Vaccine development within industry.
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Antigens↗
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Results for “Vaccine Development”
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Preventive HIV vaccine development in Thailand.
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AIDS Vaccines↗
Development of vaccines and their use in the prevention of fungal infections.
Vaccine approaches to infectious diseases are widely applied and appreciated. Disciplines such as bacteriology and virology have a rich history of successful vaccine development. The complexity of eukaryotic systems presents additional challenges to the development of vaccines against them. These challenges are being met in the fields of parasitology, and are being revisited for application in oncology. Vaccine opportunities exist in medical mycology. The National Institute of Allergy and Infectious Diseases has held a series of workshops in medical mycology where the need to develop vaccines for fungal diseases was noted and where important opportunities were discussed. Major advances in vaccinology and the technology of antigen preparation and delivery have increased feasibility and heightened interest. The recent epidemic of coccidioidomycosis in the American Southwest has demonstrated the need for developing a vaccine as an effective preventive measure for those living in and for those who subsequently move into regions with the endemic mycoses. The XIIth Congress of the International Society for Human and Animal Mycology included a symposium that summarized new vaccination strategies for selected fungi: Candida albicans, Coccidioides immitis, and Trichophyton verrucosum. The goal of the present summary is to provide representative examples of continuing efforts relating to vaccine development within the medical mycological community highlighting Blastomyces dermatidis, Cryptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Pythiumn insidiosum.
Animals↗
Microbial-gut interactions in health and disease. Progress in enteric vaccine development.
Enteric infections resulting in diarrhoea are among the most important causes of morbidity and mortality, particularly in children in developing countries. They are also a common cause of disease among travellers to Africa, Asia and Latin America. Recently, effective, live and inactivated oral and parenteral vaccines against some of the most severe enteric infections-cholera and typhoid fever-have been licensed in several countries. Different candidate vaccines against rotavirus, Shigella and ETEC diarrhoea have also been developed and tested for safety and immunogenicity in developed as well as in developing countries. The protective efficacy of several of these vaccines has also been tested, either in human volunteer challenge studies or in field trials. In this chapter we describe the properties and availability of the recently licensed vaccines and present an update on the diverse efforts being made to achieve new or improved vaccines against the most prevalent enteropathogens.
Cholera↗
HIV vaccine development in the nonhuman primate model of AIDS.
Development of a prophylactic human immunodeficiency virus type 1 (HIV-1) vaccine is a leading priority in biomedical research. Much of this work has been done with the nonhuman primate model of AIDS. In a historical context, vaccine studies, which use this model, are summarized and discussed.
AIDS Vaccines↗
Blood meal acquisition by ticks; molecular advances and implications for vaccine development.
In their quest for a blood meal, hematophagous arthropods must first defeat the host's hemostatic defense. Following injury as it occurs when hematophagous arthropods insert their proboscis into host skin to feed, the host will attempt to stop excessive blood loss through its hemostatic defense mechanism involving platelet aggregation, blood clotting and vasoconstriction. To acquire a full blood meal hematophagous arthropods inject an arsenal of bioactive enzymes which ultimately overpower the host's hemostatic defense. We have looked at a selected number of studies on the molecular biology of arthropod anti-hemostatic proteins and developed commentaries on the suitability of these molecules as target tick vaccine antigens.
Animals↗
Progress and new technologies for developing vaccines against gastrointestinal nematode parasites of sheep.
Despite the identification of highly effective native antigens for vaccination against Haemonchus contortus, particularly 'hidden' antigens derived from the intestine of adult worms, to date similar efficacy has not been shown with recombinant antigens. In addition, progress towards identification of protective antigens from other sheep gastrointestinal (GI) nematode species is limited. Coupled with this is an incomplete understanding of the mechanism of natural immunity to GI nematodes, making selection of appropriate immunization strategies and adjuvants for evaluation of candidate 'natural' antigens problematic. The current explosion in new high-throughput technologies, arising from human studies, for analysis of the genome, transcriptome, proteome and glycome offers the opportunity to gain a better understanding of the molecular pathways underlying pathogen biology, the host immune system and the host-pathogen interaction. An overview is provided on how these technologies can be applied to parasite research and how they may aid in overcoming some of the current problems in development of commercial vaccines against GI nematode parasites.
Animals↗
Ex vivo characterization of multiepitopic tumor-specific CD8 T cells in patients with chronic myeloid leukemia: implications for vaccine development and adoptive cellular immunotherapy.
