HIVIS) has been used in clinical trials in both children and adults with the aim of improving and broadening the infected individuals’ immune responses. Despite the different country locations, different regimens and the necessary variations in assays performed, this is, to our knowledge, the first attempt to compare children’s and adults’ responses to a particular HIV vaccine. Ten vertically HIV-infected children aged 4–16 years were immunized during antiretroviral therapy (ART). Another ten children were blindly recruited as controls. Both groups continued their antiretroviral treatment during and after vaccinations. Twelve chronically HIV-infected adults were vaccinated, followed by repeated structured therapy interruptions (STI) of their antiretroviral treatment. The adult group included four controls, receiving placebo vaccinations. The HIV-DNA vaccine was generally well tolerated, and no serious adverse events were registered in any group. In the HIV-infected children, an increased specific immune response to Gag and RT proteins was detected by antigen-specific lymphoproliferation. Moreover, the frequency of HIV-specific CD8+ T-cell lymphocytes releasing perforin was significantly higher in the vaccinees than the controls. In the HIV-infected adults, increased CD8+ T-cell responses to Gag, RT and viral protease peptides were detected. No augmentation of HIV-specific lymphoproliferative responses were detected in adults after vaccination. In conclusion, the HIV-DNA vaccine can elicit new HIV-specific cellular immune responses, particularly to Gag antigens, in both HIV-infected children and adults. Vaccinated children mounted transient new HIV-specific immune responses, including both CD4+ T-cell lymphoproliferation and late CD8+ T-cell responses. In the adult cohort, primarily CD8+ T-cell responses related to MHC class I alleles were noted. However, no clinical benefits with respect to viral load reduction were ascribable to the vaccinations alone. No severe adverse effects related to the vaccine were found in either cohort, and no virological failures or drug resistances were detected. Full article

(This article belongs to the Special Issue DNA Vaccines)

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Open AccessReview

Strategy for Designing a Synthetic Tumor Vaccine: Multi-Component, Multivalency and Antigen Modification

by Zhi-Hua Huang, Zhan-Yi Sun, Yue Gao, Pu-Guang Chen, Yan-Fang Liu, Yong-Xiang Chen and Yan-Mei Li

Vaccines 2014, 2(3), 549-562; https://doi.org/10.3390/vaccines2030549 - 15 Jul 2014

Cited by 10 | Viewed by 7241

Abstract

Synthetic tumor vaccines have been proven to be promising for cancer immunotherapy. However, the limitation of the specificity and efficiency of the synthetic tumor vaccines need further improvements. To overcome these difficulties, additional tumor-associated targets need to be identified, and optimized structural designs [...] Read more.

Synthetic tumor vaccines have been proven to be promising for cancer immunotherapy. However, the limitation of the specificity and efficiency of the synthetic tumor vaccines need further improvements. To overcome these difficulties, additional tumor-associated targets need to be identified, and optimized structural designs of vaccines need to be elaborated. In this review, we summarized the main strategies pursued in the design of synthetic tumor vaccines, such as multi-component, multivalency, antigen modification and other possible ways to improve the efficiency of synthetic tumor vaccines. Full article

(This article belongs to the Special Issue Peptide Vaccine)

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Open AccessReview

Peptide Dose and/or Structure in Vaccines as a Determinant of T Cell Responses

by Graham R. Leggatt

Vaccines 2014, 2(3), 537-548; https://doi.org/10.3390/vaccines2030537 - 2 Jul 2014

Cited by 11 | Viewed by 7268

Abstract

While T cells recognise the complex of peptide and major histocompatibility complex (MHC) at the cell surface, changes in the dose and/or structure of the peptide component can have profound effects on T cell activation and function. In addition, the repertoire of T [...] Read more.

While T cells recognise the complex of peptide and major histocompatibility complex (MHC) at the cell surface, changes in the dose and/or structure of the peptide component can have profound effects on T cell activation and function. In addition, the repertoire of T cells capable of responding to any given peptide is variable, but broader than a single clone. Consequently, peptide parameters that affect the interaction between T cells and peptide/MHC have been shown to select particular T cell clones for expansion and this impacts on clearance of disease. T cells with high functional avidity are selected on low doses of peptide, while low avidity T cells are favoured in high peptide concentrations. Altering the structure of the peptide ligand can also influence the selection and function of peptide-specific T cell clones. In this review, we will explore the evidence that the choice of peptide dose or the structure of the peptide are critical parameters in an effective vaccine designed to activate T cells. Full article

(This article belongs to the Special Issue Peptide Vaccine)

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Open AccessReview

Peptide Vaccine: Progress and Challenges

by Weidang Li, Medha D. Joshi, Smita Singhania, Kyle H. Ramsey and Ashlesh K. Murthy

Vaccines 2014, 2(3), 515-536; https://doi.org/10.3390/vaccines2030515 - 2 Jul 2014

Cited by 513 | Viewed by 26775

Abstract

Conventional vaccine strategies have been highly efficacious for several decades in reducing mortality and morbidity due to infectious diseases. The bane of conventional vaccines, such as those that include whole organisms or large proteins, appear to be the inclusion of unnecessary antigenic load [...] Read more.

Conventional vaccine strategies have been highly efficacious for several decades in reducing mortality and morbidity due to infectious diseases. The bane of conventional vaccines, such as those that include whole organisms or large proteins, appear to be the inclusion of unnecessary antigenic load that, not only contributes little to the protective immune response, but complicates the situation by inducing allergenic and/or reactogenic responses. Peptide vaccines are an attractive alternative strategy that relies on usage of short peptide fragments to engineer the induction of highly targeted immune responses, consequently avoiding allergenic and/or reactogenic sequences. Conversely, peptide vaccines used in isolation are often weakly immunogenic and require particulate carriers for delivery and adjuvanting. In this article, we discuss the specific advantages and considerations in targeted induction of immune responses by peptide vaccines and progresses in the development of such vaccines against various diseases. Additionally, we also discuss the development of particulate carrier strategies and the inherent challenges with regard to safety when combining such technologies with peptide vaccines. Full article

(This article belongs to the Special Issue Peptide Vaccine)

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Open AccessArticle

Caspase-1 Dependent IL-1β Secretion and Antigen-Specific T-Cell Activation by the Novel Adjuvant, PCEP

by Sunita Awate, Nelson F. Eng, Volker Gerdts, Lorne A. Babiuk and George Mutwiri

Vaccines 2014, 2(3), 500-514; https://doi.org/10.3390/vaccines2030500 - 26 Jun 2014

Cited by 14 | Viewed by 7148

Abstract

The potent adjuvant activity of the novel adjuvant, poly[di(sodiumcarboxylatoethylphenoxy)phosphazene] (PCEP), with various antigens has been reported previously. However, very little is known about its mechanisms of action. We have recently reported that intramuscular injection of PCEP induces NLRP3, an inflammasome receptor gene, and [...] Read more.

The potent adjuvant activity of the novel adjuvant, poly[di(sodiumcarboxylatoethylphenoxy)phosphazene] (PCEP), with various antigens has been reported previously. However, very little is known about its mechanisms of action. We have recently reported that intramuscular injection of PCEP induces NLRP3, an inflammasome receptor gene, and inflammatory cytokines, including IL-1β and IL-18, in mouse muscle tissue. Caspase-1 is required for the processing of pro-forms of IL-1β and IL-18 into mature forms and is a critical constituent of the NLRP3 inflammasome. Hence, in the present study, we investigated the role of caspase-1 in the secretion of IL-1β and IL-18 in PCEP-stimulated splenic dendritic cells (DCs). Caspase inhibitor YVAD-fmk-treated splenic DCs showed significantly reduced IL-1β and IL-18 secretion in response to PCEP stimulation. Further, PCEP had no effect on the expression of MHC class II or co-stimulatory molecules, CD86 and CD40, suggesting that PCEP does not induce DC maturation. However, PCEP directly activated B-cells to induce significant production of IgM. In addition, PCEP+ovalbumin (OVA) immunized mice showed significantly increased production of antigen-specific IFN-γ by CD4⁺ and CD8⁺ T-cells. We conclude that PCEP activates innate immunity, leading to increased antigen-specific T-cell responses. Full article

(This article belongs to the Special Issue Vaccine Adjuvants)

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Vaccines, Volume 2, Issue 3 (September 2014) – 10 articles , Pages 500-685

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