Identification of tumor-associated Ags is a prerequisite for vaccine-based and adoptive immune therapies. Some tumor-associated Ags elicit specific CD8 T cells in patients with chronic myeloid leukemia (CML). Here, we characterized ex vivo responses of CD8 T cells from CML patients to extrajunction bcr-abl peptides and telomerase 540-548 hTert, PR1, and WT1 peptides. CML-specific CD8 T cells were present in most treated patients and were usually multiepitopic: WT1, hTert, PR1, and bcr74 tetramer(+) cells were detected in 85, 82, 67, and 61% of patients, respectively. The breadth and magnitude of these responses did not differ significantly according to treatment or disease status. CML-specific tetramer(+) CD8 T cells had a predominantly memory phenotype, an intermediate perforin content, and low intracellular IFN-gamma accumulation in the presence of the relevant peptide. However, in short-term culture with HLA-matched leukemia cells, the patients' memory T cells were specifically reactivated to become IFN-gamma-producing effector cells, suggesting that CD8 T cell precursors with lytic potential are present in vivo and can be activated by appropriate stimulation. In conclusion, this study shows that multiepitopic tumor-specific CD8 T cell responses occur naturally in most CML patients, opening the way to new strategies for enhancing anti-CML immunity, in particular in patients with minimal residual disease.
Antigens, Neoplasm↗
IL-12 is required for induction but not maintenance of protective, memory responses to Blastomyces dermatitidis: implications for vaccine development in immune-deficient hosts.
Cellular immunity mediated by T lymphocytes, in particular CD4(+) and CD8(+) type 1 (T1) cells, is the main defense against pathogenic fungi. IL-12 initiates T1 cell development and cell-mediated immunity, but it is unclear whether IL-12 contributes to the maintenance of an antifungal T1 response. In this study, we addressed the role of IL-12 for vaccine-induced memory T cell development against experimental pulmonary blastomycosis. CD4(+) T cells absolutely required IL-12 to control a live genetically engineered attenuated strain of Blastomyces dermatitidis given s.c. as a vaccine, whereas CD8(+) T cells were significantly less dependent on IL-12. Despite differential dependency of T cell subsets on IL-12 during vaccination, neither subset acquired memory immunity in the absence of IL-12. In contrast, adoptive transfer of immune CD4 T cells from wild-type mice into IL-12(-/-) mice showed that CD4(+) T1 memory cells sustained a T1 cytokine profile and remained protective over a period of 6 mo posttransfer. Similarly, memory CD8 cells elicited in IL-12(-/-) mice with killed yeast and transient rIL-12 treatment (during vaccination) remained durable and protective after animals were rested for 3 mo. In conclusion, these studies demonstrate that once CD4 and CD8 cells have acquired a protective T1 phenotype they no longer require the presence of IL-12 to maintain antifungal protective memory.
Animals↗
Cancer vaccine development: protein transfer of membrane-anchored cytokines and immunostimulatory molecules.
Many tumor cells escape host-immune recognition by the downregulation or lack of immunostimulatory molecules. Expression of immunostimulatory molecules on tumor cells by gene transfer can be used to induce an antitumor immune response. However, we have previously shown that protein transfer of glycosyl-phosphatidylinositol (GPI)-linked costimulatory molecules is a successful alternative to traditional gene transfer in preparing such a tumor vaccine. Vaccination with membranes modified by protein transfer to express GPI-linked B7.1 (CD80), a costimulatory adhesion molecule, induces protective immunity in mice and allogeneic antitumor T-cell proliferation in humans in vitro. Our goal is to develop an optimal tumor vaccine using tumor membranes modified by protein transfer to target and stimulate antigen-presenting cells (APCs) and T cells. We have investigated the efficacy of expressing GPI-anchored cytokine molecules on the surface of tumor cells. Expression of interleukin-12 (IL-12) on tumor-cell membranes in a GPI-anchored form induces a strong antitumor immune response that is comparable to the effects of secretory IL-12. Because many cytokines act synergistically, we are testing the membrane expression and immunostimulatory effects of cytokines individually as well as in combination to determine potential complementary effects of coexpression on the antitumor immune response. Ultimately, the protein-transfer vaccination may be used in humans alone or in multimodal combination therapies to induce tumor regression and to serve as a protective measure to prevent postsurgical secondary metastases.
Adjuvants, Immunologic↗
Papillomavirus-like particles for serology and vaccine development.
Genital infection with high-risk human papillomaviruses (HPV) has been etiologically linked with the development of cervical and other anogenital cancers. There is therefore a need for an effective HPV vaccine with the potential to significantly reduce the burden of more than half a million new cervical cancer cases in women worldwide each year. The L1 major capsid protein of papillomaviruses expressed in eukaryotic cells self-assembles into virus-like particles (VLP). VLP are attractive subunit vaccine candidates since they lack potentially oncogenic papillomavirus DNA and express the conformationally dependent epitopes necessary to induce high-titer neutralizing antibodies. Prophylactic VLP vaccination has achieved a high degree of protection in animal studies. Thus VLP are now considered the immunogen of choice for human vaccine trials to prevent genital HPV infection. VLP of different HPV have been developed to study the serologic relationship between HPV types. VLP-based ELISA are able to detect antibodies in human sera and are now widely used in epidemiologic studies of the natural history of HPV infection and the associated risk of developing neoplasia.
Animals↗
T-lymphocyte epitope identification and their use in vaccine development for HIV-1.
Cellular immune responses mediated by CD8+ cytotoxic T-lymphocytes (CTL) and CD4+ helper T-lymphocytes (HTL) are needed to effectively control and clear many viral pathogens, including HIV-1. Thus, vaccines for HIV-1 capable of inducing CTL and HTL responses are now the focus of multiple academic and industry-based research and development programs. The use of defined, minimal CTL and HTL epitopes in vaccines has several potential advantages. Firstly, it is possible to use epitopes that are conserved thus targeting the majority of viral variants within a given clade or across clades. Secondly, epitopes from multiple viral structural or accessory gene products can be included in vaccines, which supports the induction cellular immune responses with significant breadth. Finally, dominance relationships between epitopes can be altered to increase immune recognition of subdominant epitopes. HTL and CTL epitopes from HIV-1 have recently been identified and characterized in numbers that are large enough to support their use in experimental vaccines. Initial studies with prototype DNA vaccines encoding epitopes indicate the need to include intracellular targeting sequences, to direct the encoded gene products to different cellular compartments, and amino acid spacer sequences between epitopes to optimize the processing, and subsequent presentation, of individual epitopes. Vaccines composed of CTL or HTL epitopes are now being developed for clinical testing.
AIDS Vaccines↗
Genetic engineering applied to the development of vaccines.
The simplest application of the modern genetic manipulation methods to vaccine development is the expression in microbial cells of genes from pathogens that encode surface antigens capable of inducing neutralizing antibodies in the host of the pathogen involved. This procedure has been exploited successfully for development of a vaccine against hepatitis B virus (HBV) that is now widely used. Similar approaches have been directed towards formulations for immunization against several other animal and human diseases and some of these preparations are now presently in trials. Of no less importance is the impact of biotechnology in providing reagents for fundamental studies of topics such as the determination of virulence, antigenic variation, virus receptors and the immunological response to viral antigens. The core antigen of HBV is a good example of a product of genetic engineering that is a valuable diagnostic reagent, and that is finding important use in immunological studies of particular pertinence to vaccine development.
Amino Acid Sequence↗
Use of T cell epitopes for vaccine development.
T lymphocytes play a major role in the recognition and subsequent elimination of tumors and intracellular pathogens. Induction of epitope-specific T cell responses can help in the clearance of diseases for which no conventional vaccines exist. However, the lack of simple methods to identify relevant T cell epitopes, the high mutation rate of many pathogens, and HLA polymorphism have made the development of efficient T cell epitope-based, or "epitope-driven" vaccines difficult to achieve. Our research over the past several years has applied bioinformatics tools in conjunction with T cell assays to identify naturally processed putative T cell epitopes from several pathogens. This strategy will accelerate the development of new generation T cell epitope-based vaccines against various pathogens including viruses such as HIV and WNV, bacteria such as M.tb., and parasites such as plasmodium. This chapter will review the use of a bioinformatics-based approach to identify putative T cell epitopes. It will summarize the current state of knowledge regarding T cell-epitope-based vaccines and discuss several ways to improve their efficacy.
Algorithms↗
Antigenicity and immunogenicity of the N-terminal 33-kDa processing fragment of the Plasmodium falciparum merozoite surface protein 1, MSP1: implications for vaccine development.
The Plasmodium falciparum merozoite surface protein 1 (MSP1), MSP1-42 and MSP1-19 are protective malaria vaccines. MSP1-42 is cleaved to form MSP1-33 and MSP1-19. The role of MSP1-33 in immunity is unclear. We investigated the antibody responses to MSP1-33; and to MSP1-33Trunc, in which major conserved sequences were excised. While anti-MSP1-33 antibodies were subdominant in the anti-MSP1-42 responses, immunizations with MSP1-33 or MSP1-33Trunc induced high levels of antibodies reactive with MSP1-42 or whole merozoites. Anti-MSP1-33 and anti-MSP1-33Tunc antibodies crossreacted with both allelic forms of MSP1-42. Anti-MSP1-33 sera were ineffective in inhibiting parasite growth in vitro; but they significantly enhanced the activities of sub-optimal concentrations of the inhibitory anti-MSP1-42 sera. Thus, immunization strategies with MSP1-based vaccines may benefit from co-induction of anti-MSP1-33 responses to enhance efficacy and potency.
Alleles↗
Yellow fever vector live-virus vaccines: West Nile virus vaccine development.
By combining molecular-biological techniques with our increased understanding of the effect of gene sequence modification on viral function, yellow fever 17D, a positive-strand RNA virus vaccine, has been manipulated to induce a protective immune response against viruses of the same family (e.g. Japanese encephalitis and dengue viruses). Triggered by the emergence of West Nile virus infections in the New World afflicting humans, horses and birds, the success of this recombinant technology has prompted the rapid development of a live-virus attenuated candidate vaccine against West Nile virus.
Amino Acid Sequence↗
Lengthy tale of varicella vaccine development finally nears a clinically useful conclusion.
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Chickenpox Vaccine↗
Rapid progress in new vaccines development, immunisation and immunotherapy.
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Animals↗